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Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

4
HEALTH OUTCOMES

Veterans who were deployed to the Persian Gulf War have reported a constellation of symptoms and medical conditions during their deployment and since their return home. Epidemiologic studies comparing veterans who were deployed to the Gulf War with veterans who were in the military during the Gulf War but were not deployed have confirmed that deployed veterans have a greater prevalence of a number of medical conditions, illnesses, and symptoms. This increased reporting of symptoms and prevalence of medical conditions has also been seen in deployed veterans from many of the countries that formed the coalition forces, including the United States, the United Kingdom (UK), Australia, Canada, and Denmark. Recently, French forces deployed to the Gulf War have also been under study, but as yet few results have been published on this cohort.

In this chapter, the studies that have examined the health outcomes that have been reported or diagnosed in Gulf War veterans are presented. In the majority of studies, the prevalence of each medical condition or symptom seen in the deployed veterans is compared with the prevalence seen in nondeployed veterans. Where the prevalence of a symptom or condition has been linked by the study authors to any specific exposures experienced during deployment such as vaccines, oil-well fire smoke, anti-nerve-gas agents, or combat, the committee reviewed those associations as well.

ORGANIZATION OF THE CHAPTER

The committee presents the health outcomes in the order they appear in the International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10),1 except for the last section, which examines the health status of female Gulf War veterans. The committee considered all possible health effects identified in the studies it reviewed, regardless of the potential cause of the health effect, with the exception of health effects related to or resulting from infectious and parasitic diseases as those outcomes were examined in Gulf War and Health, Volume 5: Infectious Diseases (IOM, 2007). The committee considered studies that attempted to link health effects seen in Gulf War veterans to specific deployment exposures such as nerve gas and oil-well fire smoke, but an exhaustive search of the toxicologic and

1

The International Statistical Classification of Diseases and Related Health Problems (ICD) provides a detailed description of known diseases and injuries. Every disease (or group of related diseases) is given a unique code. ICD is periodically revised and is currently in its 10th edition (ICD-10) and available at http://www.who.int/classifications/apps/icd/icd10online/.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

epidemiologic literature on all the possible environmental agents to which Gulf War veterans might have been exposed was not conducted.

For each health effect presented in this chapter, the committee first summarizes the primary studies and secondary or supporting studies that were included in Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War (referred to as Volume 4). The committee then identifies additional primary and secondary studies from its updated literature searches and reconsiders the studies described in Volume 4 taking into account these updates. Although many of the studies are new and were published after Volume 4 was completed in 2006, some of the additional studies cited by the Update committee were published before or during 2006 but were not discussed in Volume 4. Because the Volume 4 committee was tasked with identifying those health effects seen at greater prevalence in deployed versus nondeployed Gulf War veterans and not with determining the strength of the association between deployment and the development of a particular health effect, not every study that examined an association between a health effect and Gulf War exposures was included in Volume 4. Therefore, the Update committee reviewed the categorization (primary or secondary) of all of the studies considered for Volume 4 as well as any new studies identified from an updated literature search. All studies for each health outcome, including those originally cited in Volume 4, were reviewed and categorized as primary or secondary by the entire committee in plenary session, before it came to a consensus on the appropriate category of association to be assigned to each health outcome. Consistent with previous volumes of the Gulf War and Health series, the primary studies on which the committee based its conclusions are detailed in the evidence table at the end of each health outcome section. Using this weight-of-the-evidence approach required that the Update committee be more rigorous in its review of the studies in Volume 4; as a result some studies considered to be primary in Volume 4 were recategorized as secondary for this report and vice versa. Thus, the Update committee summarizes de novo the information from both Volume 4 and any new literature to arrive at its conclusions on the strength of the association between deployment to the Gulf War and a health outcome.

As described in Chapter 2, a primary study had to include information about the putative exposure (generally deployment) and specific health outcomes, demonstrate rigorous methods, include adequate details of its methods to allow a thorough assessment, include an appropriate control or reference group, and provide appropriate adjustment for confounders. It is of note that many of the large cohort studies examined multiple outcomes and so might be referred to in more than one place in this report. A given study might be deemed a primary study for one or more health outcome and be a secondary study for another outcome, based on how each health outcome was defined and measured. For example, a particular study might be well designed for assessing diabetes because the authors used a strong indicator such as blood glucose levels to identify this disorder, but the same study might not be well designed for assessing a psychiatric disorder because the authors used only a screening instrument to identify the disorder. In general, only primary studies appear in the evidence tables that accompany the discussion of each health outcome.

A secondary study typically had methodological limitations, such as not including a rigorous or well-defined method of diagnosis, or a lack of an appropriate control group. The secondary studies were reviewed and included in the discussion because they evaluated the same health outcomes and in some cases provided useful information on veteran populations from the same conflicts as the primary studies. For this reason it was felt that secondary studies add information that might modify (increase or decrease) confidence in the conclusions, which are

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

made based on review of primary studies. Confidence in a secondary study is substantially reduced if the statistical analysis did not include adjustment for confounders, if the data were obtained from self-reported cross-sectional surveys or from screening instruments that relied solely on self-reports of diagnoses, or if response rates were unacceptably low. Without supportive evidence from primary studies, the potential for unreliable findings due to bias, chance, or multiple comparisons may outweigh the extent to which secondary studies may contribute, even collectively, to the overall conclusion of the committee about an association between deployment and any specific health outcome. Understanding the relationship between a health outcome and deployment may also be hampered by attempts to identify specific harmful exposures based on recall many years after the war. Virtually none of the studies verified veterans’ reported exposures against military records.

This chapter excludes studies of participants in Gulf War registries established by the Department of Veterans Affairs (VA) or the Department of Defense (DoD), which were not intended to be representative of the population of Gulf War veterans. Registry participants cannot be considered representative of all Gulf War veterans in that they are self-selected, and many may have joined the registries because they believed that they have symptoms of a new medical syndrome; they were not a random sample of Gulf War military personnel, and there is no nondeployed comparison group.

CANCER

Cancer can develop at any age but about 77% of cancers are diagnosed in people aged 55 and older. Furthermore, cancer is a disease of long latency, meaning that often the diagnosis of a cancer does not occur until 15 to 20 years or longer after the exposure that caused it (Cogliano et al., 2004). Therefore, many veterans are still young for cancer diagnoses (the mean age of military personnel during the Gulf War was 28), and for most cancers, the time since the Gulf War is probably too short to expect to observe the onset of cancer. Cancers with younger average age at onset, and also possible shorter latency periods, can include testicular cancer, skin cancer, leukemias and lymphomas, and brain cancer.

The majority of observations on the association of overall and cause-specific cancers (that is, malignant neoplasms) with Gulf War deployment are discussed in studies of general mortality and hospitalizations, rather than in reports focused specifically on cancer. However, a few studies on brain and testicular cancer in Gulf War veterans have been published. All studies in which malignant neoplasms, as a group or at particular sites, are specifically identified are reviewed here and summarized in Table 4-1.

Summary of Volume 4

Brain Cancer

The Volume 4 committee identified one cohort mortality study assessing the relationship between nerve-agent exposure caused by weapons demolition at Khamisiyah with brain cancer deaths in US Gulf War veterans. Bullman et al. (2005) explored the relationship between estimated exposure to chemical munitions destruction (sarin gas) at Khamisiyah in 1991 with cause-specific mortality of Gulf War veterans through December 31, 2000. Using the DoD’s 2000 sarin plume exposure model (Rostker, 2000), 100,487 military personnel were identified as potentially exposed and 224,980 similarly deployed military personnel were considered

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

unexposed. The study reported an increased risk of brain cancer deaths in the exposed population (relative risk [RR] 1.94, 95% confidence interval [CI] 1.12-3.34; 25 exposed cases vs 27 unexposed cases) and there was a suggestion of a dose-response relationship with increased risk among those who were considered exposed for 2 days (6 cases) relative to 1 day (19 cases) (RR 3.26, 95% CI 1.33-7.96 and RR 1.72, 95% CI 0.95-3.10, respectively). The authors also discussed modeling exposure to smoke from oil-well fires as a confounder, and the effect estimates for exposure to Khamisiyah nerve agents remained elevated. There was no significant elevation in risk associated with exposure to oil-well fires as a main effect. Because brain cancer likely has a latent period of 10-20 years and Bullman et al. (2005) had fewer than 9 years of follow-up, the Volume 4 committee concluded that additional follow-up is needed to draw any definitive conclusions concerning the association between deployment to the Gulf War and the development of brain cancer.

Testicular Cancer

The Volume 4 committee identified two studies that specifically examined testicular cancer among US servicemen during the Gulf War: Knoke et al. (1998) and Levine et al. (2005), and one study of military hospitalizations where a positive association for testicular cancer was observed (Gray et al., 1996). Gray and colleagues (1996) examined all-cause hospitalizations in DoD hospitals from August 1, 1991, through September 30, 1993, for 517,223 deployed and 1,291,323 nondeployed Gulf War servicemen. They observed an increased risk of hospitalization for testicular cancer among the deployed (standardized rate ratio 2.12, 95% CI 1.11-4.02) in the last 5 months of 1991, the period immediately after the end of deployment. However, the increased risk did not carry over into 1992 or into the first 9 months of 1993. Knoke et al. (1998) focused on the cases of first diagnosis of testicular cancer in this cohort, continuing follow-up until March 31, 1996. They observed no association with deployment status (standardized rate ratio 1.05, 95% CI 0.86-1.29). This pattern of increased incidence immediately after the war with a tapering off with time likely demonstrates a healthy warrior effect. In other words, the peak probably represented a regression to the mean after healthier people were selected for deployment and there was deferment of care during deployment. The limitations of these studies are that they were restricted to active-duty military personnel and did not include veterans who may have left the service because of poor health or those who sought treatment elsewhere.

Levine et al. (2005) conducted a pilot study matching data from the District of Columbia and New Jersey cancer-registry cases with the records of 621,902 deployed Gulf War veterans and 746,248 veterans serving at the same time as the Gulf War but not deployed. Testicular cancer cases yielded a crude proportional incidence rate (PIR) of 3.05 (95% CI 1.47-6.35) that was attenuated after adjustment for state of residence, deployment status, race, and age (PIR 2.33; 95% CI 0.95-5.70). No definitive conclusions could be made until additional registries are added.

All Cancers

The Volume 4 committee included results from two primary mortality studies. Kang and Bullman (2001) compared cause-specific mortality rates in the same database of Gulf War deployed veterans and nondeployed veterans used for the Levine et al. (2005) study described above. Vital status was determined using databases of the VA and the Social Security Administration (SSA). Over the follow-up period of 1991 to 1997, there were no significant excesses of overall cancer deaths or deaths from cancer at any specific site among deployed

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

veterans compared with the controls (total cancers: males, OR 0.90, 95% CI 0.81-1.01; females, OR 1.11, 95% CI 0.78-1.57).

Macfarlane et al. (2003) conducted a cohort study among 51,721 UK servicemembers deployed to the Persian Gulf and 50,755 nondeployed servicemembers using the National Health Service Cancer Register to identify first diagnoses of malignant cancer through July 31, 2002. The rate ratio for unspecified cancer was 0.99 (95% CI 0.83-1.17), after adjusting for sex, age, service branch, and rank. In subgroups of the cohort who participated in morbidity surveys and provided information on smoking and alcohol use, the adjusted rate ratio for all cancers was 1.12 (95% CI 0.86-1.45).

Updated and Supplemental Literature

Primary Studies

The Update committee identified one new primary study of brain cancer mortality. It also identified three studies of hospitalization or incidence, one mortality study, and one combined study where cancer was specifically assessed.

Brain Cancer

In continued mortality follow-up through 2004 of the 621,902 Gulf War deployed veterans and 746,248 nondeployed veterans originally studied by Kang and Bullman (2001), Barth et al. (2009) focused on mortality from neurological causes, that is, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson’s disease, and primary brain cancer. The cases included in the Bullman et al. study (2005) described above, also were identified from this cohort and were included in the Barth et al. study. A total of 144 cases of brain cancer were identified among the deployed veterans and 228 among the nondeployed for a mortality rate ratio (RR) of 0.90 (95% CI 0.73-1.11), adjusted for race, branch of service, type of unit, age, marital status at entry to follow-up, and sex. Within the Gulf War cohort, exposure to nerve agents from the Khamisiyah explosion for 2 or more days (Winkenwerder, 2002) and exposure to oil-well fire smoke (Rostker, 2000) were both positively associated with risk of brain cancer mortality when modeled simultaneously (adjusted rate ratios 2.71, 95% CI 1.25-5.87 and 1.81, 95% CI 1.00-3.27, respectively). Of the 43 brain cancer cases exposed to oil-well fires, 20 were also exposed for at least 1 day at Khamisiyah (S. Barth, Department of Veterans Affairs, personal communication, November 30, 2009).

Medical records were obtained for 236 of the 372 cases of brain cancer (63%). The record review resulted in 204 confirmed cases, 13 probable cases, and 19 misclassified cancers. The risk of dying from brain cancer did not change with the removal of the 19 misclassified cancers.

Hospitalization Studies

Gray et al. (2000) conducted an expanded analysis of their original 1996 study of hospitalizations to include US Gulf War veterans (n = 652,979) and nondeployed veterans (random selection of n = 652,922 from 2,912,737 total) who had separated from the armed services and those who served in the National Guard or reserve. Hospitalization data from the DoD, the VA, and California Office of Statewide Health Planning and Development over the period August 1, 1991, through December 31, 1994, were assessed separately. There was no evidence of increased hospitalization from neoplasms among the Gulf War veterans compared to the nondeployed veterans in any of the three hospital systems.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Smith et al. (2006) compared cause-specific postdeployment hospitalization in DoD military treatment facilities during the period October 1, 1988, through December 31, 2000, among US active-duty servicemembers who served in the Gulf War (n = 455,465), Southwest Asia following the Gulf War (n = 249,047), or Bosnia, also following the Gulf War (n = 44,341). After adjusting for age, sex, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization, the hazard ratio (HR) for nondefined neoplasms was 1.03 (95% CI 0.93-1.15) for the Gulf War deployed veterans compared to the Southwest Asia cohort and 0.61 (95% CI 0.50-0.76) compared to the Bosnia group. The adjusted HR for testicular cancer in Gulf War veterans was 0.64 (95% CI 0.32-1.28) and 0.80 (95% CI 0.27-2.39) compared to the Southwest Asia and Bosnia groups, respectively.

Mortality Studies

The UK Defence Analytical Service Agency (DASA, 2009) published summary statistics comparing mortality rates of 53,409 UK Gulf War veterans with those of 53,143 UK armed forces personnel of similar age, sex, service status, and rank who were in service at the same time, but not deployed to the gulf (era cohort). It reported 209 and 228 malignant neoplasms among the gulf and era cohorts, respectively (age-adjusted mortality RR 0.97, 95% CI 0.81-1.18). They did not observe any significant associations for specific neoplasms.

The Canadian Department of National Defense used the national mortality database and the national cancer registry to examine mortality rates and cancer incidence among Canadian Gulf War veterans from 1991 through 1999 (Statistics Canada, 2005). Two cohorts were established—the deployed cohort consisting of 5117 servicemembers sent to the gulf between August 1990 and October 1991, and the nondeployed cohort of 6093 servicemembers who were eligible for deployment but were not deployed. During the follow-up period, 10 deaths from cancer were identified in the deployed cohort and 15 in the nondeployed. The age-adjusted HR was 0.85 (95% CI 0.38-1.90). Among the deployed and nondeployed cohorts 29 and 42 incident cancers, respectively, were identified (age-adjusted HR 0.86, 95% CI 0.54-1.39). The largest number of the cases were cancers of the digestive tract (n = 15). There were also 8 testicular cancers and 4 brain cancers (all among the nondeployed). There was no evidence of an association between deployment and these specific cancers.

In continued follow-up of the study by Macfarlane et al. (2003) (discussed above), there was still no excess risk of mortality from malignant neoplasms with 2 more years of data (RR 1.01, 95% CI 0.79-1.30) (Macfarlane et al., 2005).

Secondary Studies

The Update committee identified eight secondary studies of multiple outcomes that had been included in Volume 4, but had not been considered in that review of malignant neoplasms (Goss Gilroy, 1998; Iowa Persian Gulf Study Group, 1997; Ishoy et al., 1999a; Kang et al., 2000; Kelsall et al., 2004a; McCauley et al., 2002; Simmons et al., 2004; Steele, 2000). Because there is specific mention of cancer in these studies, they are described here in chronological order.

From September 1995 through May 1996, the Iowa Persian Gulf Study Group (1997) performed a cross-sectional telephone survey to solicit self-reported illness in Iowan military personnel active during the Gulf War (n = 4886). Members of the National Guard who had been deployed (n = 911) were more likely to report any cancer than nondeployed National Guards members (n = 831) (prevalence difference [PD] 1.3, 95% CI 0.6-2.0), but the prevalence was similar compared with the deployed (n = 985) and nondeployed regular military (n = 968) (PD 0.3, 95% CI −0.6-1.2). Specific reports of skin cancer followed a similar pattern.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

The Canadian Department of National Defense commissioned Goss Gilroy, Inc., to assess the prevalence of health outcomes in Canadian forces deployed to the Gulf War (Goss Gilroy, 1998). In 1997, a questionnaire was administered to 3113 Gulf War deployed veterans and 3439 active but nondeployed Canadian veterans. Among the respondents 20-44 years of age, 0.8% of the deployed veterans and 0.5% of the nondeployed reported any cancer, and among the 45-65 year olds, the prevalence of any cancer was 4.2% in the deployed veterans and 2.5% in the nondeployed veterans.

Ishoy et al. (1999a) conducted a cross-sectional clinical examination study during 1997. Participants included Danish servicemembers deployed to the Gulf (n = 686) and eligible but nondeployed Danish servicemembers (n = 231). Skin cancer was assessed; however, results were not presented since the p-value comparing the two groups was greater than 0.05.

Kang et al. (2000) conducted a health survey comparing self-reported health outcomes for a population based sample of 15,000 deployed and 15,000 nondeployed US Gulf War veterans. Based on the responses from 11,441 deployed and 9476 nondeployed veterans, they estimated the population prevalence rates of various medical conditions. The estimated population prevalence for skin cancer was 1.5% for the deployed and 1.4% for the nondeployed veterans, with a significant difference (rate difference 0.15, 95% CI 0.11-0.19).

A population based survey of Kansas veterans deployed to the gulf (n = 1548) and nondeployed (n = 482) examined the health outcomes of deployment through automated telephone interviews to define and establish prevalence of “Gulf War illness” symptom complex (Steele, 2000). The incidence of disease diagnosed or treated by a physician was tracked through 1998. The OR for cancers, not including skin cancer (n = 18) was 1.21 (95% CI 0.40-3.69), and the OR for skin cancer (n = 23) was 1.17 (95% CI 0.47-2.90), adjusting for sex, age, income, and level of education.

In 1999, McCauley et al. (2002) conducted a telephone survey of 2918 active or reserve Army or National Guard veterans resident in Oregon, Washington, California, Georgia, or North Carolina. Among the 1263 deployed subjects, 21 incident cancers were reported, compared to 3 among the 516 nondeployed comparison group (OR 3.0, 95% CI 1.0-13.1). Details on year of diagnosis and type of cancer were obtained for 20 of the 24 cases. When all skin cancers (n = 7) and cases that were not confirmed at the time of telephone follow-up (n = 4) were excluded, the OR was 4.94 (95% CI 0.6-38.1) and there was no apparent trend for any specific type of cancer. Among the Gulf War veterans, there was no indication of an association of cancer risk with exposure to nerve agents at Khamisiyah, defined as being within a 50-km radius of Khamisiyah between March 4, 1991, and March 13, 1991 (OR for exposed vs unexposed 0.4, 95% CI 0.1-1.4).

A cohort study of Australian service personnel who had (n = 1456) or had not (n = 1588) been deployed to the gulf was designed to investigate the association of symptoms and medical conditions with immunizations and other Gulf War exposures (Kelsall et al., 2004a). This study was included in Volume 4 as a major cohort study and specifically in the reviews of diseases of the circulatory system, diseases of the respiratory system, and symptoms in general. However, skin cancer, other than malignant melanoma, was also one of the 15 most frequently doctor-diagnosed medical conditions reported by the participants. After medical record review, 92 deployed veterans and 110 nondeployed veterans had a possible or probable diagnosis of the malignancy. The OR, adjusted for service type, rank, age, education, and marital status was 1.0 (95% CI 0.7-1.3).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Simmons et al. (2004) conducted a retrospective cohort study of male UK Gulf War deployed veterans (n = 23,358) and a comparable cohort of nondeployed veterans (n = 17,730) for self-reported health outcomes. Among the deployed veterans, 127 cancer cases, including malignant neoplasms and brain tumors were reported, compared to 88 among the nondeployed veterans (OR 1.1, 95% CI 0.9-1.5).

Finally, the Update committee identified two new secondary studies with information on cancer outcomes. From 1994 to 1996, Proctor et al. (2001a) evaluated health-related quality of life among 141 Gulf War deployed veterans and 46 veterans deployed to Germany, selected from active-duty, reserve and National Guard troops deployed through Fort Devens, Massachusetts. Among the Gulf War deployed veterans and the Germany deployed participants, 2.1% and 4.4% respectively, reported cancer, excluding skin cancer. In 2005, Kang and colleagues published a follow-up survey of the sample (15,000 deployed and 15,000 nondeployed US Gulf War veterans) described in the earlier study (Kang et al., 2000, 2009). Among the 6111 deployed and 3859 era veterans who responded, 1160 reported skin cancer diagnoses and 990 reported “other cancer.” The risk ratios, adjusted for age, sex, race, body mass index, current cigarette smoking, rank, branch of service, and unit component, for skin cancer and other cancer were 1.09 (95% CI 0.97-1.22) and 1.09 (95% CI 0.96-1.24), respectively.

Summary and Conclusions

There is no consistent evidence of a higher overall incidence of cancer in veterans who were deployed to the Gulf War than in nondeployed veterans. An association of brain-cancer mortality with possible nerve-agent exposure (based on the 2000 DoD exposure model) was observed in one study discussed in Volume 4 (Bullman et al., 2005), and the association holds up with an additional 4 years of follow-up in the same cohort (Barth et al., 2009). The association with exposure to smoke from oil-well fires became stronger with further follow-up. However, the numbers of cases of brain cancer who had possibly been exposed to nerve agents as a result of the Khamisiyah explosion was small, and there is little previous evidence of an association of sarin or organophosphate pesticides with brain cancer. Therefore, the committee concluded that there was insufficient/inadequate evidence of an association between Gulf War exposures and brain cancer. Mixed results for testicular cancer were reported by the Volume 4 committee; however, the Update committee did not identify any new studies of this cancer site. In general, many veterans are still too young for cancer diagnoses, and for most cancers the follow-up period after the Gulf War is probably too short to expect the onset of cancer. Therefore, the committee believes that further follow-up is necessary to be able to make a conclusion about whether there is an association between deployment during the Gulf War and cancer outcomes.

The committee concludes that there is insufficient/inadequate evidence of an association between deployment to the Gulf War and any cancer.


Recommendation: Due to the long latency period for cancer, there needs to be continued follow-up of Gulf War veterans and an appropriate comparison group to adequately determine any association.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-1 Cancer

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Brain cancer

Bullman et al., 2005 (Vol. 4)

Cohort mortality study (population from same source as Kang and Bullman, 1996, 2001)

100,487 US Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed Army GWVs; exposure determined from the DoD plume model

Brain cancer mortality through December 2000 ascertained from BIRLS and NDI

Exposed (25 cases) vs unexposed (27 cases) RR 1.94 (95% CI 1.12-3.34);

Exposed 1 day: RR 1.72 (95% CI 0.95-3.10)

Exposed 2+ days: RR 3.26 (95% CI 1.33-7.96)

Age at entry, race, sex, unit component, and rank

9-year follow-up likely too short to examine brain cancer risk (increases with time since exposure); multiple comparisons; death certificate diagnosis

Barth et al., 2009 (Update)

Mortality cohort study, follow-up through 2004 of same cohort as Kang and Bullman (2001)

621,902 US GWVs and 746,248 nondeployed era veterans; 98,406 GWVs exposed to Khamisiyah nerve agents; 123,478 GWVs exposed to oil-well fire smoke

Brain cancer mortality

GWVs (144 cases) compared to era veterans (228 cases) MRR 0.90 (95% CI 0.73-1.11)

Khamisiyah exposed: MRR 2.71 (95% CI 1.25-5.87)

Oil-well fire smoke exposed: MRR 1.81 (95% CI 1.00-3.27)

Race, service branch, type of unit, age, marital status, and sex

Similar results after 19 misclassified cancers were removed from analysis

Testicular cancer

Knoke et al., 1998 (Vol. 4)

Cohort study (follow-up of Gray et al., 1996)

US, all regular, active-duty male servicemembers

GWVs (n = 517,223)

NDVs (n = 1,291,323)

First diagnosis of testicular cancer at US military hospitals worldwide (7/31/1991-3/31/1996)

GWVs (134 cases) vs NDVs (371 cases)

RR 1.05 (95% CI 0.86-1.29)

Race or ethnicity, age, occupation

Short follow-up time, but right age range; no specific exposures evaluated; military hospitals only

Levine et al., 2005 (Vol. 4)

Population-based survey—pilot study

US, all personnel (including reserves) deployed to Gulf War (GWVs) and random sample of NDVs;

GWVs (n = 621,902)

NDVs (n = 746,248)

Testicular cancers diagnosed 1991-1999 and registered by DC or NJ Cancer Registries

GWVs (cases = 17) vs NDVs (cases = 11) (358 males with cancer)

PIR 2.33 (95% CI 0.95-5.70)

Age, state of residence, deployment status, race

 

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Gray et al., 1996 (Vol. 4)

Hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 non-GWVs

Hospital-discharge diagnoses of testicular cancer (ICD-9-CM Code 186)

GWVs vs nondeployed Last 5 months of 1991: 29 cases vs 14 cases, SRR 2.12 (95% CI 1.11-4.02)

1992: SRR 1.39 (95% CI 0.91-2.11)

1993: SRR 0.89 (95% CI 0.54-1.44)

Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation

Limitations: restricted to persons remaining on active duty after the war, and thus does not include veterans who may have left the service due to poor health; no adjustment for other potential confounders

All cancers

Kang and Bullman, 2001 (Vol. 4)

Cohort mortality study; follow-up from 1991 through 1997

Deployed GWVs (n = 621,902) compared to random sample of nondeployed era veterans (n = 746,248)

Overall cancer mortality ascertained from BIRLS, death certificates, and NDI

Males:

GWVs (cases = 477) vs controls (cases = 860): RR 0.90 (95% CI 0.81-1.01)

Females:

GWVs (cases = 49) vs controls (cases = 103): RR 1.11 (95% CI 0.78-1.57)

Age, race, branch of service, unit component, marital status

Short latency; low age range; death certificates

Macfarlane et al., 2003 (Vol. 4)

Cohort (follow-up of Macfarlane et al., 2000)

51,721 UK GWVs, 50,755 NDVs; random samples Subgroup of 28,518 GWVs and 20,829 era veterans with records of smoking and alcohol use

Cancers identified from National Health Service Central Register; first diagnosis 4/1/1991-7/31/2002

GWVs (cases = 270) vs NDVs (cases = 269)

Main study: RR 0.99 (95% CI 0.83-1.17)

Subgroup: RR 1.12 (95% CI 0.86-1.45)

Main analysis: sex, age group, service branch, rank Subgroup: smoking, alcohol use

Follow-up period shorter than expected latency for most cancers; low age; grouped all cancer sites due to low numbers of occurrences

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August 1991 through December 1994

652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations

Hospital-discharge diagnoses of neoplasms in DoD, VA, and COSHPD hospital systems

DoD PMR 0.98 (95% CI 0.94-1.01)

VA PMR 0.88 (95% CI 0.78-0.98)

COSHPD PMR 0.86 (95% CI 0.61-1.1)

Age, sex, race

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Smith et al., 2006 (Update)

Hospitalizations cohort study (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theatre (n = 455,465); Southwest Asia peacekeeping mission, 1991-1998 (n = 249,047); Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of malignant neoplasm (140-208), and for testicular cancer specifically

Veterans of Bosnia and veterans of SW Asia compared to GW veterans Any neoplasm:

Bosnia HR 0.61 (95% CI 0.50-0.76)

SW Asia HR 1.03 (95% CI 0.93-1.15)

Testicular cancer:

Bosnia HR 0.80 (95% CI 0.27-2.39)

SW Asia HR 0.64 (95% CI 0.32-1.28)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Active-duty personnel only; hospitalizations at DoD facilities only

DASA, 2009 (Update)

Summary statistics of causes of death from April 1, 1991 to December 31, 2007

UK GWVs (n = 53,409) vs era veterans (n = 53,143)

Mortality due to malignant neoplasms

GWVs (209 cases) compared to era veterans (228 cases) MMR 0.97 (95% CI 0.81-1.18)

No significant difference in mortality rate was found for any of the specific classes of malignant neoplasm included in the study

Single years of age structure of the Gulf cohort at January 1, 1991

 

Statistics Canada, 2005 (Update)

Retrospective cohort study (based on Goss Gilroy, 1998) Approximately 2200 members of the deployed cohort were in the gulf region during combat period

5117 Canadian GWVs; 6093 Canadian era veterans, frequency matched for age, sex, and military duty status

Mortality and cancer incidences determined from the CMD and CCD through 1999

Cancer mortality, HR 0.85 (95% CI 0.38-1.09)

Incidence of any cancer (HR 0.86, 95% CI 0.54-1.39); cancer of the digestive system (HR 2.00, 95% CI 0.62-6.12); testicular cancer (HR 0.76, 95% CI 0.18-3.24); cancer of the lymph nodes (HR 0.65, 95% CI 0.16-2.62)

Age, rank

Limitations: Small sample size with low statistical power; young age of cohort; short follow-up period; no information on confounding factors

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Macfarlane et al., 2005 (Update)

Mortality cohort; 13-year follow-up

51,753 UK GW deployed veterans and 50,808 era veterans, randomly selected, matched by age, sex, service branch, rank; also fitness for active service in the army and Royal Air Force

Mortality due to malignant neoplasms

GWVs (123 deaths) compared to era veterans (130 deaths):

MRR 1.01 (95% CI 0.79-1.30)

 

Complete and long-term follow-up; cohort of moderate size; potentially other uncontrolled confounders such as smoking

NOTE: BIRLS = Beneficiary Identification Records Locator System; CCD = Canadian Cancer Database; CMD = Canadian Mortality Database; DMDC = Defense Manpower Data Center; GW = Gulf War; GWV = Gulf War veteran; HR = adjusted hazard ratio; MMR = mortality rate ratio; NDI = National Death Index; NDV = nondeployed veteran; NHSCR = National Health Service Central Register; PHQ = Patient Health Questionnaire; PIR = proportional incidence ratio; RR = adjusted risk ratio; SEER = Surveillance Epidemiology and End Results; SF-12 = 12-item short form health survey; SIR = standardized incidence ratio; SMR = standardized mortality ratio; SRR = standardized rate ratio.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

DISEASES OF THE BLOOD AND BLOOD-FORMING ORGANS

Diseases of the blood and blood forming organs include conditions affecting blood cells (erythrocytes, leukocytes, platelets) as well as the organs where these cells are produced (bone marrow, lymph nodes, spleen). The etiology of these disorders is varied, including genetic conditions, exposure to toxins and medications, infections or nutritional deficiencies. Diseases of the blood were not considered separately from other conditions in Volume 4, thus, this section does not include a summary of that volume. Primary studies are summarized in Table 4-2.

Updated and Supplemental Literature

Primary Studies

A number of studies have compared hospitalizations for diseases of the blood in veterans deployed and nondeployed to the Gulf War. For the purpose of this review, those studies have been considered primary. In addition to hospitalization studies, three published reports have examined hematologic parameters using laboratory tests in deployed and nondeployed Gulf War veterans.

Gray et al. (1996) used a retrospective cohort approach comparing hospitalizations among 547,076 Gulf War deployed and 618,335 nondeployed active-duty personnel at DoD medical facilities. Hospitalizations for 14 ICD-9-CM diagnostic categories, which included “diseases of the blood,” were assessed across three time periods following the war: August 1, 1991, to December 31, 1991; January 1, 1992, to December 31, 1992; and January 1, 1993, to September 30, 1993. Hospitalizations for diseases of the blood, primarily anemia, were increased among the Gulf War deployed personnel (vs nondeployed) during 1992 only. Differences, however, were not consistent over time and could be accounted for by deferred diagnoses during deployment. Limitations of this study include the relatively short follow-up, the lack of outpatient data, restriction to DoD hospitals, restriction to hospitalizations of those who remained on active duty after the war, and limited adjustment for potential confounders.

A later publication expanded the previous study to include hospitalizations for reservists and separated military personnel over the same three time periods as Gray et al. (1996). In addition to examining hospitalization data from DoD hospitals, this study also included hospital stays from the VA system and the California Office of Statewide Health Planning and Development for the years 1991-1994 (Gray et al., 2000). Denominator data for this analysis (the total number of veterans in each group) were not available, which led the researchers to use proportional morbidity ratios. The results did not provide evidence that blood diseases were more frequent among deployed than nondeployed veterans. Age and sex-adjusted proportional morbidity ratios for blood diseases in deployed versus nondeployed were 1.1 (95% CI 1.0-1.2) in DoD hospitals, 0.8 (95% CI 0.5-1.0) in VA hospitals, and 1.1 (0.2-2.0) in California hospitals. This analysis is limited since outpatient diagnoses were not included. Hospitalization rates were not estimated, and the analysis did allow for adjustment for confounding.

Hospitalizations for blood disorders were examined in an additional study comparing hospitalization rates in DoD hospitals through 2000 in three cohorts of veterans: Gulf War veterans, veterans deployed to Southwest Asia after the Gulf War, and veterans deployed to Bosnia (Smith et al., 2006). After adjustment for sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalizations, the rate of

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

hospitalizations for blood diseases (identified according to ICD-9-CM discharge codes) was similar in the three cohorts (Southwest Asia vs Gulf War veterans: HR 0.93, 95% CI 0.80-1.07; Bosnia vs Gulf War veterans: HR 0.93, 95% CI 0.75-1.15).

An earlier analysis by Smith et al. (2002) compared postwar hospitalizations among 405,142 active-duty Gulf War veterans who left the region after the war. Data for DoD hospitals were compared through July 1999 according to levels of exposure to oil-well fires in 1991 ranging from unexposed to an average daily exposure of greater than 260 μg/m3 for more than 50 days. The duration and length of exposure to particulate matter from the smoke were based on meteorological data, diffusion modeling and troop location data. This study did not observe a clear association between oil-well fire exposure and hospitalizations for blood disorders. The adjusted risk ratios for blood disorder hospitalization in those with the highest exposure to oil-well fires (> 260 μg/m3 for > 50 days) was 0.9 compared to those with no exposure. As with other studies of hospitalizations in DoD hospitals, the main limitations of this study include the lack of information on outpatient diagnosis as well as hospitalizations among those who left the service.

Smith et al. (2003) also examined hospitalizations for blood disorders according to potential exposure to nerve agents from the Khamisiyah demolition. Exposure to nerve agents was modeled following the 2000 Khamisiyah gaseous hazard area modeling done by the DoD. Rate of hospitalizations in DoD hospitals for these disorders were equivalent in those potentially exposed and nonexposed (risk ratio 0.96, 95% CI 0.89-1.03).

Two studies measured hematologic parameters in deployed and nondeployed veterans. A study conducted in 1997 among 686 Danish Gulf War veterans and 231 Danish nondeployed controls measured hemoglobin and blood cell counts in both groups (Ishoy et al., 1999b). In bivariate analyses, no differences were observed between deployed and nondeployed in blood hemoglobin (9.3 mmol/L in both groups), erythrocyte count (4.8 million/L in both groups), hematocrit (0.44 in both groups), mean corpuscular volume (91 10−15 L per cell in both groups), and leukocyte count (5.8 109/L in deployed and 5.9 109/L in nondeployed). Leukocyte fractions were also comparable. Platelet counts were slightly lower in deployed compared to nondeployed (205 109/L vs 211 109/L, p < 0.05). Differences in response rate (84% in deployed and 58% in nondeployed) and lack of adjustment for potential confounders reduces the usefulness of these results.

The Australian Gulf War Veterans’ Health Study (Sim et al., 2003) measured hemoglobin and other hematologic parameters in 1355 male and 30 female Gulf War veterans and in 1361 male and 32 female nondeployed veterans. In the males, hemoglobin (153.1 g/L vs 153.4 g/L), mean corpuscular volume (91.6 femtoliters [fl]2 vs 91.5 fl2), mean corpuscular hemoglobin (30.4 picograms[pg]3 vs 30.5 pg)3, platelets (227.8 109/L vs 231.3 109/L), and leukocytes (6.3 109/L vs 6.2 109/L) were similar in deployed and nondeployed veterans. No differences were observed for leukocyte fractions. In female veterans, deployed and nondeployed also presented similar hematologic parameters (hemoglobin: 131.8 g/L vs 134.3 g/L; mean corpuscular volume: 92.8 vs 93.4 fl; mean corpuscular hemoglobin: 29.8 pg vs 30.3 pg; platelets: 263.6 109/L vs 269.6 109/L; and lymphocytes: 2.0 109/L vs 2.1 109/L).

Secondary Studies

The committee did not identify any secondary studies of diseases of the blood or blood-forming organs in Gulf War veterans.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Summary and Conclusions

A number of studies have examined hospitalization rates for blood disorders in deployed and nondeployed veterans. Overall, these studies do not provide evidence that the incidence of blood disorders was different in deployed veterans compared with nondeployed veterans. However, limitations of these studies preclude drawing firm conclusions: hospitalizations were mostly restricted to DoD hospitals, studies did not include information on outpatient visits where patients with mild disorders are most likely to be seen, most studies lacked information on potential confounders, and none of these studies differentiated between potential hematologic disorders. Two additional studies measured hematologic parameters in deployed and nondeployed veterans. Taken together, these two reports did not show any major difference according to deployment status. They were limited, however, by differential participation rate and lack of adjustment for confounding variables. Additionally, some blood disorders typically have a long latency, and hospitalization and mortality studies have limited validity to detect their prevalence and incidence.

The committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and disorders of the blood and blood-forming organs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-2 Diseases of the Blood and Blood-Forming Organs

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Gray et al., 1996 (Update)

Retrospective cohort, hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 NDVs

Hospital-discharge diagnoses of blood disease in DoD hospital system

Exact values not given 1991: OR about 0.9 (95% CI 0.8-1.05);

1992: OR about 1.1 (95% CI 1.0-1.2)

1993, OR about 1.05 (95% CI 0.9-1.15)

Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation

Short follow-up period; no outpatient data; restriction to DoD hospitals and thus to persons remaining on active duty after the war; no adjustment for other potential confounders

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August 1991 through December 1994

652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5185 COSHPD hospitalizations

Hospital-discharge diagnoses of blood disease in DoD, VA, and COSHPD hospital systems

DoD PMR 1.08 (95% CI 0.97-1.19)

VA PMR 0.77 (95% CI 0.54-1.01)

COSHPD PMR 1.09 (95% CI 0.22-1.96)

Age, sex, race (only for DoD PMR)

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders; PMR has lower sensitivity than a comparison of hospitalization rates would have

Smith et al., 2006 (Update)

Retrospective cohort study (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theatre (n = 455,465); Southwest Asia peacekeeping

mission, 1991-1998 (n = 249,047);

Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of a disease of the blood (280-289)

Compared to GW veterans, veterans of Bosnia showed similar risk (HR 0.93, 95% CI 0.80-1.07), as did veterans of Southwest Asia (HR 0.93, 95% CI 0.75-1.15)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Limitations: active-duty personnel only; hospitalizations at DoD facilities only

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Smith et al., 2002 (Update)

DoD hospitalizations 1991-1999; exposure modeling for oil-well fire smoke

405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires

Hospitalization for diseases of the blood (ICD-9-CM codes 280-289)

No clear association between exposure and blood disease across all exposure levels

Adjusted for “influential covariates,” defined as demographic or deployment variables with p values less than 0.15

Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking

Smith et al., 2003 (Update)

DoD hospitalization study (1991-2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al., 1999b)

99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model

First hospitalization for any blood disorder (ICD-9-CM codes 280-289)

Exposed vs unexposed: RR 0.96 (95% CI 0.89-1.03)

 

Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures

Ishoy et al., 1999b (Update)

Cross-sectional

686 Danish peacekeepers deployed to gulf in 1990-1997 vs 231 age- and sex-matched armed forces nondeployed controls

Blood hemoglobin, erythrocyte count, hematocrit, mean corpuscular volume, leukocyte count, and platelet count

Hemoglobin (mmol/L): 9.3 (sd = 0.5) vs 9.3 (sd = 0.6); erythrocytes (million/L): 4.8 (sd = 0.3) vs 4.8 (sd = 0.3); hematocrit 0.44 (sd = 0.25) vs 0.44 (sd = 0.26); corp. vol. (10-15 L): 91 (sd = 3.6) vs 91 ((sd = 3.8); leukocytes (109/L): 5.8 (1.7) vs 5.9 (sd = 1.8); platelets (109/L): 205 (sd = 45) vs 211 (sd = 43), p < 0.05

 

Participation rate 83.6% deployed, 57.8% nondeployed; no adjustment for possible confounding factors

Sim et al., 2003 (Update)

Cross-sectional, mailed questionnaire and clinical

1355 male and 30 female Australian GWVs; 1361 male and 32 female

Hemoglobin, MCV, MCH, lymphocyte count, platelet count

Hemoglobin (g/L), men: 153.4 (sd = 9.5) vs 153.1 (sd = 9.1); women: 131.8 vs 134.3

Service type, rank, age, education, marital status

High participation in deployed veterans (male 81%, female 79%), but low participation in

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

examination

nondeployed veterans

 

MCV (fl), men: 91.6 (sd = 4.7) vs 91.5 (sd = 4.5); women: 92.8 vs 93.4 MCH (pg), men: 30.4 (sd = 1.4) vs 30.5 (sd = 1.3); women: 29.8 vs 30.3 Lymphocyte count (109/L), men: 1.9 (sd = 0.5) vs 1.9 (sd = 0.6); women: 2.0 vs 2.1 Platelets (109/L), men: 227.8 (sd = 44.4) vs 231.3 (sd = 48.5); women: 263.6 vs 269.6

 

control group (male 57%, female 44%) possibly leading to participation bias

NOTE: CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; fl = femtoliter; GW = Gulf War; HR = adjusted hazard ratio; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; MRR = mortality rate ratio; OR = adjusted odds ratio; pg = pictogram; PHQ = Patient Health Questionnaire; PMR = patient medical record; RR = adjusted risk ratio; sd = standard deviation; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

ENDOCRINE, NUTRITIONAL, AND METABOLIC DISEASES

Among the general US population, the most frequent disorders in this group of diseases are diabetes, thyroid disease, and obesity. In Volume 4 of this series, diabetes was grouped together with cardiovascular diseases. Other specific endocrine, nutritional, or metabolic outcomes were not considered. In this chapter, we will present, separately, studies reporting hospitalizations for endocrine and metabolic disorders, mortality studies and studies reporting associations of deployment with specific diseases (diabetes, thyroid disorders, and obesity). See Table 4-3 for a summary of the primary papers reviewed for endocrine, nutritional, and metabolic disorders.

Diabetes

Diabetes is an endocrine disorder characterized by abnormally elevated levels of blood glucose. The two major types of diabetes are type 1 diabetes, caused by destruction of the pancreatic cells that produce insulin, and type 2 diabetes, caused by peripheral resistance to insulin action and impaired insulin secretion, with increased blood glucose levels. Type 1 usually affects young people, while type 2 is more prevalent in adults and is strongly associated with obesity.

Summary of Volume 4
Primary Studies

Volume 4 included one primary study examining the association of deployment with 12 primary health outcomes, including diabetes, ascertained from a medical examination (Eisen et al., 2005). The study evaluated 1061 Gulf War deployed and 1128 nondeployed veterans who had been randomly selected from 11,441 Gulf War deployed and 9476 nondeployed veterans who previously participated in the National Health Survey of Gulf War Era Veterans and Their Families. Based on physical examinations conducted 10 years after the Gulf War, the prevalence of diabetes in deployed and nondeployed veterans was 4.2% and 3.5% (OR 1.52, 95% CI 0.81-2.85). Results for self-reported conditions were similar. A major limitation was the low participation rate, with only 53% of Gulf War veterans and 39% of nondeployed Gulf War veterans participating.

Secondary Studies

Studies relying on self-reported diabetes diagnoses, without additional confirmation, were considered secondary.

In a study of Kansas Gulf War veterans, prevalence of self-reported diabetes was similar in 1545 deployed veterans and 435 nondeployed (about 1% in both groups; OR 1.2, 95% CI 0.45-3.3) (Steele, 2000). Kang and colleagues (2000) found a very similar prevalence of self-reported diabetes in 11,441 deployed and 9476 nondeployed veterans (0.1% in both groups) in the National Health Survey of Gulf War Era Veterans and Their Families conducted in 1995. Among Seabee commands, no differences in prevalence of self-reported diabetes between Gulf War deployed Seabees (1.0%), those deployed elsewhere (0.9%), and nondeployed Seabees (1.6%) (OR 1.1, 95% CI 0.7-1.7 and OR 0.8, 95% CI 0.5-1.2, respectively) (Gray et al., 2002). Finally, in a multistate study of Gulf War deployed veterans (McCauley et al., 2002), being

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

deployed near the Khamisiyah demolition site was not related to the prevalence of self-reported diabetes (OR 1.0, 95% CI 0.4-2.9). In this same report, being deployed (versus nondeployed) was not associated with the prevalence of diabetes (OR 1.0, 95% CI 0.5-2.4).

Updated and Supplemental Literature
Primary Studies

A study conducted in 1997 on 686 Danish Gulf War veterans and 231 nondeployed veterans found that mean insulin levels, which are predictive of diabetes risk, were similar in deployed (48 pmol/L) and nondeployed (52 pmol/L) (Ishoy et al., 1999b). It should be noted that Danish veterans served mostly as peacekeepers after the end of the conflict.

Finally, the Australian Gulf War veterans study (Sim et al., 2003) obtained random glucose levels in a sample of 1365 male and 30 female deployed veterans and 1365 male and 32 female controls. Levels of blood glucose were comparable in both groups: among deployed and nondeployed men, median plasma glucose was 4.7 mmol/L in both groups, while among deployed and nondeployed women, the average plasma glucose was 5.0 mmol/L and 4.5 mmol/L, respectively. In this study, response rates were higher among deployed (81% in men, 79% in women) than nondeployed veterans (57% in men, 44% in women), which could lead to selection bias. Also, blood glucose levels were not obtained from fasting blood, which limits their value to diagnose diabetes.

McDiarmid and colleagues measured levels of blood glucose in a cohort of deployed veterans exposed to depleted uranium (DU) from friendly-fire followed up with biennial exams. Though these veterans have been observed many times since 1991, levels of blood glucose have been only reported in publications corresponding to the 2005 and 2007 assessments (McDiarmid et al., 2007a, 2009). The authors did not observe any important difference in blood glucose levels between those exposed to low and high levels of DU, though these results are limited due to the small sample size of the cohort (n = 34 in the 2007 publication, corresponding to the 2005 exam; n = 35 in the 2009 publication, corresponding to the 2007 exam), and the lack of adjustment for potential confounders.

Secondary Studies

A number of large-scale epidemiologic studies included self-reported endocrine and metabolic disorders, including diabetes, with onset after the Gulf War. These studies were regarded as secondary studies for the purpose of this review.

Simmons et al. (2004) surveyed all 51,581 male UK veterans who served in the Gulf War and a demographically similar comparison cohort of 51,688 UK male veterans who were not deployed to the gulf. Among the 23,358 deployed men who responded, 0.2% reported having diabetes with onset after 1990, as did 0.4% of 17,730 nondeployed men who responded, for an OR of 0.7 (95% CI 0.5-1.0) adjusted for age at the time of the survey, service and rank at the time of the Gulf War, serving status at the time of the survey, alcohol consumption, and smoking.

A follow-up survey to the 1995 National Health Survey of Gulf War Era Veterans and Their Families conducted in 2004-2005 compared self-reported health status of deployed Gulf War veterans and nondeployed Gulf War veterans (Kang et al., 2009). This survey included 6111 deployed and 3859 nondeployed veterans, out of 15,000 in each group (response rates of 41% in deployed and 26% in nondeployed veterans). The prevalence of a self-reported diagnosis of diabetes was similar in deployed and nondeployed veterans (prevalence ratio 1.11, 95% CI 0.99-1.25), after adjustment for sociodemographic and lifestyle variables. The prevalence of “other

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

endocrine (nondiabetes) disorders,” however, was slightly higher among the deployed (prevalence ratio 1.24, 95% CI 1.11-1.39), but these disorders were not specified.

Also in the context of the National Health Survey of Gulf War Veterans Study, the frequency of self-reported diabetes was compared among Gulf War veterans according to their potential exposure to the Khamisiyah demolition (Page et al., 2005). Prevalence of diabetes (OR 0.92, 95% CI 0.57-1.48) or other endocrine disorders (OR 0.92, 95% CI 0.65-1.30) was similar in those potentially exposed and unexposed.

In a mailed survey conducted in 1997, Canadian male Gulf War veterans (n = 2924) reported a prevalence of diabetes similar to that for nondeployed male veterans (n = 3241) (0.6% vs 0.4% in those aged 20-44 years and 2.0% vs 3.8% in those aged 45-64 years) (Goss Gilroy, 1998). Another study conducted in New England between 1994 and 1996 included 141 Gulf War veterans and 46 veterans deployed to Germany. The prevalence of self-reported diabetes was comparable in the two groups (2% in Gulf War veterans vs 0% in Germany-deployed veterans) (Proctor et al., 2001a).

Smith et al. (2006) compared hospitalizations in Gulf War deployed veterans with veterans deployed in the Persian Gulf after the war (Southwest Asia veterans) and in Bosnia (details on this study are provided in the section on hospitalizations for endocrine disorders). This study is considered secondary for diabetes, since diabetes discharge codes have low sensitivity and specificity for the diagnosis of diabetes (see, for example, Kieszak et al., 1999). The incidence of diabetes was similar among Gulf War veterans and Southwest Asia veterans (rate ratio 0.95, 95% CI 0.69-1.30, comparing Southwest Asia veterans to Gulf War veterans), but lower among veterans in Bosnia (rate ratio 0.54, 95% CI 0.29-1.00). This study was limited by including only hospitalizations occurring in DoD hospitals among active-duty personnel.

Thyroid Disease

The most frequent disorders of the thyroid gland are hypothyroidism and hyperthyroidism, characterized respectively by low or high levels of thyroid hormones. Many different causes can lead to these disorders, including autoimmune diseases, infections, malnutrition, exposure to some drugs or toxins, or neoplasias. Thyroid disease was not specifically studied in Volume 4.

Updated and Supplemental Literature
Primary Studies

Thyroid disease was included as an outcome in the study by Eisen and colleagues (2005). The study has been mentioned above under diabetes. Briefly, it evaluated 1061 Gulf War deployed and 1128 nondeployed veterans from those participating in the National Health Survey of Gulf War Era Veterans and Their Families. Based on physical examinations, the prevalence of hypothyroidism (defined as having an untreated thyroid-stimulating hormone level of 10.0 mU/mL or greater, or taking medication for hypothyroidism) and hyperthyroidism (defined as having an untreated thyroid-stimulating hormone level less than 0.1 mU/mL, or taking medication for hyperthyroidism) in deployed veterans were 1.6% and 0.3%, respectively. The corresponding prevalences in nondeployed were 1.2% and 0.1% (OR of hypothyroidism: 1.70, 95% CI 0.75-3.87; OR of hyperthyroidism 4.86, 95% CI 0.68-34.58). This study had a low participation rate, which limits the reliability of its results.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

A small cohort of Gulf War veterans exposed to DU as a result of friendly-fire accidents has been followed biennially for 16 years to identify uranium-related changes in health, including serum concentrations of free thyroxine and thyroid-stimulating hormone (TSH) as measures of thyroid function (McDiarmid et al., 2000, 2001, 2004, 2006, 2007a,b, 2009). Overall, consistent differences in mean concentrations of free thyroxine and TSH have not been observed when comparing those with high to those with low urinary uranium concentrations. One exception occurred when mean free thyroxine concentrations were found to be lower in the high uranium-exposed group at the 2001 evaluation, but no differences were observed in subsequent evaluations occurring in 2003, 2005, or 2007 (McDiarmid et al., 2007a, 2009; Squibb and McDiarmid, 2006). Although up to 77 DU-exposed Gulf War veterans have been evaluated in this cohort over time, at any single time point only a small subset of individuals were assessed. For example, 35 members underwent clinical evaluation during the most recent 2007 follow-up (McDiarmid et al., 2009). Thus, comparisons are based on small numbers. Additionally, the authors did not adjust for potential confounders between the two groups.

Secondary Studies

Three secondary studies assessed thyroid function in Gulf War veterans on the basis of self-reports. In 1997, a mail survey of the entire Canadian military contingent of 2924 male veterans who served in the Gulf War and 3241 Canadian veterans who were in the military but had not been posted to the gulf region were asked about the presence of goiter (a form of thyroid disease) or thyroid trouble. Positive responses were reported by 0.9% of the Gulf War veterans and 0.7% of the nondeployed veterans 20-44 years old and by 2.0% of deployed and 1.3% of nondeployed veterans 45-64 years old; the median age of the deployed was 36 years, and that of the nondeployed was 37 years (Goss Gilroy, 1998).

In a study conducted among Kansas veterans, deployed veterans were more likely than their nondeployed counterparts to report thyroid conditions (OR 2.32, 95% CI 0.81-6.67), but numbers were small and therefore estimates of association imprecise (Steele, 2000). Gray et al. (2002), examining Seabee commands, observed an increase in thyroid conditions among the Gulf War deployed Seabees when compared to Seabees deployed elsewhere (OR 1.87, 95% CI 1.16-3.03) but not when compared to the nondeployed members of this cohort (OR 1.49, 95% CI 0.89-2.50).

Obesity

Obesity is a state of excess adipose tissue mass. The most widely used method to measure obesity is through the body mass index (BMI), defined as the weight in kilograms divided by the square of the height (in meters). Overweight is usually defined as a BMI > 25 kg/m2, while the cutoff point for obesity is a BMI > 30 kg/m2. In the year 2000, the prevalence of obesity in the United States was approximately 30%, while more than 60% of adults older than 20 were overweight. Genetic factors, sedentary lifestyles, and diet are the major determinants of obesity. Obesity was not studied separately in Volume 4.

Updated and Supplemental Literature
Primary Studies

A study of 686 Danish Gulf War veterans and 231 nondeployed veterans included measurements of weight and height (Ishoy et al., 1999b). The exams were conducted in 1997.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Average weight and waist circumference were slightly higher in deployed (84.2 kg and 90.2 cm, respectively) than in nondeployed veterans (81.9 kg and 88.3 cm).

In the study of Australian Gulf War veterans (Sim et al., 2003), researchers obtained direct measures of BMI and waist circumference in a sample of 1384 male and 30 female deployed veterans and 1379 male and 32 female nondeployed controls examined in 2002. BMI was comparable in deployed and nondeployed groups. Comparisons were adjusted for service type, rank, age, education, and marital status. In deployed men, the mean (standard deviation) of BMI was 28.1 kg/m2 (sd = 4.1) while in nondeployed men it was 28.3 kg/m2 (sd = 4.1) (adjusted difference: −0.3, 95% CI −0.6-0.02). Their corresponding mean waist circumference was 97.7 cm (sd = 10.7) and 98.2 cm (sd = 10.7) (adjusted difference: −0.6, 95% CI −1.4-0.2). Among female veterans, both deployed and nondeployed had an average body mass index of 26 kg/m2, and similar waist circumferences (86.3 cm in deployed and 83.4 cm in nondeployed). Given the small sample size in this group, the authors did not conduct statistical comparisons among women.

Secondary Studies

A small study of 111 deployed and 133 nondeployed UK veterans compared different clinical parameters, objectively measured, in the two groups (Ismail et al., 2008). These parameters included BMI, glycemia, and blood levels of thyroxine-stimulating hormone. No differences were observed between the groups. These veterans were selected from a group of approximately 12,000 UK veterans who were contacted by mail and reported physical disability according to the Short Form 36 (SF-36) Physical Functioning Scale. Being a selected subgroup of deployed and nondeployed veterans, it is unclear how these results apply to the entire veteran population.

Hospitalization Studies

Summary of Volume 4

A DoD study examined hospitalizations in relation to possible exposure to sarin and cyclosarin as a result of demolishing weapons at Khamisiyah, Iraq, in March 1991 (Smith et al., 2003). As an update to a previous report (Gray et al., 1999b), the investigators analyzed hospitalizations from 1991 to 2000 among 431,762 active-duty military deployed to the Gulf War theater during the time of the Khamisiyah demolition. Investigators studied discharge diagnoses from 15 ICD-10 categories, including “endocrine, nutritional, and metabolic diseases.” The incidence of hospitalizations for endocrine and metabolic diseases was the same in veterans exposed and nonexposed to the Khamisiyah plume (risk ratio 1.00, 95% CI 0.94-1.06). Limitations of this study include: diagnoses not severe enough to require hospitalization would not be captured in these data, lack of outpatient data, restriction to DoD hospitals in those on active duty, and limited adjustment for potential confounding exposures.

Updated and Supplemental Literature

Since the publication of Volume 4, four additional primary studies reporting hospitalizations for endocrine and metabolic disorders have been identified (Gray et al., 1996, 2000; Smith et al., 2002, 2006). Like Smith et al. (2003), however, these studies evaluated hospitalizations for major diagnostic categories, and thus were limited to assessing events serious enough to warrant hospitalization.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Gray et al. (1996) compared DoD hospitalizations among Gulf War deployed and nondeployed active-duty personnel. Discharge diagnoses for 14 ICD-9-CM categories, which included “endocrine, nutritional, and metabolic diseases,” were assessed across three time periods following the war: August 1, 1991, to December 31, 1991 (included 1,165,411 subjects on active duty on the first day of this time period); January 1, 1992, to December 31, 1992 (1,075,430 subjects); and January 1, 1993, to September 30, 1993 (839,389 subjects). Hospitalizations for endocrine and metabolic diseases were not increased among the Gulf War deployed personnel (vs nondeployed) during any of the three time periods. Limitations of this study include the relatively short follow-up, the lack of outpatient data, restriction to DoD hospitals, restriction to hospitalizations of those who remained on active duty after the war, and limited adjustment for potential confounding exposures.

The authors later expanded the study above to include reserve and former military personnel hospitalized in non-DoD hospitals (Gray et al., 2000). Hospitalization for the 14 major discharge diagnoses during the period of August 1, 1991, and December 31, 1994, were compared for Gulf War veterans and nondeployed veterans in three hospital systems (DoD, VA, and the California Office of Statewide Health Planning and Development). Because the population eligible for hospitalization in the VA and California systems could not be identified to calculate hospitalization rates, the investigators estimated proportional morbidity ratios (PMRs) within each hospital system. Gulf War veterans did not experience an increased probability of hospitalizations for endocrine, nutritional, and metabolic diseases compared to nondeployed veterans during the 4 years after the war. This finding was consistent among hospitalizations within the DoD (n = 182,164), VA (n = 16,030), and California (n = 5185) hospital systems. The authors acknowledge the proportional morbidity approach is likely to be less sensitive for detecting differences in hospitalizations than a comparison of hospitalization rates. However, the results within the DoD system were consistent with the finding reported in Gray et al. (1996), which observed no differences in the odds of hospitalization for endocrine and metabolic disorders over the 2-year observation period.

Postwar hospitalizations in US military personnel were also examined in relation to exposure to smoke from oil-well fires (Smith et al., 2002). Hospitalizations within DoD treatment facilities were identified for 405,142 active-duty personnel who were in the Gulf War theater of operations during the Kuwaiti oil-well fires (February 2, 1991, to October 31, 1991) and did not remain in the region after the war. Hospitalizations for “endocrine, nutritional and metabolic diseases” and other major ICD-9-CM categories were evaluated over an 8-year follow-up period. Exposure to oil-well fire smoke was estimated by combining smoke-plume modeling data and troop unit location. Exposure was categorized into seven levels based on combinations of average daily dose (none, 1-260 μg/m3, > 260 μg/m3) and duration of exposure (1-25 days, 26-50 days, > 50 days). When compared to those with no exposure to smoke from oil-well fires, there was no increase in the incidence of hospitalization for endocrine and metabolic diseases at any level of exposure (adjusted risk ratio comparing those with the highest exposure to those with no exposure, 0.84). The limitations of this study are the same as those described above for Gray et al. (1996) and Smith et al. (2003).

More recently, the hospitalization experience of the Gulf War veterans (n = 455,465) was compared with that of veterans deployed to Southwest Asia after the Gulf War (n = 249,047) and veterans deployed to Bosnia (n = 44,341) (Smith et al., 2006). Only hospitalizations occurring in DoD hospitals through the end of 2000 while the veteran was on active duty were considered. Compared to veterans deployed to the Gulf War, the rate ratio of hospitalizations for endocrine

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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and metabolic disorders was 1.02 (95% CI 0.92-1.13) in those deployed to Southwest Asia after the conflict and 0.69 (95% CI 0.57-0.84) in those deployed to Bosnia. As with other studies of hospitalizations in DoD hospitals, a major limitation of this analysis is the exclusion of hospitalizations in other hospitals and the restriction to active-duty personnel.

Mortality Studies

Updated and Supplemental Literature

For the purpose of this review, mortality studies of endocrine, nutritional, and metabolic diseases were considered secondary, given the expected low sensitivity of death certificates for the accurate identification of these disorders.

Only one report of mortality for endocrine, nutritional, or metabolic diseases was identified (Macfarlane et al., 2005). This study examined mortality from 1991 through June 30, 2004, of 51,753 UK Gulf War veterans and 50,808 nondeployed veterans in service on January 1, 1991. Nondeployed veterans were matched with deployed by age, sex, service branch, rank, and fitness for active service. Vital status and cause of death, if applicable, was obtained from linkage with the National Health Service central register. Only three deaths (one in Gulf War veterans, two in nondeployed veterans) were attributed to endocrine, nutritional, or metabolic disorders (mortality rate ratio 0.5, 95% CI 0.1-5.8).

Summary and Conclusions

Primary studies found no clinically relevant differences in prevalence of different endocrine and metabolic disorders, including diabetes, thyroid disease, and obesity, between deployed and nondeployed veterans. Because five of the eight primary studies were limited to hospital discharge data, conditions not requiring hospitalization have not been sufficiently evaluated. Furthermore, the grouping of all endocrine, nutritional, and metabolic disorders into a single outcome, as presented in all hospitalization studies, may obscure potential associations with specific conditions. Results from secondary studies were similarly inconclusive, with deployment status unrelated to the prevalence of self-reported diabetes but with less consistent findings observed for “other endocrine disorders.” Overall, existing evidence does not support an increased risk of endocrine, nutritional, or metabolic disorders among Gulf War veterans compared to other veterans. However, the Gulf War veteran population is still relatively young, and an increased risk of type 2 diabetes in deployed veterans might not be evident yet. The committee recommends that future assessments of Gulf War veterans include obtaining hemoglobin A1c samples as a more reliable indicator of type 2 diabetes.

The committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and endocrine, nutritional, and metabolic diseases.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-3 Endocrine, Nutritional, and Metabolic Diseases

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Cross-sectional, prevalence, population-based (Derived from Kang et al. 2000)

1061 GWVs and 1128 NDVs

Diabetes, hypothyroidism, hyperthyroidism

 Diabetes (OR 1.52, 95% CI 0.81-2.85); hypothyroidism (OR 1.70, 95% CI 0.75-3.87); hyperthyroidism (OR 4.86, 95% CI 0.68-34.58); no outcomes tested were significant

Age, sex, race, smoking, duty type, service branch, education, rank (hyperthyroidism not adjusted for service branch or rank)

Low participation rates, deployed (53%), nondeployed (39%)

Smith et al., 2003 (Vol. 4)

DoD hospitalization study (1991-2000) of those potentially exposed to nerve agent

99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model

Hospitalization due to endocrine, nutritional, and metabolic diseases (ICD-9 classification)

RR 1.00 (95% CI 0.94-1.06)

One or more hospitalizations in a specific diagnostic category

Diagnoses not requiring hospitalization not captured; no outpatient data; DoD hospitals and active duty only; not possible to adjust for confounding exposures

Ishoy et al., 1999b (Update)

Cross-sectional

686 Danish peacekeepers deployed to gulf in 1990-1997 vs 231 age- and sex-matched armed forces nondeployed controls

Plasma insulin levels Avg. weight and waist circumference

No significant difference in insulin levels between deployed (48 pmol/L) and nondeployed (52 pmol/L) Weight and waistline were higher (p < 0.05) for deployed (84.2 kg, 90.2 cm) than for nondeployed (81.9 kg, 88.3 cm)

 

Participation rate 83.6% deployed, 57.8% nondeployed

Sim et al., 2003 (Update)

Cross-sectional, mailed questionnaire and clinical examination

1384 male and 30 female Australian GWVs; 1379 male and 32 female NDVs (Only 1365 GWVs and 1365 for plasma glucose analysis)

Plasma glucose; BMI; waist circumference

Plasma glucose, men: 85 mg/dL in both groups; women: 90 mg/dL vs 81 mg/dL

BMI, men: 28.1 kg/m2 (sd = 4.1) vs 28.3 kg/m2 (sd = 4.1), OR -0.3 (95% CI -0.6, 0.02); women: 26 kg/m2 in both groups

Waist circumference, men:

Service type, rank, age (< 20, 20-24, 25-34, ≥ 35 years), education and marital status

High participation in deployed veterans (male 81%, female 79%), but low participation in control group (male 57%, female 44%) possibly leading to participation bias

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

97.7 cm (sd = 10.7) vs 98.2 cm (sd = 10.7), OR −0.6 (95% CI −1.4, 0.2) ; women: 86.3 cm vs 83.4 cm

 

 

McDiarmid et al., 2007a, 2009 (Update)

Case series

Population for 2005 exam (2007a study): n = 34 Population for 2007 exam (2009 study): n = 35

Blood glucose

Low-uranium compared to high-uranium group: 107 mg/dL vs 109 mg/dL in 2005 exam (p = 0.67), 111 mg/dL vs 90 mg/dL in 2007 exam (p = 0.07)

None

Very small sample size, no adjustment for potential confounders

Smith et al., 2003 (Vol. 4)

DoD hospitalization study (1991-2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al. 1999b)

99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model

First hospitalization for any endocrine, nutritional, and metabolic diseases (ICD-9-CM codes 240-279)

Exposed vs unexposed: RR 1.00 (95% CI 0.94, 1.06)

 

Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures; diagnoses not severe enough to require hospitalizations are not captured

Gray et al., 1996 (Update)

Retrospective cohort, hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 NDVs

Hospital-discharge diagnoses of endocrine, metabolic, or nutritional system diseases in the DoD hospital system (ICD-9 classification)

OR about 0.85-0.90 (95% CI 0.80-0.95) across all three years, 1991-1993. Exact values not given

Prewar hospitalization, sex, age, race, branch of service, marital status, rank, length of service, salary, occupation

Very short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August

652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD

Hospital-discharge diagnoses for endocrine, nutritional, and metabolic disease in

DoD PMR 0.99 (95% CI 0.93-1.06)

VA PMR 1.08 (95% CI 0.92-1.24)

Age, sex, race (only for DoD PMR)

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

1991 through December 1994

hospitalizations; 16,030 VA hospitalizations; 5185 COSHPD hospitalizations

three hospital systems: DoD, VA, COSHPD

COSHPD PMR 0.81 (95% CI 0.48-1.14)

 

PMR has lower sensitivity than a comparison of hospitalization rates would have

Smith et al., 2002 (Update)

DoD hospitalizations 1991-1999; exposure modeling for oil-well fire smoke

405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires

Association of exposure level with hospitalizations for endocrine, nutritional, and metabolic disease

No significant difference between RR for exposure at any level vs nonexposed

Adjusted for “influential covariates,” defined as demographic or deployment variables with p values less than 0.15

Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking

Smith et al., 2006 (Update)

Retrospective cohort study; cohort data from DMD

Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping

mission, 1991-1998 (n = 249,047);

Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of an endocrine disease (240-279)

Veterans of Bosnia, HR 0.69 (95% CI 0.57-0.84)

Veterans of SW Asia, HR 1.02 (95% CI 0.92-1.13)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Limitations: active-duty personnel only; hospitalizations at DoD facilities only

NOTES: BMI = body mass index; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veterans; NDV = nondeployed veterans; OR = adjusted odds ratio; PHQ = Patient Health Questionnaire; PMR = patient medical records; RR = risk ratio; sd = standard deviation; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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MENTAL AND BEHAVIORAL DISORDERS

War is a known risk factor for psychiatric conditions (Pizarro et al., 2006; Wessely, 2005). The description of the extent and type of psychiatric affliction and its course has depended on the development of modern psychiatric diagnostic systems and epidemiologic methods. The development of a structured diagnostic system and diagnostic instruments has facilitated the diagnosis of behavioral disorders. Moreover, the prevalence of psychiatric disorders in epidemiologic samples drawn from the general population has become available (Kessler et al., 2005a,b) and provides baseline data with which to compare data from specific inquiries. Thus, after the Persian Gulf War, many methodological and scientific details were in place to support an assessment of the psychological consequences of war. The Persian Gulf War was highly unusual in that the air war lasted 40 days and the ground war concluded in 5 days, so there was a limited theater and set of conditions amenable in many respects to scientific study. In fact, each of the large cohort studies of Gulf War veterans, described in Chapter 3, included items pertaining to mental health. Nested within them was analysis of mental health characteristics based on direct interview techniques or validated symptom scales.

Types of psychiatric ill health that could be associated with the Gulf War, particularly posttraumatic stress disorder (PTSD), were predicted on the basis of their descriptions from previous wars (O’Toole et al., 1996; Roy-Byrne et al., 2004). Psychiatric disorders in the general population are not uncommon, and are often disabling and chronic (Kessler et al., 2005a,b). Diagnosable psychiatric disorders are found in about one-third of the US adult population at any given time, but their prevalence in military populations is lower, which may be largely as a result of the healthy-warrior effect. Psychiatric disorders can be grouped into several classes, such as mood disorders (that is, depression and bipolar disorder); anxiety disorders (that is, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, PTSD, and social phobia); disorders involving perceptions of physical symptoms and health, which are called somatoform disorders (for example, hypochondriasis and somatization disorder); and substance use disorders (for example, abuse of and dependence on drugs and alcohol). Specific criteria for diagnosing those mental health disorders are given in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) (American Psychiatric Association, 2000) or the ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research.

The specification of characteristics of mental diagnoses has made research on their incidence and prevalence possible, so that there are guidelines differentiating them from transient experiences of distress or sadness that do not signify the presence of mental disease. Major depression, a type of mood disorder, is characterized by lifelong vulnerability to episodes of depressed mood and loss of interest and pleasure in daily activities accompanied by other symptoms such as sleeping too little or too much, reduced appetite and weight loss or increased appetite and weight gain, restlessness, irritability, difficulty concentrating, feeling guilty, hopeless or worthless, and thoughts of suicide or death. A major depressive episode is categorized as major depressive disorder (MDD) or, when it accompanies mania, as bipolar disorder. PTSD is a subtype of anxiety disorder.

PTSD is diagnosed on the basis of exposure to a traumatic event. After this exposure, the person experiences a specific constellation of symptoms such as severe distress on recollection of the event, avoidance of reminders of the situation, numbing of general responsiveness, and such signs of hyperarousal as irritability, sleep disturbance, or exaggerated startle reflexes. The

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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presence of a few PTSD symptoms after a trauma is common and does not signify the presence of disease, but the presence of the full syndrome itself is much less common and is associated with significant disability.

Substance abuse is defined as a maladaptive pattern of substance use (there are many types of abused substances, but alcohol abuse is the most common) that results in a failure to fulfill major social roles (such as work or family-care performance), that involves use of the substance despite physical hazards and in association with legal consequences, and that involves use despite deleterious social and interpersonal consequences.

Substance use disorders include substance abuse and substance dependence. Substance abuse is defined as a maladaptive pattern of substance use that results in a failure to fulfill major social roles (such as work or family-care performance), that involves use of the substance despite physical hazards and in association with legal consequences, and that involves use despite deleterious social and interpersonal consequences. Substance dependence involves persistent and sustained maladaptive desire for and/or preoccupation with the substance, manifesting physiologically as symptoms of withdrawal when the substance is not taken, or as tolerance—a need to imbibe markedly increased amounts of the substance in order to continue to feel the desired outcome. Psychological manifestations of substance use disorders dependence include taking the substance over longer periods than intended, making unsuccessful efforts to cut down, and/or continuing to use the substance despite knowledge of having a significant physical or psychological problem resulting from its use. There are many types of substances for which abuse and dependence can be diagnosed; in most societies nicotine dependence is the most common and hazardous substance use disorder, currently responsible for half a billion deaths a year worldwide (Ezzati and Lopez, 2003). The studies of Gulf War veterans were generally limited, however, to assessment of the use of alcohol and illegal drugs, and therefore, the committee restricts its comments to these substances.

The prevalence of those disorders among young and middle-aged adults in the general population has now been addressed in several large studies, including the National Survey of Drug Use and Health, the National Epidemiologic Survey on Alcohol and Related Conditions, and the US National Comorbidity Survey Replication, a nationally representative face-to-face household survey conducted from February 2001 to April 2003 (Kessler et al., 2005a,b). The most recent data show that the prevalence estimates for all anxiety disorders were 28.8% (lifetime) and 18.1% (in the last 12 months); for all mood disorders, 20.8% (lifetime) and 9.5% (in the last 12 months); and for all substance use disorders, 14.6% (lifetime) and 3.8% (in the last 12 months). It should be noted that there is substantial variation by gender, and also by age group, even within the limited age range covered. It is also well established that because of difficulties associated with recall, lifetime prevalences tend to provide underestimates of the likelihood that an individual has had a particular condition, and recall about whether the condition has occurred in the last 12 months is more accurate (Susser and Shrout, 2009).

The prevalence estimates for the general population are generally higher than those in deployed veterans exposed to combat and much higher than in the control nondeployed veteran populations. As noted above, this is partly explained by a healthy warrior outcome. Thus, both military screening and self-selection are likely to ensure that individuals enter the military with better mental and physical health than the general population.

Primary studies provided the basis of the committee’s findings on the relationship between deployment to the Gulf War and psychiatric outcomes (see Table 4-4). Primary studies were those in which veterans were categorized as deployed, not deployed, or deployed to a

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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nonwar zone (for example, Germany). To diagnose psychiatric disorders, primary studies also included an in-person standardized diagnostic interview. Some studies used clinician interviews such as the Structured Clinical Interview for DSM-III-R (SCID); the Schedule for Clinical Assessment and Diagnosis (SCAN); or for PTSD, the Clinician Administered PTSD Scale (CAPS). Others used interviews administered by trained lay interviewers, such as the Composite International Diagnostic Interview (CIDI), a comprehensive and standardized diagnostic interview that is very widely used. The CIDI has been adapted to many forms that limit the diagnoses covered and the length of interview, and these alternative forms often produce less precise diagnoses. Studies of Gulf War veterans often used versions of the CIDI that were abbreviated from the full standard CIDI. Secondary studies typically failed to use diagnostic interviews to diagnose mental health disorders and often screened for mental health disorders using symptom checklists such as the PTSD Checklist developed by the VA.

Summary of Volume 4

Primary Studies

Many of the large epidemiologic studies of Gulf War veterans’ health included items pertaining to mental health. Moreover, there was often a nested case-control study of mental health characteristics in the primary epidemiologic cohort studies that used direct-interview techniques. In Volume 4, eight primary studies were reviewed that used direct-interviews of the large Gulf War cohorts described in Chapter 3. These studies often used validated instruments, such as the CIDI, SCID, and CAPS, to complement the interview. Black et al. (2004b) reanalyzed the population-based, telephone interviews from the Iowa cohort of 4886 randomly selected veterans (military and reserve), deployed and nondeployed (Iowa Persian Gulf Study Group, 1997). The initial cohort study had uncovered higher than anticipated levels of anxiety; therefore, this analysis of the interview data looked more carefully into the features of anxiety in that population. The original cohort was interviewed by telephone using the Primary Care Evaluation of Mental Disorders (PRIME-MD), the Post Traumatic Stress Disorder Checklist-Military (PCL-M), and the CAGE2 to estimate alcoholism. Additional structured questions identified medical conditions and military preparedness. Compared with nondeployed veterans, deployed veterans had a twofold increase in the prevalence of generalized anxiety disorder, panic disorder, PTSD, and any anxiety disorder (OR 2.3, 95% CI 1.5-3.5). Participation in combat increased the likelihood of the development of anxiety disorders, particularly PTSD (OR 2.1, 95% CI 1.7-4.2). Anxious Gulf War veterans were more likely to have had a pre-existing psychiatric condition, to have taken psychotropic medications, or to have had a psychiatric hospitalization prior to deployment. Anxiety conditions were comorbid with several psychiatric and medical conditions, particularly symptoms of cognitive dysfunction, any depression, major depression, and symptoms of fibromyalgia.

Barrett et al. (2002) analyzed the same data as Black et al. (2004b) to assess PTSD. A score of 50 or more on the PCL-M defined PTSD. PTSD-positive veterans had a mean score of 58.7, whereas those without PTSD had a mean score of 19.7; the prevalence of PTSD was 1.09%. The PTSD score was significantly associated with decreased functioning and quality of life, as well as increased reporting of symptoms and medical conditions.

2

The CAGE is a four-item scale to assess cutting down (C), feeling annoyed by people criticizing your drinking (A), feeling guilty about drinking (G), and using alcohol as an eye-opener in the morning (E).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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In a nested case-comparison study, Black et al. (2004a) conducted face-to-face interviews with 602 veterans in 1999-2002. They used the SCID with a random group of veterans drawn from strata of the PRIME-MD-interviewed group who reported one or more of the following symptom-based conditions during their previous interview: depression (major or minor depression), widespread chronic pain (established criteria for generalized, severe, and chronic pain), and cognitive dysfunction (amnesia or cognitive impairment of a moderate and prolonged intensity). Veterans were stratified by each symptom combination (one, two, or all) and by deployed or nondeployed status. Controls had not met screening criteria for any of these conditions and might have been deployed or not deployed. The veterans were selected randomly for interview from each stratum to optimize the match between cases and controls.

Personality disorders were screened for with the Schedule for Nonadaptive and Adaptive Personality (SNAP). Level of functioning was assessed using the SF-36. The Whiteley Index was used to determine hypochondriasis. The study found that 32% of the veterans met the criteria for a lifetime depression diagnosis (all types), and that rate was the same in deployed and nondeployed veterans (36.6% vs 30.3%, not significant). There were few diagnostic differences between the depressed deployed and the depressed nondeployed veterans, except for lifetime and current PTSD (OR 4.50, 95% CI 1.80-11.27 and OR 7.13, 95% CI 2.10-24.20, respectively), any lifetime and current anxiety disorders (OR 2.89, 95% CI 1.52-5.47 and OR 3.19, 95% CI 1.62-6.27, respectively), and any current psychiatric disorder (OR 2.00, 95% CI 1.0-3.74). The deployed depressed veterans were also more likely to have a diagnosis of any lifetime, but not current, substance-use disorder (OR 2.15, 95% CI 1.15-4.03), particularly lifetime alcohol-use disorder (OR 2.0, 95% CI 1.07-3.74). What was most surprising about the direct interview analysis was that there was little difference between the deployed and the nondeployed veterans in aspects of depression; the largest difference was found in the prevalence of any anxiety disorder (51.5% for deployed vs 25.0% for nondeployed).

Kang et al. (2003) conducted a population-based stratified random sample of 15,000 US Gulf War troops compared to a similar sample of nondeployed troops. Phase 1 was a mail survey and phase 2 was a telephone-based survey of PTSD symptoms using the PCL-M and chronic fatigue symptoms. In the interview cohort, 12.1% of Gulf War veterans and 4.3% of other veterans had symptoms of PTSD, with an adjusted OR of 3.1 (95% CI 2.7-3.4) for PTSD in the Gulf War group; 5.6% of the Gulf War veterans, and 1.2% of the other veterans (OR 4.8, 95% CI 3.9-5.9) had chronic fatigue symptoms. It was interesting to note that PTSD symptoms showed a dose-response relationship to intensity of war stress, whereas the chronic fatigue symptoms did not show any relationship to war stress. Estimates of PTSD as determined by a cutoff score of 50 or above tracked rates of stressors closely. Deployment, but not war stress, was associated with chronic fatigue symptoms.

Wolfe et al. (1999a,b) and Proctor et al. (1998) examined cohorts of veterans randomly sampled and stratified from the Fort Devens, Massachusetts, and New Orleans Gulf War veterans, as well as a cohort deployed to Germany. The Gulf War deployed veterans from Fort Devens were followed longitudinally from the day of their arrival home from the gulf (time 1) to about 2 years later (time 2) with a 78% participation rate. The Fort Devens cohort was mainly male, caucasian, and National Guard; rates of PTSD measured at time 1 were 3%. From those cohorts, stratified random samples were selected for closer study with direct interview (220 of the Fort Devens cohort, 73 of the New Orleans cohort, and 48 of the Germany deployed). The researchers used questionnaires (the 52-item expanded Health Symptoms Checklist [HSC] and the Expanded Combat Exposure Scale), a neuropsychologic test battery, an environmental

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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interview, and psychiatric diagnostic instruments (the Clinician-Administered PTSD Scale [CAPS] or the Mississippi Scale for Combat-Related PTSD) (Proctor et al., 1998). Current PTSD (time 2) was diagnosed in 8.1% of the Fort Devens group, 7.6% of the New Orleans group, and none of the Germany group based on the CAPS. Health status and function were lower in the Gulf War deployed cohorts than the Germany deployed cohort (19.7-20.7% of deployed cohorts reported fair or poor health vs 6.4% of Germany deployed cohort). The three most prevalent symptoms in the Fort Devens group were “forgetfulness,” “fatigue,” and “unsatisfactory sleep” (Proctor et al., 1998).

Wolfe et al. (1999b) also recruited cases from the Fort Devens, New Orleans, and Germany cohorts with a stratified random-sampling strategy (148 from the Fort Devens group, 56 from the New Orleans group, and 56 from the Germany group). They used the Laufer Combat Scale to assess exposure to combat situations and the Mississippi Scale for Combat-Related PTSD to assess PTSD. The deployed Fort Devens group had significantly (p < 0.05) higher levels of current and lifetime PTSD (5.4% and 6.5%, respectively) and current and lifetime MDD (6.6% and 22.5%, respectively) than the Germany group (0% for both). Deployed personnel from New Orleans also had higher levels of current and lifetime PTSD (7.2% and 8.2%, respectively) and current and lifetime MDD (4.5% and 10.2%, respectively) than the Fort Devens or Germany deployed groups, although the difference was not significant. The prevalence of the other eight psychiatric disorders was similar between the three groups. Compared with the PTSD prevalence in the general population (7.8%) (Kessler et al., 1995), the Germany group (controls) had much lower rates of PTSD (0%). However, the low prevalence estimates in the controls increases from zero to 5-8% when the veterans are deployed to active war situations. A strength of this study is that it is characterized by direct interview.

In another analysis of these data (Wolfe et al., 1999a) looked at the course and predictors of PTSD and found that there was a higher rate of PTSD at time 2 (8%) than at time 1 (3%) (OR 3.2), indicating the development of new cases. Responders at time 2 were more likely to be younger, belong to racial minorities, and be deployed; however, the absence of differences in PTSD rates due to those characteristics indicates a lack of selection bias at time 2. Women were significantly more likely to have PTSD than men at either time (OR 3.2 at time 1, 95% CI 1.9-5.5; OR 2.3 at time 2, 95% CI 1.5-3.5), although their numbers were very low at each assessment. For men, 1% exceeded the cutpoint for PTSD at time 1 and time 2, 1% exceeded it at time 1 only, and 6% exceeded it at time 2 only.

Brailey et al. (1998) studied Gulf War veterans on their return from service (an average of 9 months after their return) with a face-to-face debriefing and psychological assessment with self-administered questionnaires, comparing Gulf War deployed (n = 876) with nondeployed veterans (n = 396 mobilized but not deployed), including National Guard and reserve troops. A subset of 349 received a followup assessment an average of 16 months later. Investigators used standard psychiatric rating scales for their assessments including: the Beck Depression Inventory (BDI), the State Anger, the State Anxiety, the Brief Symptom Inventory (BSI) Depression, BSI Anxiety, BSI Hostility, and the HSC. The deployed veterans had higher scores than the nondeployed on the BDI, the State Anger, the BSI Anxiety, and the HSC. When the Gulf War deployed veterans were reassessed on average of 16 months later, they showed increases on all scales, including the BDI, the State Anger, the BSI Anxiety, the BSI Hostility, HSC, and on both PTSD scales (the 17-item DSM-III R PTSD Checklist and the Mississippi Scale for Desert Storm War Zone Personnel). They showed increased rates of depression (6.9% to 13.8%), PTSD (2.3% to 10.6%), and hostility (4.9% to 13.8%). The authors correlated war stress with those symptoms

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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and found that the higher the war-zone stress, the more severe the depressive and anxiety symptoms. Compared with nondeployed troops, troops who were assigned to high-risk activities, such as grave registration, showed a high prevalence of PTSD (0% vs 48%).

Ikin et al. (2004) conducted a comprehensive health assessment of 1424 male Gulf War veterans (86.5% Navy) and 1548 male Australian Defence Force members who were not deployed to the Gulf War, including an interview-administered psychological health assessment with the Composite International Diagnostic Interview (CIDI), a structured interview of demonstrated reliability and validity. The CIDI data allowed them to make an estimate of pre-Gulf War disorder, post-Gulf War disorder, and current (last 12 months) disorder. Those interview data were used with postal questionnaire data to form a complete workup of 1381 Gulf War veterans, and 1377 comparison veterans. Both the veterans and the controls completed the health assessment and the postal questionnaire. The two groups were demographically similar, although the Gulf War veterans were significantly younger, more likely to have been in the Navy, and less highly ranked than the comparison veterans. The two veteran groups were similar in prevalence of prewar psychiatric disorders. However, the Gulf War veterans were more likely than the comparison group to have developed any disorder after the war (31% vs 21%). The greatest risks were for the anxiety disorders, for example, PTSD (OR 3.9, 95% CI 2.3-6.5), major depression (OR 1.6, 95% CI 1.3-2.0), and alcohol dependence/abuse (OR 1.5, 95% CI 1.2-2.0). The rates of somatoform disorders (referred to as “any somatic disorders” by the study authors) were low in both groups (OR 1.9, 95% CI 0.8-4.5). In addition, the Gulf War group was significantly more likely to have any anxiety disorder (OR 2.2, 95% CI 1.6-3.2), PTSD (OR 4.1, 95% 2.4-7.2), obsessive-compulsive disorder (OCD) (OR 5.2, 95% CI 1.6-16.7), social phobia (OR 3.4, 955 CI 1.7-6.6), or panic disorder (OR 2.6, 95% CI 1.0-6.3), than the comparison group in the preceding 12 months. On average, the Gulf War veterans had twice as many current psychiatric disorders as the comparison veterans. The strengths of this study were the large sample, the comparable control group, the use of well-validated psychological interviews, and the analyzed participation bias, which was estimated to be low.

A study of DoD postwar hospitalizations for mental disorders (June 1, 1991, to September 30, 1993) using 10 categories from the International Classification of Diseases, 9th revision, Clinical Modification, 6th edition (ICD-9-CM) was conducted by Dlugosz and colleagues (1999). It compared all active-duty personnel during the Gulf War era (n = 1,984,996) with those who did not serve. It also sought to identify risk factors for hospitalization. Nearly half the postwar hospitalizations were for alcohol-related disorders. Gulf War veterans were at greater risk for hospitalizations than nondeployed veterans due to drug-related disorders (RR 1.29, 95% CI 1.10-1.52) and acute reactions to stress (RR 1.45, 95% CI 1.08-1.94). Adjustments were made for age, sex, and military service branch. Although the database of ICD-9 codes does not allow determination of whether stress reactions expressly included PTSD, the authors noted that if posttraumatic stress was diagnosed, it would probably have been coded as an unspecified acute reaction to stress (ICD-9 code 308.9). Alcohol-related diagnoses were not increased. Exposure to the ground war in Iraq was associated with a greater risk of alcohol-related hospitalizations in men (RR 1.13, 95% CI 1.04-1.23). Serving as support for the ground war without being in direct combat was associated with a greater risk of drug-related hospitalizations in men (RR 1.42, 95% CI 1.03-1.96) and women (RR 3.61, 95% CI 1.70-7.66). The limitation of this study is that it examined only hospitalizations and thus was not representative of most psychiatric disorders that require outpatient treatment rather than hospitalization. It also did not include veterans who left the military after the Gulf War.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Secondary Studies

Findings on many other major cohorts of Gulf War veterans support what has been found in primary studies (Gray et al., 2002; McCauley et al., 2002). The most important limitation was their reliance on self-reports of “physician-diagnosed disorders” rather than measurement of symptoms with validated questionnaires or face-to-face interviews. In the UK cohort studied by Unwin et al. (1999), investigators asked some questions taken from the Mississippi Scale for Combat-Related PTSD but did not administer the entire questionnaire. They found that some symptoms were about 2-3 times more likely in deployed than in two nondeployed groups. The magnitude of the increase is consistent with that seen in the primary studies. Several other secondary studies have found an association between serving in the Gulf War and psychiatric disorders (Holmes et al., 1998; Magruder et al., 2005; Simmons et al., 2004; Steele, 2000; Stretch et al., 1996a,b; Sutker et al., 1995).

Goss Gilroy (1998) assessed all 3113 Canadian Gulf War veterans deployed to the war zone and a comparison group of nondeployed veterans with a mail questionnaire. Using the PCL-M, the investigators found that symptoms of PTSD were 2.5 times more prevalent in the deployed than in the nondeployed veterans (OR 2.69, 95% CI 1.7-4.2). Using the PRIME-MD, the investigators found that the deployed had higher prevalences of major depression (OR 3.67, 95% CI 3.0-4.4), chronic dysphoria, and anxiety. Anxiety and depression were more severe in lower-income veterans.

The studies of psychological outcomes in Australian Gulf War veterans were distinguished by inclusion of the entire deployed population (unclear what is meant by “direct assessment”). The instruments described below are self-administered screening questionnaires. McKenzie et al. (2004) used the SF-12, the PCL-M, and the GHQ-12 (12-item version of the General Health Questionnaire) to assess 1424 male Gulf War veterans (86.5% Navy) and 1548 male Australian Defence Force members who were not deployed to the Gulf War. On those self-rating instruments, the Gulf War-deployed had overall poorer psychological health (OR 1.4, 95% CI 1.2-1.6) and more PTSD-like symptoms (OR 2.0, 95% CI 1.5-2.9) than control veterans. The psychological distress increased with age in the comparison group but decreased with age in the Gulf War veterans (that is, the youngest Gulf War veterans had the worst psychological ill health). Moreover, the perceived level of exposure to war stress was associated with both psychological ill health and PTSD-like symptoms, although very few experienced direct combat.

Updated and Supplemental Literature

The Update committee identified four new primary studies (Fiedler et al., 2006; Ismail et al., 2002; Kang et al., 2009; Toomey et al., 2007) and five new secondary studies (Al-Turkait and Ohaeri, 2008; Axelrod et al., 2005; Black et al., 2006; Kang et al., 2005; Rona et al., 2007).

Primary Studies

Using a standardized clinician interview, Ismail and colleagues (2002) assessed mental health of random samples of UK Gulf War veterans who reported disability (n = 111) and those who did not (n = 98) and compared them to random samples of era veterans and Bosnia veterans reporting disability (n = 54 and 79, respectively). Individuals who had a known disease or serious medical condition were excluded from the study. One-month prevalences of DSM-IV disorders were assessed using the WHO schedule of clinical assessment in neuropsychiatry, a clinician-administered interview on which they achieved good inter-rater reliability. This is the

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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only study that used a clinician-administered interview and reported kappa values for inter-rater reliability. It was also unique in that it compared rates of unexplained physical disability between veterans who served in the Gulf and veterans who served in other wars. The main result was that a great majority of disabled Gulf War veterans (76%) did not have a formal psychiatric disorder. Indeed, the prevalence of mental disorders was similar for veterans disabled after the Gulf War and veterans disabled after other Gulf War-era deployments (prevalence of any psychiatric disorder 24% vs 19%); 12% of nondisabled Gulf War veterans had any psychiatric disorder. Compared with disabled veterans from Bosnia or era veterans, disabled Gulf War veterans were no more likely to have an alcohol-related disorder (OR 1.9, 95% CI 0.4-9.1), mood disorder (OR 1.0, 95% CI 0.3-3.2), anxiety disorder (OR 1.4, 95% CI 0.4-4.3), PTSD (OR 1.1, 95% CI 0.1-9.1), sleep disorder (OR 1.1, 95% CI 0.4-3.2), or any psychiatric disorder (OR 1.3, 95% CI 0.5-3.4); only the presence of somatoform disorder approached significance (OR 3.1, 95% CI 1.0-9.6). When compared to nondisabled Gulf War veterans, disabled Gulf War veterans were at increased risk only for anxiety disorders (OR 6.8, 95% 1.4-33.4). The authors inferred that psychiatric disorders do not explain the elevation in self-reported ill health in Gulf War veterans.

This study also compared disabled with nondisabled Gulf War veterans. There was a more than twofold increase (16% for disabled vs 7% for nondisabled) in undifferentated somatoform disorder (OR 3.3, 95% CI 0.8-13.8), which represents the presence of one or more unexplained medical symptoms. Also, the overall prevalence of psychiatric disorders was twofold higher (24% in disabled Gulf War veterans vs 12% in nondisabled Gulf War veterans; OR 2.4, 95% CI 0.8-7.2). It should be noted, however, that the prevalences of some specific disorders—notably PTSD and alcohol-related disorders—were not significantly different between the disabled and nondisabled veterans.

Ten years after the war, Fiedler and colleagues (2006) conducted telephone interviews using the CIDI Short Form. In a random sample drawn from all US troops deployed and not deployed to the Gulf War from August 1990 to July 1991, the response rates were 59% for deployed and 51% for nondeployed veterans. This study used the largest random sample of US Gulf War deployed and era veterans in which a layperson-administered structured interview was used to assess 12-month prevalences of psychiatric disorders. When compared with era veterans, those deployed to the Gulf War had significantly higher prevalences of psychiatric disorders. Thus, there were increases in the prevalence of MDD (14.2% in deployed vs 7.2% nondeployed male veterans and 25.3% vs 11.8% for deployed vs nondeployed female veterans); PTSD (3.4% vs 0.7% for male veterans and 4.0% vs 2.2% for female veterans); and of substance dependence (5.3% vs 3.3% male veterans and 2.7% vs 2.2% in female veterans). Comparing all deployed veterans with nondeployed veterans, the OR for anxiety disorder was 1.81 (95% CI 1.34-2.45) and the OR for MDD was 2.07 (95% CI 1.50-2.85). Lower rank, female gender, and divorced or single marital status were significant independent predictors of psychiatric disorders other than substance use disorders. For substance use disorders, being male, having lower rank, divorced or single marital status, and deployment other than to the Persian Gulf were significant independent predictors.

These results are consistent with those found by Ikin et al. (2004) who used the CIDI to assess 1381 deployed Australian Gulf War veterans and 1377 nondeployed veterans. They also reported elevated rates of any depressive disorder (OR 1.7, 95% CI 1.3-2.1) and any anxiety disorders (OR 2.9, 95% CI 2.0-4.2), specifically MDD (OR 1.6, 95% CI 1.3-2.0), PTSD (OR 3.9, 95% CI 2.3-6.5), OCD (OR 5.6, 95% CI 1.7-24.2), or social phobia (OR 3.1, 95% 1.6-6.0), but no cases of somatization disorder. It is important to note that somatization disorder is not a

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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measure of the presence or absence of physical (somatic) symptoms because it does not include medically explained symptoms, only medically unexplained symptoms. Unfortunately, prevalences of somatic symptoms were not measured in these studies, and the rate of somatization disorder does not provide a basis for estimating prevalences of somatic symptoms.

Approximately 10 years after the Gulf War, Toomey et al. (2007) used clinical interviews to estimate the current prevalence of mental disorders that had onset during the Gulf War. They studied a subset of deployed (n = 1061, participation rate = 53%) vs nondeployed (n = 1128, participation rate = 39%) veterans who had been interviewed in the National Health Survey of Gulf War Veterans and their Families (Kang et al., 2000). The interviews were carried out between 1998 and 2001. Gulf War-onset mental disorders were more prevalent in deployed (18.1%) versus nondeployed veterans (8.9%). with increased rates of PTSD as measured by the CAPS in Gulf War veterans (6.2% vs 1.1%; OR 5.78, 95% CI 2.62-12.74). Elevations in anxiety disorders, other than PTSD, as measured by the CIDI were elevated almost fourfold (OR 3.79, 95% CI 1.8-7.99) as was MDD (7.1% vs 4.1%; OR 1.81, 95% CI 1.03-3.19). Approximately 10 years after the war, era-onset major depression continued to be more prevalent among deployed (3.2%) versus nondeployed veterans (0.8%), as were rates of PTSD (1.8% vs 0.6%), although both decreased over time and for PTSD, the difference was no longer significant at 10 years. Somatoform disorders were rare in both groups (1.0% in deployed vs 0.3% in nondeployed), and the difference was not significant in this category overall. There was a significant difference in pain disorder (0.9% vs 0.01%) that represents the presence of one unexplained pain symptom. There was no significant difference in rates of somatization disorder between deployed and nondeployed veterans. Independent predictors of war-era onset mental disorders included female gender, higher levels of combat exposure, and the presence of prewar mental disorders.

Six years after the Gulf War, Al-Turkait and Ohaeri (2008) conducted a cross-sectional study in a stratified random sample of 200 Kuwaiti military men who had served in the Gulf War, using both self-administered questionnaires and a validated interview, the CAPS. Subjects were divided into four groups of 50 men each: retired from the military before the war, active duty but not in combat, active duty and in combat, and prisoners of war (POWs). The overall prevalence of PTSD as determined by the CAPS was 31.7%. The rate was highest for the most highly exposed group, POWs (48%), 22% for those with frontline combat exposure, 32% for those who were active-duty but had not been exposed to combat, and 24% for the retired control group. Higher rates of PTSD were associated with higher rates of depression and anxiety and lower self-esteem. Although this study included comparison groups and diagnostic interviews, the timeframe for prevalence is not reported, which limits its usefulness.

Secondary Studies

The committee identified five secondary studies (Axelrod et al., 2005; Black et al., 2006; Kang et al., 2005, 2009; Rona et al., 2007). Two of these studies focused on women veterans (Kang et al., 2005; Rona et al., 2007) and are discussed in the section on female veterans at the end of this chapter. Secondary studies also focused on borderline personality traits and the possibility that there may be an interaction between these traits and PTSD after deployment.

Axelrod et al. (2005) assessed 94 Operation Desert Storm veterans from the Connecticut National Guard study at several points following their return from the gulf for PTSD symptoms, combat exposure, and personality traits. The study asked retrospectively about pre- and postwar traits associated with borderline personality disorder, a chronic condition characterized by mood instability and difficulty with relationships. They reported that the presence of prewar borderline

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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personality traits was associated with the development of some features of PTSD after combat exposure, and that PTSD symptoms at 1 month were associated with increases in endorsement of borderline personality traits at 6 months postwar.

In 2005, a third survey of the National Health Survey of Gulf War Era Veterans and Their Families population was conducted by Kang and colleagues (2009). This survey used self-administered questionnaires, rather than validated diagnostic interviews on a much larger sample of deployed (n = 6111) versus era veterans (n = 3859), although the overall response rate was low (34%). The study reported elevations in all mental disorders among those deployed to the Persian Gulf when compared to era veterans. In contrast to the previous report, which found no persistent significant differences in rates of PTSD, this study reported persistent two to threefold elevations in the rates of PTSD (in the past 4 weeks) in deployed versus nondeployed veterans based on the PCL-C (15.2% vs 4.6%; OR 2.98, 95% CI 2.54-3.50) as well as persistent elevations in major depression (in the past 4 weeks) (14.9% vs 5.8%; OR 2.34, 95% CI 2.03-2.70). Rates of functional impairment and reports of physical symptoms were also elevated about twofold in those deployed to the Gulf War when compared with the nondeployed. The authors did not report on whether PTSD or the presence of mental disorders was associated with the presence or magnitude of physical symptoms or disability.

Summary and Conclusion

The Committee draws four main conclusions on the relationship between deployment to the Gulf War and mental disorders.

First, combat exposure in the Gulf War was causally related to PTSD. Although the available evidence from Gulf War studies is somewhat limited, it is, however, sufficient to support the conclusion that the causal relationship of combat exposure to PTSD shown for other wars also pertains to combat exposure and the development PTSD in the Gulf War. In addition, the Gulf War studies suggest that future research should evaluate whether, in some instances, deployment to a war zone, without combat experience, could be a cause of PTSD.

Second, there is sufficient evidence of an association between deployment to the Gulf War and several other psychiatric disorders. These include generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. For these disorders, the available evidence is not sufficient to establish whether or not the association is due to a causal relationship between the deployment and the psychiatric outcome.

Third, the associations between Gulf War deployment and psychiatric disorders were still evident 10 years after deployment (Fiedler et al., 2006; Kang et al., 2009; Toomey et al., 2007). For many of the psychiatric disorders that were measured in long-term follow-up studies, their prevalence even 10 years after the war was more than twofold higher in veterans who had been deployed compared with nondeployed veterans.

Fourth, from several lines of evidence, it can be inferred that the high prevalence of medically unexplained disability in Gulf War veterans cannot be reliably ascribed to any known psychiatric causes or disorders. It is not possible to attribute the high prevalence of medically unexplained disability in Gulf War veterans to somatoform disorder, based on available evidence. For example, a comparison of disabled Gulf War veterans with disabled veterans from other wars did not support such an attribution (Ismail et al., 2002), although veterans with known diseases or serious medical conditions were excluded from the disabled groups in this study. The majority of disabled Gulf War veterans did not have a diagnosable psychiatric disorder. Moreover, the prevalence of psychiatric disorder among disabled Gulf War veterans was similar

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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to the prevalence among disabled veterans of other wars. Reports on somatization disorder in Gulf War veterans also do not support such an attribution. Somatization disorder, which is rare, requires eight symptoms that are not caused by a medical illness. Fiedler et al. (2006) and Toomey et al. (2007) found almost no cases of somatization disorder among Gulf War veterans, nor was there a significant elevation in somatization disorder among deployed versus nondeployed veterans. Therefore, somatization disorder cannot account for the high prevalence of medically unexplained disability in Gulf War veterans.

Finally, studies of somatoform disorder in Gulf War veterans also do not support the hypothesis that their medically explained symptoms results from this disorder. Somatoform disorder includes many specific diagnoses, of which the most relevant for this report is undifferentiated somatoform disorder. This disorder requires only one symptom without known medical causes, and is therefore a relatively common and nonspecific diagnosis. In the study by Ismail et al. (2002), somatoform disorder was more common in deployed versus nondeployed Gulf War veterans (16% vs 6%) and also more common in disabled Gulf War veterans than in disabled veterans from other wars (16% vs 7%). It was, however, present in only a small minority of disabled Gulf War veterans (after exclusion of those with known diseases, see above). Furthermore, the medical investigations in this study were not sufficiently comprehensive to rule out medical explanations for the symptoms in those who did have somatoform disorder.

Therefore, the committee concludes there is sufficient evidence of a causal relationship between traumatic war exposures experienced during deployment to the Gulf War and PTSD. The committee also concludes that there is sufficient evidence of an association between deployment to the Gulf War and other psychiatric disorders, including generalized anxiety disorder and substance abuse, particularly alcohol abuse. Furthermore, these disorders persist for at least 10 years after deployment. Finally, the excess of unexplained medical symptoms reported by deployed Gulf war veterans cannot be reliably ascribed to any known psychiatric disorder.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-4 Mental and Behavioral Disorders

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Black et al., 2004b (Vol. 4)

Population-based interview study, by telephone; stratified random sample with proportional allocation (Iowa Persian Gulf Study Group, 1997)

1896 deployed vs 1799 nondeployed veterans listing Iowa as home state at time of enlistment

PRIME-MD (major depression, panic disorder, GAD) PCL-M, combat exposure assessed in basic demographic questionnaire. CAGE questionnaire (alcohol abuse)

Panic disorder (OR 2.2, 95% CI 1.2-3.8); GAD (OR 2.5, 95% CI 1.5-4.1); PTSD (OR 2.5, 95% CI 1.2-5.0); any anxiety disorder (OR 2.3, 95% CI 1.5-3.5)

Age, sex, race, branch of military, rank, military status, prior mental-health condition

Large, population-based sample

Barrett et al., 2002 (Vol. 4)

Population-based survey; completed telephone survey about their health status

3682 GWVs and control subjects

PCL-M, SF-36

Persons screened positive for PTSD more likely to have been deployed to Gulf War (OR 2.02, 95% CI 0.97-4.23)

PTSD associated with: Current smoking status (OR 3.83, 95% CI 1.40-10.46)

Number of self-reported symptoms (19.83 symptoms with PTSD vs 3.64 with no PTSD, p < 0.0001)

Number of medical conditions (1.73 conditions with PTSD vs with no PTSD 10.18)

Lower SF-36 scores for physical functioning (93 vs 66, p < 0.0001) and general health (80 vs 33, p < 0.0001)

Deployment status, age, sex, race, rank, branch, military status, and smoking status

Brief PTSD screen used; used 50 as the cutoff score with the PCL-M; low number of subjects who screened positive for PTSD; the sample from Iowa might not be representative of all US military personnel

Black et al., 2004a (Vol. 4)

Nested case-comparison; face-to-face interviews

602 veterans and controls

SCID (face-to-face interviews); SNAP; SF-36; Whitely Index

PTSD (27% vs 5% in deployed vs controls, OR 7.1, 95% CI 2.1-24.2); anxiety disorders (52% vs 25%, OR 3.2, 95% CI 1.6-6.3); any disorder (68% vs 52%, OR 2.0, 95% CI 1.0-3.7)

Validated PTSD checklist against SCID (70.4% sensitivity and 86.2% specificity of questionnaire

 

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

 

for the 192/602 subjects who met the criteria for depression)

 

Kang et al., 2003 (Vol. 4)

Cross-sectional; population-based stratified random sample of GWV deployed compared with those deployed elsewhere

11,441 deployed vs 9476 nondeployed

Mail survey and telephone-based survey of PTSD symptoms

GWV (12.1%) compared to era veterans (4.3%); OR 3.1 (95% CI 2.7-3.4)

Sex, age, marital status, rank, and unit component

Nationally representative sample, questionnaire only

Wolfe et al., 1999a,b; Proctor et al., 1998 (Vol. 4)

Cross-sectional survey and interviews from larger cohorts followed longitudinally

220 Fort Devens vs 73 New Orleans vs 48 Germany; New Orleans and Germany cohorts only studied at time 2

Health Symptom Checklist, Mississippi PTSD Scale (times 1 and 2), SCID, CAPS (clinician diagnostic interviews, time 2 only)

Risk factors for PTSD were being female (time 1 OR 3.2, 95% CI 1.9-5.5; time 2 OR 2.3, 95% CI 1.5-3.5) and having high combat exposure (time 1 OR 1.22, time 2 OR 1.12, p < 0.05 for both); PTSD also highly correlated with current major depression (r = 0.35, p < 0.001) Lifetime occurrence of PTSD more prevalent in Fort Devens (8.1%) and New Orleans (7.6%) vs Germany (0%), no p-value reported Prevalence of PTSD increased from time 1 (3%) to time 2 (8%) in Fort Devens, 2% of the study group had PTSD at both time 1 and time 2, 1% had PTSD at time 1 but not time 2, and 6% had PTSD at time 2 but not time 1

Sex, reported health symptoms

Small sample deployed to Germany, 78% participation rate; Wolfe et al., 1999b, used direct interviews

Brailey et al., 1998 (Vol. 4)

Longitudinal; psychological interviews 9 months after war,

876 deployed (349 at time 2, 16 months later) vs 396

BDI-II, State Anger; State Anxiety; the BSI Depression; BSI Anxiety; BSI

Prevalence of depression increased over time in deployed veterans from time 1 (6.9%) to time 2 (13.8%), as did prevalence of PTSD (2.3% to

Age, education

Large attrition by time 2 (39.8% response rate at follow-up)

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

and subgroup follow-up at 16 months; Louisiana National Guard and Reserve troops (Marine, Army, Air Force, Navy)

nondeployed

Hostility, the HSC, PTSD Checklist, and the Mississippi Scale

10.6%) and hostility (4.9% to 13.8%); no p-values reported

 

 

Ikin et al., 2004 (Vol. 4)

Cross sectional survey of all Australian deployed veterans

1381 GWVs vs 1377 comparison veterans

CIDI

Prevalence of any disorder: 31% in GWVs vs 21% in comparison group;

PTSD: OR 3.9 (95% CI 2.3-6.5); major depression:

OR 1.6 (95% CI 1.3-2.0); alcohol abuse: OR 1.5 (95% CI 1.2-2.0)

Service type, rank, age, education, marital status

GWVs younger, more likely in the Navy, and lower ranked than comparison group Large sample, well-validated psychological interview tool; low participation bias

Dlugosz et al., 1999 (Vol. 4)

Post-war hospitalizations June 1991-September 1993

Active-duty men (1,775,236) and women (209,760) June 1991-September 1993; GWVs vs NDV

ICD-9 CM categories for 10 mental disorders

GWVs had increased risk of hospitalizations due to: acute reactions to stress (RR 1.45, 95% CI 1.08-1.94); drug-related disorders (RR 1.29, 95% CI 1.10-1.52) No general increase in alcohol-related diagnoses, but serving in ground war in Iraq associated with alcohol-related hospitalizations in men (RR 1.13, 95% CI 1.04-1.23)

Age, sex, service-branch adjusted rates

Active duty only; no assessment of outpatient treatment

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

Ismail et al., 2002 (Update)

Two-phase cohort study

Random sample of UK GWVs with reported disability (n = 111) and no disability (n = 98) and era and Bosnia veterans with disability (n = 54) and no disability (n = 79); Disability defined as score < 72.2 on SF-36

DSM-IV disorders assessed during clinician-administered interview

Disabled GWVs compared to disabled controls: No increase in prevalence of any mental disorder except undifferentiated somatoform disorder (OR 3.1, 95% CI 1.0-9.6)

 

Response rate good in GWV (67% disabled and 62% non-disabled), but low in controls (55% and 43%) Strength: clinician administered interview

Fiedler et al., 2006 (Update)

Cross-sectional, random sampling of all US troops deployed vs nondeployed (era veterans); assessment by computer-assisted telephone interview

967 deployed vs 784 nondeployed veterans

CIDI

Deployed veterans had significantly higher 12-month prevalence of any psychiatric disorder compared to nondeployed, (26.1% vs 16.1%, p < 0.05)

Increase in major depressive disorder (14.2% vs 7.2% for males and 25.3% vs 11.8% for females) and PTSD (3.4% vs 0.7% for males and 4.0% vs 2.2% for females), no p-value reported

All deployed vs all controls: Any anxiety disorder (OR 1.81, 95% CI 1.34-2.45); depression (OR 2.07, 95% CI 1.50-2.85)

Males: alcohol dependence (4.8% vs 3.3%, NS); drug dependence (1.2% vs 0.0% p < 0.05)

 

Response rate 59% for deployed, 51% for era veterans Female gender, divorced, and lower rank were significant independent risk factors

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Toomey et al., 2007 (Update)

Cross-sectional survey; stratified random sample of deployed vs nondeployed veterans; structured interview, self-report of symptoms

1061 deployed vs 1128 nondeployed US veterans (same cohort as Eisen et al., 2005)

CAPS; CIDI; PTSD Checklist; BDI-II; BAI; SF-36; QoLI; CES

Gulf War era onset: PTSD (6.2% deployed vs 1.1%, nondeployed), (OR 5.78, 95% CI 2.6-12.7); non-PTSD anxiety disorders (4.3% deployed vs 1.4% nondeployed), (OR 3.79, 95% CI 1.8-8.0); major depression (7.1 % deployed vs 4.1% nondeployed), (OR 1.81, 95% CI 1.0-3.2)

Age, sex, ethnicity, years of education, duty type (active vs reserve/guard), service branch, rank

Response rate: 53% for deployed; 39% for nondeployed Prevalence of non-PTSD anxiety disorders significantly higher in deployed (12.5%) vs nondeployed (9.2%), p = 0.02

 

 

 

 

10 years post-Gulf War era: PTSD (1.8% vs 0.06% deployed vs nondeployed, p = 0.12); non-PTSD anxiety disorders (2.8% vs 1.2% deployed vs nondeployed, p = 0.01); major depression (3.2% deployed vs 0.8% nondeployed, p = 0.01) Symptom self report: deployed reported more severe symptoms of PTSD, depression, anxiety; lower level quality of life; SF-36 scores significantly lower

 

Al-Turkait and Ohaeri, 2008 (Update)

Retrospective Cohort; stratified random sampling of four groups of veterans: retired from military prior to war; active duty with no combat; active duty with combat; POW

200 Kuwaiti Gulf War veterans, 50 from each group

PTSD, determined by CAPS

POWs: 48.4%

Combat: 32%

No combat: 22%

Retired: 24%

Higher rates of anxiety, depression, and low self-esteem in those with PTSD compared to those without PTSD (p = 0.0001)

 

Potential bias resulting from application of questionnaire to a foreign population

NOTES: BAI = Beck Anxiety Inventory; BDI-II = Beck Depression Inventory; BSI = Bried Symptom Inventory; CAPS = Clinician Administered PTSD scale; CES = Combat Exposure Scale; CIDI = Composite International Diagnostic Interview; GAD = generalized anxiety disorder; GWV = Gulf War veteran; HSC = Health Symptoms Checklist; NS = not significant; PCL-M = PTSD Checklist-Military Version; POW = prisoner of war; PRIME-MD = Primary Care Evaluation of Mental Disorders; PTSD = posttraumatic stress disorder; QoLI = Quality of Life Inventory; SCID = Structured Clinical Interview for DSM Disorders; SF-36 = 36-Item Short Form Health Survey; SNAP = Special Needs Assessment Profile.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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NEUROCOGNITIVE AND NEUROBEHAVIORAL OUTCOMES

This section contains an overview and update on neurocognitive and neurobehavioral performance in Gulf War veterans compared with nondeployed veterans. In Gulf War and Health, Volume 4: Health Effects of Serving in the War the committee defined primary studies as “high-quality studies that used neurobehavioral tests that had previously been used to detect adverse effects in population-based research on occupational groups.” Furthermore the committee presented findings separately for those studies that (a) compared neurobehavioral performance in deployed veterans and nondeployed veterans, and (b) compared neurobehavioral performance in deployed veterans reporting symptoms that met various definitions of Gulf War syndrome with neurobehavioral performance in deployed veterans who did not report symptoms.

The major issues that distinguished secondary studies from primary studies were lack of adjustment for potential confounding effects of age, sex, education, native intellectual ability (as measured by the Wechsler Adult Intelligence Scale, National Adults Reading Test [NART], Armed Forces Qualifying Test [AFQT]), and lack of blinding of testers to deployment and/or symptom status. Studies in which neurocognitive and neurobehavioral performance was measured only based on self-report were not included. Table 4-5 summarizes the primary studies for neurocognitive and neurobehavioral outcomes.

Summary of Volume 4

Studies in Nonsymptomatic Veterans

In consideration of the comparison of neurobehavioral performance in Gulf War deployed veterans compared with nondeployed veterans there were two primary studies (David et al., 2002; Proctor et al., 2003) and three secondary studies (Axelrod and Milner, 1997; Vasterling et al., 2003; White et al., 2001).

David et al. (2002) compared 209 UK veterans deployed to the Persian Gulf with 54 UK Bosnian peacekeepers and 78 nondeployed veterans. In this analysis no differences were found in neurobehavioral performance taking into account age, education, the National Adults Reading Test, and a depression score (Beck Depression Inventory). In the study of Proctor et al. (2003) the findings were verified with no differences found between 143 Danish Gulf War veterans and 72 non deployed veterans of the Danish military.

Of the secondary studies, only one (Axelrod and Milner, 1997) found differences between deployed and nondeployed veterans on the Stroop test of directed attention, following adjustment for age and education. White et al. (2001) combined two quite different samples (a cohort from Fort Devens and a second cohort from New Orleans) and compared this group to a small group of Germany-deployed veterans.

Studies in Symptomatic Veterans

In considering the neurobehavioral performance of symptomatic versus nonsymptomatic Gulf War veterans, two primary studies (David et al., 2002; Storzbach et al., 2001) and six secondary studies (Axelrod and Milner, 1997; Bunegin et al., 2001; Goldstein et al., 1996; Hom et al., 1997; Lange et al., 2001; Sillanpaa et al., 1997) were identified in Volume 4. Overall the definition of symptomatic was variable ranging from “any one of memory loss, confusion, mood

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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swings, etc.” to categorization based on SF-36 scores. The committee identified the core symptoms as cognitive in all of the studies except Lange et al. (2001), in which the only symptom was fatigue.

One of the primary studies, David et al. (2002), categorized Gulf War veterans as ill (n = 151) and well (n = 188) based on SF-36 physical function scores. Subjects were also classified as symptom reporting (n = 65) or symptom not reporting (n = 33) based on the Centers for Disease Control and Prevention (CDC) working definition of Gulf War-related symptoms (Fukuda et al., 1998). Following adjustment for age, education, the National Adults Reading Test, and depression, and correction for multiple testing, there were no identified differences in neurobehavioral performance.

Storzbach et al. (2001) compared 239 Gulf War veterans who reported at least one symptom associated with Gulf War syndrome with 112 nonsymptomatic Gulf War veterans. This analysis found poorer performance among the symptomatic group on the Oregon Dual Task Procedure errors and latency, Digit Span Backward, and the Simple Reaction Time. Results were adjusted for age, education, AFQT, and for multiple testing.

There were six secondary studies that compared symptomatic to nonsymptomatic Gulf War veterans. These studies varied in design including the definition of symptomatic although in general the same performance tests were used. All but one found performance differences between symptomatic and nonsymptomatic Gulf War veterans. However, only two studies included an adjustment for age and education, and only one took multiple comparisons into account.

Updated and Supplemental Literature

The Update committee identified two additional studies both of which were classified as secondary (Proctor et al., 2006; Toomey et al., 2009).

Proctor et al. (2006) was considered secondary (rather than primary) because the comparison was not between deployed Gulf War veterans and nondeployed veterans but across deployed Gulf War veterans classified within putative sarin exposure categories. In this study, a subset of the Fort Devens cohort neurobehavioral/neurocognitive performance was assessed in 1994-1995 and examined in relation to putative sarin exposure during the Gulf War. Sarin exposure was based on the 2000 Khamisiyah plume analyses, which produced four modeled hazard areas—one for each day between March 10 and March 13, 1991, when it was believed that sarin and cyclosarin were released following the detonations. Individuals in the study were classified in an exposure category based on the estimated dosages assigned to the 11 Fort Devens cohort study units. Study participants who served in units with exposure levels of greater than 0.072 mg-min/m3 were classified as having high exposure (n = 23); those in units with exposure levels greater than the general population limit of 0.01296 mg-min/m3 but no more than > 0.072 mg-min/m3 were defined as moderately exposed (n = 47). Those participants in areas where no exposure level was estimated because they were not in an area within the plume areas were classified as low-to-no exposure (n = 70).

The outcomes of interest were based on neuropsychological tests of five cognitive domains: attention, executive function, psychomotor function, visuospatial abilities, and short-term memory. The selected tests were chosen from those known to be sensitive to the effects of neurotoxicants that were believed to have been present in the Gulf War. The authors reported that sarin and cyclosarin exposure were associated with a reduced proficiency on functional domains of psychomotor function (Purdue pegboard) and visuospatial abilities (WAIS block

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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designs. The high-exposure group and the moderate-exposure group had significantly poorer performance in these tests than the low-to-no exposure group. The analysis adjusted for age, sex, unit group, rank, PTSD scores, handedness, and history of head injury. The authors interpreted these reductions in proficiency on the Purdue pegboard test for an individual with an estimated exposure of 0.1 mg-min/m3 as being approximately one point lower than individuals in the low-to-no exposure group. This difference is equivalent to a performance of someone approximately 20 years older on the task. For the block designs for the same hypothetical individual the estimated difference would be approximately 4 points or the equivalent of being 15 years older.

A particular strength of this study was that the neurobehavioral and neurocognitive testing was performed in the vast majority of subjects (95%) prior to the 1996 public announcement that the munitions at Khamisiyah contained sarin. Limitations of this study include the fact that, like others studies, there was no predeployment testing available for comparison, and there may have been misclassification of individuals across the three exposure categories.

In 2009, Toomey et al. published a study that examined the neuropsychological functioning of Gulf War veterans 10 years after deployment. This study was classified as a secondary (rather than primary) study for several reasons. First, the study was conducted 10 years after the Gulf War, thus the findings were interpreted under the assumption that any observed differences in neuropsychological functioning in a subgroup of deployed versus nondeployed veterans is attributable to deployment and there was no account taken of events that took place in the years since the Gulf War. While this may be the case, one would also wish to consider life events and comorbidities that may have occurred in the 10-year period between the Gulf War and the time of assessment. This is particularly problematic given that there are no predeployment baseline neuropsychological measures with which to compare the measures at 10 years. In addition, the participation rates for both deployed and nondeployed are low (53% in the deployed and 39% in the nondeployed) and quite different, possibly resulting in selection bias (Toomey et al., 2009). While in an earlier study the same group of authors report on an assessment of the differences between participants and nonparticipants in both the deployed and nondeployed groups (Eisen et al., 2005), in the discussion Toomey et al. (2009) concede that the low study participation may have “biased results.”

The source of participants for this study was the National Health Survey of Gulf War Era Veterans and Their Families Study (Eisen et al., 2005). Based on the 11,441 deployed and 9476 nondeployed participants in the 1995 study, 1996 and 2003 veterans, respectively, were solicited to participate. In the deployed group, 1061 (53%) agreed to participate, and only 39% (1128/2883) of the nondeployed agreed to participate. Measures of neuropsychological functioning were based on those that had been suggestive of differences in the deployed and nondeployed cohorts previously and included measures of general intelligence, attention/executive functioning, motor ability, visuospatial processing, and verbal and visual memory. Factor analysis was used to derive eight neuropsychological test variables (verbal memory, attention/working memory, visual memory, executive functioning, perceptual motor speed, visual organization, motor speed, and sustained attention) from 27 individual variables. Deployed and nondeployed veterans were compared on mean factors scores as well as on the mean scores of the 27 individual variables included in the factor analysis.

In comparing the factor scores, the results of this study indicated that participants in the deployed group did worse on two of the eight factors, motor speed (p = 0.03) and sustained attention (p = 0.04), while nondeployed participants did worse on visual organization. Concerned

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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about an education effect the authors conducted a sensitivity analysis excluding those participants with postgraduate education and the worse performance on motor speed and sustained attention remained. In the comparison between the two participant groups across the 27 individual variables and controlling for multiple testing using a Bonferroni adjustment, the deployed veterans performed worse only on the Trails B–Trails A time (p = 0.002, which was equal to the Bonferroni correct p value). The authors themselves concluded from this study that “Gulf War deployment is associated with subtle declines in motor speed and sustained attention, despite overall intact neuropsychological functioning.”

Summary and Conclusions

The Volume 4 committee concluded that the primary studies reviewed in that volume showed nonsignificant trends of poorer neurobehavioral performance when Gulf War veterans were compared with nondeployed veterans or those deployed to Germany. However, when PTSD (White et al., 2001) or depressed mood (David et al., 2002) was treated as a confounder in the statistical analyses those trends disappeared. The results were adjusted for depression because it is often found to coexist with PTSD. That adjustment could have made it impossible to detect cognitive differences.

One study concluded that Gulf War veterans who report symptoms associated with the Gulf conflict performed more poorly on neurobehavioral tests than veterans who did not report symptoms (Storzbach et al., 2001). Another study found substantial neurobehavioral deficits in deployed veterans but had intentionally recruited veterans who experienced a high prevalence of post-Gulf War illness (Hom et al., 1997). That study, however, failed to adjust for key confounders and for the large number of statistical comparisons in their study, raising doubt about the validity of their findings.

In this update, two studies were added to those presented in Volume 4. While each of these studies presents some results indicating an effect of either deployment (Toomey et al., 2009) or putative sarin exposure amongst deployed soldiers (Proctor et al., 2006), the differences between and the limitations within these studies suggests that they may only be considered as secondary studies.

In conclusion, primary studies of deployed Gulf War veterans versus veterans not deployed to the Gulf do not demonstrate differences in cognitive and motor measures as determined through neurobehavioral testing. However, returning Gulf War veterans who had at least one symptom commonly reported by Gulf War veterans (fatigue, memory loss, confusion, inability to concentrate, mood swings, somnolence, gastrointestinal distress, muscle or joint pain, or skin or mucous membrane complaints) demonstrated poorer performance on cognitive tests than returning veterans who did not report such symptoms.

Therefore, the committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and neurocognitive and neurobehavioral performance.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-5 Neurobehavioral and Neurocognitive Outcomes

Reference

Study Design

Population

Outcomes

Results

Adjustments

Comments

David et al., 2002 (Vol. 4)

Case-control, clinical evaluations

200 male UK GWVs, 54 Bosnia-deployed, 78 era nondeployed soldiers randomly selected from larger cohort of UK veterans who participated in earlier postal survey (see Unwin et al., 1999)

WAIS-R scaled scores: Vocabulary Digit span Arithmetic Similarities Picture arrangement Block design Object assembly Digit symbol PASAT Sustained attention to response task Stroop Trail-making test, A & B WMS: Logical memory (Immediate and delayed recall) Verbal paired associates (Immediate and delayed recall) Camden recognition memory test Purdue pegboard Individually administered tests, blinded examiners

GWVs had significantly lower scores on 5 cognitive tests after demographic confounder and LSD corrections: Digit symbol Trail-making Stroop PASAT Verbal associates After final Bonferroni adjustments for multiple comparisons and BDI, only the results of the Purdue pegboard remained significantly different

ANCOVA adjusted for education, age, NART, BDI; multiple comparison adjustment for least significant difference procedure and Bonferroni adjustments

Careful treatment of potential confounders, such as depression, mood, IQ, education

Proctor et al., 2003 (Vol. 4)

Cross-sectional

143 male Danish GWVs, 72 male nondeployed troops randomly selected from 84% and 58% of total Danish armed forces deployed and nondeployed, respectively, at time of Gulf War

WAIS-R Information subscale, continuous performance test, trail making, WCST, Purdue pegboard, WAIS-R block design, CVLT, WMS visual reproductions, TOMM; individually administered tests except in computer-based NES; blinded examiners

No overall differences in neuropsychologic domains, significant test differences in domains (p ≤ 0.05) for CVLT and WCST

MANCOVA by neuropsychologic domain, adjusted for age

Response rate 75%

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Reference

Study Design

Population

Outcomes

Results

Adjustments

Comments

Storzbach et al., 2001 (Vol. 4)

Case-control

239 randomly selected male and female GWVs with symptoms vs 112 deployed with no symptoms; case = one of memory loss, confusion, inability to concentrate, mood swings, somnolence, gastrointestinal distress, fatigue, muscle and joint pain, skin or mucous membrane lesions lasting 1 month or longer, starting during or after service in gulf, and present during 3 months before questionnaire received

Symbol digit Serial digit learning ODTP Selective attention test Digit span Simple reaction time BARS computer-based testing system Blinded examiners

Cases significantly worse than controls on: Digit span backward Simple reaction time ODTP Errors Latency (including a slow group of 13% of sample with scores > 2 sd slower than control mean latency) PCA showed the slow ODTP (slow case in 1999) were responsible for group differences in neurobehavioral performance; 2 of 354 excluded for possible poor motivation because of excess errors in ODTP

ANCOVA, adjusted for age, sex, and AFQT, but effect was small so t-tests were used; Bonferroni correction for multiple comparisons

 

NOTE: AFQT = Armed Forces Qualifying Test; ANCOVA = analysis of covariance; BARS = Behavioral Assessment and Research System; BDI = Beck Depression Inventory; CVLT = California Verbal Learning Test; GWV = Gulf War veteran; IQ = intelligence quotient; MANOVA = multivariate analysis of variance; NART = National Adult Reading Test; ODTP = Oregon Dual Task Procedure; PASAT = Paced Auditory Serial Addition Test; PCA = principal-components analysis; TOMM = Test of Memory Malingering; WAIS = Wechsler Adult Intelligence Scale; WCST = Wisconsin Card Sorting Test; WMS = Wechsler Memory Scale.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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DISEASES OF THE NERVOUS SYSTEM

Neurologic diseases are common afflictions, with risk for specific disorders dependant on such factors as age, family history, and environmental exposures. The battlefield environment might be associated with an increase in risk for a variety of neurologic problems. These range from the known consequences of traumatic brain and nerve injury, which can include epilepsy, cognitive disturbances, headache, and nerve or bodily pains, to the likely relationship between battlefield deployment and an increase in risk for amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). Multiple sclerosis (MS) is another neurologic disorder of interest in this context, as risk for MS has been associated with exposure to highly stressful experiences including war. Immune-mediated neuropathies, including Guillain Barré syndrome, are also known to follow a variety of infectious illnesses or vaccinations to which servicemembers may have been exposed. The special circumstances of the Gulf War theater, with exposures to extreme heat, poor sanitation in some circumstances, exposure to unfamiliar biological agents, as well as known and unknown exposures to drugs such as pyridostigmine bromide (PB), pesticides, fumes, and other environmental toxins might contribute to the development of a variety of neurologic disorders. As examples, peripheral neuropathy or myopathy are known to occur with exposures to a number of different toxins and drugs, and Parkinson’s disease is associated with pesticide exposure. For these reasons, a broad analysis was undertaken to review the literature on a wide range of neurologic outcomes identified to date in servicemembers who participated in the Gulf War mission. The review is organized by specific neurologic afflictions including peripheral neuropathy and myopathy, MS, ALS, and other neurologic disorders. Some common neurologic disorders such as Parkinson’s and Alzheimer’s diseases rarely ever occur until later in life (after age 60), and it is highly unlikely that Gulf War veterans would have developed these disorders to date, even though a very long latency period of decades for such health outcomes is a possibility. Thus current studies have insufficient follow-up time to allow drawing any conclusions on increases of risk for these disorders among Gulf War veterans. Other disorders of unknown but possible neurologic etiology, including chronic fatigue syndrome, fibromyalgia, and multisystem illness, are discussed in other sections.

Peripheral Neuropathy and Myopathy

This section reviews studies of peripheral neuropathy, polyneuropathy, or neuromuscular symptoms, as identified by the investigators’ conducting the studies. Peripheral neuropathy, broadly defined, is a disease of the peripheral nerve tissues (that is, nerve fibers ensheathed by Schwann cells, including nerve roots), which transmit information from the brain and spinal cord to other parts of the body.

Numerous types of peripheral neuropathy have been characterized, each with its own set of symptoms, patterns of development, and prognosis. Peripheral neuropathy can be classified by a variety of factors, such as the population of nerve fibers affected (for example, motor, sensory, or autonomic). Additionally, neuropathy can be classified by the time course (acute, subacute and chronic, remitting, or relapsing) and by pathology (axonal, demyelinating, or other). Peripheral neuropathy might be inherited (for example, resulting from inborn errors in the genetic code or mutations) or acquired (for example, from physical injury, tumors, toxins, autoimmune responses, nutritional deficiencies, alcoholism, vascular and metabolic disorders, or

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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infections from conditions such as leprosy, human immunodeficiency virus, herpes simplex and zoster, or hepatitis associated) (National Institute of Neurological Disorders and Stroke, 2006, 2009). Polyneuropathy is a neurologic disorder characterized by progressive weakness and impaired sensory function in arms and legs. The committee notes that an objective inquiry of peripheral neuropathy depends on clinical recognition of absent ankle reflexes, distal symmetric leg and foot weakness and atrophy, sensation loss in toes and feet, and abnormalities in nerve conduction. The committee also regards studies with objective and quantitative measures, such as those with nerve-conduction tests, to be optimal. The importance of obtaining neurophysiologic studies is especially helpful in determining the presence of neuropathy whenever the clinical evaluations alone are inconclusive or the type of neuropathy is uncertain (for example, does the disorder primarily affect the myelin sheath or the axon of the nerve cell?). For disorders that affect small nerve fibers (resulting in pain, temperature, and autonomic symptoms only) more sophisticated neurophysiologic tests and in some cases nerve biopsies may be required to reveal the underlying pathology.

Summary of Volume 4

The best population-based questionnaire study for assessment of peripheral neuropathy is that of Cherry and colleagues (Cherry et al., 2001a,b), who studied UK troops deployed to the Gulf War. Almost 35% of Gulf War veterans who reported handling pesticides for more than a month indicated numbness or tingling on mannequin diagrams compared with 13.6% of veterans who did not report handling pesticides. The handling of pesticides and side effects of handling nerve agent prophylaxis were associated with self-reports of peripheral neuropathy (OR 1.26; p < 0.001). However, although the study was well designed and suggested a dose-response relationship, it was limited by recall bias, lack of clinical evaluations, and the absence of nerve-conduction studies. Self-reporting of peripheral neuropathy symptoms has poor diagnostic accuracy (Franse et al., 2000). Because of those limitations, the committee defined primary studies as requiring, at a minimum, medical evaluations.

Primary Studies

In the medical evaluation component of the large, population-based cohort assembled by the VA, Davis and colleagues (2004) reported on the presence of distal symmetric polyneuropathy in deployed and nondeployed veterans. That condition was evaluated through history, physical examination, and standardized electrophysiological assessment of motor and sensory nerves in 1047 deployed veterans and 1121 nondeployed veterans. Spouses of deployed and nondeployed veterans were also studied, as was a population of 240 Khamisiyah-exposed veterans. Exposure to potential nerve agents was assessed with one of the first DoD models of atmospheric dispersion (Winkenwerder, 2002). Blood studies were performed to rule out metabolic causes of neuropathy. Although the study provided results on distal symmetric polyneuropathy as distal sensory or motor neuropathy identified on the basis of the neurologic examination, nerve conduction study, or both, the committee favored distal symmetric polyneuropathy identified with a nerve conduction study as the best, most reliable measure of peripheral neuropathy. No significant differences between adjusted population prevalence of distal symmetric polyneuropathy in deployed and nondeployed veterans were found (OR 0.65, 95% CI 0.33-1.28). There also were no differences on physical examination or self-reported peripheral neuropathy, although at the time of examination, deployed veterans reported more numbness and tingling than did nondeployed veterans. The veterans exposed to the Khamisiyah ammunition depot explosion did not differ significantly from nonexposed deployed veterans (OR

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

1.04, 95% CI 0.25-4.37). The prevalence of distal symmetric polyneuropathy in the spouses of deployed and nondeployed veterans also did not differ; however, the measure of distal symmetric polyneuropathy was obtained through self-reports as opposed to medical evaluation or nerve conduction study. One limitation of the study is potential participation bias: only 53% of deployed veterans and 39% of nondeployed veterans invited to participate were actually examined.

Neuromuscular symptoms of UK veterans were evaluated with objective testing of peripheral nerves, skeletal muscles, or neuromuscular junctions in a case-control study (Rose et al., 2004; Sharief et al., 2002). Ill veterans (with more than four neuromuscular symptoms and lower functioning according to the SF-36) were compared with healthy deployed veterans, 13 symptomatic Bosnian veterans, and 22 symptomatic Gulf War-era controls. All groups had been randomly selected from 8195 male military personnel. In the first publication, veterans underwent nerve-conduction studies, quantitative sensory and autonomic testing, and concentric needle and single-fiber electromyography. In the second, they underwent quantitative myometry through the ischemic forearm exercise test, the subanaerobic bicycle exercise test, and a muscle biopsy. The studies revealed no significant differences between deployed and nondeployed veterans who had symptoms of Gulf War illness. The sole exception was the greater effort required for the bicycle exercise test with increased lactate production; this finding could reflect mitochondrial damage or inactivity resulting from ill health. See Table 4-6 for a summary of the peripheral neuropathy findings.

Secondary Studies

Other studies supporting the absence of findings include those of Amato et al. (1997), Eisen et al. (2005), Pasquina et al. (2004), and Rivera-Zayas et al. (2001). Eisen et al. (2005) appear to have reported in less detail on the peripheral neuropathy findings in the same cohort as previously reported by Davis and colleagues (2004), but the precise relationship between the two publications is not clear. The Pasquina et al. study (2004), a retrospective review of electrophysiologic testing of 56 Gulf War veterans and 120 nondeployed veterans, showed no objective evidence of a higher incidence of neuromuscular disease in deployed veterans than in nondeployed veterans. In the Rivera-Zayas et al. (2001) study, 12 of 162 Gulf War veterans tested electrophysiologically with positive questionnaires for neuropathy had normal results except for two subjects who had carpal tunnel syndrome. Amato et al. (1997) showed that in 20 Gulf War veterans who had severe muscle fatigue, weakness, and myalgias, nerve conduction studies, repetitive nerve stimulation, quantitative and single-fiber electromyography, and muscle biopsies were inconclusive.

Updated and Supplemental Literature

Kelsall et al. (2005) performed a cross-sectional analysis of the entire cohort of 1871 Australian Gulf War veterans and a comparison group of 2924 nondeployed veterans, matched by age, sex, and service type. Postal and telephone questionnaires were administered followed by evaluations at 10 clinics across the country. Increased reporting of lower-extremity symptoms possibly indicative of neuropathy was present in the deployed Gulf War group (OR 1.6; 95% CI 1.0-2.7), Increased reporting of lower-extremity symptoms possibly indicative of neuropathy was present in the deployed Gulf War group (OR 1.6; 95% CI 1.0-2.7), but results of neurologic examinations were similar in both groups. There was no clinical evidence of an increased risk of myopathy or muscle weakness. An increase in the reporting of neurological symptoms was associated with self-reports of immunizations and exposure to various chemical agents including

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

PB and pesticides. Symptoms possibly indicative of neuropathy were not associated with self-reports of immunizations or chemical exposures however (conclusion stated in paper but data not presented). Electrophysiologic studies were not performed.

Summary and Conclusions

Several well-designed studies from the United States, United Kingdom, and Australia found no evidence of excess peripheral neuropathy in Gulf War veterans. Several other secondary studies supported a conclusion of no excess risk. Some studies, such as that of Cherry et al. (2001a), did report higher rates of peripheral neuropathy, but they used self-reports, which the committee did not accept as a reliable measure of peripheral neuropathy. Furthermore, because researchers use different case definitions of peripheral neuropathies, there are problems of ascertainment, which makes comparisons among groups difficult.

The committee finds no increase in the prevalence of peripheral neuropathy in deployed versus nondeployed veterans, as defined by history, physical examination, and electrophysiologic studies. Detailed quantitative analyses to investigate small-fiber polyneuropathy have not, as yet, been reported in Gulf War veterans.

Therefore the committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and peripheral neuropathy.

Multiple Sclerosis

MS is a chronic inflammatory disease of the brain and spinal cord. It is caused by an immune-mediated attack on the myelin membrane that surrounds and insulates nerve fibers (axons) that are responsible for normal transmission of electrical and chemical information in the nervous system. Strong circumstantial evidence indicates that MS is an autoimmune disease in which normal myelin, and perhaps also nerve cells themselves, are misread as “foreign” by the immune system. Numerous immune cell types—T cells, B cells, and microglia—as well as a variety of immune molecules including antibodies, cytokines, and chemokines are all believed to contribute to destruction of myelin and scarring (gliosis) that are the hallmarks of MS. MS can vary from a relatively benign illness to a rapidly evolving and incapacitating disease. Symptoms of MS—such as weakness of the limbs, numbness, visual loss or blurring, pain, imbalance, fatigue, slowed thinking, and bladder/bowel/sexual dysfunction—reflect the loss of neural connections required for normal function. Treatments are available for many people with relapsing forms of MS; however, no useful therapies exist for progressive symptoms.

MS is a common disease in most parts of the developed world; it affects about 350,000 people in the United States and 2.5 million people worldwide. In Western societies, MS is second only to trauma as a cause of neurologic disability beginning in early to mid adulthood.

MS is approximately three times more common in women than men. The age of onset is typically between 18 and 40 years of age, but the disease can present across the lifespan. MS also appears to be increasing in frequency, especially in women. The environmental factors that lead to MS are not known; however, evidence implicates a lack of sun exposure associated with vitamin D deficiency, and exposure to Epstein Barr virus resulting in a strong antibody response to the virus, as possible contributors.

Several aspects of the Gulf War theater could, in theory, heighten the risk of MS. The first relates to exposure to the hot desert environment. Symptoms of MS may first appear, or can transiently worsen, upon exposure to heat; this is due to the “short-circuiting” of impulses carried

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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across demyelinated nerves when the core body temperature is raised. Second, a variety of infections can increase the risk of MS attacks, and it is well established that soldiers in both the Gulf War and in the conflicts in Iraq and Afghanistan experienced numerous infectious illnesses (see IOM, 2007). A third potential deployment-related risk is that of multiple vaccinations; however, there is no convincing evidence that any vaccinations are risk factors for MS (reviewed in Compston, 2006). Finally, it is possible that psychological and physical stress associated with war might increase MS risk, as has been recently reported from Israel (Golan et al., 2008).

Updated and Supplemental Literature
Primary Study

There was no information related to MS at the time of the last IOM review in 2006. Barth et al. (2009) reviewed mortality from MS as well as from ALS, Parkinson’s disease, and brain cancer from 621,902 veterans who served in the Gulf War between August 1, 1990, and March 1, 1991, and compared these with 746,248 veterans who served concurrently but were not deployed to the gulf. Follow-up was terminated on December 31, 2004. Records from the VA database Beneficiary Identification and Records Locator Subsystem (BIRLS), a file consisting of all veterans eligible for VA benefits, and the SSA Death Masterfile were examined. Death certificates and medical records were reviewed by experts who were blinded to deployment status and classified using the McDonald criteria (McDonald et al., 2001). A total of 19 deaths due to MS were identified; 6 in the deployed group and 13 nondeployed. The adjusted relative risk estimates for MS mortality did not suggest an increased risk of mortality from MS (RR 0.67, 95% CI 0.24-1.85; Cox proportionate hazard model).

Secondary Studies

Kelsall et al. (2005) performed a cross-sectional analysis of the entire cohort of 1871 Australian Gulf War veterans, and a comparison group of 2924 nondeployed veterans, matched by age, sex and service type. Postal and telephone questionnaires were administered followed by evaluations at 10 clinics across country. MS was self-identified in one Gulf War veteran and in three in the comparison group (OR 0.3, 95% CI 0.00-3.5). Because of the small size and limitations of this study, and the fact that MS was determined by self-report, no conclusions can be drawn about the prevalence of MS in this cohort; therefore, this study is considered to be secondary for this health outcome.

Summary and Conclusions

No excess in MS mortality was identified in Gulf War veterans in a single well-executed primary study. However, for several reasons the design of the study is likely to be insensitive to the detection of any MS risk associated with deployment. First, the study could detect deaths from MS within 13 years or less from the time of deployment, yet epidemiologic data suggest that the interval between a critical environmental exposure and the clinical onset of MS may be a decade or longer. Second, any excess mortality due to MS is likely to be only minimal during the first 15 years of the illness. Thus a mortality endpoint with a short duration study is unlikely to have power to detect an increase in the occurrence of clinical MS among those deployed in the 1990-1991 conflict.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Therefore, the committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and multiple sclerosis.


Recommendation: Well-designed, adequately powered studies of MS incidence following deployment are needed.

Amyotrophic Lateral Sclerosis

ALS is a neuromuscular disorder; it is often referred to as Lou Gehrig’s disease and might also be called motor neuron disease or Charcot’s disease. It affects approximately 20,000 to 30,000 people in the United States (ALS Association, 2008; National Institute of Neurological Disorders and Stroke, 2006, 2009). ALS affects all races and ethnic backgrounds, and the risk is higher in men than women of the same age (Annegers et al., 1991). The disease is often relentlessly progressive and almost always fatal. The rate of progression is quite variable from patient to patient.

ALS causes degeneration of the motor neurons in the cerebral motor cortex (called upper motor neurons) and the brain stem and spinal cord (called lower motor neurons) (Rowland, 2000). The motor neurons are nerve cells that provide communication between the highest levels of the nervous system and the voluntary muscles of the body (National Institute of Neurological Disorders and Stroke, 2006). When the upper motor neurons degenerate, their connections to the lower motor neurons and spinal interneurons are disrupted. That disruption leads to weakness of muscles in a characteristic distribution and the development of spasticity. Lower motor neuron degeneration disrupts nerve contact to the muscles resulting in muscle atrophy. Spontaneous muscle activity, called fasciculation, occurs. Eventually, affected people are unable to move their arms and legs and cannot speak or swallow. When the connection is disrupted between the neurons and the muscles responsible for breathing, patients either die from respiratory failure or require mechanical ventilation to continue to breathe. The majority of persons with ALS die from respiratory failure within 5 years from the onset of symptoms. To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes (such as progressive muscular atrophies and varieties of peroneal muscular atrophy, Kennedy’s syndrome, or multifocal motor mononeuropathy).

Five to ten percent of ALS cases are familial (inherited), and the remainder are sporadic (Rowland, 2000; Siddique et al., 1999). Only one parent needs to carry the mutant gene for ALS to occur in about half of the children in cases of familial ALS. The specific gene mutations causing the majority of familial ALS cases are unknown. However, about 20% of familial cases are believed to be caused by a mutation in a gene that encodes the enzyme superoxide dismutase 1 (National Institute of Neurological Disorders and Stroke, 2006).

The cause of sporadic ALS is unknown. Despite a number of epidemiologic studies examining occupations (for example, farmers and electricians), occupational toxins (such as lead or pesticides), physical trauma, transmissible agents (such as viruses or other microorganisms) strenuous physical activity (for example, Italian professional soccer players), lifestyle factors (for example, diet, body mass index, cigarette use, and alcohol consumption), race/ethnicity, socioeconomic status, and possibly latitude (such as a north-south gradient of risk), to date there are no accepted nongenetic risk factors for ALS (Armon, 2003, 2004; Armon et al., 1991; Cermelli et al., 2003; Chio et al., 2005; Kamel et al., 2002; McGuire et al., 1996, 1997; Nicolson et al., 2002; Rowland, 2000; Valenti et al., 2005).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×
Summary of Volume 4
Primary Studies

Horner and colleagues (2003) conducted a nationwide, epidemiologic case-ascertainment study to determine if Gulf War veterans have elevated rates of ALS relying on both active and passive methods of case ascertainment. Active methods included screening of inpatient, outpatient, and pharmacy medical databases of VA or DoD. Passive methods included establishment of a toll-free telephone number, solicitations through relevant Internet sites, and mass mailings of study brochures to practicing neurologists in the VA and to members of the American Academy of Neurology. The ALS diagnosis in study participants was verified by medical record review.

Among nearly 2.5 million eligible military personnel active during the Gulf War period, nearly 700,000 had been deployed to the Gulf War between August 1990 and July 1991. Mostly based on active ascertainment methods, this study identified 107 eligible cases of ALS (40 in the Gulf War deployed and 67 in the nondeployed troops), for an overall occurrence of 0.43 per 100,000 persons per year between August 1990 to December 1999. The ALS risk was estimated to be about twofold for all deployed compared to the nondeployed military personnel (RR 1.92, 95% CI 1.29-2.84) with an attributable risk (that is, the risk difference or excess risk) due to deployment estimated as 18% (95% CI 4.9-29.4). The foremost limitation of the study was potential underascertainment of cases, particularly among nondeployed veterans, because nondeployed veterans had less incentive to participate. Because of the rarity of ALS, underascertainment of a few cases, particularly if it is greater among the nondeployed, can substantially exaggerate the risk among the deployed by comparison. The finding that the incidence of ALS in deployed veterans was actually lower than that of an age-matched sample from Washington state (McGuire et al., 1996) contributed to this concern; however, such a difference between military personnel and the general population might also reflect a healthy warrior bias. Another but less important study limitation raised in a letter by another ALS researcher was failure to consider smoking as a possible confounding factor in the study design under the assumption that smoking is a risk factor for the development of ALS (Armon et al., 2004; Nelson et al., 2000). In response, the authors of the original study pointed out that there is little reason to believe that smoking rates are different among deployed and nondeployed veterans reducing the likelihood for confounding bias.

More importantly, however, the same authors undertook a secondary analysis to address concerns about differential case ascertainment among deployed versus nondeployed veterans. In this secondary analysis (Coffman et al., 2005) they assessed case ascertainment bias by estimating the occurrence of ALS employing three capture–recapture analysis methods: log-linear models, sample coverage, and ecologic models. The investigators concluded that there might have been some modest underascertainment of cases in nondeployed military personnel but little underascertainment in the deployed. After correcting the rates for underascertainment, the investigators still found a higher age-adjusted risk of ALS among the deployed than among the nondeployed (RR 1.77, lower bound 1.21, with log-linear model). These analyses confirmed the original findings of an increase in ALS among deployed veterans assuming that the modeling assumptions they had to make for this exercise are correct. See Table 4-6 for a summary of the primary ALS studies discussed above.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×
Secondary Studies

Haley (2003) found an excess incidence of ALS among deployed veterans in comparison with the expected incidence based on US vital statistics. Similar to the first Horner et al. study (2003), this analysis spanned a short war or postwar period from 1991 to 1998 only. In the first half of that period an increased incidence was not apparent; from 1995 to 1998, the incidence more than doubled (standardized mortality ratio [SMR] 2.27, 95% CI 1.27-3.88). Although the study used passive and active means of case ascertainment similar to those of Horner et al., it differed in several key aspects: it restricted cases to those below the age of 45 years (instead of all ages); it used 8 years of follow-up (instead of 10 years), and it used for comparison the age-adjusted rates from US mortality statistics (instead of the age-adjusted rates in nondeployed veterans). Use of mortality statistics for the general population to estimate an “expected” incidence is a major limitation (Armon et al., 2004), since this assumes that the case ascertainment methods for the comparison population are similar to those for the deployed military population when deriving SMRs. The case ascertainment methods used by Haley (2003) are not comparable to those in the general population and may have overascertained cases among veterans.

Several US and UK mortality studies have not found an excess risk of ALS, but they did not have sufficiently long follow-up or sufficiently detailed methods (DASA, 2005; Kang and Bullman, 1996; Macfarlane et al., 2000). Recently, the original Kang and Bullman (1996) mortality study has been updated (Barth et al., 2009) and included data through December 2004. This study did not find any increase in ALS mortality in Gulf War veterans compared to nondeployed veterans (adjusted RR 0.96; 95% 0.56-1.62), but these results were based on less than half the number of ALS cases identified in the primary study by Horner et al. (2003) (23 cases in deployed and 38 in nondeployed veterans). A hospitalization study (Smith et al., 2000) also found no difference in relative risk of ALS (RR 1.66, 95% CI 0.62-4.44), but the authors acknowledge that they had too few cases to make valid comparisons between deployed and nondeployed veterans. The study was also limited by inclusion of only active-duty military personnel and only 6 years of follow-up. Nicolson and colleagues, studying eight Gulf War veterans with ALS and two other comparison populations, found that ill Gulf War veterans had the highest frequency of systemic mycoplasm infections (Nicolson et al., 2002). Although the authors suggest that mycoplasma might be involved in the pathogenesis or progression of ALS, insufficient information was given regarding the selection of cases and controls to evaluate bias in ascertainment.

Updated and Supplemental Literature

Horner et al. (2008) extended their follow-up for 1 year to December 2001 and investigated temporal patterns of ALS occurrence. Among all 2.5 million military personnel on active duty during the 1991 Gulf War a total of 124 ALS cases were confirmed; 48 of these cases occurred among those deployed, while 76 cases were found among the nondeployed; the percentage of young onset cases (< 45 years of age) was similar in both groups (69% vs 64%). The main increase in ALS cases in this study occurred within the decade following the war, that is, prior to 1999. The authors proposed that Gulf War-specific neurotoxins may have caused the short-period increase in ALS rates after the war among deployed military personnel. The results for nondeployed troops—found as in the original study to have experienced lower rates of ALS than the western Washington State population—contrast with another high-quality study that reported increased rates among men who had served in the military or had been deployed to a

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

war zone between 1910 and 1982 (Weisskopf et al., 2005). On the basis of this study a previous IOM committee (2006) termed the evidence for ALS and military deployment as limited and suggestive. Horner et al. (2008), however, also emphasized that their follow-up period was still too short to draw any conclusions about ALS in nondeployed military personnel when compared to a general population. However, due to small numbers of cases overall, it remains unclear whether the observed pattern represents random fluctuations in ALS rates among the deployed or an episodic post war increase as suggested by the authors.

Summary and Conclusions

One primary study with extended follow-up and one secondary study found that deployed veterans appear to be at increased risk for ALS. The primary study by Horner et al. (2003, 2008) possibly underascertained cases in the nondeployed population. However, they investigated ascertainment bias analytically and concluded that it was unlikely to explain their results (in Coffman et al., 2005); they also extended follow-up through 2001 and described a short-term increase in ALS risk in the deployed during the decade after the war. These analyses together support an estimate of a nearly doubling in risk among deployed veterans compared with nondeployed veterans. A secondary study by Haley (2003), using general population rates for comparison purposes, found a similar increase in relative risk. Other US and UK mortality studies and a hospitalization study have not found excess risk of ALS.

Therefore, the committee concludes that there is limited but suggestive evidence of an association between deployment to the Gulf War and ALS; however, further follow-up is warranted.

Other Neurodegenerative Diseases

Alzheimer dementia is the most common neurodegenerative disorder in the elderly population and Parkinson’s disease—primarily considered a movement disorder—is the second most common. Both have progressive courses and no known cure. The dopaminergic neurodegeneration in Parkinson’s disease is thought to be caused by a combination of repeated, prolonged, or chronic exposures to toxicants, genetic factors, gene–toxicants interactions, and aging-related effects. Over the last decade and a half, evidence has accumulated that exposure to certain pesticides can produce the anatomical, neurochemical, behavioral, or neuropathological features of Parkinson’s disease in animal models (Sherer et al., 2001), and recently some high-quality studies have confirmed the pesticide hypothesis for Parkinson’s disease in humans (Elbaz et al., 2009; Kamel et al., 2007; Ritz et al., 2009).

Environmental factors are also suspected to contribute to Alzheimer disease to a lesser degree. High-quality human studies are not available except for lead exposures (Shih et al., 2007), for which data from both animal experiments and human epidemiologic studies suggest an influence of lead exposure on Alzheimer-like cognitive impairment. Of special importance for Gulf War veterans is that brain injuries are an established risk factor for Alzheimer dementia, especially among susceptible individuals (for example, carriers of the APOE 4 allele). Brain injury has been shown to result in widespread hippocampal damage in mice and may lead to Alzheimer disease in humans (reviewed in Van Den Heuvel et al., 2007).

The committee was unable to identify any studies of dementia or Alzheimer’s disease in Gulf War veterans and only one study on Parkinson’s disease. Barth et al. (2009) compared mortality from neurological disease in 621,902 deployed and 746,248 nondeployed veterans

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

between May 1991 and December 2004. The adjusted mortality rate ratio for Parkinson’s disease was 0.77 (95% CI 0.17-2.99); there were three cases among the deployed male veterans, eight cases among the nondeployed males, and no cases in either group of female veterans.

Summary and Conclusion

Parkinson’s and Alzheimer’s diseases generally present late in life (usually after age 60); thus, it is unlikely that Gulf War veterans would manifest symptoms or signs of these neurodegenerative disorders until they reach at least the sixth decade of life. The Update committee strongly believes that a very long latency period for these health outcomes is a possibility, and current studies have inadequate follow-up time to assess whether risk for these disorders is increased among Gulf War veterans.

Therefore, the committee concludes that there is inadequate/insufficient evidence of an association between deployment to the Gulf War and other neurodegenerative diseases. The committee recommends continued monitoring of Gulf War veterans (both deployed and nondeployed) for neurologic outcomes such as Parkinson’s disease, Alzheimer’s disease, and dementia.

Other Neurological Outcomes

Haley and colleagues performed detailed neurologic assessments in several case-control studies of the original cohort of Seabee reservists. The cases were veterans who had met criteria for factor-derived syndromes. Under the hypothesis that those veterans were ill from neurotoxic exposures, especially to organophosphates, the assessments covered broad neurologic function (Haley and Kurt, 1997), autonomic function (Haley et al., 2004), vestibular function (Roland et al., 2000), basal ganglia injury (Haley et al., 2000a,b), normalized regional cerebral blood flow (Haley et al., 2009); and paraoxonase (PON) genotype and serum concentrations (Haley et al., 1999). Separate groups of investigators also studied PON genotype or activity (Hotopf et al., 2003; Mackness et al., 1997). A case-control study of neuropsychologic functioning (Hom et al., 1997) is discussed elsewhere in this chapter.

The committee regarded those case-control studies as secondary studies primarily because of their lack of generalizability and strong potential for selection bias. Although their study design was characterized as nested case-control, the studies of Haley et al. were not true nested case-control studies. Cases were, appropriately, selected from the original cohort, but controls were not. Ten of the 20 controls were from 150 newly discovered members of the battalion who had not been deployed. Those 10 were not from the original cohort, and there is no indication that they were tested to determine whether they should be treated as cases. The selection of those controls raises the possibility of selection bias. With regard to the other concern, lack of generalizability, the authors selected as cases the most severely affected veterans—that is, those who scored highest on factor analysis-derived syndromes—rather than a random sample of those who met a particular case definition.

Summary and Conclusion

Haley and colleagues found evidence of basal ganglia injury and other abnormalities with detailed neurologic assessments in several case-control studies. The committee regarded the

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

studies as secondary because of their lack of generalizability and their strong potential for selection bias.

Therefore, the committee concludes that there is inadequate/insufficient evidence of an association between deployment to the Gulf War and other neurologic outcomes.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-6 Nervous System Diseases

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Peripheral Neuropathy and Myopathy

Davis et al., 2004 (Vol. 4)

Cross-sectional, prevalence, medical evaluation, exposure-specific component

1047 deployed veterans vs 1121 nondeployed veterans; 240 Khamisiyah-exposed deployed veterans vs 807 non-Khamisiyah-exposed deployed veterans

Distal symmetric polyneuropathy identified by nerve-conduction studya

Deployed vs nondeployed veterans: OR 0.65 (95% CI 0.33-1.28); Khamisiyah-exposed veterans vs non-Khamisiyah-exposed veterans: OR 1.04 (95% CI 0.25-4.37)

Excludes coexisting conditionsb

Low participation rate: 53% in deployed veterans, 39% in nondeployed veterans

Rose et al., 2004; Sharief et al., 2002 (Vol. 4)

Case-control

49 symptomatic deployed UK veterans vs 26 healthy deployed UK veterans, 13 symptomatic Bosnia deployed veterans, 22 symptomatic Gulf War-era veterans

Nerve-conduction studies, quantitative sensory and autonomic testing, concentric needle and single-fiber, electromyography, ischemic forearm exercise test, subanaerobic bicycle exercise test, muscle biopsy

No significant differences between symptomatic deployed and nondeployed veterans, except deployed veterans had increased lactate production in bicycle exercise test

 

Positive finding from bicycle test could reflect mitochondrial damage or inactivity resulting from ill health

Kelsall et al., 2005 (Update)

Cross-sectional survey

1382 Australian male GWVs, 1376 nondeployed male era veterans frequency matched by age and service type (Same study population as Kelsall et al., 2004a,b)

Self-reported neurologic symptoms corroborated during neurological examination; SF-12; modified NIS

Lower limb neurological type symptoms and signs: OR 1.6 (95% CI 1.0-2.7) Neuropathy Score: GWV (2.0, sd = 4.3) vs controls (2.0, sd = 4.7) RoM 1.1 (95% CI 0.9-1.3) Association of neurological symptoms in self-reported nonexposed compared to exposed: PB (RoM 1.5, 95% CI 1.2-1.8)

Antibiological warfare

Age, rank, service type, current marital status, highest level of education, alcohol consumption, and history of diabetes

Exposure data self-reported; response rate 80.5% for deployed, 56.8% for nondeployed

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

tablets (RoM 1.8, 95% CI 1.3-2.5)

Solvents (RoM 1.8, 95% CI 1.4-2.2)

Pesticides (RoM 1.7, 95% CI 1.4-2.0)

Insect repellents (RoM 1.3, 95% CI 1.1-1.5)

No association with self-reports of immunizations or chemical exposure

 

 

Multiple Sclerosis

Barth et al., 2009 (Update)

Mortality cohort study, follow-up through 2004 of same cohort as Kang and Bullman (2001)

621,901 US male GWVs and 746,247 nondeployed male veterans

Mortality due to multiple sclerosis (McDonald criteria)

GWVs (6 cases) compared to era veterans (13 cases) MRR 0.67 (95% CI 0.24-1.85)

Race, service branch, type of unit, age, marital status

 

Amyotrophic Lateral Sclerosis (ALS)

Horner et al., 2003 (Vol. 4)

Retrospective cohort

All active, GWVs (1990-1991) compared with NDVs

ALS

All deployed forces, significant increased risk of ALS (RR = 1.92, 95% CL −1.29-2.84)

Age-adjusted average, annual 10-year incidence; attributable risk

Case ascertainment through screening of VA and DoD medical databases and benefit files (and TriCare) by ICD-9 code for ALS or riluzole use; tollfree telephone enrollment; Internet notices; mass mailings to neurologists, VA centers, and veteran service organizations

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Coffman et al., 2005 (Vol. 4)

Capture–recapture reanalysis of Horner et al., cohort

See Horner et al., 2003

ALS

Found no underascertainment of ALS cases among deployed

Log-linear models; sample coverage; ecologic models

Possible slight undercounts not likely to substantively affect results

Horner et al., 2008 (Update)

Retrospective cohort, follow-up from 1991-2001 (follow-up of Horner et al., 2003)

All active, Gulf War-deployed military personnel (n = 696,118), compared with NDVs

ALS

Deployed (48 cases) vs nondeployed (76 cases), no significant difference in SIR during additional follow-up period Similar percentage of young onset between deployed (69%) and controls (64%)

Age-adjusted average, annual 10-year incidence; attributable risk

Small number of cases and short follow-up period limit the ability of the study to determine long-term trends

NOTES: CI = confidence interval; GWV = Gulf War veteran; MRR = mortality rate ratio; NDV = nondeployed veteran; NIS = Neuropathy Impairment Score (Mayo Clinic version); OR = odds ratio; PB = pyridostigmine bromide; RoM = ratio of means; sd = standard deviation; SF-12 = 12-item Short Form Health Survey; SIR = standardized incidence ratio.

aAlthough the study defined distal symmetric polyneuropathy as distal sensory or motor neuropathy identified on basis of neurologic examination, nerve conduction study, or both, the committee defined it by nerve-conduction study alone.

bAlcohol dependence, diabetes mellitus, renal insufficiency, hypothyroidism, AIDS/HIV, collagen vascular disease, and neurotoxic medications.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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DISEASES OF THE CIRCULATORY SYSTEM

Cardiovascular disease is a broad term for any disorder of the heart or the blood vessels, such as artherosclerosis and hypertension. Cardiovascular disease, which includes coronary heart disease and stroke, is the leading cause of death of both women and men in the United States. In 2005, 864,480 people (53% of them women) died of cardiovascular disease, accounting for 34% of all US deaths. The age-adjusted death rate was 262.9 per 100,000 of population. Over 40% of deaths in those aged 65 or older is the result of cardiovascular disease (Lakatta, 2002). Major risk factors for cardiovascular disease include hypercholesterolemia, diabetes, smoking, obesity, and physical inactivity. Primary studies for circulatory system diseases are presented in Table 4-7.

Summary of Volume 4

Primary Studies

Volume 4 included two primary studies considering cardiovascular outcomes. The first study (Eisen et al., 2005) examined the prevalence of different health outcomes in a group of 1061 Gulf War deployed veterans and 1128 nondeployed veterans between 1999 and 2001; veterans were part of the larger National Health Survey of Gulf War Era Veterans and Their Families, who had completed mailed questionnaires about their health status in 1995 (Kang et al., 2000). Hypertension, defined as systolic blood pressure greater or equal than 140, diastolic blood pressure greater or equal than 90 mmHg, or use of antihypertensive medication, was equally prevalent in deployed and nondeployed veterans (adjusted OR 0.90, 95% CI 0.60-1.33). The major limitation of this study was the differential, low response rate (53% in Gulf War veterans and 39% in nondeployed).

The second study examined hospitalizations in DoD hospitals among Gulf War veterans according to their exposure to the demolition of the Khamisiyah weapons depot. An initial report of this analysis, published in 1999 (Gray et al., 1999b), was updated in a later publication (Smith et al., 2003). Among those potentially exposed to sarin and cyclosarin the risk ratio of being hospitalized with a cardiovascular condition was 1.07 (95% CI 1.01-1.13) compared to nonexposed. The increased risk was specific for cardiac dysrhythmias (risk ratio 1.23, 95% CI 1.04-1.44). This study could not ascertain outpatient diagnoses as well as hospitalizations in those who did not remain in active duty after the war.

Secondary Studies

Several large epidemiologic studies examined self-reported cardiovascular outcomes occurring in Gulf War veterans. The committee classified studies relying on self-report of cardiovascular disease as secondary. In an Australian study, prevalence of self-reported physician-diagnosed high blood pressure was similar in 1456 veterans deployed to the Gulf War and 1588 nondeployed (OR 1.2, 95% CI 0.9-1.6) (Kelsall et al., 2004a). Similarly, Kansas veterans were as likely as their nondeployed counterparts to report physician-diagnosed high blood pressure (OR 1.24, 95% CI 0.82-1.89) or heart disease (OR 1.56, 95% CI 0.69-3.56) (Steele, 2000). In a study including 11,441 Gulf War veterans and 9476 nondeployed veterans, Kang and colleagues (2000) found an increased prevalence of self-reported high blood pressure in deployed versus nondeployed veterans (prevalence difference 3.84%, 95% CI 3.75-3.93) and a

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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similar prevalence of stroke (−0.01%, 95% −0.003-−0.01). Studying all Seabee commands, Gray and colleagues (2002) found a higher prevalence of self-reported hypertension in those deployed to the Gulf War versus those deployed elsewhere (OR 1.63, 95% CI 1.36-1.95). A study including 2918 Gulf War veterans from five US states (California, Georgia, North Carolina, Oregon, and Washington) did not find differences in self-reported conditions among deployed veterans potentially exposed to nerve agents from the Khamisiyah demolition compared to deployed but unexposed veterans. Compared with nondeployed veterans, however, deployed veterans (exposed and nonexposed combined) did have a higher prevalence of self-reported high blood pressure (OR 1.7, 95% CI 1.3-2.4) and heart disease (OR 2.5, 95% CI 1.1-6.6) (McCauley et al., 2002). Finally, one study of UK male Gulf War veterans found a higher prevalence of self-reported high blood pressure in 3284 deployed veterans compared to 1815 veterans deployed to Bosnia (OR 1.3, 95% CI 1.0-1.8) or 2408 nondeployed Gulf War era veterans (OR 1.2, 95% CI 1.0-1.6) (Unwin et al., 1999). The main limitation, shared by these secondary studies, is the use of self-reported information and, therefore, the potential for differential misclassification if deployed veterans were more likely to report cardiovascular conditions than their nondeployed counterparts.

Updated and Supplemental Literature

Primary Studies

Since the publication of Volume 4, a series of studies examining hospitalizations and mortality for cardiovascular diseases have been identified. The committee considered that cardiovascular disease hospitalizations and mortality had adequate validity and, therefore, studies considering these outcomes should be classified as primary studies.

Gray et al. (1996) compared DoD hospitalizations among Gulf War deployed and nondeployed active-duty personnel. Hospitalizations for 14 ICD-9-CM diagnostic categories, which included “circulatory system diseases,” were assessed across three time periods following the war: August 1, 1991, to December 31, 1991 (included 1,165,411 subjects on active duty on the first day of this time period); January 1, 1992, to December 31, 1992 (1,075,430 subjects); and January 1, 1993, to September 30, 1993 (839,389 subjects). Hospitalizations for cardiovascular diseases were not increased among the Gulf War deployed personnel versus nondeployed during any of the three time periods. Limitations of this study include the relatively short follow-up, the lack of outpatient data, restriction to DoD hospitals, restriction to hospitalizations of those who remained on active duty after the war, and limited adjustment for potential confounding exposures.

A later publication complemented the above study adding reserve and former military personnel hospitalized in non-DoD hospitals (Gray et al., 2000). Hospitalizations for the 14 major discharge diagnoses during the period of August 1, 1991, and December 31, 1994, were compared for Gulf War veterans and nondeployed veterans in three hospital systems (DoD, VA, and the California Office of Statewide Health Planning and Development). Because the population eligible for hospitalization in the VA and California systems could not be identified to calculate hospitalization rates, the investigators estimated proportional morbidity ratios within each hospital system. Gulf War veterans did not experience an increased proportion of hospitalizations for “diseases of the circulatory system” compared to nondeployed veterans during the 4 years after the war. This finding was consistent among hospitalizations within the DoD (n = 182,164), VA (n = 16,030), and California (n = 5185) hospital systems (PMRs ranged

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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between 0.85 and 0.94). The use of proportional morbidity ratios results in a lower sensitivity for detecting differences in hospitalizations than does a comparison of hospitalization rates.

Postwar hospitalizations in US military personnel were also examined in relation to exposure to smoke from oil-well fires (Smith et al., 2002). Hospitalizations within DoD treatment facilities were identified for 405,142 active-duty personnel who were in the Gulf War theater of operations during the Kuwaiti oil-well fires (February 2, 1991, to October 31, 1991) and did not remain in the region after the war. Hospitalizations for “diseases of the circulatory system” and other major ICD-9-CM categories were evaluated over an 8-year follow-up period. Exposure to oil-well fire smoke was estimated by combining smoke-plume modeling data and troop unit location. Exposure was categorized into seven levels based on combinations of average daily dose (none, 1-260 μg/m3, > 260 μg/m3) and duration of exposure (1-25 days, 26-50 days, > 50 days). When compared to those with no exposure to smoke from oil-well fires, there was no increase in the incidence of hospitalization for cardiovascular disorders at any level of exposure: risk ratios ranged between 0.9 and 1.2 for the different levels of exposure (all 95% CIs included 1.0), without a clear dose-response trend. Considering hospitalizations for ischemic heart disease as the outcome, veterans exposed to oil-well fires had a slightly lower risk than unexposed veterans (risk ratio 0.82, 95% CI 0.68-0.99). The limitations of this study are the same as those described for other hospitalization studies in the DoD system.

A more recent study compared hospitalizations in DoD hospitals among Gulf War veterans and other veterans and found no evidence of an increased risk of cardiovascular disease among the former group (Smith et al., 2006). Specifically, this study compared incidence of postdeployment hospitalizations among active-duty servicemembers deployed to the Gulf War (n = 455,465) to those deployed to Southwest Asia following the Gulf War (n = 249,047) or those deployed to Bosnia (n = 44,341). Electronic information on hospitalizations was collected from DoD hospitals through December 2000. The incidence of hospitalizations for diseases of the circulatory system was similar in Southwest Asia veterans and Gulf War veterans (HR 1.06, 95% CI 0.97-1.16). Incidence of hospitalizations for cardiovascular disease in Bosnia veterans was lower than in the Gulf War veterans (HR 0.70, 95% CI 0.59-0.83). All analyses were adjusted for potential confounding factors (sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalizations). Limitations of the study include the inclusion of active-duty personnel only and restricting the outcomes to those identified in DoD hospitals only.

Five published reports have examined mortality for cardiovascular diseases in Gulf War veterans. Kang and Bullman (2001) compared cardiovascular mortality from 1991 through the end of 1997 in 621,902 US Gulf War veterans and 746,248 nondeployed veterans, by sex, adjusting for age, race, marital status, branch of service, and type of unit. Adjusted mortality rate ratios for cardiovascular diseases in deployed versus nondeployed were 0.90 (95% CI 0.81-1.01) in men and 0.96 (95% CI 0.55-1.69) in women. Limitations of this study include the lack of adjustment for predeployment health status and for lifestyle variables, such as smoking or alcohol consumption.

Another study in US Gulf War veterans compared cardiovascular mortality through 2000 according to potential exposure to nerve agents from the Khamisiyah demolition (Bullman et al., 2005). Analyses were adjusted for age, sex, race, rank, and unit component. Among 100,487 potentially exposed veterans, 170 cardiovascular deaths were identified, while 407 were identified among 224,980 unexposed veterans (adjusted risk ratio 0.89, 95% CI 0.74-1.06).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Results were similar when exposed veterans were further classified as having 1 day of exposure or 2 or more days of exposure.

The Canadian Persian Gulf Cohort Study explored total and cause-specific mortality in 5117 Gulf War deployed and 6093 nondeployed Canadian veterans (Statistics Canada, 2005). Mortality and cause of death through the end of 1999 was ascertained from the Canadian Mortality Data Base. Analyses were adjusted for age, sex, rank, and marital status. During the 8-year follow-up, 17 cardiovascular deaths were identified. The adjusted mortality rate ratio (MRR) of cardiovascular mortality in deployed versus nondeployed veterans was 0.49 (95% CI 0.17-1.40). Limitations of this study include its limited sample size (and therefore low statistical power to detect associations if these exist), the relatively short follow-up (which would not allow the identification of long-term effects of deployment), and the lack of information on potential confounding factors, such as smoking and other lifestyle factors.

Two publications reported cardiovascular mortality among UK Gulf War veterans. Macfarlane et al. (2005) compared mortality from April 1991 to June 2004 among 51,753 UK Gulf War veterans and a cohort of 50,808 military personnel not deployed to the Persian Gulf, matched by age, sex, rank, service and level of fitness. Mortality was determined through linkage with the National Health Service central register. Cardiovascular mortality was similar in both cohorts (adjusted mortality rate ratio 0.87, 95% CI 0.66-1.14). A later publication, extending the follow-up of these cohorts through the end of 2007 found comparable results (adjusted rate ratio 0.87, 95% CI 0.70-1.07) (DASA, 2009).

A study conducted in Denmark measured blood pressure in a group of 686 Danish veterans deployed to the Gulf area between August 1990 and December 1997, and 231 nondeployed controls (Ishoy et al., 1999b). In bivariate analysis, systolic blood pressure was similar in deployed and nondeployed: means were 127 mmHg (sd = 12) and 126 mmHg (sd = 11), respectively. Differences were also absent for diastolic blood pressure (78 mmHg, sd = 9 and 76 mmHg, sd = 10, respectively).

In addition to obtaining self-reports of diagnoses of medical conditions, including high blood pressure (Kelsall et al., 2004a), the study of Australian Gulf War veterans included physical examinations of 1424 Gulf War male veterans and a sample of 1548 nondeployed male veterans conducted by April 2002 (Sim et al., 2003). Response rates were 81% among eligible deployed veterans and 57% among nondeployed. All analyses in this study were adjusted for age, service type, rank, education, and marital status. Levels of blood pressure were similar in deployed and nondeployed. In polytomous logistic regression, adjusted ORs of high-normal blood pressure and hypertension in deployed (n = 1371) versus nondeployed (n = 1368) were 1.1 (95% CI 0.9-1.3) and 1.1 (95% CI 0.9-1.4), respectively. Likewise, the prevalence of hypertension was the same (3%) among 30 female Australian Gulf War veterans compared to a control group of 32 nondeployed women (Sim et al., 2003). Response rates for female veterans were comparable to their male counterparts: 79% in deployed and 44% in nondeployed.

Secondary Studies

Seven studies provided self-reported prevalence of different cardiovascular disorders, including high blood pressure, palpitations, stroke, heart attacks, and unspecified heart problems by deployment status. Given the low validity of self-reported information to diagnose cardiovascular disease, these studies are considered to be secondary.

A mailed survey assessed health status of 4334 veterans in Pennsylvania and Hawaii, 1739 of them deployed as result of Operation Desert Shield/Storm (Stretch et al., 1995). Results

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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of this survey conducted within 2 years of deployment were reported separately for active-duty and reserve personnel. Self-reported high blood pressure was more frequent in deployed versus nondeployed veterans (23% vs 10% in active-duty veterans, and 11% vs 4% in reserve veterans). Similarly, heart problems were more frequently reported in deployed than nondeployed veterans (7% vs 2% and 4% vs 1% in active-duty and reserve veterans, respectively). Limitations of this study included the low response rate (31%) and the lack of adjustment for potential confounders.

Proctor and colleagues (1998) studied 186 Gulf War deployed veterans from New England, 66 deployed veterans from New Orleans, and a group of 48 veterans deployed to Germany during the Gulf War. Information on cardiovascular conditions was collected using mailed questionnaires. Prevalence of palpitations (described as irregular heart beat or racing heart) was approximately twice as frequent among the deployed than nondeployed veterans in analyses adjusted for age, sex, and education (ORs ranged from 1.8-4.1). In a later publication comparing the same Gulf War deployed New England cohort with the Germany deployed cohort (Proctor et al., 2001a), self-reported prevalence of hypertension was higher among Gulf War veterans (14% vs 4%), but the prevalence of other heart problems was similar between the Gulf War deployed compared with those deployed to Germany (3% vs 4%).

A follow-up survey to the 1995 National Health Survey of Gulf War Era Veterans and Their Families (Kang et al., 2000) assessed the self-reported prevalence of different health outcomes in Gulf War veterans and a group of nondeployed veterans (Kang et al., 2009). Information on health status was collected through mailed questionnaires or phone calls. Of 30,000 eligible participants, 9970 participated (34% response rate; 40% among Gulf War veterans, 27% among nondeployed veterans). In a multivariable analysis, deployment to the Gulf War was associated with a higher prevalence of self-reported tachycardia (RR 1.42, 95% CI 1.26-1.60), stroke (RR 1.32, 95% CI 1.14-1.52), coronary heart disease (RR 1.22, 95% CI 1.08-1.39), and hypertension (RR 1.11, 95% CI 1.04-1.19). This study, however, has limited validity given the low participation rate and the lack of objective confirmation of the outcomes.

Self-reported cardiovascular disorders were assessed in 1995-1997 for 5555 Gulf War veterans included in the 1995 National Health Survey of Gulf War Veterans. Veterans were categorized as to whether they had potential exposure to nerve gas from the Khamisiyah demolition (n = 1898) or were unexposed (n = 3336) (Page et al., 2005). Information was obtained from mailed or telephone surveys. Analyses were adjusted for age, sex, race, rank, marital status, and unit component. Palpitations were reported with the same frequency for exposed (5.1%) and unexposed (5.7%) veterans (OR 0.88, 95% CI 0.69-1.11). Likewise, the prevalence of self-reported heart disease (OR 0.98, 95% CI 0.64-1.48), hypertension (OR 1.03, 95% CI 0.90-1.07), stroke (OR 0.89, 95% 0.42-1.88), and tachycardia (OR 0.92, 95% CI 0.79-1.07) were similar for the potentially exposed and unexposed groups.

In 1997, a mail survey of the Canadian military contingent of 2924 male veterans who served in the Gulf War and 3241 Canadian veterans who were in the military but had not been deployed to the gulf region asked about the presence of heart disease or circulatory problems. The prevalence of circulatory problems was higher in deployed than nondeployed veterans (5% vs 2%) and in those younger than 45 versus older veterans (6% vs 5%), while the prevalence of self-reported heart disease was similar in deployed and nondeployed (1% in younger veterans, and 4-5% in older ones) (Goss Gilroy, 1998).

Finally, a study was conducted among 23,358 male UK Gulf War veterans and 17,730 nondeployed veterans who answered a mailed questionnaire collecting information on a number of health conditions (Simmons et al., 2004). Self-reported prevalence of cardiovascular disorders

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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with incidence after 1990 was higher in deployed than nondeployed veterans (OR 1.3, 95% 1.1-1.4) after adjustment for age, service, rank, serving status at time of survey, alcohol, and smoking. A low response rate (53% in deployed and 42% in nondeployed veterans) could introduce selection bias, limiting the results of this study.

Summary and Conclusions

Several studies have explored whether deployment to the Gulf War was associated with higher risk of cardiovascular disease. Available primary studies did not report an increased risk of cardiovascular hospitalizations or mortality in those deployed compared to nondeployed veterans during the 10-15 years after the Gulf War. The few studies measuring blood pressure in deployed and nondeployed veterans similarly did not find differences between the two groups. The only study that found an increase in cardiovascular disease was limited to hospitalizations in deployed veterans who were possibly exposed to the Khamisiyah plume and those who were not exposed. The increase was due entirely to a higher risk of cardiac dysrhythmia (Smith et al., 2003). No studies have confirmed this association in other populations. In the secondary studies, deployed veterans were generally more likely to self-report hypertension, palpitations, and other cardiovascular disease, but those reports were not confirmed in medical evaluations. Additionally, many of those studies could be affected by selection bias. Therefore, their validity is poor.

The committee concludes that there is limited/suggestive evidence of no association between deployment and mortality from cardiovascular disease in the first 10 years after the war, and that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and cardiovascular disorders.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-7 Circulatory System Diseases

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Population-based; cross-sectional; prevalence; medical evaluation; 1999-2001

1061 deployed, 1128 nondeployed

Hypertension = blood pressure > 140/90 mmHg or history of hypertension and use of antihypertensive medications

Hypertension: OR 0.90 (95% CI 0.60-1.33)

Age, sex, race, years of education, smoking, duty type, service branch, rank

Low response rates, especially in control group (53% in GWVs, 39% in era controls), but analysis of nonparticipants and participants reveals no differences in hypertension or diabetes

Smith et al., 2003 (Vol. 4)

DoD hospitalization study (1991-2000); analysis of health outcomes and exposure to nerve agents

99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model

First hospitalization for any disease of the circulatory system (ICD-9-CM codes 390-459); hospitalization for cardiac dysrhythmia

Circulatory system diseases: RR 1.07 (95% CI 1.01-1.13); Cardiac dysrhythmia: RR 1.23 (95% CI 1.04-1.44)

 

Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures

Gray et al., 1996 (Update)

Retrospective cohort, hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 NDVs

Hospital-discharge diagnoses of circulatory system disease in DoD hospital system (ICD-9 classification)

OR about 0.90-0.95 (95% CI 0.85-1.05) across all 3 years, 1991-1993. Exact values not given

Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation

Very short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders such as smoking

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August 1991 through December 1994

652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5185 COSHPD hospitalizations

Hospital-discharge diagnoses of circulatory system disease in DoD, VA, and COSHPD hospital systems

Circulatory system disease: DoD PMR 0.94 (95% CI 0.91-0.98); VA PMR 0.85 (95% CI 0.76-0.93); COSHPD PMR 0.98 (95% CI 0.82-1.14)

Age, sex, race (only for DoD PMR) Age, sex (for VA and COSHPD PMR)

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates would have

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Smith et al., 2002 (Update)

DoD hospitalizations 1991-1999; exposure modeling for oil-well fire smoke

405,142 active-duty GWVs who were in theater during the time of Kuwaiti oil-well fires

Hospitalization for diseases of the circulatory system and for ischemic heart disease specifically

Significant decrease in risk ratio for exposed to oil-well fire smoke vs nonexposed in 3 of 5 exposure categories Lower risk of ischemic heart disease in all exposed vs nonexposed (RR 0.82, 95% CI 0.68-0.99)

Adjusted for “influential covariates,” defined as demographic or deployment variables with p values less than 0.15

Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking

Smith et al., 2006 (Update)

Retrospective cohort study (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping mission, 1991-1998 (n = 249,047); Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of a disease of the circulatory system (390-459)

Compared to GWVs, veterans of Bosnia showed reduced risk (HR 0.70, 95% CI 0.59-0.83), and veterans of Southwest Asia showed similar risk (HR 1.06, 95% CI 0.97-1.16)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Lower hazard ratio observed in veterans of Bosnia may be partially explained by shorter follow-up period Limitations: active-duty personnel only; hospitalizations at DoD facilities only

Kang and Bullman, 2001 (Update)

Cross-sectional, mortality 1991-1997

621,902 GWVs, 746,248 NDVs

Mortality and vital status determined with VA BIRLS database and SSA Master Beneficiary Record database

Men RR 0.90 (95% CI 0.81-1.01)

Women RR 0.96 (95% CI 0.55-1.69)

Age, race, service branch, type of unit, marital status

Study had good power to detect small increases in risk; limited by relying on death certificates rather than medical records and no adjustment for predeployment health status or confounders such as smoking

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

Bullman et al., 2005 (Update)

Retrospective cohort; followup from March 1991 through 2000

100,487 US Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed Army GWVs (derived from Kang and Bullman, 2001); exposure determined from the DoD (2000) plume model

Association of exposure to chemical warfare agents and mortality due to diseases of the circulatory system, determined through BIRLS, SSA; COD data from NDI

1.76% exposed vs 1.88% nonexposed (RR 0.89, 95% CI 0.74-1.06)

Age, race, sex, rank, unit component

Possible exposure misclassification, possible bias due to healthy warrior effect

Statistics Canada, 2005 (Update)

Retrospective cohort study (Cohort based on Goss Gilroy, 1998)

5117 Canadian GWVs; 6093 Canadian NDVs, frequency matched for age, sex, and military duty status

Mortality due to diseases of the circulatory system determined from the CMD and CCD

MRR 0.49 (95% CI 0.17-1.40)

Age, sex, rank, marital status

Limitations: Small sample size results in low statistical power; short follow-up; young age of cohort; no information on confounding factors such as smoking Approximately 2200 members of the deployed cohort were present in the Persian Gulf during the period of fighting

Macfarlane et al., 2005 (Update)

Cohort; 13-year follow-up

51,753 UK GWVs and 50,808 NDVs, randomly selected, matched by age, sex, service branch, rank; also fitness for active service in the Army and Royal Air Force

Mortality due to diseases of the circulatory system

MRR 0.87 (95% CI 0.66-1.14)

 

Complete and long-term follow-up; cohort of moderate size; potentially other uncontrolled confounders such as smoking

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

DASA, 2008 (Update)

Summary statistics of causes of death from April 1, 1991, to December 31, 2007

UK GWVs (n = 53,409) vs era veterans (n = 54,143)

Mortality due to diseases of the circulatory system

MRR 0.87 (95% CI 0.70-1.07)

Age

Roughly the same cohort as MacFarlane et al., 2005

Ishoy et al., 1999b (Update)

Cross-sectional

686 Danish peacekeepers deployed to gulf in 1990-1997 vs 231 age- and sex-matched armed forces nondeployed controls

Blood pressure measured by physician

Deployed vs nondeployed:

Systolic: 127 (sd = 12) vs 126 (sd = 11) mmHg

Diastolic: 78 (sd = 9) vs 76 (sd = 10) mmHg

 

Participation rate 83.6% deployed, 57.8% nondeployed

Sim et al., 2003 (Update)

Cross-sectional, mailed questionnaire and clinical examination

1371 male and 30 female Australian GWVs; 1368 male and 32 female NDVs

Blood pressure measured by a physician

High-normal blood pressure, males: OR 1.1 (95% CI 0.9-1.3) Hypertension, males: OR 1.1 (95% CI 0.9-1.4); females: similar prevalence (3%) in both groups

Service type, rank, age, education, marital status

High participation in deployed veterans (male 81%, female 79%), but low participation in control group (male 57%, female 44%) possibly leading to participation bias

NOTES: BIRLS = Beneficiary Identification Records Locator Subsystem (VA); BMI = body mass index; CCD = Canadian Cancer Database; CI = confidence interval; CMD = Canadian Mortality Database; COD = cause of death; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veteran; HR = adjusted hazard ratio; MI = myocardial infarction; mmHg = millimeters of mercury; MRR = mortality rate ratio; NDI = National Death Index; NDV = nondeployed veteran; OR = adjusted odds ratio; PHQ = Patient Health Questionnaire; PMR = patient medical record; RR = adjusted risk ratio; sd = standard deviation; SSA = Social Security Administration; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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DISEASES OF THE RESPIRATORY SYSTEM

Respiratory conditions such as asthma, bronchitis, chronic obstructive pulmonary disease, and various symptoms consistent with respiratory disease, such as wheezing and shortness of breath, have consistently been self-reported more frequently by deployed Gulf War veterans than controls. Exposures of concern in the theater include smoke from oil-well fires, high levels of ambient dust, pesticide sprays, and nerve gas exposure. A primary study met the committee’s criteria for methodological rigor (Chapter 2) and used objective measures of pulmonary function or death from respiratory disease. In a secondary study, the determination of a respiratory illness was based on veterans’ self-reports of symptoms or self-reported physician-diagnosed conditions. Primary studies are summarized in Table 4-8.

Summary of Volume 4

Primary Studies

The Volume 4 committee identified five primary studies that undertook to explore the association between pulmonary conditions and deployment to the Gulf War. Two of these studies were analysis of data from the 1995 National Health Survey of Gulf War Era Veterans and Their Families (Kang et al., 2000) conducted by the VA on 1061 Gulf War veterans and 1128 nondeployed veterans. This population was derived from a cohort of randomly selected participants from the previous 1995 study who had completed the earlier mailed questionnaire on self-reports of health conditions. Eisen et al. (2005) reported on the prevalence of self-reported asthma, bronchitis, and emphysema and found no significant differences between the two groups after adjusting for smoking and demographic variables. In a further study that applied spirometry and symptom interviews to a random selection of 1036 Gulf War deployed veterans compared with 1103 nondeployed US veterans, Karlinsky et al. (2004) found that only a history of smoking and wheezing among the respiratory outcomes studied were significantly elevated in the deployed veterans. No significant difference in the number of self-reported physicians’ visits or hospitalizations for respiratory disorders was seen between the groups. Spirometric measurements also showed no significant difference between the two groups. The study did not report participation rate. The study also looked at the effect of potential exposure to the Khamisiyah nerve gas releases by selectively comparing veterans deployed into the geographic areas potentially affected by the release. No significant differences were noted in the measured pulmonary functions of these veterans when compared to nondeployed controls or veterans who were unlikely to have been exposed to the nerve gas.

Gray et al. (1999a) also found that between 527 Gulf War Seabees and 970 nondeployed Seabees, pulmonary function parameters (force vital capacity [FVC] and forced expiratory volume in 1 second [FEV1]) showed no significant difference between the two groups, whereas respiratory symptoms (cough: OR 1.8, 95% CI 1.2-2.8; shortness of breath: OR 4.0; 95% CI 2.2-7.3) were significantly more common among deployed veterans compared with nondeployed veterans after adjustment for age, height, race, and smoking status.

Two studies of non-US Gulf War era veterans included an examination of respiratory outcomes. Australian Gulf War veterans were studied by Kelsall et al. (2004b) for respiratory outcomes. The prevalence of respiratory symptoms such as wheezing, chest tightness, cough, and dyspnea was higher (ORs ranged from 1.2-1.8; 95% CIs ranged from 0.9 to 2.3) among 1456

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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deployed veterans than among 1588 nondeployed veterans. Self-reported physician diagnosis of respiratory diseases such as asthma, chronic bronchitis, and emphysema was also higher in deployed veterans but not significant except for chronic bronchitis (OR 1.9, 95% CI 1.2-3.1), and pulmonary function were similar between the two groups. Danish peacekeepers, both military and nonmilitary, deployed to the gulf after the end of the conflict were studied by Ishoy and colleagues (1999b). They found that that the respiratory symptom of shortness of breath were more common among 686 deployed personnel when compared to a 231 professionally matched group of nondeployed subjects (14% vs 3.5%, p < 0.001). However, no significant difference was found on pulmonary function testing (FVC, FEV1, peak flow) between the two groups.

Several primary studies examined the association between exposure to smoke from the Kuwaiti oil-well fires and respiratory outcomes. Cowan et al. (2002) conducted a case-control study examining the effect of exposure to oil-well fire smoke using exposure estimates based on troop locations and National Oceanographic and Atmospheric Administration (NOAA) modeling. They found that the risk of physician-diagnosed asthma increased with increasing exposure categories after controlling for sex, age, race, rank, smoking history, and self-reported exposure. They did not use pulmonary function tests and did not distinguish preexisting asthma from new onset asthma. A large population-based study of 1560 Iowa veterans found no association between modeled oil-well fire exposure and the risk of asthma or bronchitis as defined by interview questions about wheezing and chest tightness and cough (Lange et al., 2002). However, when the risk of asthma or bronchitis was compared to self-reports of exposure to oil-well fires a significant association was found with increasing self-reported exposure.

Smith and colleagues (2002) studied post war hospitalizations and estimates of exposure to oil-well fire smoke based on troop location and NOAA modeling. Among 405,142 active-duty veterans, no association was found between modeled exposures and hospitalizations for asthma or acute or chronic bronchitis. A modest but non significant increase in risk for hospitalizations for emphysema was associated with exposure (RR 1.36, 95% CI 0.62-2.98).

Secondary Studies

The Volume 4 committee reviewed numerous multiple secondary studies, most of which relied on self-reported respiratory symptoms. Most of the studies consistently found increased self-reports of respiratory symptoms and illness among Gulf Was veterans compared with nondeployed counterparts. This finding was true both for US studies (Eisen et al., 2005; Gray et al., 2002; Iowa Persian Gulf Study Group, 1997; Kang et al., 2000; Kroenke et al., 1998; Petruccelli et al., 1999; Steele, 2000) as well as studies of veterans from the United Kingdom (Cherry et al., 2001b; Nisenbaum et al., 2004; Simmons et al., 2004; Unwin et al., 1999), Denmark (Ishoy et al., 1999b), Australia (Kelsall et al., 2004b), and Canada (Goss Gilroy, 1998).

Secondary studies that focused on exposure to oil-well fires were relatively few. One found an increase in respiratory symptoms associated with self-reports of exposure to oil-well fire smoke (Proctor et al., 1998). A prospective study of British veterans deployed to Kuwait found no significant changes in FEF25%-75%3 across across a period of presumed oil-well fire smoke exposure; however, the exposure appears to have been low (Coombe and Drysdale, 1993). Two ecological studies of asthma hospitalizations among Kuwaiti residents found no significant difference after the conflict (Abul et al., 2001; Al-Khalaf, 1998).

3

FEF25%-75% = Forced expiratory flow, midexpiratory phase.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Two studies addressed the potential association between nerve agent exposure and respiratory illness. Gray et al. (1999b) found a slightly increased risk of hospitalizations for respiratory illness to be associated with modeled exposure to the Khamisiyah detonation based on the 1997 modeling, while Karlinsky et al. (2004) found no association between pulmonary function test and DoD modeling from 2000.

Updated and Supplemental Literature

Primary Studies

The Update committee identified three additional primary studies of respiratory outcomes and the Gulf War combat experience.

In a study by Smith et al. (2006), three cohorts were defined and followed for hospitalizations from their exposure window until hospitalization, separation from the military, or December 31, 2000, whichever came first. The investigators used Cox hazard modeling and looked at hospitalizations for 14 ICD-9 categories of diagnosis. The cohorts represented Gulf War veterans, veterans deployed to Southwest Asia after the war, and veterans deployed to the Bosnian conflict. The study found a nonsignificant increase in respiratory disease hospitalizations for veterans deployed to Southwest Asia after the Gulf War as compared to Gulf War veterans (OR 1.08, 95% CI 1.00-1.16). Bosnian veterans had a significant decrease in respiratory disease hospitalizations when compared to Gulf War veterans (OR 0.73, 95% CI 0.63-0.84).

A study by MacFarlane et al. (2000) identified 53,462 UK Gulf War veterans who had served in the gulf between September 1990 and June 1991. A 53,462 member reference group composed of Gulf War era nondeployed UK veterans was assembled. The study selected the referent cohort through a stratified randomized sample of era vets matched on age, sex, rank, service branch, and level of fitness. Mortality as of March 31, 1999, was determined by use of a National Health Service central registry that was coded using ICD-9 codes. The study found 376 deaths among deployed and 352 deaths among nondeployed vets. At the time of mortality ascertainment, 1485 and 2257 were lost to follow-up in the cohorts respectively. There were no excess deaths due to diseases of the respiratory system found in either cohort. An update of the same cohort through 2004 (Macfarlane et al., 2005) again found no significant excess in deaths related to respiratory disease among Gulf War veterans versus nondeployed veterans.

Bullman et al. (2005) examined the relationship between estimated exposure to chemical munitions destruction (sarin gas) at Khamisiyah in 1991 with cause-specific mortality of Gulf War veterans through December 31, 2000. Using the DoD’s 2000 sarin plume exposure model (Rostker, 2000), 100,487 deployed military personnel were identified as potentially exposed, and 224,980 were considered unexposed. The authors reported no increase in mortality risk due to respiratory diseases among exposed veterans as compared to unexposed veterans (RR 1.03, 95% CI 0.62-1.72). Similarly, no increased risk for respiratory disease mortality was observed when the authors divided the exposed group into persons exposed for either 1 or 2 days for comparison with the unexposed group.

Secondary Studies

Four secondary studies not previously reviewed were identified that addressed respiratory illness among Gulf War veterans and relied on self-reports.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Steele (2000) conducted a telephone survey of veterans who were Kansas residents and had served during the Gulf War. Of 2211 locatable and eligible veterans, 2030 agreed to participate (92%). Fifty were eliminated because their self-reported deployment status could not be verified. A total of 1548 Gulf War deployed veterans and 482 nondeployed veterans were interviewed about the presence of physician-diagnosed or physician-treated disorders with new onset after the Gulf War. Respiratory disorders were more commonly reported among deployed than nondeployed. Gulf War deployed veterans were twice as likely to report suffering from asthma (OR 2.08, 95% CI 1.02-4.26) and were almost 5 times as likely to report suffering from lung disease (OR 4.77, 95% CI 1.14-20.04). The study adjusted for sex, age, income and education level and suffered from a slight differential participation rate between groups (93% in deployed veterans vs 88% nondeployed veterans).

Proctor et al. (2001a) compared responses to questionnaires between 148 Gulf War deployed veterans of the Fort Deven’s cohort, and 50 Germany deployed veterans. The authors found that Gulf War deployed veterans reported more chronic respiratory allergies (16% vs 13%) and more chronic lung problems (11.8% vs 6.5 %). Neither of these differences reached statistical significance, and no adjustments were made in the comparisons.

McCauley et al. (2002), using a telephone survey, interviewed three groups of US Gulf War veterans with different deployment experiences. These included Gulf War deployed veterans in proximity to the Khamisiyah detonations, veterans deployed to the gulf during the war but not in proximity to the Khamisiyah detonations, and veterans who were on active duty during, but not deployed to, the Gulf War. The authors found a nonsignificant excess in self-reported diagnosis of lung disease among deployed versus nondeployed veterans (OR 1.8, 95% CI 0.8-4.1) and no excess among Khamisiyah exposed versus Khamisiyah nonexposed veterans (OR 0.3, 95% CI 0.2-0.8).

In a mailed symptom survey to a sample of veterans from the National Health Survey of the Gulf War Era Veterans and Their Families conducted in 1995 (Kang et al., 2000), Kang et al. (2009) found a significant excess of self-reports of physician-diagnosed emphysema or chronic bronchitis and asthma among 6111 randomly surveyed Gulf War veterans when compared to 3859 nondeployed era veterans. The study suffered from a very low response rate (34% overall) and lacked a mechanism for verification of self-reports.

Statistics Canada (2005) conducted a mortality follow-up study of Canadian Gulf War veterans and compared them to a reference group of randomly selected Canadian veterans eligible but not deployed to the Gulf War and to the general Canadian population. There were 5117 members in the deployed cohort and 6093 members in the nondeployed population. Probabilistic matching of the military records of the cohorts to mortality records from the Canadian Mortality Data Base was conducted. The study authors estimated the study power to be 80% to find a 60% increase in total mortality; however, there were insufficient deaths from respiratory disease (ICD-9, code 460-519) to make a meaningful comparison between veteran cohorts or with the general population.

Kang and Bullman (1996) examined standardized mortality rates (SMRs) for multiple causes of death among Gulf War veterans up to September 1993 compared to the general US population and to nondeployed veterans. They found a significant decrease in deaths due to respiratory illness (SMR 0.14, 95% CI 0.07-0.23) when Gulf War veterans were compared to the US population and a slight but insignificant increase when compared to nondeployed veterans. These observations were based on very small numbers including only 14 deaths in both the deployed and nondeployed groups. A second study updated the same cohort for mortality

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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outcomes up to December 31, 1997, using the same methods (Kang and Bullman, 2001). Again, no significant differences were noted between deployed and nondeployed veterans for respiratory causes of mortality. Again, both veteran cohorts showed significantly lower mortality for respiratory outcomes when compared to the general US population.

Summary and Conclusions

Studies based on self reported symptoms and self reported diagnoses related to respiratory disease have inconsistently but frequently shown an excess among Gulf War veterans. However there appears to be no increase in respiratory disease among Gulf War veterans when examined with objective measures of disease. Pulmonary function studies and mortality studies have shown no significant excess of lung function abnormalities or of death due to respiratory disease among Gulf War veterans.

Therefore, the committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and respiratory disease. The committee also concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and decreased lung function in the first 10 years after the war.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-8 Respiratory System Diseases

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Population-based, cross-sectional, prevalence, medical evaluation

1061 US deployed vs 1128 nondeployed

Self-reported asthma, bronchitis, or emphysema; obstructive lung disease (history of disease or symptoms plus use of bronchodilators or 15% improvement in FEV1 after bronchodilator use)

Asthma, bronchitis, or emphysema: OR 1.07 (95% CI 0.65-1.77)

Obstructive lung disease: OR 0.91 (95% CI 0.52-1.59)

Age, sex, race, years of education, smoking, duty type, service branch, rank

Low participation rates, especially among nondeployed

Karlinsky et al., 2004 (Vol. 4)

Cross-sectional, medical evaluation

1036 US deployed vs 1103 nondeployed

PFT results classified into five categories: normal, nonreversible obstruction, reversible obstruction, restrictive, small-airways obstruction

No association of PFT-based classifications with deployment status, nor with exposure to nerve agents at Khamisiyah based on 2002 DoD exposure models

 

No adjustment for smoking or other confounders; description of sampling strategy inadequate to evaluate bias; no explanation of “matching” or control of matching in analysis

Gray et al., 1999a (Vol. 4)

Cross-sectional, medical evaluation

527 Gulf War veterans vs 970 nondeployed from 14 US Navy Seabees commands

Cough; shortness of breath; FVC (L); FEV1 (L)

Cough : OR 1.8 (95% CI 1.2-2.8)

Shortness of breath: OR 4.0 (95% CI 2.2-7.3)

FVC (L): 4.96 vs 4.99, p = 0.77

FEV1 (L): 4.05 vs 4.04, p = 0.81

Age, height, race, smoking status

No use of modeled oil-fire exposures

Kelsall et al., 2004b (Vol. 4)

Cross-sectional, medical evaluation

1456 Australian deployed vs 1588 nondeployed

Asthma; bronchitis; FEV1/FVC% < 70%

Asthma: OR 1.2 (95% CI 0.8-1.8);

Bronchitis: OR 1.9 (95% CI 1.2-3.1);

FEV1/FVC% < 70%: OR 0.8 (95% CI 0.5-1.1);

Service type, rank, age, education, marital status

Generally well done; substantial potential for selection bias (response rates: deployed 81%, comparison 57%); no

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

FVC, but not FEV1, associated with self-report of oil-fire exposure

 

use of modeled oil-fire exposures

Ishoy et al., 1999b (Vol. 4)

Cross-sectional, population-based, medical evaluation

686 peace-keeping Danish deployed to Gulf War theater vs 231 nondeployed controls

Shortness of breath; FVC; FEV1; peak flow

14% vs 3.5% Percent of predicted:

100.7 vs 100.7, NS

95.6 vs 96.4, NS

94.0 vs 92.8, NS

None

Appropriate population-based controls but differential participation: 84% deployed vs 58% nondeployed; smoking histories similar in deployed and nondeployed

Smith et al., 2006 (Update)

Hospitalizations cohort study (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); Southwest Asia peacekeeping mission, 1991-1998 (n = 249,047); Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of respiratory disease (140-208), and for testicular cancer specifically

Veterans of Bosnia compared to GWV: HR 0.73 (95% CI 0.63-0.84)

Veterans of Southwest Asia compared to GWV: HR 1.08 (95% CI 1.00-1.16)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Active-duty personnel only; hospitalizations at DoD facilities only

Macfarlane et al., 2000, 2005 (Update)

Cohort study

2000: 53,462 UK GWVs vs 53,450 nondeployed UK veterans 2005: 51,753 UK GWVs and 50,808 nondeployed UK veterans

Mortality (1991-1999/2004) due to diseases of the respiratory system

2000: 3 deaths in GWVs compared to 3 deaths in control group, MRR 1.0 (95% CI 0.1-7.5)

2005: 9 deaths in GWVs compared to 6 deaths in control group, MRR 1.64 (95% CI 0.58-4.66)

Matching by sex, age, branch, fitness for service

 

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Studies of respiratory outcomes specifically associated with modeled oil-well fire exposure

Cowan et al., 2002 (Vol. 4)

Case-control study of exposure to smoke from oil-well fires; DoD registry, Army only

873 with asthma vs 2464 controls

Physician-assigned diagnosis of asthma 3-6 years after war

Self-reported exposure: OR 1.56 (95% CI 1.23-1.97) Cumulative modeled exposure: OR 1.24 (95% CI 1.00-1.55) for intermediate cumulative modeled exposure; OR 1.40 (95% CI 1.11-1.75) for high exposure. Number of days at > 65 µg/m3: OR 1.22 (95% CI 0.99-1.51) for 1-5 days; OR 1.41 (95% CI 1.12-1.77) for 6-30 days

Sex, age, race, military rank, smoking history, self-reported exposure

Effect seen in former smokers and never-smokers, but not current smokers. Key strength: modeled exposure rather than only self-reported exposure. Limitations: self-selected population; no specified criteria for asthma diagnosis and no pulmonary function data; pre-exposure asthma status unknown

Lange et al., 2002 (Vol. 4)

Cross-sectional study of exposure to smoke from oil-well fires; derived from cohort study

1560 Iowa veterans

Asthma symptoms; bronchitis symptoms; structured interviews conducted 5 years after the war

For modeled exposure, adjusted ORs for quartiles of exposure, 0.77-1.26 with no dose-response relationship; for self-reported exposure, asthma ORs 1.77-2.83, bronchitis ORs 2.14-4.78

Sex, age, race, military rank, smoking history, military service, level of preparedness for war

Key strengths: modeled exposure rather than only self-reported exposure, population-based sample. Key limitation: symptom-based case definition of bronchitis and asthma

Smith et al., 2002 (Vol. 4)

DoD hospitalizations 1991-1999; exposure modeling for oil-well fire smoke

405,142 active-duty Gulf War veterans

ICD-9-CM codes for: Asthma Acute bronchitis Chronic bronchitis Emphysema Respiratory conditions due to chemical fumes and vapors Other respiratory

Exposed vs nonexposed:

RR 0.90 (95% CI 0.74-1.10)

RR 1.09 (95% CI 0.62-1.90)

RR 0.78 (95% CI 0.38-1.57)

RR 1.36 (95% CI 0.62-2.98)

RR 0.71 (95% CI 0.23-2.17)

“Influential predictors” of p < 0.15 included in analyses

Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no information on smoking or other exposures that may be

 

 

 

RR 1.45 (95% CI 0.86-2.46)

 

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

 

 

diseases related to respiratory symptoms, most adults with asthma or chronic bronchitis have never been hospitalized for that condition

Study of respiratory outcomes specifically associated with exposure to Khamisiyah nerve agent

Gray et al., 1999b (Vol. 4)

DoD hospitalizations 1991-1995, exposure to nerve agents at Khamisiyah based on 1997 DoD exposure models

Not exposed (n = 224,804), uncertain low-dose exposure (n = 75,717), exposed (n = 48,770)

Respiratory system disease (vs not exposed): Uncertain low dose < 0.013 mg-min/m3 0.013-0.097 mg-min/m3 0.097-0.514 mg-min/m3

 

Sex, age group, prewar hospitalization, race, service type, marital status, pay grade, occupation

See Smith et al., 2002. Probable substantial exposure misclassification as models were revised, lack of a clear dose-response pattern, little biologic plausibility given that no effect was seen for nervous system diseases

OR 0.92 (95% CI (0.85-0.99)

OR 0.90 (95% CI 0.77-1.04)

OR 0.89 (95% CI 0.79-1.02)

OR 1.26 (95% CI 1.05-1.51)

Bullman et al., 2005 (Update)

Cohort mortality study; follow-up from March 1991 through 2000

100,487 US Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed army GWVs; exposure determined from the DoD plume model (Rostker, 2000)

Association of exposure to chemical warfare agents and respiratory disease mortality, determined through BIRLS, SSA; COD data from NDI

Exposed vs unexposed RR 1.03 (95% CI 0.62-1.72)

Age, race, sex, rank, unit component

 Limitations: short latency, possible exposure misclassification

NOTE: BIRLS = Beneficiary Identification and Records Locator Subsystem (VA); CI = confidence interval; COD = cause of death; DMDC = Defense Manpower Data Center; FEV1 = forced expiratory volume in the first second of expiration; FVC = forced vital capacity; GWV = Gulf War veteran; HR = adjusted hazard ratio; NDI = National Death Index; NS = not significant; OR = adjusted odds ratio; PFT = pulmonary function test; RR = adjusted risk ratio; SSA = Social Security Administration.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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DISEASES OF THE DIGESTIVE SYSTEM

Digestive disorders may be functional (Drossman, 2006; Drossman et al., 2006), structural, or in some cases combinations of both (Grover et al., 2009). The functional gastrointestinal (GI) disorders (FGIDs), such as irritable bowel syndrome (IBS) or functional dyspepsia, are syndromes—that is, recurrent or prolonged clusters of symptoms that occur together. They result from known disturbances in GI functioning and central dysregulation of this GI function and should be differentiated from psychiatric multisymptom syndromes (for example, somatization disorder) that are determined by central amplification of normal somatic and visceral neural signaling (Drossman et al., 2002, 2006). The FGIDs range in severity from occasional mild episodes to more persistent and disabling symptoms with impaired health-related quality of life. These disorders fit a biopsychosocial construct (Drossman, 1998) and are understood as brain–gut axis dysfunction where psychosocial factors may disrupt gut functioning and vice versa (Jones et al., 2006). Genetic or early environmental predisposing factors including family enablement of illness behaviors (Levy et al., 2000) or early trauma or abuse history (Drossman et al., 1995), in many cases coupled with exposure to acute GI infection (Spiller and Campbell, 2006), can precipitate or exacerbate the clinical expression of FGIDs, causing them to manifest as disturbed motility (that is, constipation, diarrhea, nausea, vomiting), or visceral hypersensitivity (that is, pain, bloating, abdominal fullness). The symptoms can be sustained or perpetuated in the presence of psychological comorbidities including PTSD, anxiety, and depression; maladaptive coping style; or impaired social networks (Creed et al., 2006; Drossman et al., 2002; Levy et al., 2006).

Relevant to this review is the concept of postinfectious IBS, where the FGID is triggered by exposure to infectious agents, which normally cause acute gastroenteritis, but with coexistent stress, in this case deployment to the Gulf War, the symptoms are sustained (Drossman, 1999; Dunlop et al., 2003; McKeown et al., 2006; Spiller and Campbell, 2006). In a recently completed study using the Defense Medical Surveillance System, 31,866 cases of active-duty soldiers with FGIDs registered between 1999 and 2007 were matched to non-FGID active-duty controls. Researchers found a highly significant association of prior infectious gastroenteritis (greatest effect for bacterial gastroenteritis) to those with FGIDs (all p < 0.001), including functional diarrhea (OR 6.28), IBS (OR 3.72), functional constipation (OR 2.15), and functional dyspepsia (OR 2.39), and 28.8% of the active duty personnel studied still received care for the FGID 2 years after initial diagnosis. Thus there is a strong association of prior acute gastroenteritis (Riddle et al., 2009).

The pathophysiology of the FGIDs relate specifically to dysregulation of neural pathways between the brain and gut (that is, the brain–gut axis) that produce motility and sensory disturbances (visceral hypersensitivity), dysregulation of the hypothalamic-pituitary adrenal axis, altered corticolimbic pain modulation, and inflammation of the bowel mucosa associated with altered bacterial flora pain modulation, and inflammation of the bowel mucosa associated with altered bacterial flora (Drossman, 2006; Drossman et al., 2002; Kassinen et al., 2007).

The diagnosis of a functional GI disorder is made by fulfilling standardized symptom-based criteria (Rome criteria) for a minimal period of time, usually 6 months (Drossman, 2006). These criteria have not been used in published studies of Gulf War veterans with the exception of one physiological study (Dunphy et al., 2003). However, recently there have been several research abstracts published using Rome III criteria that describe increased incidence rates of

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

IBS after wartime exposure (Tuteja et al., 2008; Wurzelmann et al., 2008) as well as one published study of increased adult Rome III-diagnosed IBS incidence rates that related to severe early-life wartime exposure during World War II (Klooker et al., 2009).

GI diseases, sometimes called “organic” or structural diseases, such as peptic ulcer and inflammatory bowel disease (that is, ulcerative colitis and Crohn’s disease), are characterized by morphological abnormalities seen on x-ray, endoscopy, or through laboratory tests. For example, with Crohn’s disease the intestine may be inflamed and have ulcerations, strictures, fistulas, or abscesses. The diagnoses of these diseases need to be validated by medical records since some physicians may place an organic label on the patient’s symptoms (such as gastritis or peptic ulcer) but without proper morphological correlation. Such labeling will confound the diagnosis of these diseases when surveys are used, particularly when the data are based on the individual’s recollection of a physician’s diagnosis.

For the purposes of this section, the committee defined primary studies by their methodological rigor (see Chapter 2) and outcome assessment requiring sufficiently valid symptom clusters consistent with a functional GI diagnosis, or in the case of structural diseases, physical examination. The primary studies are summarized in Table 4-9.

Summary of Volume 4

Primary Studies

In Volume 4, three studies were identified that met that committee’s criteria for primary studies: Eisen et al. (2005), who conducted a survey and physical examinations, and two hospitalization studies by Gray et al. (1996, 2002).

Ten years after the Gulf War, in the National Health Survey of Gulf War Era Veterans and Their Families, a nationally representative population-based study, the VA conducted medical evaluations to determine the prevalence of common diseases in deployed veterans (Eisen et al., 2005). In 1999-2001, 1061 deployed and 1128 nondeployed veterans were evaluated at several VA centers. The veterans had been randomly selected from 11,441 deployed and 9476 nondeployed veterans who had participated in a 1995 VA survey (Kang et al., 2000) that used a self-report questionnaire. Dyspepsia was diagnosed through in-person interviews according to two criteria: a history or symptoms of dyspepsia (frequent heartburn and recurrent abdominal pain) and use of antacids, histamine-2 receptor blockers, or other medications to treat dyspepsia. The prevalence of dyspepsia was 9.1% and 6.0% in deployed and nondeployed veterans, respectively (OR 1.87, 95% CI 1.16-2.99). Reports of gastritis were 5.9% and 4.2%, respectively (OR 1.57, 95% CI 0.88-2.78). Study limitations for these outcomes are: dyspepsia was diagnosed crudely as recurrent abdominal pain or frequent heartburn, which is more commonly associated with gastroesophageal reflux disease; IBS, a more common functional GI disorder, was not evaluated; and despite three recruitment waves, participation was only 53% of eligible Gulf War and 39% of eligible nondeployed veterans.

A study by Gray et al. (1996) showed no excess hospitalizations in DoD hospitals for digestive system disorders, as broadly defined by a range of ICD codes, from 1991 to 1993. That study compared hospitalizations of almost 550,000 Gulf War veterans and almost 620,000 nondeployed veterans who remained on active duty until 1993. Another further hospitalization study conducted by Gray et al. (2000) covered the years 1991-1994 and examined DoD, VA, and California hospitals. The study examined hospitalizations at nonfederal hospitals in California to eliminate potential bias related to veterans seeking care outside DoD and VA facilities.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Proportional morbidity ratios (PMRs) of hospital-discharge diagnoses (14 diagnostic categories from ICD-9) in Gulf War deployed and nondeployed veterans were compared. Hospitalizations for digestive system diseases for deployed versus nondeployed veterans were increased in VA hospitals (PMR 1.12, 95% CI 1.05-1.18) and in California hospitals (PMR 1.11, 95% CI 0.97-1.24), but not in DoD hospitals (PMR 0.98, 95% CI 0.96-0.99). The limitation of these studies is their inability to capture any but the most severe digestive system disorders (most would be treated on an outpatient basis).

Secondary Studies

In Volume 4, two studies were identified as secondary: Sostek et al. (1996) and Ishoy et al. (1999a,b). Sostek et al. is discussed in the section “Updated and Supplemental Literature.” Ishoy et al. (1999a,b) analyzed self-reported GI symptoms in relation to Gulf War exposures among deployed Danish Gulf War veterans and nondeployed controls. Eight of 14 GI symptoms were reported significantly more frequently by veterans than by controls but only the prevalence of recurrent diarrhea for 1 year and rumbling in the stomach more than two times per week remained significant after adjustment.

Updated and Supplemental Epidemiologic Literature

Other primary and secondary studies were identified by the Update committee. A primary study by Sostek et al. (1996) focused on evaluating the prevalence and spectrum of GI complaints in a group of 57 Gulf War deployed National Guard veterans and 44 nondeployed veteran controls. Notably, the self-reporting of medical, including GI, symptoms occurring before the war was low (0-9%) and not different between groups. However, after the war, Gulf War veterans reported qualitatively and quantitatively markedly higher rates (p ≤ 0.001) of GI symptoms than the nondeployed veterans, which persisted many years after deployment: intra- or supraumbilically located abdominal pain (70% vs 9%); excessive gas (74% vs 23%); abdominal pain with increased or watery bowel movements (44% vs 5%); loose or > 3 stools per day (74% vs 18%); incomplete rectal evacuation (60% vs 7%), and decreased appetite (42% vs 7%), and about 80% remained symptomatic after the war. Postwar comparisons showed less significant differences (p = 0.05) between deployed veterans and controls in other GI symptoms: relief of pain with bowel movements (47% vs 16%), postprandial pain (46% vs 14%), mucus in the stools (19% vs 0%), rectal pain with bowel movements (26% vs 5%), nausea and vomiting (23% vs 2%), and heartburn (33% vs 7%). However, these individuals also reported high frequencies of other non-GI symptoms, suggesting that there may be a tendency to report physical symptoms in general. The frequency of blood in the stool was low and not significantly different between groups, and this may likely reflect local sources such as hemorrhoids. Histopathological assessment of colonic biopsies many years after deployment in the symptomatic Gulf War veterans showed that 6 out of 15 had mild chronic inflammation of the lamina propria, a finding that by current standards would be considered a feature of IBS possibly originating from infectious exposure (Chadwick et al., 2002; Dunlop et al., 2003). This finding has also been reported in 53 Gulf War veterans being evaluated by endoscopy and biopsy for chronic GI complaints (Lang and Saylor, 1995). The strength of this study is the histopathological evidence for inflammation suggestive of postinfectious IBS. In addition, the survey questions were highly specific for functional GI disorders as they reflect physiological disturbance of the gut (for example, pain relieved by defecation, sense of incomplete evacuation) and together are more

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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than sufficient to meet the Rome III criteria for IBS and possibly other functional GI disorders (Drossman, 2006; Longstreth, 2006; Longstreth et al., 2006). For these reasons this study is considered to be primary.

An update of previous data by Gray and colleagues (2002) was a survey of nearly 12,000 active-duty Seabees, from 14 commands, still on active duty for at least 3 years after the Gulf War. The study subjects were queried about self-reported physician-diagnosed illnesses, symptoms, and exposures. IBS was one of the physician-diagnosed illnesses listed on the survey. Deployed Gulf War Seabees were much more likely than nondeployed Seabees to report being diagnosed with irritable bowel syndrome (2.48% vs 0.81%, OR 3.57, 95% CI 2.22-5.73). Irritable bowel syndrome was one of a cluster of four physician-diagnosed conditions—along with PTSD, chronic fatigue syndrome, and multiple chemical sensitivity syndrome—found to be more prevalent among Gulf War deployed Seabees than nondeployed Seabees, and these four conditions were highly associated with one another. Among the deployed Seabees, being diagnosed with one of these four conditions also was associated with reporting many other symptoms (16 other symptoms) whereas other deployed Seabees not reporting any of these four conditions had fewer (6) other symptoms. Because the focus of this study was to cluster symptoms and conditions that might shed light on a unique Gulf War illness, the analysis undertook no further evaluation of GI conditions in isolation.

Numerous studies have queried deployed and nondeployed US Gulf War veterans about gastrointestinal or stomach symptoms generally (Lindem et al., 2003a,b,c; Steele, 2000); they have also been asked about a number of specific gastrointestinal symptoms such as gas (Fukuda et al., 1998; Proctor et al., 1998), bloating (Fukuda et al., 1998), cramps (Fukuda et al., 1998; Proctor et al., 1998; Steele, 2000), abdominal pain (Fukuda et al., 1998; Knoke et al., 2000; Steele, 2000); diarrhea (Fukuda et al., 1998; Kang et al., 2000; Knoke et al., 2000; Proctor et al., 1998; Steele, 2000), constipation (Knoke et al., 2000; Proctor et al., 1998), loose bowel movements (Knoke and Gray, 1998), and nausea or upset stomach (Kroenke et al., 1998; Proctor et al., 1998; Steele, 2000). In all of these studies deployed veterans reported more GI symptoms than their nondeployed counterparts.

Kang et al. (2000) asked Gulf War veterans about whether they had any of three specific digestive conditions: gastritis, enteritis, or colitis. The sample included active-duty, reserve, and National Guard personnel as well as an oversampling of female veterans who were in the military between September 1990 and May 1991. The prevalence of gastritis was more than doubled in the deployed veterans compared with the nondeployed veterans (25% vs 12%). In 2004-2005, Kang et al. (2009) conducted a follow-up study of the 15,000 deployed and 15,000 nondeployed veterans originally surveyed in 1995 (Kang et al., 2000). Veterans were asked via a mailed questionnaire if their doctor had ever told them they had any of 23 medical conditions, including gastritis and irritable bowel syndrome. Both gastritis and IBS were among the top five medical conditions with the greatest relative risk; the relative risk was 1.52 (95% CI 1.40-1.65) for gastritis and 1.50 (95% CI 1.35-1.66) for IBS, adjusted for age, sex, race, body mass index, current cigarette smoking, rank, branch of service, and unit component. This study is limited by the use of a self-report survey, and indeed gastritis using symptom reports is more likely to be functional dyspepsia. Because the questionnaire items were not sufficiently detailed to make a diagnosis of a functional digestive disorder (via Rome criteria) or to identify structural disorders by endoscopy, this study is considered to be secondary.

Surveys of deployed Gulf War troops from other countries showed similar results to those of the Danish veterans (Ishoy et al., 1999a,b). UK Gulf War veterans self-reported more

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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diarrhea, feeling bloated, stomach pain, heartburn, constipation, vomiting (Cherry et al., 2001a); flatulence, or burping (Unwin et al., 1999); and digestive, stomach, and intestinal disorders (Simmons et al., 2004) than nondeployed veterans. Australian Gulf War veterans also self-reported more moderate to severe flatulence or burping (OR 1.6, 95% CI 1.3-2.1), indigestion (OR 1.7, 95% CI 1.3-2.3), diarrhea (OR 2.4, 95% CI 1.6-3.5), stomach cramps (OR 2.2, 95% CI 1.5-3.3), constipation (OR 1.8, 95% CI 1.0-3.0), and nausea (OR 2.5, 95% CI 1.4-4.5). Although the Australian study used a postal questionnaire to initially ask veterans about having received a physician’s diagnosis of or treatment for a medical condition, the veterans were later asked in person about their responses by a physician. The physician then determined whether the diagnoses or treatments reported on the questionnaire and discussed with the patient were a possible or probable diagnosis based on the veterans’ responses. Based on this approach (which added a level of medical judgment to the self-reports but did not verify the self-reported diagnoses with additional testing such as an endoscopy or x-ray), compared with nondeployed veterans, deployed veterans were more likely to have a possible or probable diagnosis of stomach or duodenal ulcers (OR 1.6, 95% CI 1.1-2.75) and irritable bowel syndrome (OR 2.4, 95% CI 1.4-4.3) (Sim et al., 2003). Canadian Gulf War veterans reported more digestion problems other than stomach ulcers that did nondeployed Canadian veterans (13.4% vs 6.6%) (Goss Gilroy, 1998).

A recent systematic review evaluated the risk of developing painful conditions among Gulf War deployment versus nondeployed veterans. Using six studies (Cherry et al., 2001a; Gray et al., 2002; Kang et al., 2000; Knoke et al., 2000; Sostek et al., 1996; Steele, 2000). Thomas et al. (2006) found that pain from various conditions was more likely to occur in deployed veterans, and the most significant effect was seen with abdominal pain (OR 3.23, 95% CI 2.31-4.51).

In summary, numerous studies indicate that Gulf War veterans self-report more GI symptoms than nondeployed veterans. Most of these studies are limited because their methods are insufficient to determine a clear association between deployment and the onset of a functional disorder by standard Rome criteria (Drossman et al., 2006) or of a structural disorder (Drossman and Ringel, 2004). Furthermore, the diagnosis of structural diseases should be validated by medical records because physicians not infrequently place an organic label on a patient’s symptoms (for example, gastritis or peptic ulcer) without performing diagnostic studies, and this will confound the diagnosis in a survey, particularly if the data are based on the subjects’ recollections of physicians’ diagnoses.

Other studies have evaluated hospitalizations and mortality of Gulf War veterans for digestive diseases. To avoid criticism when comparing deployed personnel with nondeployed personnel as may have occurred in the Gray et al. (1996, 2000) hospitalization studies (creating a “healthy deployer” effect), Smith et al. (2006) compared postdeployment hospitalizations for active-duty military personnel deployed to the Gulf War, deployed to southwest Asia after the war, or deployed to Bosnia. Hospitalizations were based on ICD-9 discharge diagnoses from military hospitals from August 1, 1990, to December 31, 2000. Active-duty personnel deployed to Bosnia were at reduced risk of hospitalization for digestive system diseases or conditions compared with Gulf War veterans (HR 0.60, 95% CI 0.54-0.67). There was no difference in hospitalizations for digestive system diseases between those deployed during the Gulf War and those deployed to the region after the war (HR 0.99, 95% CI 0.94-1.05). Hazard ratios were adjusted for sex, age, marital status, pay grade, ethnicity/race, service branch, occupation, and predeployment hospitalization.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Two studies assessed mortality in UK Gulf War veterans from diseases of the digestive system (DASA, 2009; Macfarlane et al., 2005). Macfarlane et al. (2005) assessed mortality of the UK Gulf War (51,753) and era (50,808) veteran cohorts from April 1, 1991, to June 30, 2004. Based on data from the National Health Service, the Gulf War veterans experienced fewer deaths from digestive diseases than the era cohort (mortality rate ratio 0.77, 95% CI 0.40-1.46), adjusted for age. The UK Defence Analytical Services Agency (DASA) published summary statistics on causes of deaths in Gulf War veterans between April 1, 1991, and December 31, 2007 (DASA, 2009). Mortality rates for the 53,409 Gulf War veterans were compared with the 53,143 era veterans. The adjusted mortality rate ratio for diseases of the digestive system was 0.71 (95% CI 0.46-1.11).

Finally, one study is notable for using specific Rome III criteria for the diagnosis of irritable bowel syndrome in war-time situations. Tuteja et al. (2008) studied 247 Gulf War deployed and nondeployed veterans from Salt Lake City who were in the reserves or National Guard and deployed between 1990-1991. It was found that there was an increased reporting of IBS from before deployment (5.8%) to during deployment (38.9%; p = 0.03) and this continued after deployment 18 years later (33.6%). Similar significant findings were seen with symptoms of diarrhea, constipation, and bloating. Furthermore, a history of an enteric infection was a risk factor for developing IBS (OR 3.6, 95% CI 1.9-6.9) now called postinfectious IBS. These data are presently available in abstract form only, and therefore this study is considered to be secondary.

Summary and Conclusions

There were many reports of gastrointestinal disturbances in Gulf War deployed veterans and the symptoms have persisted during the 19 years since the war. Notably all studies are in the direction favoring a greater prevalence of various GI symptoms and primarily functional GI disorders including IBS and dyspepsia.

Several of the papers attempted to link the symptoms to various exposures including side effects from nerve agent prophylaxis, using contaminated water, and burning of animal waste, but support from this is also limited and nonconfirmatory. More compelling is the emerging evidence for exposure to enteric pathogens during deployment leading to the development of postinfectious IBS. These data have been strengthened in recent years as a result of several lines of evidence:

  • The incidence of acquiring an acute gastroenteritis among deployed veterans is higher than nondeployed veterans, over 50% in some series (IOM, 2007).

  • Deployed veterans or other individuals experiencing war trauma who are exposed to an infectious gastroenteritis are at greater risk to be later diagnosed with IBS (Pulling et al., 2008; Riddle et al., 2009; Tuteja et al., 2008).

  • Deployed veterans that have IBS symptoms have increased microscopic inflammatory changes in the bowel mucosa which can result from prior mucosal infection (Lang and Saylor, 1995; Sostek et al., 1996).

  • Microscopic inflammation in IBS is associated with increased cytokine activity and mast cell degranulation that produces visceral hypersensitivity and abdominal pain (Barbara et al., 2004; Chadwick et al., 2002).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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  • Postinfectious IBS symptoms are facilitated by psychological distress via central nervous system (such as the hypothalamic-pituitary adrenal axis) effects on mucosal inflammation and enhanced pain via anterior cingulate cortex activation (Barbara et al., 2008; Drossman, 1999; Dunlop et al., 2003; Gwee et al., 1999).

Furthermore there is a large body of physiological data in IBS including among Gulf War veterans that demonstrate altered physiological functioning (such as diarrhea and constipation caused by altered migrating motor complexes and high-amplitude propagated contractions) that separates this condition from mere symptom reporting tendency (somatization). One study showed lowered visceral sensitivity, pain intensity, and anxiety in relation to rectal distention and cutaneous hand stimulation among Gulf War veterans compared to nondeployed veterans and civilians (Dunlop et al., 2003). Another study showed altered autonomic activity and lowered pain thresholds in response to acute physical and psychological stress (Murray et al., 2004) and an association of altered gastrointestinal motility and GI symptoms when IBS subjects are administered CRF, a stress hormone (Fukudo et al., 1998). A full review of this area can be found elsewhere (Kellow et al., 2006a,b).

The data on organic disorders are scanty and negative. See Table 4-9 for a summary of the primary studies reviewed above.

There are some limitations in the epidemiological body of evidence, mostly related to methods of effect assessment. One is that with the exception of two published abstracts, the self-reporting of GI symptoms did not fulfill the criteria for diagnosing a functional GI disorder, although in at least one published case series the diagnoses can be inferred (Sostek et al., 1996). In addition, existing studies in the deployed military population cannot yet determine the degree to which the gastrointestinal symptoms are specific to IBS and other FGIDs or are part of a larger spectrum of illness (that is, multisystem disease; see also the section on multisymptom illnesses in this chapter). Within civilian populations persons with these disorders exist on a spectrum where mild to moderate symptoms are limited to the GI tract, but more severe illness is associated with increased comorbidities. Therefore, the committee recommends that further studies in a deployed military population be undertaken to determine the presence of medical and psychosocial comorbidities in those with FGIDs. Finally, the committee concludes that there was also a lack of adequate medical diagnostic testing to identify a GI structural disease.

Nevertheless, taken together, the overall pattern of symptoms found in the few primary and numerous secondary studies confirms an association between deployment to the Gulf War and functional GI symptoms, including abdominal pain, diarrhea, nausea, and vomiting, and a few studies exist that provide presumptive data to allow standardized diagnosis of functional GI disorders. These studies are strengthened by physiological and mechanistic data in war veterans with IBS, and particular reference is made to the emerging evidence for preexisting acute gastroenteritis as a predictive factor in postinfectious IBS and dyspepsia. The committee recommends that further studies be conducted to determine the role of prior acute gastroenteritis among deployed soldiers in the development of FGIDs. Thus, the association of deployment-related stress with GI symptoms is accepted, the association with functional GI disorders is supported but not complete, and an association with structural GI diseases cannot be determined.

The committee concludes that there is sufficient evidence for an association between deployment to the Gulf War and gastrointestinal symptoms consistent with functional GI disorders such as irritable bowel syndrome and functional dyspepsia. The committee also concludes that there is inadequate/insufficient

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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evidence to determine whether an association exists between deployment to the Gulf War and the development of structural gastrointestinal diseases.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-9 Digestive System Diseases

Study

Study Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Cross-sectional, prevalence

1061 GWVs, 1128 NDVs

Physician evaluation, questionnaire for dyspepsia; GI symptoms and medical conditions reported from earlier survey

Dyspepsia (OR 1.87, 95% CI 1.16-2.99); self-reported gastritis (OR 1.57, 95% CI 0.88-2.78)

Age, sex, race, smoking, duty type, service branch, rank, years of education

Study limited by low participation rate, length of time since war; weak diagnostic criteria

Gray et al., 1996 (Vol. 4)

Retrospective cohort study (hospitalization records)

DoD hospitals: 547,076 GWVs; 618,335 NDVs

Digestive system diseases

All ORs < 1.0

Hospitalization rates and rate ratios adjusted for age, sex; multiple logistic-regression models adjusted for all observed demographic differences between groups

Study data reflect only hospitalization experience of persons who remained on active duty through September 1993

Gray et al., 2000 (Vol. 4)

Retrospective cohort study (hospitalization records)

GWVs (August 1990-July 1992, n = 652,979) and NDVs (n = 652,922) stratified by California residence, service, and service branch of all nondeployed veterans (n = 2,912,737)

Digestive system diseases

VA hospitals: PMR 1.12 (95% CI 1.05-1.18); DoD hospitals: PMR 0.98 (95% CI 0.96-0.99); COSHPD hospitals: PMR 1.11 (95% CI 0.97-1.24)

Hospitalization records were matched on sex, age

Findings might be influenced by chance or by potential confounders, including health registry participation

Sosteck et al., 1996 (Update)

Cross-sectional, prevalence

57 male GWVs, 44 NDVs of National Guard unit

Questionnaire about GI and non-GI symptoms with recall before, during, after Gulf War period

Prevalence of GI symptoms: abdominal pain 70% vs 9%; diarrhea 74% vs 18%; incomplete rectal evacuation 60% vs 7%; gas 74% vs 23%; decreased appetite 42% vs 7% (all p < 0.001)

 

Response rate 74%; limitations include small sample (recall before, during, after Gulf War), questionnaire (at time of assessment)

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Study Design

Population

Outcomes

Results

Adjustments

Comments

Gray et al., 2002 (Update)

Retrospective, case-control

US Navy Seabees: 3831 GWVs, 4933 veterans deployed elsewhere, 3104 NDVs

Self-reported physician diagnoses, self-reported symptoms from postal questionnaire

Gulf War Seabees vs nondeployed: self-reported peptic ulcer disease (OR 3.11, 95% CI 1.67-5.78); self-reported IBS (OR 3.57, 95% CI 2.22-5.73); new GI disease diagnosed since September 1990 (OR 2.10, 95 % CI 1.39-3.17); clustering of CFS, PTSD, MCS, IBS: Seabees who had one averaged 13-18 other symptoms, Seabees without and averaged only 6 other symptoms

Age, sex, active-duty or reserve status, race or ethnicity, current smoking, current alcohol drinking

Study limited by recall bias, IBS not analyzed exclusively, response rate 70%, large sample

NOTE: CFS = chronic fatigue syndrome; CI = confidence interval, COSHPD = California Office of Statewide Health Planning and Development; DIS = Diagnostic Interview Schedule; DoD = Department of Defense; GI = gastrointestinal; GWV = Gulf War veteran; IBS = irritable bowel syndrome; MCS = multiple chemical sensitivity; MMR = adjusted mortality ratio; NDV = nondeployed Gulf War veterans; OR = odds ratio; PCL-C = PTSD Checklist-Civilian, PMR = proportional morbidity ratio; PTSD = posttraumatic stress disorder; SF-36 = Short form 36; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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SKIN DISEASES

Skin conditions, particularly rashes, are among the most frequent health problems reported by Gulf War veterans (Murphy et al., 1999). Rash usually refers to dermatitis, an umbrella term covering several subtypes, including atopic dermatitis, contact dermatitis, seborrheic dermatitis, and psoriasis. During the Gulf War, troops were exposed to several toxicants that could cause allergic skin reactions, including pesticides and solvents.

In reviewing studies that included dermatologic symptoms and diseases, the committee defined a primary study according to methodological rigor (Chapter 2) and use of a dermatologic examination to diagnose or verify a skin disorder. In a secondary study, the determination of a dermatologic effect was based on veterans’ self-reports of symptoms or self-reported physician-diagnosed conditions. Primary studies for skin disorders are summarized in Table 4-10. Skin cancers are discussed in the section on cancer.

Summary of Volume 4

Primary Studies

To determine the link between deployment to the Gulf War and dermatologic diseases, the Volume 4 committee identified two primary studies: Eisen et al. (2005) who used a large, nationally representative study of US Gulf War veterans; and Higgins et al. (2002) who conducted in-person dermatologic evaluations of UK Gulf War deployed veterans (111 disabled and 98 nondisabled) and 133 disabled veterans not deployed to the Gulf War. These studies were conducted 10 and 8 years after the Gulf War, respectively. Eisen et al. (2005) used medical evaluation data derived from the 1995 VA National Health Survey of Gulf War Era Veterans and their Families (Kang et al., 2000). A dermatologist used teledermatology, at least two digital photographs, and the results of a standardized history and physical examination to assign dermatologic conditions into two categories: group 1 consisted of freckles, seborrheic keratoses, moles, cherry hemangiomas, skin tags, and scars; group 2 consisted of dermatologic diagnoses not included in group 1. The prevalence of group 1 diagnoses did not differ between deployed and nondeployed veterans (OR 0.87, 95% CI 0.68-1.12); the prevalence of a diagnosis of one or more group 2 skin conditions was 34.6% in deployed veterans and 26.8% in nondeployed veterans (OR 1.38, 95% CI 1.06-1.80). The most common group 2 skin conditions among deployed veterans were onychomycosis (4.1%) and folliculitis (4.0%). After adjustment of individual group 2 skin conditions, two skin conditions in this group were diagnosed more frequently (p = 0.02) in deployed than in nondeployed veterans: verruca vulgaris (warts) (OR 4.02, 95% CI 1.28-12.6) and atopic dermatitis (OR 8.1, 95% CI 2.4-27.7).

In the cross-sectional study by Higgins et al. (2002) the prevalence of any skin condition was 47.7% in disabled Gulf War veterans, 36.7% in nondisabled Gulf War veterans, and 42.8% in disabled nondeployed veterans, as determined on physical examination by a dermatologist. The investigators found no differences among groups in any dermatologic conditions other than seborrheic dermatitis: 7.2% in disabled deployed veterans and 9.2% in nondisabled deployed veterans versus 2.3% in disabled nondeployed veterans.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Secondary Studies

The Volume 4 committee identified two large well-designed studies of Gulf War veterans that were considered secondary studies because they lacked a dermatologic examination or were imprecise regarding specific dermatologic diagnoses: Kang et al. (2000) and Proctor et al. (1998). In the first phase of the VA National Health Survey of Gulf War Era Veterans and Their Families, Kang et al. (2000) compared 11,441 deployed veterans with 9476 nondeployed veterans identified by the DMDC. Dermatitis other than eczema and psoriasis was among the five most frequently reported medical conditions diagnosed by a physician in the preceding 12 months. The skin conditions reported by the deployed and nondeployed veterans were eczema or psoriasis (7.7% vs 4.4%; rate difference 3.34, 95% CI 3.26-3.42), other dermatitis (25.1% vs 12.0%; rate difference 13.16, 95% CI 13.04-13.28), and diseases of the hair or scalp or hair loss (16.9% vs 7.2; rate difference 9.65, 95% CI 9.55-9.75). A sample of participants were later evaluated by clinical examination in the Eisen et al. study (2005). Proctor et al. (1998) assessed the prevalence of dermatologic conditions—such as rashes, eczema, and skin allergies—in US veterans. The estimated prevalence was 15.5% for the 186 Gulf War deployed veterans from the Fort Devens cohort, 11.7% for the 66 deployed veterans from the New Orleans cohort, and 1.9% for the 48 veterans deployed to Germany during the Gulf War.

Updated and Supplemental Literature

Primary Studies

The Update committee identified one new primary study: Ishoy et al. (1999b). This study reported on Danish peacekeepers deployed to the Persian Gulf area during 1990-1997. The 686 deployed veterans and 231 nondeployed age-, sex-, and profession-matched veterans each received a medical examination and were interviewed for a full medical history by a physician based on a previously administered questionnaire. Veterans indicated whether any medical condition had its onset before or after deployment to the gulf. The examinations found that the prevalence of the following conditions with onset during or after deployment or August 1990 was higher in deployed veterans than in nondeployed veterans: eczema (15.0% vs 3.0%, p < 0.001), retarded wound healing (6.0% vs 1.7%, p < 0.01), other skin problems (17.1% vs 5.2%, p < 0.001), hair loss or hair disease (4.2% vs 0.9%, p < 0.01), and sweaty, clammy, or damp hands (7.9% vs 3.9%, p < 0.05). There were no significant differences in the prevalence of psoriasis and nettle rash between deployed and nondeployed troops. Although the examination process used to verify the veteran’s actual skin conditions at the time of the interview by the physician is somewhat unclear in the report, the use of a physician to discuss the veterans’ responses to the questionnaire provides support for the designation of this report as primary.

Secondary Studies

The Update committee also reassessed the two primary studies from Volume 4 and determined that the Eisen study was a primary study based on a dermatologist’s diagnosis of two specific skin disorders: vulgaris (warts) and atopic dermatitis. However, for the Higgins et al. (2002) study, the committee also found that based on its study design that compared disabled deployed and disabled nondeployed veterans, as well as the lack of an appropriate comparison group (that is nondeployed nondisabled veterans serving in the same era), this study could not be considered a primary study.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Several large cohort studies conducted in other countries reported similar findings in Gulf War veterans based on self-reports via questionnaires. Based on the lack of a physician’s examination or diagnosis, these studies are considered to be secondary. The population-based survey of UK deployed veterans found the prevalence of dermatitis to be 21%, a rate higher than that in two control groups: one dispatched to Bosnia (OR 1.6, 95% CI 1.3-2.0) and the other era controls (OR 1.6, 95% CI 1.4-1.9) (Unwin et al., 1999). A higher prevalence of the following physician-diagnosed skin conditions was also reported in 1456 deployed veterans compared with 1588 nondeployed veterans in an Australian population-based study by Kelsall et al. (2004a): moderate to severe rash and skin irritation (OR 2.0, 95% CI 1.6-2.5); dermatitis (OR 1.8, 95% CI 1.3-2.6); and skin diseases other than dermatitis, skin cancer, eczema, or psoriasis (OR 1.3, 95% CI 1.1-1.7).

Several additional secondary studies were identified that indicated that the prevalence of generally nonspecified skin diseases or conditions in deployed Gulf War veterans was greater than in nondeployed veterans, but all of these studies relied on self-reports:

  • Goss Gilroy (1998)—Skin allergies or other skin conditions in Canadian veterans.

  • Cherry et al. (2001a)—Skin rashes, sweating, itching skin, hair loss, boils, or abscesses in UK veterans.

  • Simmons et al. (2004)—Skin allergies in UK veterans (OR 3.3, 95% CI 3.0-3.7).

  • Steele (2000)—Physician-diagnosed or treated skin conditions other than skin cancer (OR 3.83, 95% CI 2.50-5.87); rashes (OR 5.73, 95% CI 3.41-9.62); moderate or multiple skin symptoms (OR 4.09, 95% CI 2.53-6.63) in Kansas veterans.

  • Wolfe et al. (1998)—Akin rashes, eczema, skin allergies in veterans from Massachusetts and Louisiana.

  • Proctor et al. (2001a)—Skin rash (14.0% vs 4.3%).

  • Gray et al. (1999a)—Rash (OR 4.3, 95% CI 2.8-6.5).

A more recent secondary study is that of Kang et al. (2009), who in 2004-2005 conducted a follow-up study of the 15,000 deployed and 15,000 nondeployed veterans originally surveyed in the 1995 National Health Survey of Gulf War Era Veterans and Their Families (Kang et al., 2000). A mailed questionnaire asked veterans if their doctor had ever told them they had any of 23 medical conditions, including dermatitis or any other skin trouble. The relative risk for skin problems was 1.41 (95% CI 1.32-1.51) adjusted for age, sex, race, body mass index, current cigarette smoking, rank, branch of service, and unit component.

Three studies examined hospitalizations of Gulf War veterans for skin disorders. Gray et al. (1996) found no excess hospitalizations in 1991-1993 of Gulf War veterans compared with other veterans for skin diseases, as broadly defined by a range of ICD codes. That study compared hospitalizations at DoD facilities of almost 550,000 Gulf War veterans and almost 620,000 nondeployed veterans. The multivariate ORs ranged from about 0.97 in 1991 to almost 1.0 in 1993 (actual values and confidence intervals not given). An expansion of this study to capture veterans who may have left the military was conducted by Gray et al. (2000). This study covered the years 1991-1994 and examined records from DoD, VA, and California hospitals. Proportional morbidity ratios (PMRs) of hospital-discharge diagnoses for skin diseases in Gulf War deployed and nondeployed veterans were compared. PMRs for hospitalization for skin disease were not increased for Gulf War veterans in DoD hospitals (PMR 1.01, 95% CI 0.97-1.05), VA hospitals (PMR 1.14, 95% CI 1.00-1.27), or California hospitals (PMR 0.84, 95% CI

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

0.54-1.14. Smith et al. (2006) compared postdeployment hospitalizations from August 1, 1990, to December 31, 2000, for active-duty military personnel deployed to the Gulf War, deployed to southwest Asia after the war, or deployed to Bosnia. Active-duty personnel deployed to Bosnia were at reduced risk of hospitalization for skin diseases or conditions compared with Gulf War veterans (HR 0.57, 95% CI 0.46-0.71). There was no difference in hospitalizations for skin diseases between those deployed during the Gulf War and those deployed to the region after the war (HR 0.99, 95% CI 0.88-1.11). The limitation of these studies is their inability to capture any but the most severe skin diseases as most would be treated on an outpatient basis.

Summary and Conclusions

The committee placed the greatest weight on studies that included medical evaluation and identification of specific dermatologic diagnoses. Both primary studies showed a higher prevalence of some skin diseases or conditions in deployed than in nondeployed Gulf War veterans. A nationally representative study of US Gulf War veterans found a relationship between deployment and atopic dermatitis and verruca vulgaris (warts) but not other skin conditions (Eisen et al., 2005), and a Danish study found increased prevalence of eczema and other unspecified skin conditions in deployed veterans (Ishoy et al., 1999b).

Secondary studies are largely consistent with the primary studies but lack specificity regarding dermatologic outcomes or rely only on self-reported symptoms or physician-diagnosed dermatologic conditions. Three secondary studies are somewhat more specific in reporting a greater prevalence of eczema or psoriasis in deployed veterans (Kang et al., 2000; Proctor et al., 1998; Wolfe et al., 1998).

In summary, there is a high frequency of self-reports of various types of rash and other skin conditions among deployed versus nondeployed veterans, and, in general, these reports are confirmed by dermatologic examination. Overall, very few studies have rigorously assessed the prevalence of skin conditions in Gulf War veterans, and results are mixed, with increases for some skin conditions but not for others. Furthermore, there is no consistency across these studies, which suggests that the findings could be occurring by chance. Finally, most of the studies are weak in design and limited by self-selection and possible reporting bias.

On the basis of the few studies of dermatologic conditions, unrelated skin conditions occur more frequently among Gulf War deployed veterans, but the findings as to specific skin conditions are not consistent among the studies. See Table 4-10 for a summary of the primary papers that the committee considered for dermatologic outcomes.

The committee concludes that there is inadequate/insufficient evidence of an association between deployment to the Gulf War and skin disorders.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-10 Skin Diseases

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Population-based, cross-sectional, prevalence, medical evaluation

1061 US deployed and 1128 nondeployed

Atopic dermatitis and verruca vulgaris (warts)

Atopic dermatitis: 1.2% vs 0.3% (OR 8.1, 95% CI 2.4-27.7); verruca vulgaris (warts): 1.6% vs 0.6% (OR 4.02, 95% CI 1.28-12.6)

Age, sex, race, years of education, smoking, duty type, service branch, rank

Low participation rates, especially among nondeployed

Higgins et al., 2002 (Vol. 4)

Prospective case-comparison study

111 disabled and 98 nondisabled UK GWVs; 133 disabled NDV controls (54 deployed to Bosnia and 79 nondeployed era controls) (population randomly sampled from Ismail et al., 2002, cohort)

Skin conditions

No significant difference in prevalence of all skin conditions combined: Disabled GWVs: 47.7% Nondisabled GWVs: 36.7% Disabled NDVs: 42.8% Sebhorrheic dermatitis: 8.1% in disabled deployed vs 2.3% in disabled nondeployed (p = 0.06)

Age, sex, rank, smoking, and alcohol

Response rates: Disabled GWVs: 67% Nondisabled GWVs: 62% Disabled Bosnia: 55% Disabled NDVs: 43%

Ishoy et al., 1999b (Update)

Cross-sectional, prevalence

686 Danish peacekeepers deployed to gulf in 1990-1997 vs 231 age- and sex-matched armed forces nondeployed controls

Health examination by physician, self-report questionnaire

Prevalence of skin conditions with onset after gulf: eczema 15.0% vs 3.0%, p < 0.001; retarded wound healing 6.0% vs 1.7%, p < 0.01; other forms of skin problems 17.1% vs 5.2%, p < 0.001; hair loss or hair disease 4.2% vs 0.9%, p < 0.01; sweaty, clammy, or damp hands 7.9% vs 3.9%, p < 0.05

 

Participation rate 83.6% deployed, 57.8% nondeployed; lack of information on adjustment for confounders in multivariate analysis

NOTES: CI = confidence interval; GWV = Gulf War veteran; NDV = nondeployed veteran; OR = adjusted odds ratio.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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DISEASES OF THE MUSCULOSKELETAL SYSTEM

Arthritis is the most common form of joint disease. Several powerful risk factors are major trauma, repetitive joint use, and age. Arthritis is diagnosed according to a combination of clinical features and radiographic findings. Arthralgia, which is a self-reported symptom of arthritis, refers to painful joints. In the absence of other clinical features and radiographic findings, arthralgias are not necessarily diagnostic of arthritis. Some disorders such as fibromyalgia are considered separately in this report. Reports of musculoskeletal symptoms, such as lower back pain (lumbago), muscle stiffness, and joint stiffness, which have not been diagnosed as a medical condition, are discussed in the section on multisymptom illness. Primary studies of musculoskeletal diseases are summarized in Table 4-11.

Summary of Volume 4

Primary Studies

Arthralgias were one of 12 primary health outcome measures studied by Eisen and colleagues (2005). They conducted medical evaluations in phase III of VA’s nationally representative, population-based study of Gulf War Veterans. From 1999-2001, 1061 deployed and 1128 nondeployed veterans were evaluated. They had been randomly selected from 11,441 deployed and 9476 nondeployed veterans who had participated in the phase I questionnaire in 1995 (Kang et al., 2000). Researchers were blinded to deployment status. Arthralgias were defined as persistent and clinically significant bone or joint symptoms with or without joint effusion, and treatment with anti-inflammatory agents, narcotic pain medications, or nonnarcotic pain medications. There was no significant difference in arthralgias between deployed and nondeployed veterans (OR 1.15, 95% CI 0.70-1.89). One study limitation was that despite three recruitment waves, the participation rate in the Eisen et al. (2005) study was low: only 53% of Gulf War veterans and 39% of nondeployed veterans participated. To determine nonparticipation bias, the authors obtained previously collected findings on participants and nonparticipants from the DMDC and gathered sociodemographic and self-reported health findings from the 1995 VA study (Kang et al., 2000). Both deployed and nondeployed participants were more likely than nonparticipants to report arthritis of any kind.

Secondary Studies

Two other studies examined differences in prevalence of arthritis, but they relied on self-reporting. Kang et al. (2000), using a stratified random-sampling method, compared data from the DMDC on 693,826 Gulf War veterans and 800,680 nondeployed veterans, and asked about arthritis as a self-reported condition. They found a significant difference in such reporting between deployed and nondeployed veterans (22.5% vs 16.7%, rate difference of 5.87, 95% CI 5.74-6.00). Gray et al. (2002) looked at 3831 Gulf War deployed veterans, 4933 veterans deployed elsewhere, and 3104 nondeployed Seabees. The authors found increased reporting of arthritis among Gulf War than deployed compared with Seabees deployed elsewhere (5.87% vs 4.42%). The latter, in turn, were similar to other nondeployed Seabees (4.42% vs 4.38%). The OR for Gulf War veterans versus veterans deployed elsewhere was 1.44 (95% CI 1.17-1.76), and that for Gulf War deployed versus nondeployed veterans was 1.63 (95% CI 1.29-2.08).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Updated and Supplemental Literature

Primary Studies

The new primary studies identified by the committee consisted of hospitalization studies that had discharge diagnoses of some form of musculoskeletal disease. Specific diagnoses were not provided in any of the studies.

Gray et al. (1996) used a retrospective cohort approach to compare hospitalization discharge diagnoses for 547,076 Gulf War deployed and 618,335 nondeployed active-duty personnel at DoD medical facilities. Hospitalizations for 14 ICD-9-CM diagnostic categories, which included “musculoskeletal system diseases,” were assessed across three time periods following the war: August 1, 1991, to December 31, 1991; January 1, 1992, to December 31, 1992; and January 1, 1993, to September 30, 1993. Hospitalizations for musculoskeletal system diseases were not increased among the Gulf War deployed personnel versus nondeployed for 1991 or 1992, and were only marginally increased (OR about 1.01, exact value not given; 95% CI included 1.0) for 1993. This study is limited, however, because of the relatively short follow-up, the lack of outpatient data, restriction to DoD hospitals, restriction to hospitalizations of those who remained on active duty after the war, and limited adjustment for potential confounders.

A later publication expanded the Gray et al. (1996) study to include hospitalizations for reserve and separated military personnel over the same three time periods. This study also included discharge diagnoses for hospital stays from DoD hospitals, the VA system, and the California Office of Statewide Health Planning and Development for the years 1991-1994 (Gray et al., 2000). Because the total number of deployed and nondeployed veterans was not available, the researchers calculated proportional morbidity ratios (PMRs). The PMRs for musculoskeletal system diseases for the DoD hospitals, the VA hospitals, and the California hospitals were 1.01 (95% CI 0.99-1.02), 0.86 (95% CI 0.81-0.91), and 0.79 (95% CI 0.64-0.93), respectively. This analysis is limited since it did not include outpatient diagnoses, it could not determine hospitalization rates, and it did not allow adjustment for confounding.

Musculoskeletal system diseases were examined in an additional study comparing hospitalization rates in DoD hospitals through 2000 in three cohorts of veterans: Gulf War veterans, veterans deployed to southwest Asia after the Gulf War, and veterans deployed to Bosnia (Smith et al., 2006). After adjustment for sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalizations, the rate of hospitalizations for musculoskeletal system diseases (identified according to ICD-9-CM discharge codes) was slightly increased in the southwest Asia deployed veterans compared with the Gulf War veterans (HR 1.06, 95% CI 1.01-1.12) and decreased for the Bosnia deployed veterans compared with the Gulf War veterans (HR 0.78, 95% CI 0.71-0.86).

Gray et al. (1999b) assessed hospitalizations for Gulf War veterans potentially exposed to the nerve agents sarin and cyclosarin following the Khamisiyah demolition. Discharge diagnoses from DoD hospitals between March 1991 and September 1995 were examined for 349,291 Army Gulf War active-duty veterans. Plume estimates were overlaid on military unit locations to classify the veterans as no exposure, uncertain low exposure, and three levels of possible subclinical exposures. There was no increased risk of hospitalization for musculoskeletal system diseases for any of the exposure groups (risk ratios all less than 1.0). A follow-up to this study (Smith et al., 2003) examined DoD hospitalization data for active-duty personnel through December 2000. Comparing 99,614 exposed veterans to 318,458 nonexposed veterans, the

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

adjusted risk ratio for hospitalization for musculoskeletal system diseases was 0.99 (95% CI 0.96-1.02). Exposure was based on the 2000 Khamisiyah gaseous hazard area modeling done by the DoD.

A similar assessment of DoD hospitalizations between August 1991 through July 1991 for 405,142 active-duty Gulf War veterans who had been exposed to smoke from the Kuwaiti oil-well fires compared with nonexposed veterans was conducted by Smith et al. (2002). Exposure to particulate matter from the fires was estimated based on meteorological data, diffusion modeling, and troop location data; seven exposure levels were developed ranging from no exposure to an average daily exposure of > 260 μg/m3 for more than 50 days. No increased risk of hospitalization for musculoskeletal system diseases was seen for any of the exposure groups (risk ratios all less than 1.0).

Secondary Study

The committee identified one secondary study that reported on musculoskeletal diseases in Gulf War veterans. Bourdette et al. (2001) conducted physical examinations of 443 Gulf War deployed veterans residing in the northeast United States, 244 of whom met the authors’ definition of unexplained illness and 113 of whom did not meet the case definition served as controls. The prevalence of osteoarthritis was similar between cases and controls, and there were no reports of autoimmune or inflammatory rheumatic diseases. The authors noted that four veterans were diagnosed with spondyloarthropathy, but they did not indicate whether these veterans were cases or controls.

Summary and Conclusion

Among those examined, there was no significant difference in arthralgias, a surrogate for arthritis, but data on self-reports indicate that arthritis was more common among those deployed to the gulf. The data, however, suffer from the problem of self-reporting of a common condition that can be easily confused with other symptoms without a thorough diagnosis by a physician. There appears to be no significant increase in the prevalence of arthralgias among veterans who underwent a medical examination.

The hospitalization studies reviewed by the committee also showed no increased risk of hospitalization for musculoskeletal system diseases among Gulf War deployed veterans compared with their nondeployed counterparts. Possible exposure to oil-well fire smoke and nerve agents from the Khamisiyah demolition also failed to result in increased hospitalizations. The committee notes, however, that many musculoskeletal diseases, such as arthritis, do not typically require hospitalization and are more likely to be treated on an outpatient basis.

Therefore, the committee concludes that there is insufficient/inadequate evidence of an association between deployment to the Gulf War and musculoskeletal system diseases.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-11 Musculoskeletal Diseases

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Population-based, cross-sectional, prevalence, medical evaluation

1061 deployed vs 1128 nondeployed

Persistent and clinically significant bone or joint symptoms with or without joint effusion, and treatment with anti-inflammatory agents, narcotic pain medications, or nonnarcotic pain medications

Prevalence: 6.4% vs 6.8% (OR 1.15, 95% CI 0.70-1.89)

Age, sex, race, years of education, smoking, duty type, service branch, rank

Low participation rates, especially among nondeployed

Gray et al., 1996 (Update)

Retrospective cohort, hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 NDVs

Hospital-discharge diagnoses of musculoskeletal system diseases in DoD hospital system

Exact values not given 1991: OR < 1.0 (95% CI < 1.0); 1992: OR < 1.0 (95% CI < 1.0) 1993, OR about 1.01 (95% CI 0.9-1.15)

Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation

Short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for other potential confounders

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August 1991 through December 1994

652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5185 COSHPD hospitalizations

Hospital-discharge diagnoses of musculoskeletal system diseases in DoD, VA, and COSHPD hospital systems

DoD PMR 1.01 (95% CI 0.99-1.02) VA PMR 0.86 (95% CI 0.81-0.91) COSHPD PMR 0.79 (95% CI 0.64-0.93)

Age, sex, race (only for DoD PMR)

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates would have

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Smith et al., 2006 (Update)

Retrospective cohort study (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); southwest Asia peacekeeping mission, 1991-1998 (n = 249,047); Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of a musculoskeletal system disease (ICD-9 codes 710-739)

Compared to GWVs, veterans of Bosnia showed reduced risk (HR 0.78, 95% CI 0.71-0,86), veterans of southwest Asia at slightly increased risk (HR 1.06, 95% CI 1.01-1.12)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Limitations: active-duty personnel only; hospitalizations at DoD facilities only

Smith et al., 2002 (Update)

DoD hospitalizations 1991-1999; exposure modeling for oil-well fire smoke

405,142 active-duty Gulf War veterans who were in theater during the time of Kuwaiti oil-well fires

Hospitalization for musculoskeletal system diseases (ICD-9-CM codes 710-739)

No association between exposure and musculoskeletal system diseases across all exposure levels

Adjusted for “influential covariates,” defined as demographic or deployment variables with p values less than 0.15

Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for potential confounders such as smoking

Gray et al., 1999b (Vol. 4)

DoD hospitalizations 1991-1995, exposure to nerve agents at Khamisiyah based on 1997 DoD exposure models

Not exposed (n = 224,804), uncertain low-dose exposure (n = 75,717), exposed (n = 48,770)

Musculoskeletal system disease (vs not exposed): Uncertain low dose; < 0.013 mg-min/m3; 0.013-0.097 mg-min/m3; 0.097-0.514 mg-min/m3

 

Sex, age group, prewar hospitalization, race, service type, marital status, pay grade, occupation

See Smith et al. (2002); also, probable substantial exposure misclassification as models were revised, lack of a clear dose-response pattern, little biologic plausibility given that no effect was seen for nervous system diseases

 

OR 0.90 (95% CI 0.86-0.94)

OR 0.90 (95% CI 0.83-0.98)

OR 0.90 (95% CI 0.83-0.96)

OR 0.98 (95% CI 0.87-1.09)

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Smith et al., 2003 (Update)

DoD hospitalization study (1991-2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al., 1999b)

99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model

First hospitalization for any musculoskeletal system disease (ICD-9-CM codes 710-739)

Exposed vs unexposed: RR 0.99 (95% CI 0.96-1.02)

 

Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures

NOTE: CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; NDV = nondeployed veteran; OR = odds ratio; PMR = proportional mortality ratio; RR = risk ratio; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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FIBROMYALGIA AND CHRONIC WIDESPREAD PAIN

Fibromyalgia is characterized by widespread muscle and skeletal pain in combination with point tenderness at numerous soft tissue sites, according to the American College of Rheumatology (ACR) (Wolfe et al., 1990). Fibromyalgia cannot be confirmed through pathologic or laboratory tests, and thus diagnosis is dependent upon clinical examination. The case definition requires both widespread pain (pain on both sides of the body, above and below the waist, and including axial skeletal pain) lasting for at least 3 months and pain (not just tenderness) in at least 11 of 18 tender point sites on palpation with an approximate force of 4 kg. The presence of a second clinical disorder does not exclude a diagnosis of fibromyalgia. Other symptoms of fibromyalgia include fatigue, sleep disturbance, morning stiffness, and cognitive impairment, but those are not sensitive and specific enough to use for classification (Wolfe et al., 1990). Early characterization of the condition as an inflammation of muscle (hence the label fibrositis) has not been borne out through research (Goldenberg et al., 1990). There are no widely accepted causative factors for fibromyalgia, but in the general population its prevalence is about 3.4% in women and 0.5% in men, making it one of the more common rheumatologic disorders (Wolfe et al., 1995). Prevalence of fibromyalgia increases with age (Wolfe et al., 1995), and on the basis of longitudinal studies, the course is chronic but variable in intensity (Wolfe et al., 1997). It should be noted that the existence of fibromyalgia as a distinct disease entity is considered controversial by some expert commentators (Nimnuan et al., 2001; Pearce, 2004).

Summary of Volume 4

Primary Studies

The Volume 4 committee considered as primary only those studies that based diagnosis of fibromyalgia on symptom reporting and physical examination, rather than only on symptom-reporting alone. In phase III of VA’s national population-based study, Eisen et al. (2005) examined the prevalence of fibromyalgia in Gulf War deployed veterans (n = 1061) compared to a nondeployed era veteran control group (n = 1128). The cohorts were randomly selected from 11,441 deployed and 9476 nondeployed veterans, who had participated in the phase I questionnaire in 1995 (Kang et al., 2000). The authors conducted medical evaluations from 1999-2001, and based diagnosis of fibromyalgia on the ACR criteria (Wolfe et al., 1990). Self-reported diagnoses of fibrositis or fibromyalgia did not vary between deployed and nondeployed veterans (0.6% and 0.8% respectively; adjusted OR 1.21, 95% CI 0.36-4.10). However, fibromyalgia diagnosed on the basis of physical examination was present in 2.0% of deployed and 1.2% of nondeployed veterans (adjusted OR 2.32, 95% CI 1.02-5.27). Strengths of the study include the population-based sampling strategy, blinding of evaluating physicians, and use of validated diagnostic criteria based on physical examination. Limitations include the potential for substantial selection bias due to modest participation rates (53% of Gulf War veterans and 39% of nondeployed veterans).

Smith and colleagues (2000) examined the association of hospitalizations for fibromyalgia between 1991 and 1997 with deployment status among 551,841 deployed and 1,478,704 nondeployed active-duty personnel. The study found higher risk of fibromyalgia hospitalization among the deployed group (RR 1.23, 95% CI 1.05-1.43). However, survival curves suggest that the higher observed risk results from a spike in hospitalizations due to the

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

DoD Comprehensive Clinical Evaluation Program (CCEP), which ran for 1 year between 1994 and 1995 in an attempt to provide evaluation and treatment for all Gulf War veterans who believed they were suffering a medical condition related to their deployment. Deployed veterans who participated in the CCEP had more than 26 times the risk of being hospitalized for fibromyalgia than did nonparticipants. By comparison, the authors found that for the 3-year period prior to the CCEP, the rate of hospitalization for fibromyalgia was similar between Gulf War veterans and their nondeployed contemporaries (RR 0.92, 95% CI 0.74-1.13). The Smith et al. study has the advantage of a large, population-based sample and good statistical power for the detection of an effect. Its major limitations are the inclusion of only active-duty personnel, changes in hospitalization rates for fibromyalgia in association with the practices of the CCEP, and the fact that few cases of fibromyalgia are severe enough to warrant hospitalization. The findings on fibromyalgia are summarized in Table 4-12.

Secondary Studies

The Iowa study (Iowa Persian Gulf Study Group, 1997) surveyed 1896 deployed and 1799 nondeployed Iowa veterans. No physical examinations were conducted; fibromyalgia was assessed from the symptom criteria described by Wolfe and colleagues (Wolfe et al., 1995). Symptoms of fibromyalgia were present in 18.2% and 23.8% of deployed regular military and National Guard veterans, respectively, and 9.2% and 13.2% of nondeployed regular military and National Guard veterans, respectively, with an adjusted prevalence difference of 9.3% (95% CI 7.3-11.2). Steele (2000) conducted a similar telephone interview study among 1545 deployed and 435 nondeployed Kansas Gulf War veterans. Of the deployed and nondeployed veterans, 2% (n = 24) and less than 0.5% (n = 2), respectively, reported having received a physician’s diagnosis of fibromyalgia with new onset between 1990 and 1998 (adjusted OR 3.69, 95% CI 0.86-15.84).

A survey of the entire cohort of Canadian Gulf War deployed veterans (Goss Gilroy, 1998) found that they were more likely than nondeployed veterans—group-matched to cases on sex, age, and regular versus reserve status—to report symptoms of fibromyalgia (16% vs 10%; adjusted OR 1.81, 95% CI 1.55-2.13).

Bourdette et al. (2001) studied 244 Oregon and Washington Gulf War veterans who had unexplained illness after clinical evaluation to exclude “explainable” illness. Of these veterans, 50 (20.8%) fulfilled the ACR criteria for fibromyalgia. The study’s main limitations are its lack of a nondeployed comparison group and lack of clarity about the nature of the clinical examination for fibromyalgia.

Updated and Supplemental Literature

Primary Studies

The Update committee identified only one new primary paper that looked specifically at CWP in deployed and nondeployed Gulf War veterans. A random sample of a population-based cohort of regular military and National Guard and reserve veterans (Iowa Persian Gulf Study Group, 1997), 1896 deployed and 1799 nondeployed, who listed Iowa as their home state at the time of enlistment were surveyed in 1995-1996. Veterans were identified through the DMDC. The study was conducted through structured telephone interviews to determine the prevalence of CWP on the basis of responses to the SF-36. Gulf War veterans reported significantly more bodily pain than did nondeployed veterans (p < 0.01). In a follow-up study of a subset of this

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

cohort 5 years after the baseline survey, Ang et al. (2006) conducted in-person follow-up examinations of 370 Gulf War veterans who had not met the case definition of CWP at baseline. The goal of the follow-up study was to identify predictors of delayed-onset CWP. Of the 370 veterans, 69 (18.6%) had met the classification criteria for CWP at the follow-up evaluation: 51 in the deployed group and 18 in the nondeployed group. According to a logistic multiple-regression model, CWP was significantly associated with perceived life stress (based on responses to the Brief Life Stress Questionnaire) at the time of the Gulf War, whether military related or not (OR 1.4, 95% CI 1.0-2.0), and with perceived life stress in the 6 months after returning home (OR 1.3, 95% CI 1.0-1.8). CWP also correlated with combat exposure during deployment (OR 1.5, 95% CI 1.1-2.0) although not specifically with deployment to the gulf itself (OR 1.1, 95% CI 0.6-2.0). Symptoms of alcohol use at the 5-year baseline survey were protective for CWP at 10 years (OR 0.2, 95% CI 0.1-0.6, p = 0.0039). The authors used the Expanded Combat Exposure Scale in the baseline survey and reported that for every 5-point increase in combat exposure score, there was a 50% increase in the likelihood that a veteran would develop CWP. Although the study had the advantage of using an in-person evaluation for the medical diagnosis of CWP and had a relatively large population of deployed and nondeployed veterans, there was a possibility of recall bias for life and deployment stressors reported 5 years after the conflict, and only veterans from Iowa were evaluated. Furthermore, only veterans who did not meet the CWP criteria at baseline were considered for the follow-up evaluation; veterans who may have developed CWP during the first 5 years after the conflict were not included in the follow-up examination.

Secondary Studies

Using data from the Iowa Persian Gulf Study Group (1997), Forman-Hoffman et al. (2007) analyzed information from the structured telephone interview conducted with 1896 deployed veterans and 1799 nondeployed veterans in 1995-1996. CWP was based on the following criteria: the veteran reported having fibromyalgia or fibrositis in the previous 12 months or reported overall body pain that occurred almost every day for at least 3 months during the previous 12 months, and had body pain in the 24 hours before the interview. The deployed veterans reported significantly more symptoms of CWP than did nondeployed veterans (OR 2.03, 95% CI 1.60-2.58); the OR was adjusted for age, sex, race, rank, branch of service, military status, smoking, and current income.

Stimpson et al. (2006) surveyed UK veterans who had served only in the Gulf War (n = 2959), only in Bosnia (n = 2052), or both in the Gulf War and in Bosnia (n = 570), and a comparison era group of veterans who had not been deployed to either the Gulf War or Bosnia (n = 2614) for self-reports of CWP. A mailed questionnaire containing a pain manikin to ascertain the pattern and intensity of pain was sent to 12,592 male and female veterans in 1997; the response rate for the three groups was 60-70%. Data from the shaded manikins were used to determine whether the pain pattern met the ACR definition of CWP. The prevalence of reporting of CWP in the Gulf War deployed group (16.8%) and the Gulf War and Bosnia deployed group (15.8%), but not in the Bosnia only deployed group (7.6%), was significantly higher (p < 0.0001) than that in the era group (8.5%). Veterans who reported pain in one limb were also 30 times more likely to report pain in the symmetrically opposite limb rather than a second limb on the same side of the body; the authors found this suggestive of “systemic pain” rather than pain from an injury. Although the sample was large, the study is limited by a lack of physical examination

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

and a lack of indication as to whether the veterans had sustained injuries during deployment or were using pain medication at the time of the survey.

A similar study by Cherry et al. (2001a,b) 6-8 years after the Gulf War also used a pain manikin to identify whether and where veterans had experienced pain for at least 24 hours in the preceding month. Among the 9588 male and female UK Gulf War veterans in all service branches, 12.2% reported widespread pain on a manikin compared with 6.5% of 4790 nondeployed veterans; widespread pain was considered to be present if the manikin showed axial skeletal and contralateral body pain. CWP was associated with exposure to insect repellent, medical attention, and side effects of nerve-agent prophylaxis.

Several studies have reviewed the presence of chronic pain in veterans, but the definition of chronic pain varied with the study (Hyams et al., 1996; Kuzma and Black, 2006; Thomas et al., 2006). Kuzma and Black (2006) noted that many studies of Gulf War veterans reported increased pain symptoms that could be clustered into CWP, but the terminology used in the studies was not consistent and included joint pain and general aches and pain; these pain clusters may or may not have met the ACR criteria for CWP.

Summary and Conclusion

The diagnosis of fibromyalgia is based entirely on symptoms and physical examination; there are no pathologic or laboratory tests with which to confirm it. Among the available cross-sectional studies that include both Gulf War deployed and nondeployed veterans, only Eisen and colleagues (2005) used the full ACR case definition of fibromyalgia, including criteria based on physical examination. The study by Smith and colleagues (2000) found no association between Gulf War deployment and hospitalization for fibromyalgia. That finding does not appear inconsistent with positive findings in the Eisen et al. study, in that few cases of fibromyalgia are severe enough to warrant hospitalization. Notably, the prevalence of a diagnosis of fibromyalgia in the Eisen et al. study is about 300 times the prevalence of hospitalization for fibromyalgia in the Smith et al. study. Two secondary studies from Iowa and Canada both found significantly increased fibromyalgia symptoms among deployed veterans compared with nondeployed veterans, but lacked a physical examination to enable the use of the full criteria for diagnosis. In conclusion, largely on the basis of the Eisen et al. study, which used the criteria of the ACR for diagnosis of fibromyalgia but could have been subject to unrecognized selection bias, there is a higher prevalence of fibromyalgia among deployed Gulf War veterans than among nondeployed veterans.

The committee reviewed one primary study and three secondary studies on Gulf War deployment and CWP. Although each of the studies found a higher prevalence of CWP in deployed than nondeployed veterans, all had considerable limitations. In Ang et al. (2006), the prevalence of CWP was found to increase both with increased combat exposure and with increased perception of life stress at the time of deployment; the study is limited in that only veterans with no pain 5 years after the conflict were evaluated 10 years after the conflict. The Stimpson et al. study (2006) also found an increase in CWP associated with deployment. The other two secondary studies also showed more CWP in deployed than in nondeployed veterans.

The committee concludes that there is limited but suggestive evidence of an association between deployment to the Gulf War and both fibromyalgia and chronic widespread pain.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-12 Fibromyalgia and Chronic Widespread Pain

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Eisen et al., 2005 (Vol. 4)

Population-based, cross-sectional, prevalence, medical evaluation

1061 deployed, 1128 nondeployed

Symptoms and physical examination using criteria of American College of Rheumatology (Wolfe et al., 1990)

Prevalence: 2.0% vs 1.2%, OR 2.32 (95% CI 1.02-5.27)

Age, sex, race, years of education, cigarette smoking, duty type, service branch, rank

Uses gold standard for diagnosis of fibromyalgia; low participation rates, especially among nondeployed

Smith et al., 2000 (Vol. 4)

Postwar hospitalization study

551,841 deployed, 1,478,704 nondeployed

Hospitalization (1991-1997); Cox proportional-hazards models ICD-9 codes for fibromyalgia (729.1)

RR 1.23 (95% CI 1.05-1.43); however, survival curves indicate excess due to hospitalization only for purposes of evaluation during the CCEP; before CCEP: RR 0.92 (95% CI 0.74-1.13)

Sex, age, branch of service

No increase after accounting for CCEP effect; limited to active duty; most cases of fibromyalgia are not severe enough to warrant hospitalization

Ang et al., 2006 (Update)

Cohort of veterans from IPGWSG

370 veterans who were free of CWP at 5 years were examined 10 years after war: 267 GWVs, 103 NDVs

Structured telephone interview about 5 years after the war; in-person follow-up medical examination 10 years after war of 370 veterans who did not report chronic widespread pain 5 years after war

Neither deployment to nor time in gulf significantly correlated with CWP: OR 1.1, 95% CI 0.6-2.0 and OR 1.0, 95% CI 0.7-13.0, respectively; combat exposure correlated: OR 1.5, 95% CI 1.1-2.0; perception of stress due to military experience at time of war correlated more significantly with CWP: OR 1.6, 95% CI 1.1-2.3, p = 0.0084

Controls matched for age, sex, branch of service

Potential for recall bias; only veterans who were free of CWP at 5 years were assessed 10 years after war

NOTE: CCEP = Comprehensive Clinical Evaluation Program; CI = confidence interval; CWP = chronic widespread pain; GWV = Gulf War veteran; IPGWSG = Iowa Persian Gulf War Study Group; NDV = nondeployed veteran; OR = odds ratio; RR = risk ratio.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

DISEASES OF THE GENITOURINARY SYSTEM

Genitourinary outcomes were not addressed separately in Volume 4 of the Gulf War and Health series. Major conditions in this group include kidney disease, urolithiasis (“kidney stones”), urinary tract infections, prostatitis, and sexual difficulties. Gynecologic outcomes including abnormal cervical pathology and inflammatory disease of the ovary have also been assessed in studies of Gulf War veterans and are discussed in this section. Cancers of the genitourinary system such as testicular cancer are not addressed in this section, but are discussed in the section on cancer. Table 4-13 summarizes the findings of primary studies of genitourinary system diseases.

Genitourinary Outcomes

Updated and Supplemental Literature
Primary Studies

Frommelt et al. (2000) used existing clinical records on Papanicolaou (Pap) smears to assess differences in cervical pathology among female Gulf War veterans. The authors evaluated Pap smear results from a cohort of 6715 Air Force women who served on active duty between August 7, 1990, and March 1, 1991, and had routine Pap smears conducted in 1994. A subset also had Pap smear data available for 1995 and/or 1996. Pap smear test results evaluated by the Armed Forces Institute of Pathology, which is the cytology laboratory used by 28 military treatment facilities, were collected for 1446 female Gulf War veterans and 5269 female veterans who were not deployed to the gulf. Overall, there were no observed differences in cervical pathology between the two groups. Among veterans aged 26-30 years, a diagnosis of “other than within normal limits” occurred more frequently among Gulf War veterans (11.5%) compared to nondeployed veterans (6.6%) (p = 0.013) in 1994, but no differences were detected among other age groups ranging from 20 and younger to over 50 years of age. The data were too sparse in 1995 and 1996 to conduct age-stratified analyses. The authors suggest there is no biologically plausible evidence to support an age-specific association between Gulf War service and abnormal cervical cytology.

McDiarmid and colleagues have followed a small cohort of 77 survivors of friendly-fire accidents who were exposed to depleted uranium (DU). The researchers conducted biennial clinical exams for uranium-related health effects. Clinical assessments included numerous urinary and serum markers of renal function as well as semen analyses and neuroendocrine measures as indicators of reproductive health (McDiarmid et al., 2000, 2001, 2004, 2006, 2007a,b, 2009). Over the 16 years of follow-up, biomarkers of renal function have not differed meaningfully (statistically or clinically) between those with low (< 0.1 microgram U/g creatinine) and high (≥ 0.1 microgram U/g creatinine) DU exposure. Similarly, no adverse DU effects on semen parameters or serum concentrations of testosterone, leutinizing hormone, or follicle-stimulating hormone have been observed. The comparisons, however, were based on small numbers (n = 35 for the 2007 exam) and did not control for potential confounders.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×
Secondary Studies

Several large-scale surveys addressed self-reported genitourinary conditions among Gulf War deployed and nondeployed military personnel. For the purpose of this review, these studies are considered secondary, mostly because of the lack of objective medical measures.

The first wave of the National Survey of Gulf War Veterans and Their Families conducted in 1995 sampled 15,000 Gulf War deployed veterans and 15,000 nondeployed era veterans (Kang et al., 2000). Responses from 11,441 Gulf War veterans (75% response) and 9476 Gulf War Era veterans (64% response) were used to estimate the population prevalence of chronic medical conditions within the previous 12 months. Gulf War veterans reported bladder infections (difference in prevalence proportions 1.54%, 95% CI 1.49-1.59) and “any disease of the genital organs” (difference in prevalence proportion 2.51%, 95% CI 2.45-2.57) slightly more frequently than nondeployed veterans. A follow-up survey was conducted in this same population in 2005 (Kang et al., 2009). The prevalence of self-reported conditions 14 years after the war was re-examined among 6111 Gulf War veterans (40% response) and 3859 Gulf War era veterans (27% response). Consistent with the previous findings in this cohort, an increased prevalence of bladder infections (prevalence ratio 1.32, 95% CI 1.17-1.49) and “any disease of the genital organs” (prevalence ratio 1.23, 95% CI 1.10-1.38) was observed among Gulf War veterans.

In a 1997-1999 study of all US Navy Seabees (Gray et al., 2002), deployment was associated with increased self-reports of physician-diagnosed conditions (with onset after August 1991) including impotence (OR 3.06, 95% CI 1.95-4.83), prostatitis (OR 1.54, 95% CI 1.07-2.21), and urinary tract infection (OR 2.50, 95% CI 1.83-3.44), but not kidney disease or kidney stones. A total of 11,868 (62.6%) of 18,945 Seabees responded to the mailed questionnaire: 3831 Gulf War deployed, 4933 deployed elsewhere, and 3104 nondeployed Seabees.

A survey of UK veterans conducted between 1998 and 2001 compared self-reported health outcomes among 23,358 male Gulf War veterans (53% response) and 17,730 male Gulf War era veterans (42% response) (Simmons et al., 2004). Reports of new medical conditions since 1990 were collected using open-ended questions and coded into 36 categories based loosely on ICD-10 classifications. The prevalence of genitourinary system disorders was higher among Gulf War veterans (OR 1.8, 95% CI 1.5-2.1). More specifically this category consisted of genital system and bladder problems (OR 2.2, 95% CI 1.7-2.7) and kidney disease or symptoms (OR 1.5, 95% CI 1.2-1.9). The subgroup of “genital system and bladder problems” included 13 reports of “burning semen” among Gulf War veterans and 1 among nondeployed veterans (0.1% vs 0.0%).

Proctor et al. (1998) compared the frequency of self-reported symptoms classified into nine groups of body systems. Using responses to a 52-item symptom checklist, the prevalence of genitourinary symptoms was evaluated among 186 Gulf War veterans from the New England area, 66 Gulf War veterans from the New Orleans area, and 48 Gulf War era veterans deployed to Germany. The Gulf War deployed veterans reported a higher prevalence of individual genitourinary symptoms, which included frequent urination and pain during intercourse, when compared to the group deployed to Germany. The frequency of each symptom was reported on a scale of 0-4 (0 = no symptom, 1 = rarely, 2 = some, 1-2 times/week, 3 = often, several times/week, 4 = very often, almost every day), and the frequencies were also summed to create “body-system symptom” scores for each system. Of the nine symptom categories assessed, genitourinary system symptom scores were the only system scores that were not statistically

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

increased among either group of Gulf War veterans when compared to the Germany deployed veterans. The study was limited by small numbers and the potential for differential recall.

Unwin et al. (1999) conducted a 1997-1998 survey of male Gulf War veterans (n = 2735), nondeployed veterans (n = 2422), and servicemembers deployed to Bosnia (n = 2393) (65% response rate). Participants were asked to respond to a questionnaire that inquired about the presence of 50 symptoms and 39 medical disorders during the previous month. Gulf War veterans who had been deployed had an increased prevalence of sexual problems compared with nondeployed (OR 3.2, 95% CI 2.4-4.2) and with Bosnia deployed (OR 2.2, 95% CI 1.5-3.1). Gulf War deployed veterans also had a greater prevalence of disease of the genital organs than either comparison group (deployed vs nondeployed: OR 1.5, 95% CI 1.1-2.2; deployed vs Bosnia deployed: OR 1.6, 95% CI 1.1-2.4).

In a 1998 phone survey of Kansas veterans, the 1548 deployed Gulf War veterans were more likely than 482 nondeployed veterans to report that they or their partner felt a burning sensation after sex (OR 3.75, 95%CI 1.88-7.49) (Steele, 2000). This condition was reported by 8% of Gulf War veterans and 2% of nondeployed veterans. The Iowa Persian Gulf Study Group (1997) also compared self-reported medical conditions between deployed and nondeployed Iowa veterans within the regular military and within the National Guard or reserve. Gulf War veterans in the National Guard or reserves reported a higher prevalence of symptoms of sexual discomfort for their female partner (prevalence difference 3.6, 95% CI 2.3-4.8) compared with their nondeployed counterparts. No differences in sexual discomfort were reported for the respondents themselves. Sexual discomfort was not associated with Gulf War deployment among members of the regular military.

Self-reported genitourinary and reproductive problems were also assessed among Gulf War veterans according to their potential exposure to sarin or cyclosarin at the Khamisiyah demolition (Page et al., 2005). In the National Health Survey of Gulf War Era Veterans Study, the prevalence of genitourinary conditions including frequent or painful urination (OR 0.91, 95% CI 0.70-1.19), bladder infection (OR 0.98, 95% CI 0.80-1.20), and any disease of the genital organs (OR 0.94, 95% CI 0.76-1.17) was similar among the exposed and unexposed Gulf War veterans. Sexual difficulties such as painful sexual intercourse (OR 1.16, 95% CI 0.81-1.65) or impotence/other sexual problems (OR 0.85, 95% CI 0.65-1.12) were also similar between the two groups.

Pierce (1997) assessed the effects of Gulf War service on women’s health by administering two surveys to a stratified sample of all women serving in the US Air Force during the Gulf War, including active-duty personnel, reserve, and National Guard. For the first survey, 153 Gulf War deployed veterans and 331 women deployed elsewhere (92% response) reported gynecologic, reproductive, and general medical conditions for which they had sought medical care since joining the Armed Forces. The prevalence of abnormal Pap smears and genital herpes did not differ by deployment status at this time. However, when asked 2 years later (87% response) about conditions experienced in the previous 12 months, Gulf War deployed veterans reported an increased prevalence of abnormal Pap smears (10.4% vs 4.9%, p < 0.036). Among the deployed veterans, no statistical differences in the prevalence of abnormal Pap smears were observed by duration of deployment. The results of a later survey conducted in a larger sample (n = 1164) of the same female veteran population showed that Gulf War deployed veterans were more likely to report 29 of 48 symptoms when compared to women deployed elsewhere (Pierce, 2005). Among the symptoms reported more frequently by deployed veterans “urinary urgency and frequency” was the only genitourinary condition identified in the report. This condition was

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

reported by 16% of Gulf War deployed veterans compared with 11% of women deployed elsewhere (p < 0.05).

Hospitalization for Genitourinary System Diseases

Updated and Supplemental Literature
Primary Studies

Of the six postwar hospitalization studies that assessed diseases of the genitourinary system, three compared the hospitalization experiences between Gulf War deployed and nondeployed veterans and three examined the effects of environmental exposures to nerve agents or oil-well fires within Gulf War veterans. Most studies were restricted to active-duty personnel treated in DoD hospitals and evaluated the broad outcome of “diseases of the genitourinary system.”

Gray et al. (1996) examined DoD hospitalizations among 547,076 Gulf War veterans and 618,335 Gulf War era veterans across three post-war time periods encompassing August 1991 through September 1993 (that is, 1991, 1992, 1993). Discharge diagnoses for 14 ICD-9-CM categories of hospitalization including “diseases of the genitourinary system” were assessed. Only subjects on active-duty were included in the cohort. The odds of hospitalization for genitourinary conditions were slightly higher for Gulf War veterans in the 5 months (1991) following the war (OR about 1.8, exact number not given, 95% CI greater than 1.0), but similar patterns were not observed in 1992 or 1993 (ORs less than 1.0 for both years). When specific diagnoses within this category were examined, the observed association was attributed to inflammatory disease of the ovary, fallopian tube, pelvic cellular tissue, and peritoneum (standardized rate ratio [SRR] 1.35, 95% CI 1.11-1.65) and infertility among females (SRR 1.59, 95% CI 1.19-2.11), redundant prepuce and phimosis among males (a diagnosis typically associated with elective circumcision) (SRR 1.59, 95% CI 1.22-2.07), and other disorders of the breast among males and females (SRR 1.30, 95% CI 1.03-1.63). The authors suggest these patterns were consistent with elective hospitalization deferred until after the war. Conditions with latency periods greater than the 2-year observation period would be missed in this study of active-duty personnel, along with outcomes occurring in individuals who did not remain on active duty following the war.

In an effort to address the limitations of studies restricted to active-duty personnel, Gray et al. (2000) compared hospitalizations for Gulf War deployed veterans and nondeployed veterans within three hospital systems providing care for active-duty, reserve, and former military personnel. Hospitalization data for the 14 major ICD-9-CM diagnostic categories were collected from DoD, VA, and COSHPD hospital systems for the period of August 1, 1991, through December 31, 1994. The lack of denominator data on the population eligible for hospitalization in the VA and COSHPD systems precluded the calculation of hospitalization rates. Thus, proportional morbidity ratios were estimated within each hospital system. The authors acknowledge PMRs may be less sensitive than hospitalization rates for detecting differences in hospitalizations between deployed and nondeployed groups. During the four years following the war, deployed veterans had similar or lower proportions of hospitalizations for “diseases of the genitourinary system” than nondeployed veterans in all hospital systems (DoD PMR 1.01. 95% CI 0.98-1.03; VA PMR 0.96, 95% CI 0.87-1.05; COSHPD PMR 0.80, 95% CI 0.59-1.00). Study limitations include the inability to assess less severe outcomes and limited control for confounding.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Smith et al. (2006) compared the postdeployment hospitalizations of 455,465 Gulf War veterans with servicemembers deployed for peacekeeping missions in southwest Asia (n = 249,047) and Bosnia (n = 44,341). DoD hospitalizations for 14 ICD-9-CM diagnostic categories were identified for active-duty personnel through the end of 2000. To account for differences in existing illness before deployment, the models were adjusted for predeployment hospitalization. When compared to those deployed to the Gulf War, hospitalization rates for genitourinary system diseases were similar for those deployed to southwest Asia (HR 1.00, 95% CI 0.92-1.09) and lower for those deployed to Bosnia (HR 0.60, 95% CI 0.51-0.70). Similar patterns were observed when hospitalization for the specific diagnosis of nephritis was considered. The authors reasoned that the lower hospitalization rates among personnel deployed to Bosnia reflect differences in access to care while in theater. Limitations consisted of restriction to DoD hospitals, no inclusion of outpatient data, and the exclusion of personnel who did not remain on active duty.

DoD hospitalizations among 405,142 Gulf War deployed personnel were assessed in relation to exposure to smoke from oil-well fires (Smith et al., 2002). Hospitalizations through July 31, 1999 (8-year observation period) were identified for active-duty personnel who were in the Gulf War theater of operations during the Kuwaiti oil-well fires (February 2, 1991, to October 31, 1991) and did not remain in the region after the war. Exposure to oil-well fire smoke was determined by whether troop unit location was within the smoke plume area defined by the Hybrid Single-Particle Lagrangian Integrated Trajectories model. Seven categories of smoke plume exposure were created using combinations of average daily dose (none, 1-260 μg/m3, > 260 μg/m3) and duration of exposure (1-25 days, 26-50, and > 50 days). Risk of hospitalization for genitourinary system diseases was not increased at any level of smoke plume exposure. The rate ratio for the most highly exposed group (average daily exposure > 260 μg/m3 for > 50 days) compared to the nonexposed group was 0.95 (described as not significant, confidence interval not reported). The limitations noted above for Gray et al. (1996) and Smith et al. (2006) apply to this study as well.

Smith et al. (2003) updated results of a previous analysis (Gray et al., 1999b) by comparing hospitalizations among 431,762 Gulf War deployed personnel who were and were not likely to have been exposed to nerve agents released by the Khamisiyah demolition. The more recent study improved exposure estimates by applying the revised meteorologic-dispersion models and updated unit location data to estimate exposure to sarin and cyclosarin (Winkenwerder, 2002). The study also incorporated 5 additional years of hospitalization data to extend the observation period to almost 10 years. DoD hospitalization data for 15 major ICD-9-CM diagnostic categories were collected through December 31, 2000. Postwar hospitalizations for genitourinary system diseases were similar among military personnel who were and were not exposed to gaseous nerve agents resulting from the demolition of chemical weapons at Khamisiyah (rate ratio 0.96, 95% CI 0.91-1.00). The results for genitourinary system diseases were consistent with the finding previously reported in Gray et al. (1999b). Like Gray et al. (1996) and Smith et al. (2006), this study did not include outpatient visits, only addressed hospitalizations in DoD facilities during active-duty status, and had limited ability to control for potential confounding by behavioral or other environmental factors.

Summary and Conclusions

Based on a single study using clinical confirmation of Pap smear results among female veterans, current evidence does not support an association between Gulf War deployment and

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

cervical pathology. Of note, however, a secondary study of self-reported Pap smear results was not consistent with these findings. Similarly, the results of large-scale surveys addressing other self-reported genitourinary conditions have been largely inconsistent with the results of the cause-specific hospitalization studies. In the 10 secondary studies assessing the effects of Gulf War deployment on self-reported genitourinary outcomes, the prevalence of various self-reported genitourinary conditions was greater among Gulf War deployed veterans compared to nondeployed veterans. Exposure to nerve agents released by the Khamisiyah demolition, however, does not appear to be related to increased reporting of genitourinary conditions among Gulf War veterans. However, this evidence is also limited to a single study. Depleted uranium exposure also does not appear to alter biomarkers of renal function or semen parameters. The specific conditions being evaluated in surveys of Gulf War veterans have varied across studies, generally addressing frequency of urination, urinary tract infections, sexual problems, or broadly defined “disease of the genital organs.” Furthermore, secondary studies addressing deployment and genitourinary conditions are limited by self-reported outcomes, lack of clinical confirmation, potential recall bias, and generally poor response rates. However, the consistency with which sexual problems are reported more frequently among Gulf War veterans is notable, given assessment of such conditions is generally limited to symptom reporting. The discrepancies between hospitalization studies and survey studies of genitourinary outcomes may reflect variation in the severity and types of genitourinary outcomes ascertained by the different approaches; differences in active-duty, reserve, and former military personnel; the influence of reporting and selection biases; or the role of chance.

The results of hospitalization studies suggest that excess hospitalization due to diseases of the genitourinary system did not occur among active-duty Gulf War veterans within the 10 years following the war. There is also some suggestion that postwar hospitalizations for genitourinary conditions were similar among Gulf War deployed veterans who were and were not exposed to nerve agents or oil-well fire smoke. The results, however, are not generalizable to the entire cohort of Gulf War veterans since most studies were restricted to personnel remaining on active duty during the observation period. Furthermore, by limiting such studies of genitourinary outcomes to hospitalizations, conditions that are not severe enough to require inpatient care are not assessed. Combining all genitourinary conditions into a single broad diagnostic category of “diseases of the genitourinary system” may also have limited the ability to detect associations with more specific, but etiologically distinct, outcomes.

The committee concludes there is limited/suggestive evidence of no association between Gulf War deployment and hospitalization for genitourinary diseases.


The committee concludes there is limited/suggestive evidence of an increased prevalence of self-reported sexual difficulties among Gulf War veterans.


The committee concludes there is inadequate/insufficient evidence to determine whether an association exists between Gulf War deployment and other specific conditions of the genitourinary system.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-13 Diseases of the Genitourinary System

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Frommelt et al., 2000 (Update)

Retrospective cohort

1446 female GWVs and 5269 female NDVs with routine Pap smears conducted in 1994

Pap smear results

Nonnormal diagnosis more frequent in deployed veterans (11.5%) compared to controls (6.6%) in 26-30 year old age group (p = 0.013); no significant difference in occurrence of nonnormal diagnoses detected in any other age group

5-year age groups (20-50, over 50), marital status, race, rank

 

McDiarmid et al., 2009 (Update)

Case series (Follow-up of McDiarmid et al., 2000, 2001, 2004, 2005, 2006, and 2007; see IOM, 2008, for detailed summary)

35 GWVs exposed to DU during friendly-fire incidents in 1991, divided into low-and high-exposure groups; examined in April-June 2007, 16-year follow-up

Urinary and serum markers, semen analyses, neuroendocrine measures

Biomarkers of renal function do not differ meaningfully (statistically or clinically) between low and high exposure to DU after 16 years of followup

 

Very small cohort, no control for potential confounders

Gray et al., 1996 (Update)

Retrospective cohort, DoD hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 NDVs

Hospital-discharge diagnoses of a disease of the genitourinary system in DoD hospital system (ICD-9 classification)

Any genitourinary disease (exact values not given) 1991: OR about 1.1 (95% CI 1.0-1.15); 1992 and 1993: ORs about 1.0 (95% CI 0.95-1.05) Inflammatory disease of ovary, fallopian tube, pelvic cellular tissue, and peritoneum: RR 1.35 (95% CI 1.11-1.63) Other disorders of the breast: RR 1.30 (95% CI 1.03-1.63) Redundant prepuce and phimosis: OR 1.59 (95% CI 1.22-2.07) Infertility, female: RR 1.59 (95% CI 1.19-2.11)

Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation

Very short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders such as smoking

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August 1991 through December 1994

652,979 GWVs, 652,922 randomly selected NDVs 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5,185 COSHPD hospitalizations

Hospital-discharge diagnoses of a disease of the genitourinary system in DoD, VA, and COSHPD hospital systems

DoD PMR 1.01 (95% CI 0.98-1.03); VA PMR 0.96 (95% CI 0.87-0.1.05); COSHPD PMR 0.80 (95% CI 0.59-1.00)

Age, sex, race (only for DoD PMR)

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates would have

Smith et al., 2006 (Update)

Retrospective cohort study of DoD hospitalizations (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); southwest Asia peacekeeping mission, 1991-1998 (n = 249,047); Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000) for an ICD-9-CM diagnosis of a disease of the genitourinary system (580-629) and nephritis specifically

Compared to GWVs, veterans of Bosnia showed reduced risk (HR 0.60, 95% CI 0.51-0.70), and veterans of southwest Asia showed similar risk (HR 1.00, 95% CI 0.92-1.09) Nephritis, Bosnia: HR 0.47 (95% CI 0.20-1.08); SW Asia: HR 1.30 (95% CI 0.84-2.01)

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

Lower hazard ratio observed in veterans of Bosnia may be partially explained by better access to care in theater Limitations: activeduty personnel only; hospitalizations at DoD facilities only; no outpatient data

Smith et al., 2002 (Update)

Retrospective cohort study of DoD hospitalizations 1991-1999; exposure modeling for oil-well fire smoke

405,142 active-duty Gulf War veterans who were in theater during the time of Kuwaiti oil-well fires

Hospitalization for diseases of the genitourinary system

Risk was not increased at any level of smoke plume exposure

Adjusted for “influential covariates,” defined as demographic or deployment variables with p values less than 0.15

Objective measure of disease not subject to recall bias; no issues with self-selection; however, only DoD hospitals, only active duty, no adjustment for other potential confounders

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

Smith et al., 2003 (Update)

Retrospective cohort study of DoD hospitalizations (1991-2000); analysis of health outcomes and exposure to nerve agents (follow-up of Gray et al. 1999b)

99,614 active-duty military considered exposed vs 318,458 nonexposed, according to revised DoD exposure model

Hospitalization for any disease of the genitourinary system (ICD-9-CM codes 580-629)

RR 0.96 (95% CI 0.91-1.00)

 

Restricted to DoD hospitals; restricted to hospitalizations for only Gulf War veterans who remained on active duty after the war; no adjustment for confounding exposures

NOTE: CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; DU = depleted uranium; GWV = Gulf War veteran; HR = adjusted hazard ratio; MRR = mortality rate ratio; NDV = nondeployed veteran; OR = adjusted odds ratio; PHQ = Patient Health Questionnaire; PMR = patient medical record; RR = adjusted risk ratio; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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ADVERSE REPRODUCTIVE AND PERINATAL OUTCOMES

This section evaluates the findings on birth defects in the offspring of veterans, adverse pregnancy outcomes, infertility, and sexual problems. As appropriate, the major results from each study are addressed by whether the father or the mother served in the gulf and by outcome. Table 4-14 summarizes all the primary studies on adverse reproductive and perinatal outcomes reviewed by the committee.

Birth Defects

Birth defects occur in about 3% of live births. The numerous types of serious or disabling birth defects include structural defects, chromosomal abnormalities, and birth defect syndromes (California Birth Defects Monitoring Program, 2009). Because of that diversity, epidemiologists attempting to calculate whether birth defects are increased in a particular group such as deployed veterans, sometimes encounter the problem of making multiple comparisons; that is, the greater the number or the more types of comparisons, the greater the likelihood that one or more of them will appear significant when no true differences exists. Several statistical techniques are used to adjust for, or minimize, the problem of multiple comparisons, but they are not foolproof.

Summary of Volume 4
Primary Studies

In the most comprehensive population-based study, Araneta et al. (2003) identified birth defects among infants of military personnel born from January 1, 1989, to December 31, 1993, from population-based birth defect registries in six states: Arizona, Hawaii, Iowa, and selected counties of Arkansas, California, and Georgia (metropolitan Atlanta). They compared the prevalence of 48 selected congenital anomalies diagnosed from birth to the age of 1 year between Gulf War veterans’ and nondeployed veterans’ infants conceived before the war; between Gulf War veterans’ and nondeployed veterans’ infants conceived during or after the war; and between infants conceived by Gulf War veterans before and after the war. The authors performed separate analyses on the basis of whether the mother or the father was engaged in military service. If both parents were in the military then the birth was categorized as an infant of a military mother. The study found higher prevalence of three cardiac defects (tricuspid valve insufficiency, aortic valve stenosis, and coarctation of the aorta), and one kidney defect (renal agenesis and hypoplasia) among infants conceived after the war to Gulf War veteran fathers. There also was a higher prevalence of hypospadias (malformation of the urethra and urethral groove), a genitourinary defect among sons conceived postwar to Gulf War veteran mothers compared to their nondeployed counterparts. Aortic valve stenosis, coarctation of aorta, and renal angenesis and hypoplasia were also elevated among infants conceived among the Gulf War veteran fathers postwar compared to those conceived prewar. There was only 1 birth defect recorded among 142 births conceived prewar to Gulf War veteran mothers, and this precludes comparisons with this group.

This study is particularly informative because it relies on active surveillance systems to identify medically confirmed outcomes diagnosed through the first year, rather than at birth, and uses information from population registries, as opposed to information from voluntary participation by study subjects. Because both nonmilitary and military hospitals participated in

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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the registries in all states except California (nonmilitary only), births among reservists, National Guard, and former military personnel were eligible, as well as among those on active duty. The study also included comparisons of births to Gulf War veterans before and after deployment. One limitation is that the study relied on availability of unique personal identifiers in military and birth certificate data, which leads to the possibility that some military offspring might be missed among the cases, and that would make the observed prevalence more conservative than the actual. Another is the study’s low power to assess individual defects that are rare. The authors also published the results of the pilot study of their method, which was performed in only Hawaii (Araneta et al., 2000); because the data are incorporated in the larger six-state study, they are not reviewed separately here.

Anecdotal reports raised the possibility of increased prevalence of Goldenhar syndrome, a rare craniofacial abnormality, among children of Gulf War veterans. External features of the syndrome are ear abnormalities, such as microtia, anotia, and preauricular tags. In a case-control study performed by Werler et al. (2005), birth records of infants born with the malformation hemifacial microsomia were examined to determine whether there was an association between Gulf War service of the parents and the birth defect. Hemifacial microsomia was identified in 232 cases from craniofacial clinics in 26 cities and matched to 832 controls by pediatrician and child’s age. Mothers of case subjects and controls were interviewed by telephone in 1996-2002 to identify pregnancy exposures, including military service, particularly in the Gulf War, of the mother or father 5-11 years before the child’s birth. Of the cases, four mothers and 30 fathers had served in the military, as had 10 control mothers and 100 control fathers; of those, four case parents (all in the Army) and 23 control parents (including nine in the Army) had served in the Gulf War. The association with Army service overall was significant (OR 2.4, 95% CI 1.4-4.2), but the association with having served in the Gulf War was not (OR 0.8, 95% CI 0.3-2.3). Study limitations include self-reported military service, small numbers of exposed and limited control for potential confounding. The study by Werler et al. (2005) was described in Volume 4, but the primary or secondary status of the paper was not classified. For the purpose of this review, the study was considered primary.

Secondary Studies

Additional studies of birth defects are considered secondary either because they rely on self-reports (and thus introduce potential recall bias), because they rely exclusively on birth records from military hospitals and are likely to incompletely ascertain malformations, or because they consider only groups of birth defects. Studying groups of birth defects, although useful in identifying patterns, makes it difficult to determine which specific defects may be increased.

Cowan et al. (1997) examined routinely collected data on all live births in 135 military hospitals in 1991-1993 to compare the frequency of birth defects in children of active-duty Gulf War veterans and nondeployed active-duty veterans. Information on 33,998 infants born to Gulf War deployed veterans (30,151 men and 3847 women) and 41,463 born to nondeployed veterans (32,638 men and 8825 women) was reviewed. The prevalence of any birth defect (that is, any ICD-9-CM code related to congenital malformations) was 7.45% for deployed veterans and 7.59% for nondeployed veterans (RR 0.98, 95% CI 0.93-1.03). There was no significant association between service in the Gulf War and the prevalence of any birth defect for male veterans (OR 0.97, 95% CI 0.91-1.03) or female veterans (OR 1.07, 95% CI 0.94-1.22) after adjustment for mother’s age at delivery, race or ethnicity, and marital status of parent at the time of the Gulf War. The unadjusted OR for having an infant with severe birth defects was 1.03

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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(95% CI 0.92-1.15) for male active-duty veterans, 0.92 (95% CI 0.71-1.20) for female active-duty veterans, and 1.00 (95% CI 0.90-1.10) for men and women combined. The authors note that when the adjusted ORs were calculated, no associations were seen, but they did not provide the data. When birth defects were evaluated by ICD-9-CM diagnostic groupings for the five most common severe anomalies, no statistical increases in associations were observed for male or female veterans. A limitation of the study is that it examined data only from live births to active-duty personnel in military hospitals. It is likely that higher risk pregnancies were referred to civilian hospitals. Since not all congenital malformations are evident at birth, some outcomes may have been underascertained when relying on hospital birth records.

A population-based study of male Canadian veterans (Goss Gilroy, 1998) surveyed deployed and nondeployed veterans for self-reported birth defects. Overall, deployed veterans reported a higher prevalence of birth defects (a combined category that included births before, during, and after the Gulf War). Birth defects that occurred at similar frequencies included urogenital and kidney defects.

Two additional secondary studies assessed broad groups of birth defects. In a population-based survey in the United States, Kang et al. (2001) observed an excess prevalence of self-reported “likely birth defects” and specifically “moderate to severe defects” among infants of Gulf War deployed fathers and mothers compared with nondeployed fathers and mothers. Most defects were isolated anomalies, and no clear patterns were found. First pregnancies ending after June 30, 1991, were considered in this analysis. The observed number of birth defects among children (liveborn and stillborn) born after deployment to National Guard personnel in two units in southeast Mississippi was not greater than expected on the basis of population-based registries (Penman et al., 1996).

Updated and Supplemental Literature
Primary Studies

Doyle et al. (2004) was considered secondary in Volume 4, but it is considered primary in this review, primarily due to medical confirmation of self-reported outcomes. Doyle and colleagues (2004) evaluated the prevalence of self-reported birth defects among the offspring of all UK veterans (male and female) deployed to the gulf and among the offspring of nondeployed veterans who responded to a postal questionnaire. Response rates were higher among the Gulf War veterans (53% of men, 72% of women) than the comparison group (42% of men, 60% of women). The authors considered pregnancies conceived after deployment (after January 1, 1991, for nondeployed veterans) through November 8, 1997. Medical confirmation was requested for all fetal deaths at 16 weeks or more or of unknown gestation and for liveborn children in whom a congenital abnormality, serious childhood medical condition, or death was reported. Among infants conceived by fathers deployed to the gulf compared with infants of fathers not deployed, the OR for any malformation was 1.5 (95% CI 1.3-1.7). Elevated ORs were observed specifically for malformations of the genital system, urinary system, musculoskeletal system, and cranial neural crest; for “other” malformations of the digestive system; for “other” nonchromosomal malformations; and for metabolic and single-gene defects. The ORs for urinary system and musculoskeletal system defects remained increased when the cases were restricted to the 55% that had clinical confirmation. No significant associations with birth defects were found for infants of mothers deployed to the gulf, although the analyses were limited by small numbers.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×
Secondary Studies

Three additional studies were identified that evaluated the effect of deployment on birth defects (Ishoy et al., 2001a; Kelsall et al., 2007; Verret et al., 2008), although none met the criteria for primary studies. In addition to the criteria for secondary studies described above, studies were considered secondary if too few birth defect cases were identified to make meaningful comparisons. Thus, Araneta et al. (1997), which was previously described but not classified as either primary or secondary in Volume 4, is considered secondary in this review.

In a study of Goldenhar syndrome, DoD hospital discharge data were used to identify all infants born to active-duty personnel after the Gulf War (or December 31, 1990, for nondeployed veterans) through September 30, 1993 (Araneta et al., 1997). In the population of 75,414 infants, five cases born to Gulf War veteran fathers and two cases born to nondeployed fathers were identified (Araneta et al., 1997). Given the small numbers, it is difficult to determine whether an excess risk is associated with service in the gulf.

A study of Danish veterans assessed self-reported “congenital disease or malformations” for children born to male veterans after 1991 (Ishoy et al., 2001a). The prevalence of congenital malformations was 2.1% among the 661 peacekeepers and 2.8% among the 215 nondeployed veterans. The difference between the groups was not significant.

Kelsall et al. (2007) surveyed Australian Gulf War veterans (n = 1424) and nondeployed (n = 1548) Australian Defense Force personnel in 2000-2002 to compare self-reported birth defects and other reproductive outcomes. No association was observed between a father’s Gulf War deployment and any reported birth defect (OR 1.0, 95% CI 0.6-1.6). Evaluations of specific malformations were not reported. Birth defects data were collected for live births only, which would exclude the most severe malformations. Additional limitations include poor response among nondeployed veterans and lack of control for maternal factors.

When compared to 10-year prevalence data from the Paris Registry of Congenital Malformations, the prevalence of major anomalies did not differ between French Gulf War veterans and the general French population, with the exception of Down syndrome which occurred less frequently among veterans (prevalence ratio 0.36, 95% CI 0.13-0.78) (Verret et al., 2008). Within the same publication, the authors also report the results of a nested case-control study conducted within the cohort of French Gulf War veterans to assess the effects of Gulf War-related exposures on all birth defects combined. No associations were observed for self-reported exposures to the smoke of oil-well fires, sandstorms, chemical alarms, or pesticides. According to the authors, an effort was made to minimize recall bias by restricting controls to veterans with at least one symptom-related hospitalization. However, the inclusion criterion was not applied equally to the cases. Because control selection was plausibly related to exposure, the results of the case-control analyses were subject to selection bias.

Summary and Conclusions

Primarily on the basis of the Araneta et al. (2004) and Doyle et al. (2004) studies, because of the availability of medical confirmation in those studies, there is some suggestion of increased risk of birth defects among offspring of Gulf War veterans. However, with the possible exception of urinary tract abnormalities, the specific defects with increased prevalence in the two studies were not consistent. Furthermore, the association between deployment and urinary tract abnormalities was not consistent when considering parent-specific exposures. That is, the association observed in Araneta et al. (2004) was specific to maternal deployment, and the association observed in Doyle et al. (2004) was confined to paternal deployment. Overall, studies

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

of Gulf War service and congenital malformations have been limited because specific birth defects are relatively rare, multiple comparisons were performed, and sample sizes were small when divided by timing of exposure (before or after conception) and whether the mother or the father was exposed. Thus, overall there is no consistent pattern of higher prevalence of birth defects among offspring of male or female Gulf War veterans, and no single defect, except urinary tract abnormalities, has been found in more than one well-designed study.

The committee concludes there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and specific birth defects.

Adverse Pregnancy Outcomes

Studies of adverse pregnancy outcomes have evaluated the prevalence of spontaneous abortions, stillbirths, ectopic pregnancies, preterm births, low birth weight and macrosomia in the pregnancies of Gulf War deployed and nondeployed men and women.

Summary of Volume 4
Primary Studies

Only one study of adverse pregnancy outcomes used hospital-discharge records, rather than relying exclusively on self-reported outcomes. Araneta and colleagues (2004) recruited women admitted to military hospitals for pregnancy-related diagnoses (including livebirths, stillbirths, spontaneous and induced abortions, ectopic pregnancies, and pregnancy-related complications) from August 2, 1990, to May 31, 1992. Reproductive outcomes were collected from surveys administered in 1997 and 1998 to the 3825 US women with pregnancy-related hospital admissions. Of the 1110 respondents with complete data, there were 415 predeployment and in-theater conceptions among Gulf War veterans (referred to as “Gulf War-exposed pregnancies”), 298 postwar conceptions among Gulf War veterans, and 427 conceptions among nondeployed women from deployed units. Self-reported outcomes were confirmed by hospital discharge data. The odds of spontaneous abortions (OR 2.9, 95% CI 1.9-4.6) and ectopic pregnancies (OR 7.7, 95% CI 3.0-19.8) were higher among Gulf War veterans’ postwar conceptions compared to conceptions among nondeployed women. The frequency of these outcomes among so called Gulf War-exposed conceptions was also increased compared to pregnancies among nondeployed veterans, but not in a significant way. Because only military hospitals were included, only information on active-duty personnel was available. The authors also acknowledge that deployment status, which was based on deployment dates for each military unit, may have been misclassified for pregnant women whose deployment orders were cancelled or delayed due to pregnancy. Furthermore, spontaneous abortions were not completely ascertained, given a substantial proportion of losses occur before pregnancies are clinically recognized (Wilcox et al., 1988).

Secondary Studies

Doyle and colleagues (2004) also studied self-reported miscarriages and stillbirths among Gulf War deployed fathers and mothers. The authors assessed clinically confirmed reports of congenital malformations. However, similar efforts to evaluate clinically confirmed reports of miscarriages and stillbirths were not described, and the outcomes assessed were limited to self-reports. Thus, when considering the analysis of other adverse pregnancy outcomes, the study is

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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considered secondary. Response rates were 53% for male Gulf War veterans, 72% for female Gulf War veterans, 42% for male nondeployed veterans and 60% for female nondeployed veterans. The authors observed no effect of Gulf War service on miscarriages reported by female veterans. The number of stillbirths among females was too small for meaningful assessment. There was a 40% increase in the odds of miscarriage among pregnancies reported by male Gulf War veterans compared with their nondeployed counterparts (OR 1.4, 95% CI 1.3-1.5), and the effect was stronger for early miscarriages (OR 1.5, 95% CI 1.3-1.6). However, in the Nuclear Industry Family Study, Maconochie et al. (1999) found evidence of underreporting of miscarriages among the nonexposed workers. The potential selection bias could explain the associations observed among the Gulf War veterans, if there was selective participation related to pregnancy outcome.

In the Kang et al. (2001) study described above, adverse pregnancy outcomes, including spontaneous abortions, stillbirths and preterm births, were compared between Gulf War deployed and nondeployed veteran mothers and fathers. There was an excess prevalence of self-reported spontaneous abortions (OR 1.62, 95% CI 1.32-1.99) among pregnancies conceived by Gulf War deployed fathers. Stillbirths were also reported more frequently among deployed fathers (OR 1.65, 95% CI 0.91-2.98), but this difference was not significant. Among veteran mothers, the odds of spontaneous abortion were modestly increased for those deployed to the Gulf War, but the 95% confidence interval did not exclude the null value (OR 1.35, 95% CI 0.97-1.89). No differences for preterm birth or infant death were observed among males or females. The limitations of this study include self-reported outcomes and differential participation rates for deployed (75% response) and nondeployed (65% response) veterans.

Updated and Supplemental Literature

Five additional secondary studies evaluating the effect of deployment on adverse pregnancy outcomes were identified (Ishoy et al., 2001a; Kang et al., 2009; Kelsall et al., 2007; Verret et al., 2008; Wells et al., 2006). All of these studies were based on self-reported data.

Interview data from 661 male Danish peacekeepers who served in the gulf in 1990-1997 and 215 male Danish military personnel who were not deployed to the gulf revealed no differences in prevalence of spontaneous abortions, live births, or infant deaths (Ishoy et al., 2001a). In addition to self-reported outcomes, the study did not control for the influence of important confounders.

One of the largest studies of reproductive outcomes in female Gulf War veterans was conducted by Wells et al. (2006). In this 1996-1997 survey of 8742 married male and female US Gulf War era veterans, no associations between deployment status and number of pregnancies reported between 1991 and 1995 were observed for males or females. Among the 2159 men and 2233 women reporting one or more pregnancies during this 4-year period, Gulf War deployment status was not associated with an increased odds of miscarriage, stillbirth, ectopic pregnancy, low birth weight, or macrosomic (> 4000 g) births among females. Among males, a weak, marginal association was observed between Gulf War deployment and miscarriage (OR 1.24, 95% CI 0.96-1.61), but no associations with other adverse pregnancy outcomes were observed. Limitations of this study include self-reported outcomes, poor response rate (51%), and limited information on maternal risk factors. Thus, the results may be susceptible to recall bias, selection bias, and confounding.

In the Australian veteran cohort described above, Kelsall et al. (2007) assessed the self-reported outcomes of pregnancies occurring in 1991 or later among 1424 Gulf War veterans

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

(80.5% response) and 1548 nondeployed military personnel (56.8% response). Among the male participants of this survey conducted between August 2000 and April 2002, deployment was not associated with miscarriages/stillbirths, pregnancy terminations, low birth weight, or preterm birth.

In a cross-sectional survey on the reproductive health of French Gulf War veterans (Verret et al., 2008), a nondeployed comparison group was not included in the study population. Thus, the effects of deployment on reproductive outcomes were not assessed in this population. According to the authors, the frequencies of reproductive characteristics, which included postdeployment miscarriage and stillbirth, were similar to frequencies in the general French population. Statistical comparisons, however, were not provided.

After conducting a 2000 follow-up survey to the 1995 National Health Survey of Gulf War Era Veterans and Their Families, Kang et al. (2009) reported the prevalence of selected self-reported reproductive characteristics among female Gulf War and Gulf War era veterans. Gulf War veterans reported an excess prevalence of “serious problems with mood before period” (OR 1.28, 95% CI 1.13-1.45) but no difference in having given birth within the last 6 months (OR 2.11, 95% CI 0.89-5.04) or having had a miscarriage in the last 6 months (OR 0.42, 95% CI 0.15-1.17). Comparison of births and miscarriages, however, were based on small numbers.

Summary and Conclusions

Although the results from the Araneta et al. (2004) study, which had hospital discharge data available, are suggestive of an increased risk of spontaneous abortions and ectopic pregnancies, the results may not be generalizable to deployed women who left the service or to pregnancy-related admissions to nonmilitary hospitals. These findings for spontaneous abortion were not replicated in the four secondary studies of female veterans, which used self-reported outcome data. Similarly, only one secondary study assessed ectopic pregnancies and observed no differences by deployment status among male or female veterans. Among males, no consistent associations with Gulf War deployment were observed for spontaneous abortion, preterm birth or low birth weight, although three studies reported modest increases in self-reported miscarriages among deployed males.

The committee concludes there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and adverse pregnancy outcomes such as miscarriage, stillbirth, preterm birth, and low birth weight.

Fertility

Studies of fertility problems have assessed semen parameters, hospitalization for infertility or genitourinary system diseases, self-reported difficulties achieving a pregnancy, and serum concentrations of reproductive hormones in males. Infertility is typically defined as trying to conceive unsuccessfully for 12 months or more after discontinuing contraception, although the quality of the outcome measurement has varied across studies and has included inference from self-reported disorders of infertility or sperm abnormalities, reports of “having difficulty getting pregnant,” reports of consulting a doctor after trying unsuccessfully for more than 1 year, and seeking treatment for childlessness.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×
Summary of Volume 4
Primary Studies

In the study by Ishoy et al. (2001a), 661 Danish peacekeepers who served in the gulf in 1990-1997 and 215 Danish military personnel who were not deployed to the gulf completed a clinical exam and a health interview that included questions about reproductive health and sexual problems. A clinical evaluation of serum concentrations of reproductive hormones—including luteinizing hormone, follicle-stimulating hormone, serum hormone-binding globulin, inhibin B and testosterone—found no significant differences between the deployed and nondeployed veterans. Furthermore, no differences in self-reported infertility, defined as “treatment due to childlessness after August 1990” were observed.

A group of 10,465 UK Gulf War veterans and 7376 nondeployed veterans (drawn from the same population as the Doyle et al. study described above) who fathered or tried to father children after the war and before August 1997 reported excess prevalence of infertility (defined as consulting a doctor after trying unsuccessfully for more than 1 year) compared to their nondeployed counterparts (OR 1.38, 95% CI 1.20-1.60) (Maconochie et al., 2004). The prevalence of type 1 infertility (never achieving pregnancy; OR 1.41, 95% CI 1.05-1.89) and type II infertility (never achieving a live birth; OR 1.50, 95% CI 1.18-1.89) were also significantly higher. Furthermore, more Gulf War veterans than nondeployed veterans experienced time to conception for planned pregnancies of more than 1 year (OR 1.18, 95% CI 1.04-1.34). Although the authors attempted to verify self-reported infertility, clinical diagnostic information was received from the subject’s physician for only one-third of those reporting fertility problems. Additional limitations include low response rates (53% for deployed veterans and 42% for nondeployed veterans), possible recall bias, and lack of information on partners’ fertility status.

Updated and Supplemental Literature
Primary Studies

Semen characteristics and neuroendocrine parameters have been assessed biennually in a small cohort of Gulf War veterans exposed to depleted uranium (DU) as a result of friendly-fire accidents (McDiarmid et al., 2000, 2001, 2004, 2007a,b, 2009). When comparing groups with high and low urinary uranium concentrations, no adverse DU effects on semen parameters or serum concentrations of testosterone, leutinizing hormone (LH), or follicle-stimulating hormone (FSH) have been observed up to 16 years after the initial exposure. Although serum prolactin concentrations have not been statistically different for the low and high uranium groups, prolactin concentrations in both groups were above normal limits in recent evaluations (McDiarmid et al., 2006, 2009). Up to 77 DU-exposed Gulf War veterans have been evaluated in this cohort over time, but only a small subset of individuals have been assessed at each time point. For example, 35 members underwent clinical evaluation during the most recent 2007 follow-up, with only 17 of those providing semen samples (McDiarmid et al., 2009). Thus, comparisons are based on small numbers and do not adjust for potential confounders.

Secondary Studies

Gray and colleagues (1996) conducted a hospitalization study (1991-1993) in which they compared almost 550,000 Gulf War veterans with almost 620,000 nondeployed veterans across three time periods following the war (1991, 1992, 1993). The study found increased hospitalizations, in 1991 only, for the broad category “genitourinary system diseases,” When

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

specific diagnoses within this category were examined, the observed association was attributed to infertility among females (OR 1.59, 95% CI 1.19-2.11), inflammatory disease of the ovary, fallopian tube, pelvic cellular tissue, and peritoneium (OR 1.35, 95% CI 1.11-1.63), redundant prepuce and phimosis among males (a diagnosis typically associated with elective circumcision) (OR 1.59, 95% CI 1.22-2.07), and other disorders of the breast among males and females (OR 1.30, 95% CI 1.03-1.63). The authors suggest these patterns were consistent with elective hospitalizations deferred until after the war. The major limitation of this study is the focus on DoD hospitalizations, which would miss hospitalizations of individuals who did not remain on active duty following the war. Furthermore, conditions associated with infertility would rarely require hospitalization, which is the predominant reason for classifying this study as secondary.

Three additional secondary studies addressed self-reported fertility problems among veterans who served in the Gulf War. All but one study assessed these conditions in males.

Using mailed questionnaires to survey Gulf War deployed and nondeployed male Australian veterans, Kelsall et al. (2007) found that before 1991 deployed veterans were no more likely than nondeployed veterans to report difficulties getting pregnant after trying for at least 12 months. Deployment, however, was associated with experiencing fertility difficulties for the first time in 1991 or later (OR 1.4, 95% CI 1.0-1.8). Of those reporting fertility problems in 1991 or later, the deployed veterans were more likely to have subsequently fathered a child. Verret et al. (2008) examined the prevalence of self-reported infertility (inferred from disorders of infertility or sperm abnormalities) and other reproductive outcomes in the cross-sectional study of French Gulf War veterans. Infertility was reported by 0.9% of the 5638 male veterans, but the lack of a comparison group hindered the assessment of the effect of Gulf War deployment on this condition.

In Kang et al. (2009), a higher proportion of female Gulf War veterans (9.9%) than Gulf War era veterans (4.3%) reported “having difficulty getting pregnant” (OR 2.2, 95% CI 1.50-3.22).

Summary and Conclusions

There is no evidence of significant differences in concentrations of male reproductive hormones between Gulf War veterans and nondeployed veterans. However, this question has been addressed by only one study. When semen parameters and reproductive hormones were compared within a DU-exposed cohort of Gulf War veterans, no differences were detected between those with high and low DU exposure. Although changes in hormonal concentrations and semen characteristics are reproductive outcomes of interest, they are not definitive indicators of infertility (with the exception of azoospermia). For the most part, studies of Gulf War deployment and infertility have relied on self-reports that give rise to a substantial opportunity for recall bias. Furthermore, studies have rarely examined this question among female veterans. Although it appears that problems with fertility are reported more frequently among Gulf War veterans compared to their nondeployed counterparts, cautious interpretation is warranted given the small number of available studies, all of which are susceptible to reporting bias and selective participation.

The committee concludes there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and fertility problems.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Sexual Dysfunction

Studies of self-reported sexual dysfunction have included reports of decreased libido, erectile dysfunction, discomfort or pain during intercourse, and a burning sensation after sex. One primary study was discussed in Volume 4. The committee identified no new primary studies of sexual dysfunction in Gulf War veterans but did consider seven secondary studies.

Summary of Volume 4

When Ishoy et al. (2001b) asked Danish military personnel whether they experienced any sexual problems (decreased libido or nonorganic erectile dysfunction) that they attributed to service in the gulf, self-reported sexual problems were higher among Gulf War veterans (12%) than among controls (3.7%) for an age-adjusted OR of 2.9 (95% CI 1.4-6.0, p = 0.003). Self-reported sexual problems were “clinically validated by the examining physician during the interview.” The deployed veterans were more likely to report sexual problems if they had seen killed or wounded people (p = 0.002), watched a friend or colleague being threatened or shot at (p = 0.02), or been threatened with arms themselves (p = 0.04) than if they had not had these experiences.

Updated and Supplemental Literature

Proctor et al. (1998) compared self-reported symptoms from random stratified samples of 186 Gulf War veterans from the New England area, 66 Gulf War veterans from the New Orleans area, and 48 Gulf War era veterans deployed to Germany. Using a 52-item symptom checklist administered between 1994 and 1996, the prevalence of self-reported pain during intercourse was 2.4% among the New England veterans, 1.9% among the New Orleans veterans, and 0% among the veterans not deployed to the gulf. The odds ratio comparing Gulf War deployed and nondeployed groups could not be calculated because the prevalence in the reference group was zero. Of note, the Gulf War deployed group reported a higher prevalence of all but one of the 52 symptoms (excessive sweating) when compared to the group deployed to Germany.

Simmons et al. (2004) used a mail questionnaire to survey all UK Gulf War veterans and demographically similar veterans who had served at the same time but were not deployed to the gulf. Of the 42,818 male veterans who responded (48% response) between 1998 and 2001, 24,379 had been deployed and 18,439 had not. Sexual dysfunction or a lack of sexual drive was reported by 0.8% and 0.2% of the deployed and nondeployed veterans, respectively, for an OR of 4.6 (95% CI 3.2-6.6, p < 0.001) adjusted for age and service status at the time of the survey, service and rank at the time of the war, alcohol consumption, and smoking. The prevalence of self-reported “genital system and bladder problems” (OR 2.2, 95% CI 1.7-2.7) was also higher among Gulf War veterans. The category of “genital system and bladder problems” included 13 (0.1%) reports of “burning semen” among Gulf War veterans and 1 (0.0%) among nondeployed veterans.

In the 1997-1999 study of all US Navy Seabees (Gray et al., 2002), 11,868 (62.6%) of 18,945 Seabees responded to a mailed questionnaire. In this study, deployment was associated with self-reports of physician-diagnosed impotence (with onset after August 1991) (OR 3.06, 95% CI 1.95-4.83). Similarly, in a 1997-1998 survey of male Gulf War deployed veterans (n = 2735), nondeployed (n = 2422), and servicemen deployed to Bosnia (n = 2393) (65% response rate), participants were asked to report whether or not they had experienced any of the 50 identified symptoms in the previous month (Unwin et al., 1999). All symptoms, including sexual

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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problems, were reported more frequently among Gulf War deployed veterans when compared to the other groups. The odds ratio for sexual problems was 3.2 (95% CI 2.4-4.2) for deployed versus nondeployed and 2.2 (95% CI 1.5-3.1) for Gulf War deployed veterans versus Bosnia deployed veterans.

In a 1998 phone survey of Kansas veterans, those deployed to the Gulf War were more likely than nondeployed veterans to report that they or their partner felt a burning sensation after sex (OR 3.75, 95% CI 1.88-7.49) (Steele, 2000). The Iowa Persian Gulf Study Group (1997) compared self-reported medical conditions between deployed and nondeployed Iowa veterans within the regular military and within the National Guard or reserve. In this phone survey conducted about 5 years after the Gulf War, symptoms of sexual discomfort were reported for the respondent and his female partner (as reported by the respondent). Gulf War veterans in the National Guard or reserve reported a higher prevalence of symptoms of sexual discomfort for their female partner (prevalence difference 3.6, 95% CI 2.3-4.8) when compared to their nondeployed counterparts. No differences in sexual discomfort were reported for the respondents themselves. Sexual discomfort was not associated with Gulf War deployment among members of the regular military.

The prevalence of selected sexual problems was also assessed among Gulf War veterans according to their potential exposure to sarin or cyclosarin at the Khamisiyah demolition (Page et al., 2005). Among participants in the National Health Survey of Gulf War Era Veterans Study, the prevalence of painful sexual intercourse (OR 1.16, 95% CI 0.81-1.65) or impotence or other sexual problems (OR 0.85, 95% CI 0.65-1.12) did not differ when comparing the exposed and unexposed Gulf War veterans.

Summary and Conclusions

Gulf War veterans consistently report an increased prevalence of sexual problems when compared with nondeployed veterans. The one study assessing exposures specific to Gulf War service reported no association between nerve agent exposure, and reported sexual problems among veterans deployed to the Gulf War. With the exception of a single study that incorporated physician interviews to verify symptom reporting, studies of sexual problems have relied exclusively on survey responses. It is acknowledged that studies assessing the prevalence of sexual problems are generally limited to self-reported symptoms. However, survey studies of self-reported conditions should be interpreted cautiously given concerns about susceptibility to selection and reporting biases.

The committee concludes there is limited/suggestive evidence of an increased prevalence of self-reported sexual difficulties among Gulf War veterans.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-14 Adverse Reproductive and Perinatal Outcomes

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Birth defects

Araneta et al., 2003 (Vol. 4)

Retrospective cohort, using population-based, birth-defect registries (active surveillance all cases identified from birth to 1 year)

Infants of military personnel born 1/1/1989-12/31/1993 in Arizona, Iowa, Hawaii, and participating counties of Arkansas, California, Georgia to GWV mothers (n = 450) NDV mothers (n = 3966) GWV fathers (n = 11,511) NDV fathers (n = 29,086)

48 birth defects identified by CDC as occurring frequently or of public health importance, excluding pulmonary artery anomalies and adding dextrocardia, chromosomal anomalies (other than trisomies 13, 18, and 21), and Goldenhar syndrome

Postwar conceptions, GWVs vs NDVs (unadjusted RRs): father: tricuspid valve insufficiency, 10/4648 vs 9/11,164 (RR 2.7, 95% CI 1.1-6.6); aortic valve stenosis, 5/4648 vs 2/11,164 (RR 6.0, 95% CI 1.2-31.0); coarctation of aorta, 5/4648 vs 3/11,164 (RR 4.0, 95% CI 0.96-16.8); renal agenesis or hypoplasia, 5/4648 vs 5/11,164 (RR 2.4, 95% CI 0.7-8.3) mother: hypospadias 4/154 vs 4/967 (RR 6.3, 95% CI 1.5-26.3) GWVs postwar vs prewar conceptions (unadjusted RRs): father: aortic valve stenosis 5/4648 vs 0/6863 (RR 16.3, 95% CI 0.9-294); coarctation of aorta, 5/4648 vs 1/6,863 (RR 7.4, 95% CI 0.9-63.3); renal agenesis and hypoplasia, 5/4648 vs 0/6863 (RR 16.3, (95% CI 0.9-294); adjustment did not change results

State, maternal and paternal age, race, marital status, education, plurality, parity, prenatal visits, gestational weight gain, branch of service, military rank, prenatal alcohol exposure, intrauterine growth retardation, low birth weight, small for gestational age, preeclampsia

Limitations: California limited to diagnoses in nonmilitary hospitals; relies on availability of unique personal identifiers in military and birth certificate data, limited power to assess individual defects, multiple comparisons, limited to live births Strengths: population-based, including reservists, National Guard, former military personnel; includes defects diagnosed through first year, medically confirmed as opposed to self-reports, comparisons with prewar experience

Werler et al., 2005 (Vol. 4)

Case-control

HFM cases ≤ 3 years old (born 1996-2002) from craniofacial clinics in 24 US cities (n = 232); controls matched by age and pediatrician (n = 832)

HFM, facial asymmetry, or Goldenhar syndrome and no evidence of Mendelian inherited or chromosomal anomaly

Adjusted ORs: cases vs controls; parental army service, (OR 2.4, 95% CI 1.4-4.2); parental GW army service, (OR 2.8, 95% CI 0.8-9.6); any parental GW service (OR 0.8, 95% CI 0.3-2.3)

Family income, race, BMI in early pregnancy, multiple gestation

Limitations: unmeasured Lifestyle factors Strengths: included cases diagnosed up to of 3 years age

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

Doyle et al., 2004 (Update)

Retrospective cohort

All UK GWVs and randomly selected cohort of NDVs. responding to postal questionnaire; conceptions from postdeployment (for NDVs—conceived after 1/1/1991) through 11/8/1997 GWV fathers (n = 16,442) NDV fathers (n = 11,517) GWV mothers (n = 484) NDV mothers (n = 377)

Fetal death: early and late miscarriage, stillbirth; congenital malformations excluding minor abnormalities among live births; self-report with clinical confirmation attempted for fetal deaths and live births with reported abnormalities

Adjusted ORs: GWVs vs NDVs father: all miscarriages 2829/15,539 vs 1525/10,988 (OR 1.4, 95% CI 1.3-1.5); any congenital malformation, 686/13,191 vs 342/9758 (OR 1.5, 95% CI 1.3-1.7); other malformations of digestive system, 69/13,191 vs 31/9758 (OR 1.6, 95% CI 1.0-2.5); genital system, 45/13,191 vs 19/9758 (OR 1.8, 95% CI 1.0-3.0); urinary system, 103/13,191 vs 48/9758 (OR 1.6, 95% CI 1.1-2.3); musculoskeletal system, 194/13,191 vs 78/9758 (OR 1.8, 95% CI 1.4-2.4); other nonchromosomal malformations, 45/13,191 vs 19/9758 (OR 1.7, 95% CI 1.0-3.0); cranial neural crest, 184/13,191 vs 101/9758 (OR 1.3, 95% CI 1.0-1.7); metabolic and single gene defects, 22/13,191 vs 8/9758 (OR 2.0, 95% CI 0.9-4.8); mothers: no significant associations

Stratum matched on branch of service, sex, age, serving status, rank; ORs adjusted by year of pregnancy end, paternal/maternal pregnancy order, maternal age, service, rank, previous fetal death, multiplicity

Response rates: GWVs: men 53%, women 72%; NDVs: men 42%, women 60% Limitations: poor response rates among men and response rates lower in NDVs, low numbers of miscarriages in NDVs. compared with NIFS population could mean participation and reporting bias; multiple comparisons Strengths: medical confirmation for some cases; fetal deaths as well as live births; external comparison groups to evaluate possible biases

 

 

External comparison populations: (1) NIFS; (2) annual registered stillbirths in England and Wales, 1991-1998

 

 

Adverse pregnancy outcomes

Araneta et al., 2004 (Vol. 4)

Retrospective cohort

Deployed women admitted to military hospitals for pregnancy-related

Self-reported stillbirths, spontaneous abortions, ectopic

Adjusted RRs: mothers: GWV vs NDV postwar conceptions:

Age, race, education, marital status, branch of service, military rank, parity, history

Overall response rate: 50% Limitations: low response rate; no

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

diagnoses (including live births, abortions, ectopic pregnancies, pregnancy-related complications) from 8/2/1990 to 5/31/1992 and who responded to mailed survey: GW-exposed conceptions (n = 415), GW postwar conceptions (n = 298), NDVs (n = 427)

pregnancies, pregnancy-related complications (ICD-9-CM codes 640-676); confirmed by discharge diagnostic data

spontaneous abortions, 68 vs 39 (RR 2.92, 95% CI 1.87-4.56); ectopic pregnancies, 32 vs 6 (RR 7.70, 95% CI 3.00-19.8); GWV vs NDV exposed conceptions: spontaneous abortions, 48 vs 39 (RR 1.44, 95% CI 0.91-2.29); ectopic pregnancies, 10 vs 6 (RR 1.91, 95% CI 0.67-5.46)

of adverse outcome

information on smoking, alcohol, caffeine, other known risk factors for fetal loss; possible limited generalizability due to restriction to military hospital admissions; recall bias Strengths: confirmation with discharge data, assessed GW-exposed and postwar conceptions

Fertility

Ishoy et al., 2001a (Vol. 4)

Cross-sectional Participation rates: GWVs, 83.6%; NDVs, 57.8%

Danish Gulf War Study, GWVs (n = 661) NDVs (n = 215)

Self-reports of sexual problems (including reduced libido); measured male reproductive hormones: serum concentrations of LH, FSH, testosterone, inhibin B

Male GWVs vs NDVs: self-reported sexual problems, 12.0% vs 3.7% (p < 0.001); reproductive hormones, no significant difference; suspected oligospermia, FSH ≥ 10 IU/L, inhibin B ≤ 80 pg/mL, 1.6% vs 1.6%; fertility rates, spontaneous abortion, congenital malformations: no differences

Age; BMI available; stratified on deployment organization, duration of deployment

Limitations: limited control for confounding, small numbers for study of fertility rates, congenital malformations Strengths: measurement of hormones objective and unbiased

Maconochie et al., 2004 (Vol. 4)

Retrospective cohort (same cohort as Doyle et al., 2004)

Male UK veterans fathering or trying to father pregnancies after GW and before 8/97 GWV (n = 10,465) NDV (n = 7376)

Self-reported fertility problems: tried unsuccessfully for > 1 year and consulted doctor; type I infertility: never achieving pregnancy; type II infertility: never achieving live birth;

Adjusted ORs: fertility problems, 732/10,465 vs 370/7376: (OR 1.38, 95% CI 1.20-1.60); type I 259/10,465 vs 122/7376 (OR 1.41, 95% CI 1.05-1.89); type II 356/10,465 vs 166/7376 (OR 1.50, 95% CI 1.18-1.89); time to conception > 1 year for planned pregnancies,

Maternal and paternal age at first infertility consult or post-GW conception, year of first consult or conception, pre-GW pregnancy history, military service and rank, smoking, alcohol,

Response rates: GWVs, 53%; NDVs, 42% Limitations: low response rates, possible recall bias, clinically evaluated only 40% Strengths: attempted clinical evaluation,

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

semen quality; time to conception; attempted clinical confirmation from both partners’ physicians

845/9968 vs 528/7408 (OR 1.18, 95% CI 1.04-1.34) (increase in risk stable with time since GW)

pregnancy order

information on nonresponders available

McDiarmid et al., 2009 (Update)

Case series (follow-up of McDiarmid et al., 2000, 2001, 2004, 2005, 2006, and 2007)

35 GWVs exposed to DU during friendly-fire incidents in 1991, divided into low- and high-exposure groups; examined in April-June 2007, 16-year follow-up

Urinary and serum markers, semen analyses, neuroendocrine measures

No adverse DU effects on semen parameters or serum concentrations of testosterone, LH, or FSH Serum prolactin concentrations non-significantly above normal limits in both groups

 

Very small cohort, no control for potential confounders

Sexual dysfunction

Ishoy et al., 2001b (Vol. 4)

Cross-sectional (elaboration of findings in Ishoy et al., 2001a)

Danish Gulf War Study: GWVs (n = 661), NDVs (n = 215)

Self-reported sexual problems

Male GWVs vs NDVs: sexual problems (80% decreased libido), 79/661 vs 8/215 (OR 2.9, 95% CI 1.4-6.0) (among GWVs associated with “having seen killed or wounded victims”; “having been threatened with arms”; “having watched colleagues being seriously threatened or shot at”; water hygienic environment)

Age

Limitations: small study, self-reported soft outcomes and exposures

NOTE: BMI = body mass index; CDC = Centers for Disease Control and Prevention; CI = confidence interval; DU = depleted uranium; FSH = follicle-stimulating hormone; GW = Gulf War; GWV = Gulf War veterans; HFM = hemifacial microsomia; LH = luteinizing hormone; NDV = nondeployed veterans; NIFS = Nuclear Industry Family Study; OR = adjusted odds ratio; RR = adjusted risk ratio.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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MULTISYMPTOM ILLNESSES

Since the mid-1990s, numerous studies have documented that deployment in the Gulf War entailed an increased risk of developing disabling complexes of self-reported symptoms among Gulf War veterans. Some reports suggest that as many as one quarter of US veterans who were deployed to the Persian Gulf in 1990-1991, about 175,000, are suffering from an array of symptoms that taken together has been called multisymptom illness, Gulf War illness, or Gulf War syndrome (RAC, 2008). However, veterans who were not deployed to the gulf also suffer from many of the same symptoms although the prevalence is not as great in this population. As summarized by Blanchard et al. (2005), these embraced a diversity of manifestations including “fatigue, musculoskeletal pain, sleep disturbances, cognitive dysfunction, moodiness and other symptoms.” Following the earliest of these reports, investigators have considered the hypothesis that these symptoms reflect the presence of a novel and distinctive Gulf War disorder, that in turn is a consequence of exposure to one or more adverse environmental influences. Many approaches have been pursued in the effort to identify specific sets of symptoms and factors that uniquely distinguish this putative Gulf War complex. The Volume 4 committee took a slightly different approach to the issue of multisymptom illnesses compared with this committee. That committee looked at “unexplained illness” and the symptom reporting by the Gulf War deployed veterans and attempted to determine whether there appeared to be a unique illness that could be defined by the symptoms. The Update committee did not attempt to make such a determination, but rather accepted that multisymptom illness was a diagnostic entity and assessed the literature regarding the association between symptom reporting indicative of multisymptom illness and deployment to the Gulf War. Primary studies on multisymptom illness are summarized in Table 4-15.

The committee that wrote Volume 6 of the Gulf War and Health series on the effects of deployment-related stress considered the long-term consequences of being in combat or deployed to a war zone. That committee concluded

People deployed to a war zone may report more symptoms than people who are not deployed—the stress response results in a cascade of physiologic changes that can have profound effects on multiple organ systems. War-zone stressors might produce disruption in brain systems that mediate responses to stress and in central pain regulatory pathways that can result in greater reporting of physical and emotional symptoms. The continuation of altered physiologic states over months and years can contribute to the accumulation of a chronic stress burden that has adverse long-term health consequences. Much progress has been made in understanding the physiologic mechanisms of the stress response, particularly in animal models, but work remains to be done in human studies. Research on the effect of stressors on the endocrine, immune, cardiovascular, and gastrointestinal systems demonstrates the complexity of the interactions between those systems.

Factor Analyses and Surveys

As discussed in detail in Volume 4, two statistical techniques have been used by investigators to identify symptom clusters that could potentially be used to develop case

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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definitions suggestive of a new syndrome: factor analysis and cluster analysis. Many of the studies reviewed by the committee use those techniques. The aims of the techniques are different: factor analysis seeks to identify groups of individuals’ most prominent symptoms, whereas cluster analysis seeks to identify people who have similar symptoms. Factor analysis has been used far more frequently than cluster analysis in the major cohort studies. It seeks to identify a small number of groups of highly related variables among a much larger number of measured variables. In the context of Gulf War research, the measured variables are the symptoms that veterans report in surveys. Factor analysis aggregates veterans’ symptoms into smaller groups to discern more fundamental, yet immeasurable, variables, which are referred to as factors.

Several factor analyses have been performed on Gulf War veterans (for example, Doebbling et al., 2000; Forbes et al., 2004) and were discussed in Volume 4. The update committee did not identify any new factor analysis studies of Gulf War veterans. In the initial such study, Haley and colleagues (1997) studied 249 Gulf War veterans and identified six factors that were suggested to constitute a Gulf War syndrome: syndrome 1—impaired cognition; syndrome 2—confusion-ataxia; syndrome 3—arthromyoneuropathy; syndrome 4—phobia-apraxia; syndrome 5—fever-adenopathy; and syndrome 6—weakness-incontinence. One potential limitation of this study was the relatively small cohort size and the absence of a nondeployed control group.

Another early factor analysis by Fukuda and colleagues at the CDC examined symptom sets in 3723 Air Force, Air Force Reserve, and Air National Guard veterans (1155 deployed and 2520 nondeployed). Two symptom complexes emerged as predominant: mood-cognition-fatigue and musculoskeletal. This group concluded that a chronic multisymptom illness (CMI) could be defined by the chronic presence (at least 6 months) of one or more symptoms from at least two of the following clusters: general fatigue, mood and cognitive abnormalities, and musculoskeletal pain (Fukuda et al., 1998). This syndrome was not completely specific to the Gulf War deployed veterans; the criteria were fulfilled by 39% of Gulf War veterans as compared to 14% of nondeployed veterans.

Nisenbaum et al. (2000) conducted a follow-up analysis of the cohort analyzed by Fukuda with the intention of defining a possible association between self-reported stressors in Gulf War deployment and the CMI. The authors surveyed 1002 (86.8%) cases including 58 (12.6%) and 401 (87.4%) classified as severe and mild to moderate. Participants were queried about potential stressors including type of primary duty, traumatic combat events, perception of a threat, preventive treatment for nerve gas exposure (pyridostigmine bromide), chemical hazards, adverse working conditions, family problems, and period of deployment. Multivariate analyses disclosed several self-reported factors that were associated with the higher likelihood of being a severe or mild-moderate case. Considering these two categories, the factors included (1) belief that biological or chemical weapons were used (OR 3.5, 95% CI 1.7-6.9, and OR 2.3, 95% CI 1.5-3.3, respectively), (2) pyridostigmine bromide use (OR 2.9, 95% CI 1.4-6.1, and OR 1.6, 95% CI 1.1-2.2, respectively), and (3) use of insect repellent (OR 2.4, 95% CI 1.3-4.5, and OR 1.7, 95% CI 1.2-2.3, respectively). Self-reported injuries were associated with severe illness (OR 2.1, 95% CI 1.1-4.3). The authors propose that “belief in a threat from biological or chemical weapons, suffering injuries that require medical attention, and use of insect repellent and pyridostigmine bromide, represent emotional, physical, and chemical stressors” that might lead to dysfunction of the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes. In

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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turn, this was thought potentially to cause “physiological and psychological changes” that might lead to chronic fatigue, mood-cognition, and musculoskeletal complaints.

In a population-based analysis, Ismail and associates (1999) identified three factors that accounted for 20% of the variance in UK Gulf War veterans: mood-cognition, respiratory symptoms, and peripheral nervous system symptoms. Comparison groups included cohorts of veterans who either served in Bosnia or were nondeployed. Many of the symptoms present in the Gulf War veterans were also present in Bosnian veterans.

Kang et al. (2002) performed another population-based factor analysis of 48 symptoms in larger cohorts of veterans either deployed (10,423 cases) or not deployed (8960) in the Gulf War. The study initially targeted 15,000 deployed veterans and 15,000 nondeployed veterans. One cluster of four symptoms was found to predominate (in mild or severe forms) in a subset of the Gulf War veterans (n = 277, 2.4%), who had also enhanced exposures to risk factors. A significantly higher prevalence of all 48 symptoms was observed among Gulf War deployed veterans compared to the nondeployed veterans (Kang et al., 2000). The four most frequently reported symptoms were runny nose, headache, unrefreshing sleep, and anxiety. Numerous chronic medical conditions—sinusitis, gastritis, and dermatitis—were reported more frequently by Gulf War veterans; many were reported about twice as often. The symptoms included blurred vision, loss of balance/dizziness, tremors/shaking, and speech difficulty. At least three of these four symptoms were present in 877 (7.7%) of the deployed veterans compared with 175 (1.8%) of the nondeployed veterans. The corresponding risk factors were consumption of contaminated food (for example, contaminated with oil or smoke), exposure to toxins (paint, solvents), and bathing in or drinking contaminated water. Kang and colleagues noted that a majority of cases (69%) with this set of four symptoms also met criteria for PTSD. Reciprocally, of cases meeting criteria for PTSD, about 11% experienced all four of these symptoms. Thus, these cases showed considerable overlap with PTSD. Also, when compared with the 6730 nondeployed veterans with none of the four symptoms, this group of 277 veterans had a higher incidence of other medical conditions, such as diarrhea, migraines, lumbago, hypertension, and tachycardia.

Ishoy et al. (1999a) conducted an epidemiological cross-sectional survey of 821 Danish veterans who had served as peacekeepers and in humanitarian relief in the Persian Gulf between April 1991 and January 1996, an interval that commenced after conclusion of the war. The veterans had a higher prevalence of neuropsychological, gastrointestinal, and skin symptoms when compared to controls. The neurological complaints included difficulty concentrating, sleep disturbance, fatigue, depression, headache, speech disturbances, and blurred vision. They also had more ICD-10 medical diagnoses compared with controls. Overall, the prevalence of these symptoms was about 20% greater, roughly comparable to the prevalence of such symptoms in US Gulf War veterans. Particularly striking was the development of these symptoms in a cohort whose tenure in the gulf began after conclusion of active war hostilities, implicating some common component of the experience that was, as the authors suggested, “independent of the actual war action.”

Responses from the Iowa Persian Gulf Study were used by Doebbeling to explore whether there was a Persian Gulf War illness. The 1896 deployed veterans and 1799 nondeployed veterans were surveyed in 1995-1996 about the presence of 137 symptoms; the prevalence of symptoms was significantly increased in deployed (50%) compared with the nondeployed veterans (14%). Factor analyis identified three symptom clusters (somatic distress, psychological distress, and panic) in both the deployed and nondeployed veterans.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Whether there was a pattern to the multitude of symptoms reported by Australian male Gulf War veterans was studied by Forbes et al. (2004) also using factor analysis. The occurrence of 62 symptoms was assessed in 1322 deployed and 1459 nondeployed veterans. Three factors were identified—psycho-physiological distress, somatic distress, and arthroneuromuscular distress—in both deployed and nondeployed veterans. The authors report that the results did not suggest a unique pattern of self-reported symptoms in the deployed veterans.

To assess the persistence of multisymptom problems in Gulf War veterans, Blanchard (2006) performed a follow-up study of about 1061 deployed and 1128 nondeployed veterans who had participated in the initial studies of Gulf War CMI in the mid-1990s. Participants underwent examinations that included detailed medical and psychiatric histories, physical examinations (general and neurological), pulmonary function and nerve conduction tests, and both laboratory and neuropsychology studies. These investigators concluded that a decade after they were first studied, the Gulf War veterans showed a persistant prevalence of CMI (28.9%) compared with the nondeployed controls (15.8%). Moreover, the difference was exaggerated when only the most severely affected individuals were considered (7.0% vs 1.6%). In the deployed group, CMI correlated with higher combat exposure, while in the nondeployed group it correlated with full-time military service. CMI was associated with more fibromyalgia syndrome, chronic fatigue syndrome, arthralgias, dyspepsia, and metabolic syndrome in both the deployed and nondeployed cohorts. Among the deployed CMI cases, chronic fatigue syndrome was higher than in the nondeployed. In both groups (deployed and nondeployed), prewar non-PTSD anxiety disorders and depression were highly associated with CMI. The authors of this study conclude that “Ten years after the 1991 Gulf War, CMI is twice as prevalent in deployed veterans but still affects 15 percent of nondeployed veterans.” They also note that at 10 years, the prevalence in the deployed group nonetheless seems to have decreased slowly over time; in the deployed group the 10-year prevalence (28.9%) is lower than it had been at 4 and 7 years (44.7% and 47%). Moreover, the authors argue that the critical predictor of CMI is stress. Blanchard and colleagues (2005) concluded with the caution that “Poor mental and physical functioning and metabolic syndrome in veterans with CMI portend a substantial future health-case burden.”

Data from multiple factor studies of veterans in the United Kingdom and the United States were reanalyzed with a different statistical methodology involving dichtonous analysis of multiple lists of symptoms (Nisenbaum et al., 2004). This was undertaken to address the concern that biased findings may result when linear analysis of symptom sets is applied to data that are essentially binary (that is, a symptom is or is not present). The study’s conclusions are broadly similar to those from other factor analyses: similar symptom categories are detected in Gulf War deployed and nondeployed veterans,

except that the gastrointestinal factor in gulf veterans included other symptom types. Correlations among factors raise the question as to whether there is a general illness, even if not unique to gulf veterans, representing the common pathway underlying the identified factors.

Hospitalization Studies

Another approach to gauging the impact of Gulf War service is to assess the rates of hospitalizations of deployed versus nondeployed veterans in the years following deployment. Four studies have taken this approach. Gray et al. (1996) performed a retrospective multivariate, logistic regression analysis of the hospitalization rates of 547,076 deployed and 618,335

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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nondeployed veterans of the US Army, Navy, Marine Corps, and Air Force who remained on active duty through September 1993. In the 25-month period following the war (defined as August 1991 through September 1993), total hospitalizations of the deployed group were not increased as compared to the nondeployed group. In the deployed group, there was a small increase in admissions for testicular cancer and for genitourinary problems, ascribed in part to delayed care for problems that developed during the deployment itself. In the 25 months following the war, the deployed cohort had increased numbers of admissions for alcohol and drug abuse, and for adjustment reactions. The authors concluded that veterans of the Gulf War who remained on active duty through September 1993 were not at risk for unexplained disorders severe enough to merit hospitalization. They acknowledge that a potential limitation of this report is that it omits consideration of data both from those who left the military immediately after the war (before September 30, 1993) and from individuals whose symptoms developed after that date.

An extension of this study was subsequently provided by Knoke and colleagues (1998). These authors tested the hypothesis that the study by Gray et al. (1996) may have underestimated admissions for veterans with obscure, undiagnosed disorders, which might be missed by conventional ICD-9 coding. In this follow-up study, Knoke reviewed all admissions that entailed any “illness of unknown cause” as defined by 77 ICD-9 categories used by the CDC Emerging Infections Program to monitor death certificates for unexplained deaths. This study reviewed records for 552,111 deployed and 1,495,751 nondeployed veterans followed through March 1996. Briefly, after excluding a surge of admissions for evaluation of symptoms of unknown causes, this study found no excess of hospitalization for unexplained illnesses in deployed versus nondeployed veteran.

To encompass in this study those veterans who left service prior to September 1993 (for example, reservists and former veterans), Gray et al. (2000) also performed an analysis of all veterans admitted to three health-care systems in California, covering the deployment period 1991-1994. Because of limitations in acquiring data for discharged veterans, this study compared proportional morbidity ratios of discharge diagnoses between deployed and nondeployed veterans in each of the three systems, rather than hospitalization rates. Most major disease categories revealed no differences (for example, infectious diseases and cancer); in general, the deployed Gulf War veterans had overall proportions of hospitalizations that were similar to the nondeployed. The deployed cohort had a slight propensity for more hospitalizations for fractures, soft-tissue injuries, asthma, and other symptoms. The significance of these factors was difficult to assess.

Recently, Smith et al. (2006) have reexamined hospitalization rates using a longer follow-up period and including three comparative groups from three military theaters: Gulf War (lapsed time 10 years, 5 months, n = 445,465), post-Gulf War southwest Asia (9 years, 5 months, n = 249,047), and Bosnia (5 years, 1 month, n = 44,341). The central finding in this study is that individuals deployed to southwest Asia had slightly more hospitalizations that the Gulf War cohort, while the risk of hospitalization was slightly decreased for the Bosnian cohort. The authors conclude “It is unlikely that Gulf War veterans are at greater risk of hospitalization due to specific exposure-related disease.”

Other Reports

In a follow-up study to Kang et al. (2000, 2002), Kang et al. (2009) conducted a survey in 2005 to obtain health information from the 15,000 Gulf War deployed and 15,000 Gulf War era

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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veterans originally surveyed in 1995. Responses to the postal questionnaire were received from 6111 deployed and 3859 era veterans. Unexplained multisymptom illness was assessed and defined as having several different symptoms that persisted for 6 months or longer and were not adequately explained by other diagnoses. Symptoms might include fatigue, muscle or joint pain, headaches, memory problems, digestive problems, respiratory problems, skin problems, or any other unexplained symptoms. Multisymptom illness was reported by 36.5% of the deployed and 11.7% of the era veterans for a risk ratio of 3.05 (95% CI 2.77-3.36), adjusted for age, sex, race, body mass index, current cigarette smoking, rank, branch of service, and unit component (active duty, National Guard, or reserve). This was the mostly widely reported medical condition for Gulf War veterans except for hepatitis. This study is limited in that only self-reports of symptoms were assessed.

To determine if framing the questions regarding health and symptoms might influence symptom reporting, Murphy et al. (2006) surveyed a group of 1647 UK active-duty military personnel about health problems 10 years after the Gulf War. Of those surveyed, 308 were subsequently identified as having served in the Gulf War while 1339 had not. Those deployed to the Gulf War were more likely than the control veterans to score above a cutoff on the 15-item symptom checklist (OR 1.84, 95% CI 1.17-2.91) and more likely to report the following individual symptoms, adjusted for age, sex, rank, and service branch: chest pain (OR 2.50, 95% CI 1.58-3.96); fatigue (OR 1.37, 95% CI 1.03-1.81); joint stiffness (OR 1.53, 95% CI 1.10-2.12); pain without swelling or redness in several joints (OR 1.60, 95% CI 1.07-2.39); feeling feverish (OR 2.66, 95% CI 1.05-6.73); feeling unrefreshed after sleep (OR 1.83, 95% CI 1.26-2.65); lump in throat (OR 3.21, 95% CI 1.39-7.41); diarrhea (OR 3.18, 95% CI 1.76-5.76); sore throat (OR 1.93, 95% CI 1.04-3.56); forgetfulness (OR 2.53, 95% CI 1.69-3.77); and ringing in ears (OR 1.82, 95% CI 1.08-3.10). The authors noted that among those surveyed, veterans who had served in the Gulf War were still in the military 10 years later whereas those who were not in the Gulf War may not have served that long, although the age distribution of the two cohorts was the same. The questionnaire did not ask any of the veterans about service in the Gulf War or other conflicts. This study is limited in that veterans who did not serve in the Gulf War may have served in other conflicts. Also, there was no assessment by a health-care professional (that is all symptoms were self-reports) and the study group was restricted to active-duty personnel, and therefore, veterans who may have served in the Gulf War or during the era and who had left the service were not included, perhaps leading to a healthy warrior bias.

Stimpson et al. (2006) surveyed UK veterans who had served only in the Gulf War (n = 2959), only in Bosnia (n = 2052), or both in the Gulf War and in Bosnia (n = 570), and a comparison era group of veterans who had not been deployed to either the Gulf War or Bosnia (n = 2614) for self-reports of CWP. A mailed questionnaire containing a pain manikin to ascertain the pattern and intensity of pain was sent to 12,592 male and female veterans in 1997; the response rate was 60-70%. Veterans were selected for each deployment group on the basis of stratified random sampling of all UK Gulf War veterans. Data from the shaded manikins were used to determine whether the pain pattern met the ACR definition of CWP. Compared with the era cohort, being deployed to the Gulf War increased the risk of reporting widespread pain (OR 1.82, 95% CI 1.51-2.20); being deployed to Bosnia did not increase the risk of reporting CWP (OR 1.06, 95% CI 0.83-1.36), but being deployed to both the Gulf War and Bosnia resulted in the most reporting of CWP (OR 2.04, 95% CI 1.52-2.73), even when adjusted for socioeconomic and demographic factors. The pattern of pain was similar in all the groups; the most common sites of pain were the back and knees. Veterans who reported pain in one limb were also 30 times

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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more likely to report pain in the symmetrically opposite limb rather than a second limb on the same side of the body; the authors found this suggestive of “systemic pain” rather than pain from an injury. Although the sample was large, the study is limited by a lack of physical examination and a lack of indication as to whether the veterans had sustained injuries during deployment or were using pain medication at the time of the survey.

Using data from a self-report questionnaire, Proctor et al. (1998) compared health problems of 252 Gulf War deployed veterans from Fort Devens, Massachusetts, and New Orleans, Louisiana, with those of 48 era veterans who had been deployed to Germany. Among the musculoskeletal symptoms reported more frequently by the Fort Devens deployed veterans were joint pains (OR 2.6) and neck aches or stiffness (OR 2.7), and among the neurological symptoms with greater prevalence in both cohorts of deployed veterans were headaches (OR 4.2); all confidence intervals excluded 1.0. About 30% of the Gulf War veterans and 11% of the comparison group reported an inability to fall asleep (OR 3.4-3.6, 95% CI excludes 1.0).

Horn et al. (2006) compared the frequency of symptom reporting between deployed and era UK veterans of Gulf War and Iraq War. Iraq War veterans did not show the difference in symptom reporting between deployed (n = 3284) and nondeployed (n = 2408) male military personnel that had been seen for Gulf War veterans. The prevalence of each of the 15 most frequently reported symptoms for Gulf War veterans was significantly greater than for era veterans (ORs 1.9-3.9, all 95% CIs exclude 1.0). Compared with era veterans, more than 50% of the Gulf War deployed veterans reported feeling unrefreshed after sleep (OR 2.8, 95% CI 2.5-3.1), irritability or outbursts of anger (OR 3.5, 95% CI 3.2-4.0), headaches (OR 2.1, 95% CI 1.9-2.3), and fatigue (OR 2.7, 95% CI 2.4-3.0). Compared with era veterans, deployed veterans were three times more likely to be a fatigue case (based on a validated 13-item fatigue scale; OR 3.39, 95% CI 3.00-3.83) and twice as likely to report fair or poor general health (OR 2.00, 95% CI 1.70-2.35). UK Iraq war veterans showed no increase in fatigue or reports of poor or fair general health compared with their nondeployed counterparts.

Summary and Conclusions

There is increased reporting of multisymptom illness among those deployed in the Gulf War as seen in most of the studies conducted on Gulf War veterans. The phenomenon, which recurs in multiple studies from several countries, is predominantly subjective, without a consistent accompanying pattern of findings on physical examination or laboratory testing. The basis for this problem remains elusive but merits further analysis, along the lines of the investigations summarized in Chapter 5.

The committee concludes that there is sufficient evidence of association between deployment to Gulf War and chronic multisymptom illness.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is marked by severe and persistent fatigue with a cluster of other symptoms that have long been the focus of considerable controversy (Straus, 1991; Wessely, 1998). The study of unexplained fatiguing illnesses was greatly facilitated and legitimized in the last decade with the development of a case definition sponsored by the CDC (Box 4-1). CDC’s case definition requires fatigue and related impairment in function, and the occurrence of four of eight other defining symptoms over at least 6 months (Fukuda et al., 1994;

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Holmes et al., 1998). Of the eight symptoms, the most commonly reported are headaches, postexertional malaise, impaired cognition, and muscle pain (Buchwald and Garrity, 1994).

CFS is a diagnosis of exclusion. The CDC criteria require that three elements be completed as part of a comprehensive evaluation. The first element, determining whether the symptom criteria for CFS are present, requires that a person be queried specifically about length and severity of fatigue and about eight ancillary symptoms. The second element, determining whether other medical conditions are present, mandates a complete physical examination, a battery of specified laboratory tests, and a medical history. The third element, assessing exclusionary psychiatric conditions, requires an interview by a trained professional to obtain diagnostic information.

The etiology of CFS is unknown, and there are no widely accepted laboratory tests or pathologic physical signs (Epstein, 1995). Several biologic correlates of the syndrome have emerged, including dysregulation of the hypothalamic-pituitary-adrenal axis, immune activation, and other measures (Goshorn, 1998), but they might be present in only a minority of patients; and those findings are not specific to CFS. Although infectious agents may trigger some cases of CFS, a complex, multifactorial etiology that incorporates biologic, psychological, and social factors is likely (Wessely, 1998). The degree of disability associated with CFS is striking, with high rates of unemployment (Bombardier and Buchwald, 1996; Buchwald, 1996) and poor quality of life related to health (Hardt et al., 2001; Komaroff et al., 1996).

Thus, in this report, a primary study for CFS is one in which CFS has been diagnosed. A secondary study is one in which a CFS-like condition has been documented. Both primary and secondary studies needed to include a suitable control group so that findings could be interpreted. Other studies that estimated the prevalence of symptoms of “chronic fatigue” (Gray et al., 1999a; Unwin et al., 1999), or multisymptom illness (Fukuda et al., 1998), are not considered further in this section. Likewise, studies that used scalar measures of disability and poor quality of life related to health (Reid et al., 2001) as surrogates for the CDC criteria are not included. Finally, self-reports of CFS (Unwin et al., 1999) and self-reports of a physician diagnosis of CFS (Gray et al., 2002) were not included among the secondary studies because diagnostic data obtained that way are highly inaccurate. For example, in the Eisen et al. (2005) study, which the committee considered to be the only primary study, only two or three of 38 deployed and eight nondeployed veterans who self-reported CFS received a formal diagnosis after a comprehensive examination. Others, using a method of classifying a case of CFS based on cutoff scores on a fatigue scale and a functional status instrument, found that only 11% of veterans reporting a diagnosis of CFS met operational CFS study criteria.

Summary of Volume 4
Primary Studies

CFS was one of 12 primary health outcome measures studied by Eisen et al. (2005), who conducted medical evaluations in phase III of the nationally representative, population-based VA study. In the period 1999-2001, 1061 of 11,441 deployed and 1128 of 9476 nondeployed veterans selected were evaluated. Those veterans had participated in the phase I survey study conducted in 1995 (Kang et al., 2000). The veterans were randomly selected, and the researchers were blinded to their deployment status. The diagnosis of CFS was based on in-person interviews, examinations, and the strict application of the CDC criteria (Fukuda et al., 1994). The authors concluded that the population prevalence of CFS was higher in deployed than in nondeployed veterans: 1.6% vs 0.1% (OR 40.6, 95% CI 10.2-161.15). Study strengths are its

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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BOX 4-1

CDC Case Definition of Chronic Fatigue Syndrome

A diagnosis of chronic fatigue syndrome requires the presence of both the following:

  • Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset (that is, has not been lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reduction in levels of occupational, educational, social, or personal activities. Clinical evaluation includes medical history, physical examination, laboratory studies, and psychiatric assessment.

  • Concurrent occurrence of four or more of the following, which must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue: self-reported impairment of short-term memory or concentration severe enough to cause substantial reduction in levels of occupational, educational, social, or personal activities; sore throat; tender cervical or axillary lymph nodes; muscle pain; multijoint pain without joint swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and postexertional malaise lasting more than 24 hours.

SOURCE: Fukuda et al. (1994).

large, population-based design, stratified sampling method, analysis of participation bias, comprehensive examination, and use of computer-based algorithms by researchers who were blinded to deployment status. Study limitations include demographic differences between the deployed and nondeployed cohorts and the relatively low rate of participation in the study.

Secondary Studies

An earlier questionnaire study, conducted during phase I of the VA study, surveyed 11,441 deployed and 9476 nondeployed veterans (Kang et al., 2003). Several items in the 48-item symptom questionnaire served as the basis for meeting the case definition for CFS. After exclusion of veterans who self-reported medical conditions that could explain their fatigue, 4.9% of deployed and 1.2% of nondeployed veterans (OR 4.2, 95% CI 3.3-5.5) met the case definition. The investigators found that CFS was not related to the severity of combat stressors. The latter was assessed according to responses to questions on wearing chemical protective gear or hearing chemical alarms, being involved in direct combat duty, or witnessing any deaths. The study was limited by its reliance on solely self-reported symptoms without a physical or laboratory examination and on self-reported physician-diagnosed conditions. Those shortcomings resulted in a higher rate of CFS-like illness than was observed when the same cohorts were sampled and underwent more rigorous medical evaluations as in Eisen et al. (2005).

Proctor and colleagues (2001b) conducted in-person interviews of 180 Army veterans selected from the larger Fort Devens cohort to determine the prevalence of CFS. The deployed veterans were compared with 46 members of an air ambulance company deployed to Germany during the Gulf War. The prevalence was determined according to the symptom criteria specified by the CDC case definition (Fukuda et al., 1994). With that approach, the rate was higher in the Gulf War deployed than the Germany deployed group (7.5% vs 0%, p = 0.02). When additional information from self-reported medical or psychiatric conditions (such as substance abuse and bipolar disorder) and clinical psychiatric interviews was considered, the prevalence in Gulf War veterans decreased to 2%, which was no longer significant. The study demonstrated the importance of performing psychiatric assessments, but it was limited by the relatively small sample and the lack of medical or laboratory evaluations.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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Canada deployed more than 4000 sea, land, and air troops to the gulf region; they participated in a naval blockade and were responsible for one-fourth of enemy interceptions in the gulf. A survey of the entire Canadian Gulf War force found that deployed veterans were at least five times as likely as nondeployed veterans to report symptoms of CFS (OR 5.27, 95% CI 3.95-7.03) (Goss Gilroy, 1998). Veterans were not interviewed or examined, and all data were obtained from self-reports. The CFS-like illness was based on responses to questions derived from the CDC criteria and a score above zero on the Chalder fatigue scale.4 With only minor modifications, the items used in this study were the same as those used by the Iowa Persian Gulf Study Group (1997). The study was limited by the lack of in-person interviews and examinations and by the nontraditional assessment of CFS.

The Iowa Persian Gulf study (1997) surveyed 1896 deployed and 1799 nondeployed veterans who listed Iowa as their home state at the time of enlistment. The presence of a CFS-like condition was based on a combination of symptoms used in the CDC criteria (Fukuda et al., 1994) and scores on the Chalder fatigue scale. The investigators found that the prevalence differed by 1.4% (95% CI 0.9-2.0) after adjusting for age, sex, race, branch of military, and rank. Study limitations were the use of self-reports of symptoms on a questionnaire and the lack of medical evaluations. Although rigorously conducted and analyzed, the study suffers shortcomings similar to those of the Canadian study.

Updated and Supplemental Literature

The Update committee identified two new primary studies: Kelsall et al. (2006), who assessed health outcomes in Australian Gulf War veterans with chronic fatigue, and Ismail et al. (2008), who assessed UK Gulf War veterans for chronic fatigue and related disorders.

Between August 2000 and April 2002, Kelsall et al. (2006) conducted a cross-sectional study of chronic fatigue in male Australian Gulf War veterans. A total of 1456 deployed veterans participated (80.5% response rate of all who were deployed), and a comparison group consisted of 1588 individuals who served concurrently but were not deployed (56.8% response rate). Ascertainment was via a postal questionnaire plus a comprehensive medical evaluation that included neurologic and psychiatric tests, as well as the following laboratory tests: complete blood examination; erythrocyte sedimentation rate; urea; creatinine; electrolytes; serum calcium and phosphate; liver function tests; random plasma glucose; C-reactive protein; and serology tests (Epstein-Barr virus IgG, cytomegalovirus IgG, and hepatitis C core antibody). One percent of the Gulf War veterans and the comparison group had been diagnosed with CFS (adjusted OR 1.2, 95% CI 0.5-2.9). However, more Gulf War deployed veterans (7.9%) had prolonged fatigue lasting more than 6 months than did the comparison group (4.2%; aOR 1.9; 95% CI 1.4-2.7); and a similar increase was noted in the complaint of fatigue at all levels in the deployed group. In a small subset of controls who had been actively deployed elsewhere, the differences in complaints of chronic or prolonged fatigue were less apparent compared with the Gulf War deployed individuals and in fact failed to reach statistical significance; thus, there was an apparent active deployment effect. The odds of fatigue increased with reports of more PB tablets used, exposure to pesticides, belief in being near chemical weapons, and being in the gulf during air war. The strengths of this study are its relatively large size and national ascertainment. The weakness is

4

The Chalder fatigue scale is widely used to measure physical and mental fatigue in CFS patients (Chalder et al., 1993).

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

that the exposure and symptom history was ascertained by self-report, raising a substantial possibility of biased recall.

Ismail et al. (2008) reported the prevalence of CFS and related disorders in UK veterans of the Gulf War. In this two-phase cohort study, randomly selected subsamples from a population-based cross-sectional postal survey of more than 10,000 military personnel were compared with control groups that included Bosnian peacekeepers and nondeployed military personnel. Comparisons were matched for total level of disability using a physical functioning scale. Gulf War veterans were more likely to be overweight, to be hypertensive, and to have elevated serum transaminase (AAT) levels. (It is possible that the AAT levels may reflect being overweight.) Among the disabled veterans, the adjusted OR for CFS was 7.8 (95% CI 2.5-24.5). CFS was present in 18% of disabled Gulf War veterans compared with only 3% of disabled nondeployed veterans. Remarkably, rates for other medically explainable conditions were not increased, indicating that the CFS symptoms were specifically increased in the Gulf War deployed population. Over half of veterans satisfying criteria for CFS had concomitant depression or anxiety disorder. The authors concluded that CFS was a medically unexplained condition associated with Gulf War service.

The Update committee identified one new secondary study. Lucas et al. (2007) administered a questionnaire about wartime exposures and symptoms experienced in 49 Gulf War veterans complaining of chronic fatigue matched to 44 healthy controls who were also deployed. For the purposes of the study, fatigue had to begin by July 1992. Fatigue was associated with exposure to oil fire, smoke, pesticides, contaminated food or water, Scud missiles, dead bodies, dead animals, and other environmental agents. There was also an association of fatigue with use of PB that increased 1.3% with every pill taken; there were also general trends toward worse health with PB exposure. This study was markedly limited by a very small sample size and a small number of individuals with PB intake data. There was also no adjustment made for multiple comparisons.

Summary and Conclusions

CFS and complaints of unexplained chronic fatigue appear to be increased in deployed Gulf War veterans compared to contemporaneous cohorts (either nondeployed or deployed elsewhere). This has been observed in several cross-sectional population-based studies that used self-reports to define CFS or chronic fatigue. However, the absolute prevalence of these symptoms has varied considerably from study to study. Associations between fatigue, subjective neurological symptoms, and exposures are also based entirely on retrospective self-reports.

Therefore, the committee concludes that there is a sufficient evidence for an association between deployment to the Gulf War and chronic fatigue syndrome. The underlying basis of the possible relationship is unclear, however, and further research is recommended.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
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TABLE 4-15 Multisymptom Illnesses

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

Factor analyses and surveys

Haley and Kurt, 1997 (Vol. 4)

Exploratory factor analysis of 52 symptoms

Active-duty and retired Navy GWVs (n = 249)

Factor-analysis derived syndromes

Impaired cognition Confusion-ataxia Arthromyoneuropathy Phobia-apraxia Fever-adenopathy Weakness-incontinence

 

Small cohort size, no nondeployed control group Accounted for 71% of observed variance

Fukuda et al., 1998 (Vol. 4)

Cross-sectional population survey; factor analysis (of 35 symptoms) to identify symptom categories in combination with clinical reasoning

3675 members of the air force, including National Guard, reserve, and active-duty components (1155 GWVs and 2520 NDVs) Factor analysis: n = 3255

Cases defined as having one or more symptoms from at least two of the three identified symptom categories: Fatigue Mood-cognition Musculoskeletal

GWV vs NDV: Mild-to-moderate cases (449 vs 354) OR 4.08 (95% CI 3.39-4.93)

Severe cases (68 vs 18) OR 16.18 (95% CI 8.99-29.14)

Rank, sex, age, smoking status

Symptom categories accounted for 39% of common variance

Nisenbaum et al., 2000

Cross-sectional survey

1002 air force GWVs selected from the population described by Fukuda et al. (1998)

Association of self-reported exposures with mild-to-moderate and severe cases, as defined by Fukuda et al. (1998)

Belief that biological or chemical weapons were used, OR 3.5 (95% CI 1.7-6.9) and OR 2.3 (95% CI 1.5-3.3); PB, OR 2.9 (95% CI 1.4-6.1) and OR 1.6 (95% CI 1.1-2.2); Insect repellent, OR 2.4 (95% CI 1.3-4.5) and OR 1.7 (95% CI 1.2-2.3); Injuries requiring medical attention, severe cases only OR = 2.1 (95% CI 1.1-4.3)

Age, sex, smoking status, current rank

All exposures self-reported

Ismail et al., 1999 (Vol. 4)

Exploratory factor analysis of 52 symptoms (Based on survey conducted by

3214 male UK GWVs compared to 1770 Bosnia veterans and 2384 nondeployed era

Symptom categories

Mood-cognition Respiratory symptoms Peripheral nervous system symptoms Frequency of symptom reporting

 

Response rates: GWVs (76%), Bosnia veterans (42%), era veterans (56%) Factor categories

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

 

Unwin et al., 1999)

veterans

 

higher in GWVs compared to Bosnia and era cohorts, but similar correlations between symptoms for all cohorts

 

accounted for 20% of the common variance

Kang et al., 2002 (Vol. 4)

Exploratory factor analysis of 47 symptoms

GWVs (n = 10,423) compared to nondeployed era veterans (n = 8960)

Symptom clusters; association of symptom clusters with self-reported exposures

Five similar symptom clusters were found in both groups: Fatigue or depression Musculoskeletal/rheumatologic Gastrointestinal Pulmonary Upper respiratory Four symptoms comprised a neurologic cluster that appeared to be unique to GWVs: blurred vision, loss of balance/dizziness, tremors/shaking, and speech difficulty. 277 (2.4%) GWVs reported mild or severe problems with these symptoms, compared to 43 (0.45%) nondeployed. In addition, at least 3 out of 4 of these symptoms were observed in 877 (7.7%) GWVs vs 175 (1.8%) nondeployed veterans Exposures associated with four-symptom cases (n = 277) vs nonsymptomatic controls (n = 6730), p < 0.0001: Contaminated food (73% vs 21%); nerve gas (42% vs 5%); DU (29% vs 7%); toxic paint (51% vs 16%); bathed in or drank contaminated water (60% vs 19%); sexual assault (3.3% vs 0.4%); sexual harassment (15% vs 3%); Botulism vaccine (26% vs 9%)

 

69% response rate in GWVs and 60% in era controls 69% of the GWVs suffering all four symptoms also met criteria for PTSD

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

Ishoy et al., 1999a (Vol. 4)

Cross-sectional

686 Danish peacekeepers deployed to gulf in 1990-1997 vs 231 age- and sex-matched armed forces nondeployed controls

Health examination by physician, including lung function and self-report questionnaire of symptoms

Deployed veterans reported higher prevalence (p < 0.05) of 17 out of 22 neuropsychological symptoms, 8 out of 14 gastrointestinal symptoms, and 8 out of 19 skin symptoms 81% of deployed veterans compared to 71% of controls had one or more ICD-10 diagnoses at examination (p = 0.002)

 

Participation rate: 83.6% deployed, 57.8% nondeployed

Blanchard et al., 2006 (Update)

Cross-sectional

1035 GWVs vs 1116 NDVs

CMI determined by medical examination in 1999-2001

Deployed vs nondeployed: CMI (all cases), 29% vs 16% (OR 2.16, 95% CI 1.61-2.90) Mild to moderate cases, 25% vs 15% (OR 1.92, 95% CI 1.41-2.63) Severe cases, 7% vs 1.6% (OR 4.65, 95% CI 2.27-9.52)

Age, sex, race, education, duty type, service branch, rank, income, combat exposure score, Khamisiyah exposure, psychiatric and other diagnoses prior to GW

Participation rate: 52% deployed, 39% nondeployed

Nisenbaum et al., 2004 (Vol. 4)

Dichotomous factor analysis (Reanalysis of survey results from Fukuda et al., 1998, and Ismail et al., 1999)

3454 male UK GWVs compared to 1979 Bosnia veterans and 2577 nondeployed era veterans 1163 deployed US Air Force veterans

Symptom clusters

UK cohort: Identified a cluster of gastrointestinal/urogenital symptoms that loaded to deployed veterans but not to either control group Confirmed factors identified by Ismail et al. (1999) were very similar across all three cohorts US Cohort: Gastrointestinal/respiratory Allergies Mood-cognition Musculoskeletal

 

No control group in US cohort

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

Hospitalization studies

Gray et al., 1996 (Update)

Retrospective cohort, hospitalizations from August 1991 through September 1993

547,076 active-duty GWVs, 618,335 NDVs

Hospital-discharge diagnoses of circulatory system disease in DoD hospital system (ICD9 classification)

No increase in any-cause hospitalization among deployed GWVs

Prewar hospitalization, sex, age, race, service branch, marital status, rank, length of service, salary, occupation

Very short follow-up period; no outpatient data; restriction to DoD hospitals, and thus to persons remaining on active duty after the war; no adjustment for potential confounders such as smoking

Knoke et al., 1998 (Update)

 

552,111 deployed vs 1,479,751 nondeployed servicemembers in service during Gulf War and remaining there through 1996

Hospitalization records: DoD only, 1991-1996, ICD 799.9 (unexplained illness)

No excess in hospitalizations in this period when effect of CCEP was eliminated

Race, rank, salary, military branch, occupation, prewar hospitalization, sex

Active duty only, no assessment of outpatient treatment, respiratory findings removed after adjustment for VA screening-program attendance

Gray et al., 2000 (Update)

Retrospective cohort, hospitalizations from August 1991 through December 1994

652,979 GWVs, 652,922 randomly selected NDVs: 182,164 DoD hospitalizations; 16,030 VA hospitalizations; 5185 COSHPD hospitalizations

Hospital-discharge diagnoses in DoD, VA, and COSHPD hospital systems

Similar rates of hospitalization between deployed and nondeployed veterans

Age, sex, race (only for DoD PMR)

Able to assess only illnesses that resulted in hospitalization; possible undetected confounders PMR has lower sensitivity than a comparison of hospitalization rates would have

Smith et al., 2006 (Update)

Retrospective cohort study (cohort data from DMDC)

Active-duty personnel with a single deployment to: Gulf War theater (n = 455,465); southwest Asia, 1991-1998 (n = 249,047); Bosnia, 1995-1998 (n = 44,341)

Postdeployment hospitalization events (1991-2000)

Veterans of southwest Asia had slightly higher rate of hospitalization compared to deployed GWVs, while veterans of Bosnia had slightly lower rate of hospitalizations

Sex, age, marital status, pay grade, race/ethnicity, service branch, occupation, and predeployment hospitalization; time-dependent

Lower hazard ratio observed in veterans of Bosnia may be partially explained by shorter follow-up period Limitations: active-duty personnel only; hospitalizations at DoD facilities only

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

 

covariate to account for changing hospitalization methods, diagnostic criteria, and procedures

 

Chronic fatigue syndrome (CFS)

Eisen et al., 2005 (Vol. 4)

Population-based, cross-sectional, prevalence, in-person medical and psychiatric evaluations

1061 GWVs vs 1128 NDVs; selected from among those who had participated in 1995 National Health Survey of Gulf War Era Veterans and Their Families (mail and telephone survey) (Kang et al., 2000)

CFS based on in-person interviews according to CDC CFS criteria and exclusionary diagnoses from history, interviews, examinations, laboratory testing

OR 40.6, 95% CI 10.2-161.2

Age, sex, race, smoking, duty type, service branch, rank

Low participation rates (53% of deployed and 39% of nondeployed), but analysis of nonparticipants and participants reveals that participants, both deployed and nondeployed, are more likely to report symptoms of CFS

Kelsall et al., 2006 (Update)

Cross-sectional survey

1424 Australian male GWVs, 1548 male NDVs frequency matched by age and service type (Same population as Kelsall et al., 2004a,b, 2005)

Association of unexplained chronic fatigue and CFS determined in clinical assessment with self-reported exposure to various stressors

CFS in deployed veterans vs control groups OR 1.2 (95% CI 0.5-2.9) Chronic fatigue (≥ 6 months) OR 1.9 (95% CI 1.4-2.7) 91 (6.6%) GWVs had unexplained chronic fatigue vs 40 (2.9%) of controls (OR 2.3, 95% CI 1.6-3.4) Unexplained chronic fatigue in GWVs associated with PB (OR 2.8, 95% CI 1.3-6.1), oil smoke (OR 2.0, 95% CI 1.2-3.4), pesticides (OR 2.4, 95% CI 1.53.8), presence in chemical weapons area (OR 4.6, 95% CI

Age, service branch, rank; also education, marital status, smoking, and alcohol use for unexplained chronic fatigue.

Relatively large study with national ascertainment; response rate 80.5% for deployed, 56.8% for nondeployed Exposures self-reported; possible recall bias

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Reference

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

 

 

2.7-7.8), and deployed during air war (OR 2.3, 95% CI 1.1-4.5)

 

 

Ismail et al., 2008 (Update)

Two-phase cohort study; first phase population-based postal survey, second phase random sample of disabled phase 2 responders

111 deployed GWVs; 133 era veterans, including Bosnia peacekeepers; must have physical disability (less than 72.2 on SF-36 physical functioning scale from phase 1 survey) (Population derived from Unwin et al., 1999, and Ismail et al., 2002)

CFS determined through clinical assessment using CDC criteria

20 disabled GWVs (18%) and 4 disabled controls (3%), OR 7.8, 95% CI 2.5-24.5

Age, sex, rank, marital status, alcohol-disorders, selection bias via probability weights

Phase 1 response rate 70% for GWVs, 60% and 63% for Bosnia and era veterans, respectively. Phase 2 response rate 67% for GWVs, 55% and 43% for Bosnia and era veterans, respectively. 54% of GWVs with CFS had concomitant depression or anxiety disorder

NOTE: CCEP = Comprehensive Clinical Evaluation Program; CDC = Centers for Disease Control and Prevention; CFS = chronic fatigue syndrome; CI = confidence interval; CMI = chronic multisymptom illness; COSHPD = California Office of Statewide Health Planning and Development; CWP = chronic widespread pain; DMDC = Defense Manpower Data Center; DoD = Department of Defense; DU = depleted uranium; GWV = Gulf War veteran; NDV = nondeployed veteran; OR = odds ratio; PB = pyridostigmine bromide; PMR = personal medical record; VA = Department of Veterans Affairs.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

EXTERNAL CAUSES OF MORTALITY

This section evaluates the findings on external causes of death among Gulf War veterans. Examples of major subgroups within this category include deaths due to accidents, such as motor vehicle accidents, and homicides and suicides. Studies of veterans of other wars, such as the Vietnam War, have found increased mortality from external causes, particularly in the years immediately following deployment (IOM, 2006). Primary studies on the mortality of Gulf War veterans are summarized in Table 4-16.

Summary of Volume 4

Primary Studies

For external causes of mortality, the Volume 4 committee identified four studies that met the criteria for primary studies (DASA, 2005; Kang and Bullman, 1996, 2001; Macfarlane et al., 2000).

In the first large mortality study of US Gulf War veterans, Kang and Bullman (1996) examined records from the VA BIRLS and deaths reported to the SSA for the period from 1991 to 1993.5 The authors identified no excess all-cause mortality in deployed (n = 695,516) veterans compared with nondeployed veterans (n = 746,291), adjusted for age, race, marital status, branch of service, and type of unit. However, they did find higher mortality from motor vehicle accidents among deployed than among nondeployed veterans (RR 1.31, 95% CI 1.14-1.49), although the risk was lower than the expected rate based on overall US mortality (SMR 0.82, 95% CI 0.75-0.89) after adjustment for age, sex, race, and year of death. No increase in suicide or homicide among Gulf War veterans was found (Kang and Bullman, 1996). In a subsequent publication, Kang and Bullman (2001) found no excess mortality from motor vehicle accidents after 1993, a mortality pattern which is consistent with that following the Vietnam War (CDC, 1987; Thomas et al., 1991; Watanabe and Kang, 1995). Suicide rates were about equal through 1997 in deployed and nondeployed veterans (MRR 0.92, 95% CI 0.83-1.02). This later study again found no difference in all-cause mortality between deployed and nondeployed veterans, although it did find that the mortality rate in both cohorts was less than half of that expected for their civilian counterparts (Kang and Bullman, 2001).

Macfarlane et al. (2000) found no significant increase in mortality between UK Gulf War veterans (n = 53,462) and a control group of contemporaneous veterans (n = 53,450) matched by sex, age, branch of service, and level of fitness, the last factor included in an attempt to account for the healthy warrior effect. A small increase in accidental death was noted, but confidence intervals included 1.0 (MRR 1.18, 95% CI 0.98-1.42). The increase was primarily due to motor vehicle accidents (MRR 1.25, 95% CI 0.91-1.72). They did not did not address changes over time in excess external cause (or motor vehicle) mortality and did not find higher suicide or homicide rates in deployed compared to nondeployed veterans.

The UK Defence Analystical Service Agency (DASA, 2005) periodically publishes cumulative mortality figures for deployed veterans compared with Gulf War era controls. From April 1, 1991, to December 31, 2007, Gulf War veterans had no significant increase in mortality;

5

The degree of completeness of these record systems was assessed with a validation study that used state vital-statistics data. Ascertainment was estimated at 89% of all deaths in the Gulf War cohort and comparison group.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

however, DASA (2005) did observe small nonsignificant increases in transportation accident mortality (SMR 1.21, 95% CI 0.96-1.51), intentional self-harm (SMR 1.08, 95% CI 0.85-1.39), and other accidental mortality—including falls, drowning, and poisoning (SMR 1.07, 95% CI 0.74-1.54), but by 2007, these differences were not significant (DASA, 2009). When compared with earlier surveillance, these data show that any difference in the rate of external cause mortality in deployed veterans versus the era controls disappeared approximately 10 years after the war (DASA, 2005).

Secondary Studies

Two studies of external cause mortality in Gulf War veterans were identified as secondary studies by the Volume 4 committee. Writer et al. (1996) found an increased rate of noncombat mortality due to accidental injury in US active-duty troops stationed in the Gulf War compared to troops on active duty elsewhere between 1990 and 1991 (69% vs 41%, no indication of significance given). In a nested case-control study using the Gulf War-deployed and nondeployed cohorts assembled by Kang and colleagues (1996), Gackstetter et al. (2002) found that deployed veterans who died in motor vehicle accidents through 1995 (n = 1,343) were more likely to be male, younger, less educated, and never married than nondeployed controls (10 controls/case). They were also more likely to be enlisted, have combat occupations, and be in the National Guard or reserves and not in the Air Force.

Updated and Supplemental Literature

Primary Studies

The Update committee identified four new primary studies of external cause mortality: DASA (2009), Lincoln et al. (2006), Macfarlane et al. (2005), and Statistics Canada (2005).

Lincoln et al. (2006) conducted a nested case-control study to assess individual characteristics of Gulf War and other veterans associated with risk of fatal motor vehicle accidents. The authors used the same cohort and method of identifying fatal crashes as in the previous study of Kang and Bullman (1996), but additional, individual characteristics were assessed. They obtained demographic data from the DMDC and motor vehicle crash data from the Department of Transportation’s Fatality Analysis Reporting System to identify 1318 motor vehicle crash fatalities between 1991 and 1995. They identified 765 motor vehicle deaths in deployed and 553 in era veterans (annual mortality rate 23.6, 95% CI 21.9-25.5) and found higher risk among those who were enlisted males, less educated, and did not use restraints. The deployed veterans may have been healthier initially, complicating the assessment of the full impact of deployment.

Macfarlane et al. (2005) conducted a cohort study of all UK Gulf War veterans (n = 51,753) and a matched cohort of 50,808 veterans not deployed to the Gulf. After 13 years of follow-up, they found little or no difference in overall mortality between those deployed and those not. A previously reported excess in non-disease-related mortality during the first 7 years of follow-up (MRR 1.31, 95% CI 1.06-1.63) was essentially absent in the later years (MRR 1.05, 95% CI 0.83-1.33). The strongest association was for transport accident deaths (MRR 1.44, 95% CI 1.13-1.84). Deployment was associated with little or no increased risk of intentional self-harm (MRR 1.04, 95% CI 0.80-1.36). Although the authors attempted to include all deployed UK veterans, the study is limited by the small size of the cohort.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Since publication of Volume 4, the Defence Analytical Services Agency (2009) has published updated summary statistics of mortality among deployed UK Gulf War veterans (n = 53,409) compared to a control group of era veterans (n = 54,143) from April 1, 1991, through December 31, 2007. The agency found no significant increase in the rate of all external cause mortality in UK Gulf War veterans versus era veterans (MRR 1.09, 95% CI 0.95-1.25), and in addition found no significant difference in the rate of mortality due to transportation accidents (MRR 1.17, 95% CI 0.94-1.45), other external cause injuries (MRR 1.04, 95% CI 0.74-1.45), or intentional self-harm and events of undetermined intent (MRR 1.12, 95% CI 0.89-1.40). The report also notes that the rate of mortality due to external causes has decreased from 1991 to 2007 for both deployed and nondeployed veterans, while the rate for a civilian cohort of similar size matched for age and sex has stayed relatively constant over the same time period.

A report from Statistics Canada (2005) used the cohort of Canadian veterans compiled by Goss Gilroy (1998) to compare mortality incidence between Gulf War deployed veterans (n = 5117) and a control group of era veterans (n = 6093), frequency matched for age, sex, and military duty status. Mortality data were obtained from the 1991-1999 Canadian Mortality Database. They found modest, but nonsignificant differences in mortality incidence among deployed veterans compared to nondeployed veterans due to all external causes (MRR 1.53, 95% CI 0.82-2.86), motor vehicle crashes (MRR 0.74, 95% CI 0.18-3.11), and suicide (MRR 1.17, 95% CI 0.46-2.95). The MRR for suicide was higher in the first 5 years of follow-up than in the second period. The overall risk of suicide was furthermore found to be comparable to (or lower than) the risk of suicide in the population (SMR 0.76, 95% CI 0.35-1.43). The report did find a significantly increased risk of mortality due to air and space crashes (MRR 5.50, 95% CI 1.16-26.0) in the deployed group, but the agency notes this might be explained by the fact that three times as many deployed veterans were in flight-related occupations (such as, pilots and navigators) as nondeployed veterans.

Bullman et al. (2005) examined the relationship between estimated exposure to chemical munitions destruction (sarin gas) at Khamisiyah in 1991 with cause-specific mortality of Gulf War veterans through December 31, 2000. Using the DoD’s 2000 sarin plume exposure model (Rostker, 2000), 100,487 deployed military personnel were identified as potentially exposed and 224,980 were considered unexposed. The authors reported no increase in external-cause mortality risk among exposed veterans as compared to unexposed veterans (RR 1.01, 95% CI 0.92-1.10), and no increased risk of suicide (RR 1.05, 95% CI 0.88-1.25) or motor vehicle fatalities (RR 1.00, 95% CI 0.86-1.17). Similarly, no increased risk for any external-cause mortality, or suicide or motor vehicle fatality specifically, was observed when the authors divided the exposed group into persons exposed for either 1 or 2 days for comparison with the unexposed group.

Secondary Studies

Several additional secondary studies were identified. Gray and Kang (2006) published results of a review of the literature concerning health of Gulf War veterans. They particularly noted the excess mortality from motor vehicle accidents and the decline in this excess over time since the war. They noted and largely discounted the possibility that deployed veterans could have been healthier initially than their nondeployed counterparts, at least in the US mortality studies. Hooper et al. (2005) conducted a nested case-control study of risk factors for deaths from motor vehicle accidents among Gulf War era veterans, using largely the same underlying cohort and nearly identical case group, methods and subjects as Lincoln et al. (2006). Using a

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

matched design and, after restrictions, 980 male cases and about 1300 controls, they identified younger age, lower education, and being unmarried as risk factors for fatal accidents among Gulf War veterans.

Summary and Conclusions

Since the last report, new studies have been published of external causes of death among Canadian and British veterans. These studies were small, reflecting the relatively small number of personnel deployed from these countries. In the British study, a previously reported increase in mortality from external causes had essentially disappeared with additional years of follow-up. In the Canadian study, there was an excess of deaths from air/space crashes among Gulf War veterans, but this may have been due to greater employment in the flight-related occupations. New studies concerning fatal motor vehicle accidents in US Gulf War era veterans focused on individual characteristics and found that younger age, lower education, and nonuse of restraints were risk factors for these fatal events. Perhaps the main limitation of all these new studies is shared with the older studies—deployed veterans may have been healthier initially, a difference which could tend to bias comparisons and obscure any effects of deployment to the gulf.

In conclusion, studies published to date have provided evidence of modestly higher mortality from transportation-related causes among Gulf War deployed veterans than other veterans. In US veterans, the excess is largely due to motor vehicle accidents, and has diminished and perhaps disappeared over time. A modestly higher mortality from airspace crashes that was noted in Canadian veterans may have been due to employment in flight-related occupations.

Therefore, the committee concludes that there is limited but suggestive evidence of an association between deployment to the Gulf War and an increase in mortality from external causes, primarily motor vehicle accidents, in the early years after deployment.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

TABLE 4-16 External Causes of Mortality

Study

Design

Population

Outcomes

Results

Adjustments

Comments

Kang and Bullman, 1996, 2001 (Vol. 4)

Retrospective cohort, 2.4-year follow-up; Retrospective cohort, approximately 7-year follow-up

695,516 GWVs vs 746,291 NDVs

Mortality 1991-1997; Cox proportional hazards models

Increased deaths from motor vehicle accidents in Kang and Bullman, 1996 (RR 1.31, 95% CI 1.14-1.49)

RRs became nonsignificant in Kang and Bullman, 2001 (RR 1.17, 95% CI 0.98-1.4) in 1994-1995;

Increased HIV deaths in NDVs; no difference in potential nerve gas exposure; no homicide or suicide increase

Sex, age, race, marital status, branch of service, type of unit

Short duration of follow-up; healthy warrior effect may obscure difference

Macfarlane et al., 2000 (Vol. 4)

Cohort study

53,462 UK GWVs vs 53,450 UK NDVs

Mortality 1991-1999

Higher mortality in Gulf War veterans from external causes (MRR 1.18, 95% CI 0.98-1.42); no increase in homicide or suicide

Matching by sex, age, branch, fitness for service

 

DASA, 2005 (Vol. 4)

Summary statistics of causes of death from April 1, 1991-June 30, 2005

53,409 UK GWVs vs 53,143 UK NDVs

Mortality 1991-June 2005

No increase in mortality except small and nonsignificant increase in “transport accidents” (SMR 1.21, 95% CI 0.96-1.51); “other external causes of accidental injury” (SMR 1.07, 95% CI 0.74-1.54); higher deaths from external causes disappeared about 10 years after Gulf War

Matching by sex, age, branch

 

Lincoln et al., 2006 (Update)

Retrospective cohort and nested case-control; risk factors for motor vehicle crash

1318 cases of motor vehicle crash mortality (1991-1995) identified from

Annual motor vehicle mortality rate by risk factor

Higher motor vehicle annual mortality rate in deployed veterans: 23.56 (95% CI 21.9-25.3) for deployed vs 15.87 (95% CI 14.6-17.3) for

 

Deployed population possibly associated with greater risk-taking behavior (younger,

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

fatality (Cohort derived from Kang and Bullman, 1996)

the VA’s 1991 Gulf War cohort: 765 deployed GWVs, 553 era veterans; COD, demographic, and military records from DMDC and FARS

 

nondeployed per 100,000

 

less educated, not married)

Macfarlane et al., 2005 (Update)

Cohort; 13-year follow-up (Follow-up of Macfarlane et al., 2000)

51,753 UK GWVs and 50,808 NDVs, randomly selected, matched by age, sex, service branch, rank; also fitness for active service in the army and Royal Air Force

Mortality rates

All causes (MRR 1.03, 95% CI 0.92-1.15); external causes (MRR 1.19, 95% CI 1.02-1.39); transport accidents (MRR 1.44, 95% CI 1.13-1.84); intentional self-harm (MRR 1.04, 95% CI 0.80-1.36)

No self-reported Gulf War theater exposure significantly associated with all cause, disease-related, or external mortality

 

Complete and long-term follow-up; cohort of moderate size; potentially other uncontrolled confounders

DASA, 2009 (Update)

Summary statistics of causes of death from April 1, 1991, to December 31, 2007

UK Gulf War veterans (n = 53,409) vs era veterans (n = 54,143)

Mortality data, causes of death classified based on ICD-10

All external cause mortality (MMR 1.09, 95% CI 0.95-1.25)

No significant difference in mortality rate was found for any of the specific external causes of mortality included in the study

Single years of age structure of the gulf cohort at January 1, 1991

 

Statistics Canada, 2005 (Update)

Retrospective cohort (Cohort based on Goss Gilroy, 1998)

5117 Canadian GWVs; 6093 Canadian NDVs, frequency matched for age,

Mortality and cancer incidences determined from the CMDB and CCDB, 1991-1999

All external causes (OR 1.53, 95% CI 0.82-2.86); motor vehicle crash (OR 0.74, 95% CI 0.18-3.11); air/space crash (OR 5.50, 95% CI 1.16-26.0);

Age, rank

 

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

Study

Design

Population

Outcomes

Results

Adjustments

Comments

 

 

sex, and military duty status

 

suicide (OR 1.17, 95% CI 0.46-2.95)

 

 

Bullman et al., 2005 (Update)

Cohort mortality study; follow-up from March 1991 through 2000 (population from same source as Kang and Bullman, 1996, 2001)

100,487 US Army GWVs exposed to chemical warfare agents at Khamisiyah; 224,980 nonexposed army GWVs; exposure determined from the DoD plume model (Rostker, 2000)

Association of exposure to chemical warfare agents and mortality, determined through BIRLS, SSA; COD data from NDI

Exposed vs unexposed Any external cause: Relative risk 1.01 (95% CI 0.92-1.10) Suicide: RR 1.05 (95% CI 0.88-1.25) Motor vehicle fatalities: RR 1.00 (95% CI 0.86-1.17)

Age, race, sex, rank, unit component

Limitations: short latency, possible exposure misclassification

NOTE: BIRLS = Beneficiary Identification and Records Locator Subsystem (VA); CI = confidence interval; CMDB = Canadian MIS Data Base; COD = cause of death; DoD = Department of Defense; FARS = Fatality Analysis Reporting System (Department of Transportation); GWV = Gulf War veteran; HR = adjusted hazard ratio; MRR = mortality rate ratio; NDI = National Death Index; NDV = nondeployed veteran; OR = adjusted odds ratio; RR = adjusted risk ratio; SMR = standardized mortality ratio; SSA = Social Security Administration.

Suggested Citation:"4 HEALTH OUTCOMES." Institute of Medicine. 2010. Gulf War and Health: Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. doi: 10.17226/12835.
×

FEMALE VETERANS’ HEALTH

Although women have always served in the military, primarily as nurses and clerks, the role of women in the military increased dramatically with the advent of an all volunteer military. During the Vietnam War, active-duty military women made up only 2.5% of the military forces. The Gulf War was among the first wars to see a sizable number of women in the military. During the Gulf War in 1990-1991, 33,000 to 37,000 military women were on the ground in the Persian Gulf, making up approximately 6.7% of the US military forces (Fricker et al., 2000).

Many of the studies discussed in this section were described in earlier sections in this chapter under specific health effects. This section pulls together the data on female veterans’ health in an attempt to provide an overview of the deployment experiences of women who deployed to the Persian Gulf region, the health effects they experienced after their deployment, including mental health effects, and their hospitalization and mortality outcomes. Although men serving in the military may be subject to sexual assault and harassment, women in the military are far more likely to be subject to this behavior and this experience is also discussed.

Deployment Experiences

Women and men who deployed to the Gulf War theater in 1990-1991 experienced many of the same exposures and stressors. Although women were not allowed to serve in combat specialties, they were deployed as administrators, air-traffic controllers, logisticians, ammunition technicians, engineering-equipment mechanics, ordnance specialists, communicators, radio operators, drivers, law-enforcement specialists, and guards. Many female truck drivers hauled supplies and equipment into Kuwait. Some took enemy prisoners of war to holding facilities, and others flew helicopters and reconnaissance aircraft. Still others served on hospital, supply, oiler, and ammunition ships or served as public affairs officers and chaplains (DoD, 2004). As a result of their service in the Gulf War theater, female military personnel were exposed to many of the same environmental agents and other stressors as were males, that is, biological and chemical agents, oil-well fire smoke, heat, pesticides, solvents, fuels, burning rubbish, and combat-related exposures, such as Scud missiles, dead and wounded people, and difficult living conditions. Female military personnel were more likely to experience sexual harassment and assault than were male personnel (Wolfe et al., 1998).

Vogt et al. (2005) queried 317 Gulf War veterans (including 83 females) about combat and other deployment experiences such as handling human remains and dealing with prisoners of war, perceived threats, difficult living and working environments, concerns about family and relationship disruptions, lack of deployment social support, and sexual harassment. There were no male-female differences for most of the stressor measures. Women reported more exposure to interpersonal stressors, such as incidents of sexual harassment, and less postdeployment social support, whereas men reported more mission-related stressors, such as combat experiences. Wolfe et al. (1993) also found that men (n = 2136) and women (n = 208) reported similar Gulf War deployment experiences, with over 70% of men and women receiving chemical and biologic attack alerts and incoming fire from large arms, and about