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Introduction AIthough individually rare, birth defects taken together account for a significant proportion of mortality and morbidity among infants and children in populations where infectious diseases are largely under control and nutritional deficiencies have for the most part been corrected (Jenkins, 19771. A birth defect is any structural or functional abnormality determined by factors operating largely before conception or during gestation. These abnormalities may be apparent immediately after birth, or they may manifest later in life. Birth defects result from a variety of factors, but most cannot yet be ascribed to a specific cause (Nelson and Holmes, 19891. There are three major categories of causes: (1) genetic, (2) environmental, and (3) complex genetic or unknown. Genetic (chromosomal and single-gene) causes are estimated to ac- count for about 25-30 percent of total birth defects. Chromosomal anoma- lies have been demonstrated in about 0.5 percent of newborn infants. This number may increase as modern cytogenetic techniques identify previously unrecognized chromosomal changes. An example of this is the recent use of telomeric probes, which found that 5-7 percent of mentally retarded chil- dren have a cryptic transiocation that had not been recognized using tradi- tional techniques (Knight et al., 19991. Approximately 1 percent of all births are characterized by a mutation at a single genetic locus. Usually there are no previously affected relatives. This is the case with lethal autosomal dominant traits, which typically arise as a result of a fresh mutation in the oocyte or sperm. Not all mutant genes manifest at birth or lead to structural malformations. However, the propor- tion of birth defects caused by known single-gene mutations is likely to be 11

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2 REDUCING THE IMPACT OF BIRTH DEFECTS higher than for chromosomal abnormalities, based on Nelson and Holmes' (1989) survey of nearly 70,000 newborns, in which there were three times as many single-gene mutations. Many mutations are likely to remain unrec- ognized until a function has been established for most of the thousands of human genes. Environmental causes are estimated to be responsible for about 5-10 percent of total birth defects (Nelson and Holmes, 19891. Environmental causes include nutritional deficiencies, maternal illnesses, infectious agents, and teratogenic drugs. Whether an exposure causes damage depends on several factors, including the actual exposure, the stage of gestation, and the individual's genetic susceptibility. Complex genetic or unknown causes are estimated to account for 65- 70 percent of all birth defects, some of which are lethal. Complex birth defects may involve a few interacting genes (oligogenic), many genes (poly- genic), the environment, or an interaction between genes and environment (multifactorial). Subtle chromosomal abnormalities may have been missed, complex genetic mechanisms may be identified when the functions of more genes are identified, and there may be previously undetected environmental influences. Families with an affected child have an increased incidence of almost all the birth defects that are restricted to a single organ system, such as cleft lip and/or cleft palate, developmental hip dysplasia, and most forms of cardiac anomalies (Simpson and Golbus, 19921. After the birth of an affected child, the risk that a subsequent child will be affected is typically 2-5 percent, which is many times higher than the incidence in the general population (less than 0.1 per cent for most single-organ malformations), but lower than the 25-50 percent expected if the etiology were due to a single gene. The birth defects discussed in this report (see Table 1-1) were selected from the thousands of known birth defects because of their severity, their prevalence in developing countries, and their representation in the medical literature from these countries. What is known, and not known, about these selected birth defects their prevalence, burden of disease, biological origins, associated risk factors, prevention, and treatment serve as the evidence base for the recommendations presented in this report on reducing the impact of birth defects in developing countries. MAGNITUDE OF THE PROBLEM The prevalence of specific birth defects varies widely with the ethnic, geographic, cultural, and economic characteristics of populations (Kuliev and Modell, 19901. The combined prevalence of all birth defects is esti- mated to be about 4-5 percent of live births in developed countries (Kuliev and Modell, 1990; World Health Organization, 1999; Penchaszadeh, 19941.

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INTRODUCTION TABLE 1-1 Causes, Classification, and Examples of Selected Birth Defectsa 13 Cause Classification Birth Defect Examples Genetic Chromosomal Single gene Environmental Infectious diseases (teratogenic) Other maternal illness Maternal nutritional deficiencies Folic acid Iodine Medications Thalidomide Misoprostol Anticonvulsants Anticoagulants Recreational drugs Alcohol Pollutants Organic mercury . . .. . Ionlzlng raalatlon Complex genetic and unknown Down syndrome Trisomy 18 Trisomy 13 or- and p-Thalassemias Sickle cell disorder G6PDb deficiency Oculocutaneous albinism Cystic fibrosis Phenylketonuria Hemophilia A and B Congenital rubella syndrome Congenital cytomegalovirus Toxoplasmosis Insulin-dependent diabetes mellitus Phenylketonuria Hyperthermia Neural tube defects Iodine deficiency disorders Reduction deformities of limbs Several Several Neurological damage Fetal alcohol syndrome Congenital malformations involving single organ systems Neurological damage Neurological damage Congenital heart disease Neural tube defects Cleft lip and/or cleft palate Talipes or clubfoot Developmental dysplasia of the hip aThese birth defects were selected on the basis of severity, prevalence in developing countries, and representation in the medical literature of developing countries. bG6PD = glucose-6-phosphate dehydrogenase.

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4 REDUCING THE IMPACT OF BIRTH DEFECTS In the developing countries with stronger health care systems and more complete data on birth defects, the birth prevalence of recognizable birth defects is estimated to be similar to that in developed countries (about 2-3 percent) (Castilla and Lopez-Camelo, 1990; International Clearinghouse for Birth Defects Monitoring Systems, 1998; Heredero, 1992; Delport et al., 1995; Venter et al., 1995; World Health Organization, 19971. Rates may be higher in some developing countries, underscoring the need for better surveillance data. Prevalence at birth represents only part of the total prevalence of birth defects because many conditions are not recognized for months or years after birth (Christianson et al., 1981; World Health Orga- nization, 1997; Venter et al., 19951. Global burden-of-disease data from 1990 show congenital anomalies to be the tenth leading cause of disability-adjusted life years in developing countries. This estimate, although the best available, is limited by a lack of accurate data on birth defects in many countries and by inadequate data on infants and children for conditions not detected at birth (Murray and Lopez, 1997; World Health Organization, 1999, 20001. What is certain, however, is that birth defects have a severe impact on individuals and their families because they manifest early in development and can cause early death or lifelong impairment. The prognosis for many children with birth defects can be improved only through surgical procedures, which may not be avail- able or affordable. Even those who receive treatment may require long-term care from their families a particular hardship for families in which more than one member is affected (Penchaszadeh, 19941. Birth defects therefore diminish the productivity and quality of life for affected individuals, for their families and communities, and ultimately for society as a whole. INCREASE IN THE IMPORTANCE OF BIRTH DEFECTS WITH DECREASING INFANT MORTALITY Over the last four decades, the average infant mortality rate in develop- ing countries has fallen from 137 to 66 per 1000 live births, largely as a result of improvements in safe childbirth and control of infectious diseases and malnutrition. Progress in lowering infant mortality rates has, however, varied greatly among developing countries. Those that have made the least progress toward this goal located mainly in sub-Saharan Africa and South Asia tend to have weaker health care systems (United Nations Children's Fund, 19981. Early progress in sub-Saharan Africa has been checked by the HIV/AIDS epidemic.) Most perinatal deaths in sub-Saharan Africa and iAlthough further discussion of HIV/AIDS is beyond the scope of this report, perinatal transmission of HIV/AIDS is discussed in detail in a companion report, Improving BirtI7 Outcomes: Meeting tile Challenge in tile DevelopingVDorld, also authored by this committee.

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INTRODUCTION 15 South Asia are caused by complicated deliveries, birth asphyxia, infections, and low birth weight. In these settings, infant mortality is best addressed by focusing on cost-effective medical services for basic reproductive care and safe delivery, control of infectious diseases, and treatment of nutritional inadequacies (Jenkins, 1977; Stoll and Measham, 20011. The most impressive reductions in infant mortality rates over the last four decades have been in Latin America and the Caribbean (from 105 to 35 per 1,000 live births), East Asia and the Pacific (133 to 41 per 1,000), and the Middle East and North Africa (154 to 50 per 1,000) (United Nations Children's Fund, 19981. By 1997, infant mortality rates had de- clined to less than 40 per 1,000 live births in 67 of the 142 developing countries, and 8 more countries had rates between 41 and 50 per 1,000. The population of the 75 countries with infant mortality rates below 50 per 1,000 was 2.8 billion, which represents 60 percent of the population of the developing world (United Nations Children's Fund, 19981. As infant mortality rates fall, birth defects are responsible for an in- creasing proportion of the infant mortality and morbidity (Modell and Kuliev, 1989; World Health Organization, 1997, 19991. In the majority of Latin American and Middle Eastern countries that have reduced infant mortality to less than 50 per 1,000, the infant mortality due to birth defects is as high as 25 percent (WorId Health Organization, 1997), which is similar to the proportion in developed countries. The increasing role of birth defects in countries that have lowered infant mortality rates is reflected in admissions to pediatric hospitals: 8-19 percent of total admissions in Middle Eastern Countries (WorId Health Organization, 1997) and 10-25 percent in some urban centers in Latin America. These hospital stays also tend to be longer and more expensive (Penchaszadeh, 1979; Carnevale et al., 19851. REDUCING BIRTH DEFECTS IN COUNTRIES WITH LOW INFANT MORTALITY Figure 1-1 shows decreases in the infant mortality rate over the last two decades for North Africa, the Middle East, and Pakistan. As these rates have decreased to a range of 20 to 40 per 1,000, several countries in these regions have introduced genetic screening programs for specific birth de- fects (Alwan and Modell, 19971. Such programs are less cost-effective than interventions that address basic reproductive care, but they have been iden- tilled by these countries as the next essential step in lowering infant mortal- ity rates cost-effectively. In 1981, Cuba established national genetic screen- ing in primary care programs, with referral to secondary and tertiary health care (Heredero, 19921. Cyprus, South Africa, and Iran also have primary care programs with genetic screening for specific birth defects (see Boxes 3-

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16 REDUCING THE IMPACT OF BIRTH DEFECTS 200 180 160 140 120 100 80 60 20 1981 o 200 180 160 140 120 100 80 60 20 t~ t~ ~d t~ ~ ~ ~ tt O ~ ~ ~ ~ O ~ Q ~ ma ~ ,,, <,, ~ ~~ i, ~ ~ ~~ ~ m a, Y ~ cn 1991 O- ~ `d ~ ~ ~ tt O tt ~ ~ .~ ~ ~ ~ Q sit E >_ CO ~t ~ o ~ ~ ~ ~~, cn ~ ~ ~ ~ .~ in O C' ~ a=, ~ ~ FIGURE 1-1 Infant mortality rates in North Africa, the Middle East, and Paki- stan over two decades.

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INTRODUCTION 180 - 160 140 In s . _ O 120 lo lo - s - 100 80 40 20 1 996 o ~ ~ t~ t~ t~ ~ to O ~ .~ ~ Q ~ ~ sit ~ 3 ~ 0 ~ ~ ~ ~ m A (3 FIGURE 1-1 continued SOURCE: Alwin and Modell, 1997 17 1 and 3-6 in Chapter 3) (Christianson et al., 1995; Christianson, 2000; Gaudet, 1999; Khoury et al., 2000~. In many other developing countries, including India and several in Latin America, genetic screening services are accessible only to middle- and high-income patients in the tertiary care centers of major cities (Jenkins, 1990; Penchaszadeh, 1992, 1993~. SOCIAL, ECONOMIC, AND HEALTH CONTEXT Effective strategies to address birth defects in developing countries must consider the competing health needs of these populations, as well as a variety of social, economic, and health system-specific factors that limit resources for health care. These factors include the following (WorId Health Organization, 1999~: Financial resources: The average per capita gross national products of developing countries are 10 to 40 times lower than those of developed countries. Income distribution: Extreme income inequalities result in a smaller proportion of the population having access to quality health care. In fact,

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18 REDUCING THE IMPACT OF BIRTH DEFECTS about one-quarter of the combined population of all cleveloping countries survives on less than $1 per clay. Eclucation: Literacy rates in cleveloping countries range from 57 to 87 percent and are generally lower among women than men. Fertility: Developing-country fertility rates are high relative to those of clevelopeci countries, particularly among less-eclucateci women. Infrastructure: Developing-country populations frequently lack ac- cess to safe water (70 percent), adequate sanitation (42 percent), transpor- . . . tattoo, anc communication. Infant mortality: Rates of infant mortality in the cleveloping world vary from as low as 9 cleaths per 1,000 live births in Cuba to as high as 191 per 1,000 live births in Niger. Burclen of disease: By the end of the twentieth century, about 42 percent of all cleaths in cleveloping countries were caused by avoidable conclitions such as infectious diseases, lack of reproductive health care, and nutritional deficiencies, compared with 6 percent in clevelopeci countries. To aciciress these challenges, programs must be tailored to the needs and resources of communities in each country. The recommendations in this report are intencleci to guicle the clevelopment of a capacity to aciciress birth defects that is integrated with and builds on current health care ser- vices for mothers, infants, and children. STUDY PURPOSE Despite major improvements in the knowledge of birth defects, their incidence and impact remain high in most countries. As infant and neonatal mortality clecline, an increasing proportion of adverse outcomes at birth are clue to birth defects. This stucly aciciresses the steps neecleci to improve the prevention of and care for birth defects by: Reviewing current knowledge and practices for a healthy pregnancy; Identifying cost-effective opportunities for prevention of birth cle- fects and support of families with a hanclicappeci infant; and Recommencling capacity-builcling, priority research, and institutional and global efforts to recluce the incidence and impact of birth defects in cleveloping countries. This report is intencleci to engage a broaci spectrum of inclivicluals and organizations that have the potential to leaci efforts to aciciress the global impact of birth defects. Such inclivicluals and groups inclucle, but are not limited to, policy makers, health ministries, United Nations agencies, multi- lateral clevelopment banks, international donor agencies, foundations, non-

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INTRODUCTION 19 governmental organizations, professional societies, pharmaceutical and medical-device companies, advocacy groups, health care professionals, re- searchers, consumer and patient advocacy groups, and interested members of the public. This diverse and influential audience holds the key to raising public awareness and generating the commitment and resources necessary to reduce the burden of birth defects in developing countries. STUDY APPROACH The Institute of Medicine (IOM) assembled a study committee with broad international expertise in public health, neonatology, obstetrics, genet- ics, epidemiology, pediatrics, and clinical research to prepare a report on improving birth outcomes in developing countries. The committee members are listed at the beginning of the report (biographies are provided in Appen- dix B). This report was prepared by the committee with the assistance of expert consultants to more fully address the issues involved in reducing birth defects. Although most committee members give highest priority to the issues covered in the broader report, they acknowledge the lack of epidemiological information on the rates and disease burden of birth defects in many develop- ing countries; the potential value of several affordable interventions; and, as countries reduce neonatal and infant mortality rates, the increasing propor- tion of the disease burden caused by birth defects. The data used for this study were assembled from bibliographic refer- ences on related topics and from databases such as MEDLINE, university libraries, and Internet sites of organizations associated with research and services for birth defects. Although much of the published information on these disorders in developing countries was found in international and national journals and reports, some of the evidence has appeared in local journals, proceedings of meetings, and unpublished reports prepared for the World Health Organization and other international organizations. To tap this broad knowledge base, the committee enlisted experts with recent research or service experience in developing countries. Data and evidence were provided by these experts through workshop presentations and tech- nical consultation on the report chapters. The framework for the com- mittee's examination of birth defects included an overview of epidemiologi- cal parameters; review of the current knowledge base on interventions; and examination of the feasibility, cost, and impact of proposed interventions. This combination of evidence, the committee believes, is an accurate repre- sentation of the state of knowledge concerning the epidemiology of birth defects, their prevention and care in developing countries, and the capacity of local health care systems to undertake prevention and care programs. Evaluation of this evidence enabled the committee to identify gaps in knowI- edge and to propose strategies for operational research to fill these gaps.

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20 REDUCING THE IMPACT OF BIRTH DEFECTS ORGANIZATION OF THE REPORT The next three chapters address the challenges of birth defects in devel- oping countries. Chapter 2 describes the causes of the major classes and types of birth defects, epidemiological parameters, and the burden of dis- ease in low-resource settings. Chapter 3 describes interventions that can reduce the impact of birth defects: first those that are effective and afford- able in settings with limited resources, and then screening services for ge- netic birth defects that are appropriate for countries in which infant and neonatal mortality rates have been lowered using the most cost-effective interventions. Examples of interventions from developing countries are de- scribed in boxes throughout the text. Chapter 4 provides a framework for implementing such interventions in primary health care systems. REFERENCES Alwan AA, Modell B. 1997. Community control of genetic and congenital disorders. Techni- cal publication series, No 24. Alexandria, Egypt. World Health Organization Regional Office for the Eastern Mediterranean. Carnevale A, Hernandez M, Reyes R. Paz F. Sosa C. 1985. The frequency and economic burden of genetic disease in a pediatric hospital in Mexico City. American Journal of Medical Genetics 20(4):665-675. Castilla EE, Lopez-Camelo JS. 1990. The surveillance of birth defects in South America: I. The search for time clusters: Epidemics. Advances in Mutagenesis Research 2:191-210. Christianson AL. 2000. Medical genetics in primary health care. Indian Journal of Pediatrics 67(11):831-835. Christianson AL, Gericke GS, Venter PA, du Toit JL. 1995. Genetics, primary health care and the Third World. SoutI7 African Medical Journal 85(1):6-7. Christianson RE, van den Berg BJ, Milkovich L, Oechsli FW. 1981. Incidence of congenital anomalies among white and black live births with long-term follow-up. American Jour- nal of Public HealtI7 71(12):1333-1341. Delport SD, Christianson AL, van den Berg HJ, Wolmarans L, Gericke GS. 1995. Congenital anomalies in black South African liveborn neonates at an urban academic hospital. SoutI7 A frican Medical Journal 8 5 ( 1 ): 1 1-15. Gaudet D. 1999. From DNA to the community. Community Genetics 2(4):139-140. Heredero L. 1992. Comprehensive national genetic program in a developing country Cuba. BirtI7 Defects Original Article Series 28(3):52-57. International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). 1998. VDorld Atlas of BirtI7 Defects. 1st edition. ICBD and European Register of Congenital Abnor- malities and Twins (EUROCAT). Jenkins T. 1977. The role of screening in the prevention of inherited disease in South Africa. SoutI7 African Medical Journal 51(23):832-837. Jenkins T. 1990. Medical genetics in South Africa. Journal of Medical Genetics 27(12):760- 779. Khoury MJ, Burke W. Thomson EJ (eds.). 2000. Genetics and Public HealtI7 in tI7e 21st Century: Using Genetic Information to Improve HealtI7 and Prevent Disease. New York: Oxford University Press.

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INTRODUCTION 21 Knight SJL, Regan R. Nicod A, Horsley SW, Kearney L, Homiray T. 1999. Subtle chromo- somal rearrangements in children with unexplained mental retardation. Lancet 354(9191):1676-1681. Kuliev A, Modell B. 1990. Problems in the control of genetic disorders. Biomedical Science 1(1):3-17. Modell B. Kuliev AM. 1989. Impact of public health on human genetics. Clinical Genetics 36(5):286-298. Murray CJ, Lopez AD. 1997. Regional patterns of disability-free life expectancy and disabil- ity-adjusted life expectancy: Global Burden of Disease Study. Lancet 349(9062):1347- 1352. Nelson K, Holmes LB. 1989. Malformations due to presumed spontaneous mutations in newborn infants. New England Journal of Medicine 320(1):19-23. Penchaszadeh VB. 1979. Frequency and characteristics of birth defects admissions to a pedi- atric hospital in Venezuela. American Journal of Medical Genetics 3(4):359-369. Penchaszadeh VB. 1992. Implementing comprehensive genetic services in developing coun- tries: Latin America. BirtI7 Defects Original Article Series 28(3):17-26. Penchaszadeh VB. 1993. Reproductive health and genetic testing in the Third World. Clinical Obstetrics and Gynecology 36(3):485-495. Penchaszadeh VB. 1994. Genetics and public health. Bulletin of tI7e Pan American HealtI7 Organization 28(1):62-72. Simpson and Golbus, 1992. Genetics in Obstetrics and Gynecology. 2nd edition. Philadel- phia: W.B. Saunders. Stoll BJ, Measham AR. 2001. Children can't wait: Improving the future for the world's poorest infants. Journal of Pediatrics 139(5):729-733. United Nations Children's Fund (UNICEF). 1998. TI7e State of tI7e VDorld's Children 1999. New York: UNICEF. United Nations Children's Fund (UNICEF). 2000. TI7e State of tI7e VDorld's Children 2001. New York: UNICEF. Venter PA, Christianson AL, Hutamo CM, Makhura MP, Gericke GS. 1995. Congenital anomalies in rural black South African neonates a silent epidemic? SoutI7 African Medi- cal Journal 85(1) :15-20. World Health Organization (WHO). 1997. Alwan AA, Modell B (eds.). Community Control of Genetic and Congenital Disorders. Alexandria, Egypt: WHO. World Health Organization (WHO). 1999. Human Genetics: Services for tI7e Prevention and Management of Genetic Disorders and BirtI7 Defects in Developing Countries: Report of a Joint VDHO/VDOAPBD Meeting. Geneva: WHO. World Health Organization (WHO). 2000. Primary HealtI7 Care ApproacI7es for tI7e Preven- tion and Control of Congenital Genetic Disorders: Report of a VDHO Meeting. Geneva: WHO.