Summary of Findings: Reducing Mortality and Morbidity from Birth Defects

  • In developing countries, more than 4 million children are born each year with birth defects. As infant mortality and morbidity due to infectious diseases, birth asphyxia, and other causes are controlled, the relative contribution of birth defects is expected to increase.

  • Birth defects have three major causes: genetic, environmental, and complex genetic or unknown. The prevalence of individual conditions varies in different populations.

  • The path to reducing the impact of birth defects may be viewed as a multistage process, beginning with the introduction of practical, low-cost interventions for prevention and early diagnosis and treatment where possible, followed by provision of more elaborate treatment and therapy, then by genetic screening and possible termination of pregnancies with a severe birth defect.

  • Basic reproductive care, including family planning and preconceptional, antenatal, and neonatal care, is the foundation for reducing birth defects.

  • Specific interventions for reducing the prevalence and impact of birth defects include: folic acid supplementation for all women of reproductive age; universal fortification of salt with iodine; rubella immunization during childhood; and efforts to encourage women to limit their childbearing years to before age 35 and to limit alcohol consumption.

  • Even where health care resources are limited, there are affordable strategies for the treatment and rehabilitation of some conditions when they are diagnosed early.

  • Countries with comprehensive health care and lower infant mortality rates can further reduce infant mortality by establishing preconceptional, antenatal, and neonatal screening programs for common and severe birth defects.



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Improving Birth Outcomes: Meeting the Challenge in the Developing World Summary of Findings: Reducing Mortality and Morbidity from Birth Defects In developing countries, more than 4 million children are born each year with birth defects. As infant mortality and morbidity due to infectious diseases, birth asphyxia, and other causes are controlled, the relative contribution of birth defects is expected to increase. Birth defects have three major causes: genetic, environmental, and complex genetic or unknown. The prevalence of individual conditions varies in different populations. The path to reducing the impact of birth defects may be viewed as a multistage process, beginning with the introduction of practical, low-cost interventions for prevention and early diagnosis and treatment where possible, followed by provision of more elaborate treatment and therapy, then by genetic screening and possible termination of pregnancies with a severe birth defect. Basic reproductive care, including family planning and preconceptional, antenatal, and neonatal care, is the foundation for reducing birth defects. Specific interventions for reducing the prevalence and impact of birth defects include: folic acid supplementation for all women of reproductive age; universal fortification of salt with iodine; rubella immunization during childhood; and efforts to encourage women to limit their childbearing years to before age 35 and to limit alcohol consumption. Even where health care resources are limited, there are affordable strategies for the treatment and rehabilitation of some conditions when they are diagnosed early. Countries with comprehensive health care and lower infant mortality rates can further reduce infant mortality by establishing preconceptional, antenatal, and neonatal screening programs for common and severe birth defects.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World 7 Reducing Mortality and Morbidity from Birth Defects About 2 to 3 percent of all children are born with a birth defect (Van Allen and Hall, 1996). In 2002, there were about 133 million births reported, 90 percent of them in less developed countries (Population Reference Bureau, 2002). Thus in developing countries, about four or more million children are born with birth defects. Birth defects or congenital anomalies are defined as any structural or functional abnormality determined by factors operating largely before conception or during gestation. Birth defects may be apparent immediately after birth or may manifest themselves later in life. As infant mortality and morbidity due to infectious diseases, birth asphyxia, and other causes are controlled, the burden of disease associated with birth defects becomes more important. Comprehensive, reliable data on birth defects are not available for most developing countries. However, there can be no doubt that birth defects cause enormous harm in circumstances where risk factors for many conditions are elevated and resources for health care are limited. Prevention of certain birth defects can be addressed in almost all settings. This chapter reviews the causes of some of the birth defects that are more prevalent in developing countries and describes ways to reduce their impact through prevention, early identification and treatment, and in settings with more resources, through screening for genetic diseases. A companion report, Reducing the Impact of Birth Defects: Meeting the Challenge in the Developing World (Institute of Medicine, 2003) discusses these topics in greater detail and describes the treatment of birth defects beyond the neonatal period.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World PATTERNS OF OCCURRENCE While individually rare, birth defects taken together account for a significant proportion of mortality and morbidity among neonates, infants, and children. Figure 3-1 in Chapter 3 shows that congenital anomalies are responsible for 11 percent of global neonatal mortality. Their contribution to neonatal morbidity is also substantial. The role of birth defects increases as other health problems are addressed and infant mortality rates are reduced. The birth prevalence of individual conditions varies widely in different populations. In low-income countries, birth defects that cause early death or chronic lifelong disability may have a birth prevalence as high as 45 per 1,000 live births—triple that in wealthy countries (World Health Organization, 1985). Two factors that contribute substantially to the birth prevalence and prevalence of birth defects in different settings are inadequate health care and advanced maternal age (Kuliev and Modell, 1990; World Health Organization, 1997, 1999). Many countries lack health-related statistics and registries, and about one-third of all births—an estimated 40 million each year—are not registered (Murray and Lopez, 1996; World Health Organization, 1997, 1999). Data are also incomplete on birth defects in developing countries, but some large-scale programs monitor the occurrence of birth defects in specific regions of the world. These include the International Clearinghouse for Birth Defects Monitoring System (ICBDMS), the Latin American Collaborative Study of Congenital Malformations (ECLAMC), the Chinese Birth Defects Monitoring Program (CBDMP), and the European Register of Congenital Abnormalities and Twins (EUROCAT). Data from these registries and from the research literature inform this chapter’s descriptions of the pathology of birth defects and their patterns of occurrence in developing countries. CAUSES OF BIRTH DEFECTS Birth defects can be divided into three classes, based on their known or suspected causes: genetic birth defects, which include chromosomal abnormalities and single-gene disorders; birth defects of environmental origin, caused solely by teratogens such as infectious agents, drugs, and nutritional deficiencies; and complex genetic or unknown causes, which may result from interactions among a few or several genes and may be influenced by environmental factors (see Table 7-1). Chromosomal abnormalities and single gene mutations are important demonstrable causes of birth defects (Nelson and Holmes, 1989). The specific conditions included in this chapter were chosen because of

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Improving Birth Outcomes: Meeting the Challenge in the Developing World TABLE 7-1 The Cause and Classification of the Birth Defects Included in This Reporta Cause Classification Selected Birth Defects Genetic Chromosomal Down syndrome Single gene α-and β-Thalassemias Sickle cell disorder G6PDb deficiency Environmental (teratogenic) Infectious diseases Congenital rubella syndrome   Insulin-dependent diabetes mellitus Cardiovascular and nervous system damage Hyperthermia Neural tube defects Maternal nutritional deficiencies   Folic acid Iodine Neural tube defects Iodine deficiency disorders Medications   Thalidomide Misoprostol Anticonvulsants Anticoagulants Limb reduction deformities Several Several Neurologic damage Recreational drugs   Alcohol Fetal alcohol syndrome Pollutants   Organic mercury Neurological damage Ionizing radiation Neurological damage Complex genetic and unknown Congenital malformations involving single organ systems Congenital heart disease Neural tube defects Cleft lip and/or cleft palate Talipes or clubfoot Developmental dysplasia of the hip aThe birth defects included in this report were selected for their severity, prevalence in developing countries, and having effective, affordable interventions to reduce their impact. Additional birth defects are included in the companion report, Reducing the Impact of Birth Defects: Meeting the Challenge in the Developing World (Institute of Medicine, 2003). bG6PD = Glucose-6-phosphate dehydrogenase.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World their severity and prevalence in developing countries, and because of the availablity of affordable, effective interventions that can reduce their impact. What is known, and not known, about these birth defects—their prevalence, burden of disease, biological origins, associated risk factors, prevention, and treatment—informs the committee’s overall recommendations. Genetic Birth Defects Chromosomal disorders Sporadic (nonhereditary) losses or rearrangements of genetic material affect at least 10 percent of conceptions, 90 percent of which end in spontaneous abortion. Surviving infants may have a congenital malformation, mental retardation, or disorders in sexual differentiation (World Health Organization, 1999). Advanced maternal age is the only well-documented risk factor (Nicolaidis and Petersen, 1998), and this is relatively constant across races and ethnic groups (Carothers et al., 2001). Down syndrome is caused by abnormalities involving chromosome 21. The most common form is the presence of an extra chromosome 21 (trisomy 21) in cells of the fetus or infant, the extra chromosome usually coming from the mother. The risk of trisomy 21 increases with maternal age, first slowly then more rapidly above 35 years of age. Affected infants have many problems, including life-threatening cardiac and gastrointestinal abnormalities, susceptibility to infection, and unpredictable and varying degrees of mental impairment, from profound to moderate or even mild (Bishop et al., 1996). Even with the best care, including antibiotics and corrective heart surgery, many die in early infancy or childhood and very few survive middle age. Congenital heart disease associated with Down syndrome is the major cause of death. In resource-poor situations, mortality is very high. Down syndrome can also result in a spontaneous abortion. The estimated incidence of Down syndrome at birth in developing countries is considerably higher than in developed countries (Kuliev and Modell, 1990; United Nations Population Fund, 1998; World Health Organization, 1996). This is consistent with the proportion of births to women over 35 years of age, which averages 11 to 15 percent in developing countries compared with 5 to 9 percent in developed countries (World Health Organization, 1999). Single-gene disorders More than 6,000 different single-gene (Mendelian or monogenic) conditions have been described (World Health Organization, 1997). Although individually rare, together they are estimated to account for a global birth

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Improving Birth Outcomes: Meeting the Challenge in the Developing World prevalence of 10 per 1,000 (World Health Organization, 1999). Single-gene disorders are classified by mode of inheritance as autosomal recessive, autosomal dominant, or X-linked recessive. For autosomal recessive traits to be expressed, two copies of the mutated gene must be present; if both parents are carriers of the same disease-causing recessive gene, each child has a 25 percent chance of having the disease and a 50 percent chance of being a carrier. Consanguineous marriage increases the birth prevalence of autosomal recessive diseases. For example, 93 percent of Palestinian Arabs who are parents of children with rare autosomal disorders have been shown to be related, while in the general population only 44 percent of couples are consanguineous (Zlotogora, 1997). Central nervous system anomalies were associated with consanguinity in studies conducted in the United Arab Emirates (al-Gazali et al., 1999) and Saudi Arabia (Murshid, 2000). Major malformations (including, but not limited to, nervous system anomalies) were found at significantly higher rates among children of consanguineous parents in south India (Kulkarni and Kurian, 1990) and in an Israeli Arab community (Jaber et al., 1992). Thalassemias are autosomal recessive conditions that result from mutations in genes that synthesize the α- and β-globin chains of the hemoglobin molecule. β-Thalassemias occur most often in Mediterranean populations and are due to the absence or malfunction of the β-globin chains. Children with β-thalassemia major do not present symptoms in the first month of life; then in the second six months they often fail to thrive and may suffer from recurrent bacterial infections, severe anemia, hepatosplenomegaly, and bone expansion, which gives rise to classical thalassemia facies. Left untreated, which is the case in many low-income settings, severe β-thalassemia is fatal in childhood or early adolescence (Weatherall and Clegg, 2001); with regular transfusions, patients live into their twenties and longer if treated to prevent iron overload. α-Thalassemias, which are most prevalent in Asia, may involve mild anemia in some heterozygotes or fetal mortality for severe homozygous states. Thalassemia has a high incidence in the geographical area extending across the Mediterranean and parts of Africa, through the Middle East, India, and Southeast Asia, and into the Pacific Islands. In these areas, the carrier frequency for β-thalassemia varies from 1 to 20 percent. Carriers for the milder form of α-thalassemia range from 10 to 20 percent of the population in parts of sub-Saharan Africa to 40 percent or more in parts of the Middle East, India, and Papua New Guinea. Carriers of the more severe form of β-thalassemia occur at high frequencies but in a more limited area, which includes parts of Southeast Asia and the Mediterranean (Weatherall and Clegg, 2001). Sickle cell disease, an autosomal recessive structural hemoglobin ab-

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Improving Birth Outcomes: Meeting the Challenge in the Developing World normality, occurs with increased incidence in populations of Africa and the Mediterranean. The high frequency of sickle cell disease in these populations is attributed to the lower mortality from malaria among heterozygotes (carriers of the sickle cell trait) compared with noncarriers (Ashley-Koch et al., 2000). Relatively high rates of consanguineous marriage in the Eastern Mediterranean region have increased the prevalence of sickle cell disease in that population (World Health Organization, 1997). Children with sickle cell disease are susceptible to episodes of painful vaso-occlusive crises and chronic anemia and are at increased risk for developing infections, including meningitis and pneumonia, which can be fatal. In sub-Saharan Africa, many children with sickle cell disease die early in life (Weatherall and Clegg, 2001). Epidemiological studies of sickle cell disease suggest a range in the birth prevalence among and within developing countries. The combined carrier rates for sickle cell disease and hemoglobin C disease would be expected to result in about 90,000 affected births per year in Nigeria alone, but the prevalence of the disorder in the general population is low because a large majority of patients with sickle cell anemia (HbSS) die undiagnosed in childhood (Akinyanju, 1989; Angastiniotis et al., 1995). Glucose-6-phosphate dehydrogenase (G6PD) deficiency results from recessive mutations in the X-linked gene for the enzyme G6PD. More than 100 variants of G6PD deficiency have been identified among the millions of affected people throughout the world. The disorder is most prevalent in Central, West, and East Africa, the Eastern Mediterranean, and South and East Asia (World Health Organization, 1997; El-Hazmi and Warsy, 1996). Individuals deficient in G6PD can develop acute hemolytic anemia as a result of infections, exposure to oxidants, or consumption of fava beans. Severe hemolysis in these cases can be fatal (Steensma et al., 2001). As with the thalassemias and sickle cell disease, carriers of G6PD deficiency have a selective advantage against infection by malaria (Roth et al., 1983). Birth Defects of Environmental Origin Maternal illness The majority of infections during pregnancy do not affect the fetus; those that do, however, can cause fetal loss or severe birth defects. Teratogenic pathogens may exert an immediate effect or initiate complex processes that cause damage throughout gestation and into infancy (Alford and Pass, 1981). Although infections cause only a fraction of total birth defects, they are an important preventable cause. Congenital rubella syndrome (CRS) results from maternal infection with rubella virus in early gestation. The condition interferes with critical

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Improving Birth Outcomes: Meeting the Challenge in the Developing World organ development in the fetus and can cause a spectrum of birth defects including blindness, deafness, cardiovascular anomalies, and mental retardation. The prognosis for infants with severe CRS is poor. For those diagnosed in the first year, mortality is high and most survivors are seriously impaired (Bos et al., 1995). In unimmunized populations, rubella epidemics occur about every 4 to 7 years (Cutts et al., 1997). Over the last 25 years, surveillance of these epidemics has documented CRS birth prevalence rates of 0.6-2.2 (Banatvala, 1998) and 0.6-4.1 (World Health Organization, 2000a) per 1,000 live births. Higher rates are found when follow-up is after two or more years, as deafness or psychomotor retardation are more likely to be detected after infancy. Noninfectious maternal conditions. Several conditions can cause birth defects. Pregnant women with preexisting insulin-dependent diabetes mellitus (IDDM) have a higher risk for fetal loss (American Diabetes Association, 2000); surviving infants are prone to central nervous system, cardiovascular, renal, and limb defects (Khoury et al., 1989). Hyperthermia (fevers of 39°C or higher for at least 24 hours) during the first 4 weeks of pregnancy is associated with higher rates of neural tube defects (NTDs) and other birth defects (Chambers et al., 1998; Warkany, 1986; Kalter and Warkany, 1983). Maternal nutrition Folate deficiency early in pregnancy is associated with NTDs such as spina bifida, encephalocele, and anencephaly (see description of NTDs in section on birth defects of complex and unknown origin.). Supplementation of the maternal diet with 400 micrograms of folic acid per day before conception and during the next 28 days protects the fetus against NTDs (Berry et al., 1999; MRC Vitamin Study Research Group, 1991; Czeizel and Dudas, 1992). Iodine deficiency disorders (IDD) include mental retardations, hypothyroidism, goiter, cretinism, and varying degrees of other growth and developmental abnormalities, which result from inadequate thyroid hormone production as a result of an insufficient iodine intake. Cretinism, the most severe form of iodine deficiency, causes profound mental retardation (Sankar et al., 1998). Severe maternal iodine deficiency begins to affect the fetus in the second trimester of pregnancy, and the damage becomes irreversible at the end of that trimester (DeLong et al, 1985). In endemic areas, where up to 100 percent of the population does not consume adequate iodine (Ali, 1995; Yusuf et al., 1996; Wyss et al., 1996; Geelhoed, 1999; Kouame et al., 1998), nearly every developing fetus is at high risk for IDD (Mittal et al., 2000). In 1990, it was estimated that 43 million people

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Improving Birth Outcomes: Meeting the Challenge in the Developing World worldwide are suffering from varying degrees of brain damage due to IDD (United Nations Children’s Fund, 1998). In several countries, the prevalence of cretinism is between 0.5 and 11 percent of the population (Bellis et al., 1998; Geelhoed 1999; Jalil et al., 1997; Kouame et al., 1998; Sankar et al., 1998; Wyss et al., 1996; Yusuf et al., 1996). Medications Several drugs taken during pregnancy can pose a risk to the fetus (Briggs et al., 1994; Koren et al., 1998). This is of particular concern in the developing world since most women do not know for several weeks that they are pregnant, and there may be access to drugs without a formal prescription. Thalidomide was withdrawn from global markets in the early 1960s when it was determined that the sedative, then commonly prescribed for morning sickness, had caused severe limb and organ defects in more than 8,000 infants in 46 countries (Koren et al., 1998; Vanchieri, 1997; Grover et al., 2000). Thalidomide is once again available in many countries for indications including leprosy and HIV (Castilla et al., 1996). As a result, 34 infants have been reported to be born with thalidomide embryopathy in areas of South America where leprosy is endemic (Castilla et al., 1996). Misoprostol, used to treat peptic ulcer and postpartum hemorrhage, has also been used to induce early abortion (Gonzalez et al., 1998; Orioli and Castilla, 2000) The drug is not always effective for this purpose, and surviving newborns have exhibited birth defects attributed to vascular disruption (Gonzalez et al., 1998; Orioli and Castilla, 2000). Anticonvulsants are estimated to be used by about 1 in 250 pregnant women (Lindhout and Omtzigt, 1992). Phenobarbital, phenytoin, and primidone have each been associated with congenital heart defects or facial clefts, and carbamazepine and valproate with neural tube and other birth defects (Samren et al., 1999). These birth defects do not appear to be associated with maternal epilepsy itself (Holmes et al., 2001). Polytherapy with anticonvulsant drugs has been shown to carry a higher risk than monotherapy for causing birth defects (Samren et al., 1999). Anticoagulants. Exposure during the first trimester of pregnancy to coumarin derivatives such as Coumadin (warfarin) can cause nasal hypoplasia, stippling of bones, and neurological damage. Exposure in the second trimester has been associated with brain damage (Vitale et al., 1999). Alcohol A safe level of alcohol has not been established for pregnant women. The teratogenic risk of maternal binge drinking during pregnancy is uncer-

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Improving Birth Outcomes: Meeting the Challenge in the Developing World tain, but studies suggest that a single heavy binge at a critical period of embryonic development can cause fetal damage (Gladstone et al., 1996). Used regularly and heavily during pregnancy, alcohol is associated with fetal alcohol syndrome (FAS) and alcohol-related neurodevelopmental disorder (ARND). This syndrome is characterized by altered facial features, fetal growth reduction, and behavioral and cognitive effects (Institute of Medicine, 1996). With or without FAS, mental retardation is the most serious and common effect of alcohol use during pregnancy. (See chapter 4.) Teratogenic pollutants Teratogens including heavy metals, pesticides, and solvents are associated with a variety of birth defects (Jacobson and Jacobson, 1996; Ramsay and Reynolds, 2000), but there is little information on exposure in developing countries. Methylmercury, an organic form of mercury, causes birth defects in the central nervous system and, to a lesser extent, the liver and kidneys (Institute of Medicine, 2000). Mass methylmercury poisoning, which occurred in Japan in the 1950s (Eto et al., 2002) and in Iraq in the 1970s (Marsh et al., 1987), resulted in severe neurological dysfunction and developmental abnormalities among children exposed in utero. The adverse effects include mental retardation, cerebral palsy, deafness, blindness, and dysarthria. Ionizing radiation Studies of atomic bomb survivors demonstrated that ionizing radiation during gestation can damage the developing brain, particularly when exposure occurs 8 to 25 weeks after ovulation (Schull and Otake, 1999). Diagnostic radiography involves a low level of X-ray exposure of the fetus so that, with protection, the risk of a birth defect is small (Fattibene et al., 1999; Fenig et al., 2001). Birth Defects of Complex and Unknown Origin The origins of most birth defects have not been established; many of them are thought to be due to the additive effects of a few (oligogenic) or many (polygenic) genes, which may interact with nongenetic (environmental) factors. These conditions are usually limited to a single organ system and include the following examples: NTDs, congenital heart disease, cleft lip and/or cleft palate, talipes, and developmental dysplasia of the hip.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World Neural tube defects (NTDs) These include a range of congenital malformations that result from incomplete development of the brain and spinal cord or their protective coverings. Worldwide, NTDs (particularly the two major types, anencephaly and spina bifida) are estimated to affect 300,000 or more infants each year (Murray and Lopez, 1998). The birth prevalence of NTDs varies widely among countries, due in part to genetic and environmental factors and to differences in the availability of antenatal screening and termination of severely affected pregnancies (Shibuya and Murray, 1998). Epidemiological studies show a strong association between NTDs and inadequate maternal consumption of folic acid during the preconceptional and periconceptional periods. Spina bifida is a birth defect in which closure of the neural tube (predecessor of the spinal cord) is incomplete. The birth outcome varies with the location of the defect and whether it affects neural tissue, skeletal components, and/or skin. In some cases, the affected infant is born with the spinal cord exposed on the surface as a neural plaque and it may include meningeal tissue. This interrupted development of the spinal cord occurs in the first 4 to 5 weeks of fetal development and causes serious clinical problems that may include paralysis, incontinence, or skeletal deformities, depending on the location and nature of the defect. There may be associated hydrocephalus. Surgery at birth helps and saves some infants, but they may be significantly handicapped (Shibuya and Murray, 1998). In resource-poor situations, the future of an affected child is severely compromised. Anencephaly is the congenital absence of the cranial vault with cerebral hemispheres missing or reduced to small masses attached to the base of the skull. This fatal condition causes significant mortality before and soon after birth. Congenital heart disease These disorders, which occur in about 1 percent of live births, are the leading cause of birth-defect-related deaths despite improvements in diagnostic and life-saving surgical treatments over the last 40 years (Pradat, 1992). A variety of conditions—maternal rubella infection, alcohol abuse, genetic abnormalities, and chromosomal disorders such as Down syndrome—are associated with congenital cardiac malformations. Typical symptoms and signs of congenital heart disease include cyanosis, pulmonary hypertension, growth retardation, and syncope. In developing countries, many cases cannot be diagnosed at birth. Left untreated, many lesions prove fatal before age 20 (Rygg et al., 1971; Kirklin and

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Improving Birth Outcomes: Meeting the Challenge in the Developing World infant foot are less pliable and surgery may be required to correct the condition (Sinha, 1987). Cleft lip and/or cleft palate Early establishment of feeding is a top priority for infants with cleft lip and/or cleft palate. Primary surgery must wait until the infant is 3 months old for repair of the lip and 6 months old for repair of the palate (Smith et al., 1991). International foundations such as Operation Smile provide such surgery during periodic missions to low-income countries. Congenital heart disease Developing countries do not have the infrastructure to treat most cases of congenital heart disease (CHD). Researchers estimate that hundreds of thousands of children are born each year with surgically treatable CHD. Without treatment, most will die as children (Pezzella, 1998; McGrath, 1992; Rygg et al., 1971, Kirklin and Barrat-Boyes, 1993). Developmental dysplasia of the hip (DDH) Diagnosis and treatment of DDH is more successful for children under two years of age (Kim et al., 1990). Early treatment maintains the thighs in a flexed and partly abducted position so that the head of each femur remains deep within the acetabulum, more completely encompassed by the acetabulum. Dislocated hips that fail to respond to early splinting, and those detected and treated in older children, can be corrected by surgical procedures (Kim et al., 1990). Stage Three: Screening for Genetic Disorders In countries where good reproductive health care is in place and infant mortality has been decreased, screening for genetic disorders becomes the next important step to further decrease infant mortality (World Health Organization, 2000b). These programs require more resources and more highly trained staff than programs for basic reproductive health care, but they too can be cost-effective.2 2   See the companion report, Reducing the Impact of Birth Defects: Meeting the Challenge in the Developing World (IOM, 2003), for more in depth coverage of this topic.

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Improving Birth Outcomes: Meeting the Challenge in the Developing World Genetic screening Whereas diagnosis of a birth defect involves accurate testing of individual patients, genetic screening involves testing of a clinically normal population and identifies most, but not all, persons at high risk for a specific disorder or condition or of producing offspring with a defect. Priority should be given to genetic testing for the birth defects that impose the heaviest burdens on the population as a whole. Genetic data should only be used to benefit members of a family or ethnic group and should be treated as confidential at all times (World Health Organization, 1997). β-Thalassemia major is easy to diagnose and effective—but costly—treatment is available. Without diagnosis and treatment, those with β-thalassemia major usually die early in childhood; thus the population prevalence is a fraction of the birth prevalence. Where diagnosis and treatment are available, patients survive longer, the population prevalence increases, and treatment costs increase. In Greece (Loukopoulous, 1996), Sardinia (Cao et al., 1991, 1996), Iran (Habibzadeh et al., 1999), and Cyprus (Modell et al., 1991), screening programs have significantly reduced the birth prevalence of β-thalassemia. Sickle cell disease (SCD) can be addressed through preconceptional genetic screening to identify and counsel couples at risk for having a child with SCD and antenatal screening followed by diagnosis and counseling regarding sickle cell in childhood. Where appropriate, families should be offered the option of termination of pregnancy. In some populations, neonates, rather than adults, are screened (Lees et al., 2002) to allow early treatment of SCD (such as penicillin prophylaxis and pneumococcal vaccination to prevent potentially fatal infections), early education of parents on the care of affected children, and education about the risk for future pregnancies. Glucose-6-phosphate dehydrogenase (G6PD) deficiency screening is primarily used to detect the disorder after birth in order to control the occurrence and severity of hematological crises. It also alerts carriers of their status (Verjee, 1993; Meloni et al., 1992). Several screening tests are quick, easy, inexpensive and suitable for large populations. Positive screening results are generally confirmed by enzyme assay. The definitive assay requires laboratory equipment generally not available in those countries where G6PD deficiency is common. Preconceptional screening Preconceptional screening of national populations or groups at high risk for carrier status can be undertaken for serious recessive birth defects where they are prevalent, a reliable test is available, and the condition is amenable to prevention. Iran and Cyprus screen nationally for β-thalas-

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Improving Birth Outcomes: Meeting the Challenge in the Developing World semia, while Cuba screens nationally for SCD. Preconceptional screening has three components: recording and evaluating a genetic history, laboratory testing where indicated, and counseling. Genetic histories can identify clinically normal couples at risk for passing an inherited birth defect to their offspring. If these couples are determined to be at risk, they should receive counseling and appropriate care. Antenatal screening and diagnosis Antenatal screening can identify most pregnancies at high risk for Down syndrome, NTDs, and single gene disorders (Baird, 1999). Screening and a follow-up diagnosis for those who screen positive are generally done before 20 weeks gestation. This timing allows parents to plan for the care of an affected child, the time and place of delivery if surgery is needed at birth, or to consider termination of the pregnancy in the case of severe birth defects. There is agreement in many countries that termination of pregnancies must not be offered for the purpose of gender selection (Wald et al., 2000). Neonatal screening and diagnosis Early diagnosis and prompt, appropriate treatment of some birth defects can reduce some life-threatening or disabling sequelae. Even when little can be done to assist the infant, accurate diagnosis of birth defects alerts parents to their risk in future pregnancies. Early neonatal screening is important for G6PD deficiency to treat jaundice and prevent kernicterus, for phenylketonuria to allow early dietary intervention, and for hypothyroidism to allow thyroid replacement therapy (Wald and Leck, 2000). The diagnosis of Down syndrome can be made clinically at birth and confirmed by chromosome analysis (karyotyping). Counseling on genetic risks Parents have the right to be appropriately informed and counseled about screening services, to choose whether to accept them, and to receive continuing support independent of that choice. When antenatal screening and diagnosis reveal a birth defect, counselors should provide information and support to parents. When a birth defect is severe and termination of the pregnancy is a consideration, counseling and health care should support the decision of the parents. Genetic counselors, whether physicians or primary care workers, need to be trained and tested in the content and delivery of the information they provide. In addition, the content of consultations with parents should be documented and monitored. Counselors provide the link between the health

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Improving Birth Outcomes: Meeting the Challenge in the Developing World care system and the social, religious, and legal foundations of society, which together determine the availability of reproductive choices. RECOMMENDATIONS Despite incomplete data on birth defects, several studies have established that birth defects are an important public health problem in developing countries. Basic reproductive health care, an essential component of primary health care, can prevent or reduce the impact of birth defects by providing education for parents regarding avoidable risks for birth defects, effective family planning, effective preconceptional and antenatal care and educational campaigns to stress their importance, and neonatal care that permits the early detection and management of birth defects. Recommendation 4. The following strategies are recommended for incorporation into preconceptional and antenatal care: Discouragement of women from childbearing after age 35 to minimize the risk of chromosomal birth defects such as Down syndrome. Immunization against rubella for women before they reach reproductive age. Routine and continuous provision of 400 micrograms of folic acid per day for all women of reproductive age Universal iodine fortification of salt (25-50 milligrams of iodine per kilogram of salt). Counseling of women to limit alcohol consumption during pregnancy. Counseling of women and their health care providers on locally relevant teratogenic medications to be avoided during pregnancy. (See Chapters 2, 3, 6, and 8 for other components of this recommendation.) RESEARCH NEEDS The priorities for research to improve existing interventions against birth defects and to create and implement additional interventions include: Operational research to monitor, evaluate, and adjust interventions for maximal clinical- and cost-effectiveness. Because there is considerable variability in the settings in which interventions are undertaken, an intervention proven effective in one setting will still require tailoring in the

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Improving Birth Outcomes: Meeting the Challenge in the Developing World delivery of services to be fully effective in another setting. The first stage of transferring an “effective” intervention may involve a pilot study that is monitored, evaluated, and adjusted before wider implementation. Surveillance to provide basic planning information on maternal, neonatal, and fetal mortality and on infants born with birth defects Effective strategies for changing maternal behaviors to minimize the risks for birth defects, including childbearing before age 35 and limiting alcohol consumption during pregnancy. CONCLUSION Birth defects have enormous personal and societal consequences in developing countries. Reducing their impact can be accomplished in a multi-stage process in line with the needs, infrastructure, and resources of countries: The first stage is the introduction of practical, low-cost interventions to reduce the occurrence of NTDs, iodine deficiency disorders, Down syndrome, FAS, and CRS. Prevention of these birth defects is affordable in almost all settings and can be pursued with little need to gather additional information. The second stage of reducing the impact of birth defects is early diagnosis and treatment of infants with birth defects such as cleft lip and/or cleft palate, talipes, and developmental dysplasia of the hip. The conditions treated and level of care will vary with the setting, but should be the best locally available. Undertaking this stage may require an assessment of the burden of different birth defects in the local setting and of the resources available. The third stage of reducing the impact of birth defects is genetic screening and counseling on severe birth defects, possibly followed by termination of a severely affected pregnancy. Such programs can be cost-effective in populations where the basic strategies for reducing infant mortality and birth defects have already been implemented, infant mortality rates have been reduced to about 20 to 40 per 1,000 live births, and adequate new resources have been committed. Increased surveillance may be needed to guide health leaders on the genetic disorder(s), such as thalassemias, SCD, and G6PD deficiency, to be screened. REFERENCES Akinyanju OO. 1989. A profile of sickle cell disease in Nigeria. Annals of the New York Academy of Sciences 565:126–136. Alford CA and Pass RF. 1981. Epidemiology of chronic congenital and perinatal infections of man. Clinics in Perinatology 8(3):397–414.

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