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Reducing Birth Defects: Meeting the Challenge in the Developing World (2003)

Chapter: 2 Impact and Patterns of Occurrence

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Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
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Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
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Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 24
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 25
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 26
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 27
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 28
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 29
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 30
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 31
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 32
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 33
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 34
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 35
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 36
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 37
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 38
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 39
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 40
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 41
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 42
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 43
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 44
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 45
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 46
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 47
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 48
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 49
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 50
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 51
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 52
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 53
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 54
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 55
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 56
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 57
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 58
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 59
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 60
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 61
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 62
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 63
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 64
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 65
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 66
Suggested Citation:"2 Impact and Patterns of Occurrence." Institute of Medicine. 2003. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington, DC: The National Academies Press. doi: 10.17226/10839.
×
Page 67

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2 Impact and Paherns of Occurrence Birth defects are, in the aggregate, a significant health problem for infants worldwide. The prevalence of individual conditions in differ- ent populations varies with the health care system; use and coverage of preventive strategies; and access to prenatal screening, diagnosis, and possible termination of pregnancy for severe birth defects (Kuliev and Modell, 1990; World Health Organization, 1997, 19991. Data on birth defects in several countries are given in Appendix A (Table A-11. At birth the prevalence is generally in the range of 10-60 per 1,000 live births depending on the conditions included. This number increases when assess- ments are made at one or five years. To understand the patterns of occurrence of birth defects, a system for collecting and monitoring reliable data is needed. Many developing countries lack health-related statistics and registries, and about one-third of all births in these countries an estimated 40 million each year are not registered (Murray and Lopez, 1996; World Health Organization, 1997, 1999; United Nation Children's Fund, 19981. Thus in much of the world, it is difficult to calculate the birth prevalence of birth defects with any precision because the number of infants afflicted and the total num- ber of surviving infants born within a specified time period is not mea- sured. In these circumstances, birth rates and the birth prevalence of disease are approximated from hospital- and community-based studies, which are not necessarily representative of the population as a whole or even the broader community. Notwithstanding these limitations, several studies have established that birth defects are a public health problem in developing countries. In addi- 22

IMPACT AND PATTERNS OF O CCURRENCE 23 tion, 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) (see Box 2-11; the Latin American Collaborative Study of Congenital Malformations (ECLAMC) (see Box 2-21; the Chinese Birth Defects Monitoring Program (CBDMP); and the European Register of Congenital Abnormalities and Twins (EURO- CAT), a network of 20 regional registries. Data from these programs and from the research literature inform this chapter's descriptions of the pathol- ogy of birth defects and their patterns of occurrence in developing coun- tries. In this chapter and the next, three categories of causes of birth defects are discussed: genetic, environmental, and complex genetic and unknown (defined in Chapter 11. GENETIC BIRTH DEFECTS Of the birth defects for which a cause has been established, most are due to chromosomal disorders and single-gene mutations. Chromosomal Disorders Sporadic (nonhereditary) losses or rearrangements of genetic material affect at least 10 percent of conceptions, 90 percent of which end in spon- taneous abortion. Surviving infants may have a congenital malformation, mental retardation, and/or disorders in sexual differentiation (WorId Health Organization, 19991. Data from the United States, Canada, and Germany show a birth prevalence of chromosomal abnormalities of 5 per 1,000 live

24 REDUCING THE IMPACT OF BIRTH DEFECTS births (Hook, 1982); however, the birth prevalence may be higher in popu- lations in which women continue to have children after age 35. This occurs more commonly in countries that lack family planning and access to con- traceptives (WorId Health Organization, 19991. As Table 2-1 shows, the risk of chromosomal abnormalities, and of Down syndrome in particular, increases rapidly with advancing maternal age (Hook, 19811. Chromosomal nondisjunction an error in cell division that admits three, rather than two, copies of one of the chromosome 21 into the cells of the affected zygote causes Down syndrome, in which three copies (tri- somy) of chromosome 21 are present. Trisomies of chromosomes 13 and 18 are also relatively common in live-born infants. Advanced maternal age is the only well-documented risk factor for nondisjunction; however, the mechanism behind the age effect is not well understood (Nicolaidis and Petersen, 19981. Young maternal age (Croen and Shaw, 1995) and ad- vanced paternal age (Kuliev and Modell, 1990) have also been associated with increased risk for birth defects in some, but not all, developed coun- tries. Maternal age-adjusted risks for chromosomal numerical anomalies show little variation across racial and ethnic groups (Carothers et al., 20011.

IMPACT AND PATTERNS OF O CCURRENCE TABLE 2-1 Maternal Age and Chromosome Abnormalities in Liveborns 25 Total Risk for Chromosomal Maternal Age Risk for Down Syndrome Abnormalities 20 1/1,667 1/526 21 1/1,667 1/526 22 1/1,429 1/500 23 1/1,429 1/500 24 1/1,250 1/476 25 1/1,250 1/476 26 1/1,176 1/476 27 1/1,111 1/455 28 1/1,053 1/435 29 1/1,000 1/417 30 1/952 1/417 31 1/909 1/385 32 1/769 1/322 33 1/602 1/286 34 1/485 1/238 35 1/378 1/192 36 1/289 1/156 37 1/224 1/127 38 1/173 1/102 39 1/136 1/83 40 1/106 1/66 41 1/82 1/53 42 1/63 1/42 43 1/49 1/33 44 1/38 1/26 45 1/30 1/21 46 1/23 1/16 47 1/18 1/13 48 1/14 1/10 49 1/11 1/8 SOURCE: Hook, 1981. Down syndrome (Trisomy 21 ) This is a common chromosomal disorder in which a child is born with three not two copies of chromosome 21. It causes varying degrees of mental and growth retardation, a characteristic facial appearance, and multiple malformations. It is associated with a major risk for heart malfor- mations, a risk of duodenal atresia in which part of the small intestine is not developed, and a small but significant risk of acute leukemia. It frequently results in spontaneous abortion. Congenital heart disease associated with Down syndrome can be fatal and is the major cause of death. Inadequate

26 REDUCING THE IMPACT OF BIRTH DEFECTS intellectual development can cause severe, lifelong disability and depen- dence. The estimated birth prevalence of Down syndrome in developing coun- tries is higher than in developed countries (see Appendix A, Table A-2) (Kuliev and Modell, 1990; World Health Organization, 19961. The higher prevalence parallels the greater proportion of births to women over 35 years of age noted above an average of 11-15 percent in developing coun- tries versus 5-9 percent in most developed countries. The rates in Catholic countries, such as Ireland and Italy, are closer to those in developing coun- tries. For example, the higher birth prevalence of Down syndrome in South America (1.5/1,000), compared with the average in developed countries (1/ 1,000), can be explained by the higher mean maternal age in that region (Castilla and Lopez-Camelo, 19901. Early infant and childhood mortality from congenital heart disease and other conditions associated with Down syndrome result in a low popula- tion prevalence of the syndrome in most developing countries (Zhang et al., 19911. In South Africa, three-quarters of children with Down syndrome die before reaching 2 years of age (Christianson, 19961. In South America, 34 percent of Down syndrome infants with congenital heart disease and 21 percent without heart problems die before the age of 1 year, about twice the rate in the United Kingdom (Castilla et al., 19981. Trisomy 18 Children with this syndrome have three instead of two copies of chro- mosome 18. The condition causes multiple malformations, profound men- tal retardation, and usually death in the first few months. It occurs in about 1 per 8,000 live births (Hook, 1992) and among stillborn infants. About three times as many females as males are born with trisomy 18, but the ratios are more equal among stiliborns and spontaneously aborted fetuses. Trisomy 13 Children with this syndrome have three instead of two copies of chro- mosome 13. They have multiple malformations, profound mental retarda- tion, and generally die soon after birth or in infancy. The condition occurs in 1 in 20,000 live-born infants (Hook, 1992) and is frequently observed in spontaneously aborted fetuses. This trisomy results in pronounced retarda- tion of intrauterine and postnatal growth and development. Nearly 50 percent of affected newborns die in their first month, and fewer than 5 percent survive past 3 years of age (Magenis et al., 1968~.

IMPACT AND PATTERNS OF O CCURRENCE Single-Gene Disorders 27 More than 6,000 single-gene (Menclelian or monogenic) clisorclers have been clescribeci (World Health Organization, 1997; Online Menclelian In- heritance in Man, 2002), and many more are suspected. These clisorclers are incliviclually rare but, taken together, are estimated to account for a global birth prevalence of 10 per 1,000 live births (World Health Organization, 19991. Single-gene clisorclers are classified by mocle of inheritance as auto- somal recessive or dominant or as X-linkeci recessive or dominant. For autosomal recessive traits to be expressed, two copies of the mutated gene must be present; thus, if both parents are carriers of the same clisease- causing recessive gene, each chilci has a 25 percent chance of having the disease. Pregnancies from consanguineous marriages marriages generally of first cousins and inclucling second cousins have an increased birth preva- lence of autosomal recessive diseases, which increases the risk of stillbirth, neonatal and chilc~hooci cleath, mental retardation, and birth defects com- pareci with pregnancies among unrelated couples (Jaber et al., 1992~. In most Western urban populations, the frequency of consanguineous mar- riages (Castilla et al., 1991) and of births procluceci from these marriages (Liascovich et al., 2001) is between 1 per 1,000 and 1 per 100. In areas . . . . . . . . w" here consanguineous marriage Is Intrinsic to t" be cu." sure, Inca uc sing parts of the Micicile East, South Asia, and Africa (Bittles et al., 1991; Khiat and Khoury, 1991; Khiat et al., 1997; Durkin et al., 1998; Mokhtar et al., 1998), 20-60 percent of all marriages involve consanguineous unions. Woric~wicle, consanguineous marriages occur regularly in at least 20 per- cent of the population, and as many as 8 percent of all children woric~wicle have parents who are related (Kuliev and Moclell, 1990; World Health Organization, 1996; Hussain and Bittles, 1998; Christianson et al., 2000~. The relationship between consanguinity and birth defects has been explored in several studies. In one stucly, for example, 93 percent of Pales- tinian Arabs who are parents of children with rare autosomal clisorclers were founci to be related, compared with a consanguinity rate of 44 percent among the general population (ZIotogora, 1997~. This stucly also founci higher-than-average rates of consanguinity among parents of children with neural tube defects (NTDs), cleft lip and palate, and other congenital mal- formations. NTDs were shown to be associated with consanguinity in stuci- ies conclucteci in the United Arab Emirates (Al-Gazali et al., 1999) and in Saucli Arabia (Murshici, 2000~. Major malformations (inclucling but not limited to nervous system anomalies) were founci 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~. The single-gene clisorclers best clocumenteci in cleveloping countries in-

28 REDUCING THE IMPACT OF BIRTH DEFECTS clude hemoglobin disorders, such as thalassemia and sickle cell disease, and glucose-6-phosphate dehydrogenase deficiency; oculocutaneous albinism, important in Africa; cystic fibrosis, the most common potentially fatal genetic disease among Caucasians, long considered rare in non-Caucasian populations but recently attracting increased attention; phenylketonuria (PKU); and hemophilia A and B. For several hemoglobinopathies, including or- and p-thalassemia and sickle cell disease, the mutation that causes the disorder also interferes with infection by the malaria parasite. This confers a selective advantage on carriers living in malaria-endemic areas, thereby explaining the increased frequency of these hemoglobinopathies in popula- tions of African and Mediterranean ancestry. Thalassemias These are a group of inherited blood disorders in which production of hemoglobin is deficient as a result of mutations in the genes that synthesize the or- and p-globin chains of the hemoglobin. Abnormal hemoglobin (Hb) genes are believed to have originated in Africa, Asia, and the Mediterranean basin and may have remained at high frequencies because of the previously noted selective advantage of malaria resistance conferred on the heterozy- gous carriers of such genes, who do not usually exhibit symptoms of thalas- semia (Weatherall, 1997; Sweeting et al., 19981. Thalassemias are generally more prevalent than sickle cell disorders in the Eastern Mediterranean region, North Africa, South Asia, East Asia, and the Pacific. p-Thalassemia, the most common thalassemia, involves a defect in the production of p-globin chains, which decreases production of normal adult hemoglobin (Hb A). It occurs most often among people of Mediterranean descent. Clinically this condition includes p-thalassemia major, the ho- mozygous state, and p-thalassemia minor, the heterozygous (carrier) state, which is usually asymptomatic. Children with p-thalassemia major do not present symptoms in the first months of life, then, in the second 6 months, they often fail to thrive and may suffer from recurrent bacterial infections, severe anemia, hepatosplenomegaly, and bone expansion, which give rise to classical thalassemia facies. Left untreated, severe p-thalassemia is fatal in childhood or early adolescence; with regular transfusions, patients live into their twenties and even longer if treated to prevent iron overload. Because of the difficulty and expense of treatment, children with p-thalassemia in poorer countries rarely receive adequate care and die young (Weatherall and Clegg, 20011. Oc-Thalassemia, the heterozygous state (with a single gene for oc-thalas- semia) is innocuous or harmless. The homozygous state (with both genes for oc-thalassemia) can be lethal before birth. The compound heterozygous forms produce a condition of variable severity known as Hb H disease,

IMPACT AND PATTERNS OF O CCURRENCE 29 with symptoms that include moderate to severe (transfusion-dependent) anemia and splenomegaly. oc-Thalassemia is most prevalent in Asia. Several populations have been screened to determine the prevalence of thalassemia genes and traits (see Appendix A, Table A-31; or and p-thalas- semia have a high incidence in a broad geographical band extending across the Mediterranean basin and parts of Africa, through the Middle East, and across India, Southeast Asia, and the Pacific Islands (see Figure 2-11. In these areas, carrier frequency for p-thalassemia ranges from 1 to 20 per- cent. Carriers of the milder form of p-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 and India, and higher in northern Papua New Guinea. Carriers of the more severe form of oc-thalassemia occur at i: :~' i ~ Hi, or- and p-Thalassemia W;,.~t~ ma] - use ~ ~~, FIGURE 2-1 Global distribution of or- and p-thalassemia. SOURCE: World Health Organization, 2001. " 'it ~ ': rim

30 REDUCING THE IMPACT OF BIRTH DEFECTS high frequencies only in parts of Southeast Asia and the Mediterranean basin; therefore, oc-thalassemias pose less of a global health problem than p-thalassemias (Weatherall and Clegg, 20011. Sickle cell disease This is a genetic blood disease that results from the pairing of an abnormal hemoglobin S (HbS) with another abnormal hemoglobin. Het- erozygote carriers have the largely asymptomatic sickle cell trait (HbAS); homozygotes (HbSS) have variable symptoms and are said to have sickle cell anemia; and HbS compound heterozygotes, the most prevalent being ~1 ID ~ ~ _ ~ ~ _? (A ~ ~ , it' ~~ . ~ ~ S ~ / ~ Jet , ~ - ~ ''' :.-~: J I' <k '~-'_ ,,,rt., \, , HbS FIGURE 2-2 Global distribution of hemoglobins S and E. SOURCE: World Health Organization, 2001. ,~'

IMPACT AND PATTERNS OF O CCURRENCE 3 hemoglobin C (HbSC) and hemoglobin E (HbSE), have the most severe symptoms. The global distribution of hemoglobins S and E is shown in Figure 2-2. The hemoglobin molecules in red blood cells stick to one an- other and cause the red cells to become crescent or sickle shaped. Sickled cells cannot pass easily through tiny blood vessels. Sickle cell disease affects millions of people worldwide but is particu- larly common among people from sub-Saharan Africa; Spanish-speaking regions; Saudi Arabia; India; and Mediterranean countries. The high fre- quency of sickle cell disease in these populations is attributed to the lower rates of mortality from malaria infection among carriers, who are asymp- tomatic, compared with noncarriers (Ashley-Koch et al., 20001. Relatively high rates of consanguineous marriage in the Eastern Mediterranean region have increased the prevalence of sickle cell disease in that population as well (WorId Health Organization, 1997~. Children with homozygous sickle cell disease or sickle cell anemia are susceptible to episodes of painful vaso-occlusive crises and chronic anemia and are at increased risk for developing infections, particularly Streptococ- cus pneumoniae, which can cause fatal sepsis, meningitis, or pneumonia. In sub-Saharan Africa, many children with sickle cell anemia die early in life (Weatherall and Clegg, 20011. While survival is influenced by several vari- ables, there is a general correlation with the frequency of crises. Extensive vaso-occlusive crises can cause ischemic damage and infarction, with result- ing splenic dysfunction, "acute chest syndrome," impaired renal function, and stroke. Patients with more than three crises per year live to a median age of 35 years, while those with fewer than one per year may live into their forties (Fauci et al., 20011. Epidemiological studies of sickle cell disease have reported a wide range of prevalence rates among, and even within, developing countries (see Ap- pendix A, Table A-41. In Nigeria, sickle cell carrier frequencies have been estimated at 25 percent in the south and 19-33 percent in the north (Akinyanju, 1989~. HbC is less common in this population, but carrier rates of 5-7 percent have been reported in the Yoruba of southwest Nigeria. Combined, these carrier rates would be expected to result in about 90,000 births per year in Nigeria alone. However, the prevalence of the disease in the general population is low because 70 percent of patients with sickle cell anemia (HbSS) die undiagnosed in childhood (Akinyanju, 1989; Anga- stiniotis et al., 19951. Sickle cell disease is also common in countries with a high proportion of African migrants. Thus in Cuba, where 30-40 percent of the population has African ancestry, the carrier frequency is 3-6 percent (Granda et al., 1991, 19941; in Brazil, the carrier frequency among people of mixed ances- try is 4.7 percent and among people of African origin is 6.2 percent (Salzano, 19851.

32 REDUCING THE IMPACT OF BIRTH DEFECTS Glucose-6-phosphate debydrogenase (G6PD) deficiency This enzyme defect results from recessive mutations in the gene for the enzyme G6PD, which is carried on the X chromosome. Hundreds of vari- ants of G6PD deficiency have been identified among the 400 million people estimated to be affected worldwide. Individuals deficient in G6PD are vul- nerable to developing acute hemolytic anemia as a result of infections, exposure to oxidant drugs (the antimalarial, primaquine, and the sulfona- mide antibiotics or sulfones), or chemicals (naphthalene in mothballs), or ingestion of fava beans. Severe hemolysis in these cases can be fatal (Steensma et al., 20011. Some affected newborns develop severe hemolytic jaundice and kernicterus, which can result in death or serious neurologic . . Impairment. The disorder is most prevalent in Central, West, and East Africa; the Eastern Mediterranean; and South and East Asia (Verjee, 1993; El-Hazmi and Warsy, 1 996; World Health Organization, 1 989, 1996, 1997~. As with thalassemias and sickle cell disease, carriers of G6PD deficiency have a selective advantage against infection by malaria (Roth et al., 1983), which increases the frequency of these carriers in populations of African and Mediterranean ancestries (Allison and Clyde, 1961~. About 7.5 percent of the worId's population carry a gene for G6PD deficiency, and about 3 percent are deficient in the enzyme; however, there is large regional variability. In Africa, for example, carrier frequencies as high as 35 percent have been reported (WorId Health Organization, 1989~. Appendix A (Table A-5) lists selected studies of G6PD prevalence among groups ranging from children in a few schools to national surveys of new- borns. Because the condition is X-linked recessive, most of those affected are hemizygous males. However, because of high gene frequency and pa- rental consanguinity in some areas, female homozygosity accounts for nearly 10 percent of cases of G6PD deficiency. In addition, 10 percent of heterozy- gote females are G6PD deficient as a result of unequal X chromosome . . . Inactivation. Oculocutaneous albinism This is an autosomal recessive disorder affecting the pigmentation of skin, hair, and eyes. There are several types of oculocutaneous albinism: in the tyrosinase negative type, there is an absence of tyrosinase; in the tyrosinase positive type, the normal tyrosinase cannot enter pigment cells. The compound heterozygote is normal so the two forms are not allelic. This birth defect is rare in many parts of the world, but in subtropical Africa it ranks as the most prevalent single-gene disorder. The high risk of squamous cell carcinoma is the most serious consequence of oculocutaneous albinism. Early mortality from

IMPACT AND PATTERNS OF O CCURRENCE 33 squamous cell carcinoma increases with proximity to the equator, resulting in the death of 90 percent of those affected in Nigeria and Tanzania before they reach age 30 (Luande et al., 19851. Additional symptoms of oculocutaneous albinism include photophobia, nystagmus, and squinting. The prevalence of oculocutaneous albinism in subtropical Africa ranges from 1 in 1,000 (in an isolated cluster in the Tonga community of Zimba- bwe) to between 1 per 3,900 and 1 per 5,000 in South Africa, Zimbabwe, and Nigeria (for selected prevalence studies in Africa, see Appendix A, Table A-61. These rates, which are two to four times those in European countries, may result from higher levels of parental consanguinity in certain African communities. Elevated rates of oculocutaneous albinism have also been noted in geographically isolated and consanguineous Latin American and Australian populations (Keeler, 1970; Okoro, 1975; Kromberg and Jenkins, 1982; Lund, 1996; Castilla and Sod, 19901. Cystic fibrosis (CF) A generalized disorder in which there is widespread dysfunction of the exocrine glands, characterized by signs of chronic pulmonary disease (due to excess mucus production in the respiratory tract), pancreatic deficiency, abnormally high levels of electrolytes in the sweat and occasionally by biliary cirrhosis. There is an ineffective immunologic defense against bacte- ria in the lungs. Without treatment, CF results in death for 95% of affected children before age 5. With diligent medical care patients with CF can survive beyond middle age. Although survival has improved in developed countries, CF often results in early mortality. The diagnosis of CF compli- cated even in developed countries requires tests for sweat chloride and, if positive, molecular screening to identify the mutation (Grody, 20011. The frequency of CF varies considerably in different parts of the world and among different ethnic groups. A summary of prevalence rates of CF in several countries is presented in Appendix A (Table A-71. Reported birth prevalences range from a high of 1 per 2,000 births among Caucasians (Brock, 1996) to a low of 1 per 680,000 births (1 per 350,000 after 1980) among Japanese (Yamashiro et al., 19971. While sufficiently common among Caucasians to be one of the first diseases considered for genetic screening, CF has long been considered rare in non-Caucasian populations. Several lines of evidence argue against this conclusion, however. For example, CF was found to have a birth prevalence of 1 per 2,560 live births in Jordan (Nazer, 1992) and 1 per 3,000 live births in Turkey (Gurson et al., 19731. African-American CF patients were shown to have a different mutation profile from white CF patients; then a South African study identified different mutations in populations of African origin and predicted the incidence of CF to range from 1 in 784 to 1 in 13,924 births in this population (Padoa et al., 19991. In Africa, CF is thought to have

34 REDUCING THE IMPACT OF BIRTH DEFECTS been misdiagnosed as chronic pulmonary infection, tuberculosis, chronic diar- rhea, and malnutrition. Thus, a lack of clinical awareness of the disorder and its misdiagnosis, rather than actual rarity, may explain the previous low CF prevalence reported in Africa (Padoa et al., 19991. Phenylketonuria (PKU) The congenital absence of phenylalanine hydroxylase (the enzyme that converts phenylalanine to tyrosine) is an autosomal recessive disorder. Phe- nylalanine accumulates in blood and seriously impairs early neuronal devel- opment. Affected neonates appear normal at birth but lose interest in their surroundings at 3 to 6 months of age and exhibit severe mental retardation by 1 year. Other clinical findings include an eczematous rash, microceph- aly, growth retardation, and decreased pigmentation of hair and skin. A musty odor may be observed in the urine or sweat of individuals with PKU as a result of increased production of pheny~pyruvate (Kiet~uriyakul et al., 1988; Cunningham, 20001. Classical PKU affects 1 in 11,000 persons and is most prevalent among Caucasians (Eisensmith and Woo, 19941. In Turkey, the incidence of PKU is particularly high (1/4,370), largely as a result of consanguineous mar- riage (see Appendix A, Table A-8) (Ozalp et al., 19901. Hemophilias A and B The disease is characterized by subcutaneous and intramuscular hem- orrhages, bleeding from the mouth, gums, lips and tongue, hematuria, and hemarthroses. Hemophilia A (classic hemophilia, factor VIII deficiency) is an X-linked disorder arising from deficiency of coagulation factor VIII, and hemophilia B (factor IX deficiency, Christmas disease), also X-linked, is due to deficiency of coagulation factor IX. Because of a sex-linked recessive inheritance pattern, if both parents are carriers for the disorder, male off- spring will be affected by the disorder, and female offspring will be carriers (Kale, 19991. Extensive spontaneous bleeding is a lifelong burden, with physical, psychological, social, and financial repercussions (Kale, 19991. Hemophiliacs are at a high risk for HIV/AIDS and hepatitis B infection if blood products are contaminated (Handin, 19981. One in 5,000 males (1/ 10,000 for the total population) is born with deficiency or dysfunction of factor VIII (hemophilia A), and one in 50,000 males or in 100,000 total population is born with deficiency or dysfunction of factor IX (hemophilia B) (Handin, 19981.

IMPACT AND PATTERNS OF O CCURRENCE BIRTH DEFECTS OF ENVIRONMENTAL ORIGIN 35 Exposure to a teratogen during embryonic or fetal life can cause func- tional disorders and malformations (Penchaszadeh, 1994; Polifka et al., 19961. The degree of teratogenicity of a given agent depends on its physical and chemical nature, as well as on the dose, route, and timing of exposure. Exposure to other agents and the biological susceptibility of the mother and embryo or fetus may also determine whether a particular exposure will produce damage (Polifka and Friedman, 19991. The major teratogens, listed in Table 2-2, include infectious pathogens, environmental toxins, recre- ational drugs, and medications. TABLE 2-2 Teratogens and Their Effects on the Frequency of Malformations Teratogen Main Defects Caused Estimated Risk Infectious agents: Cytomegalovirus . , . 1ntectlon Herpes simplex Deafness; neurological damage; eye disorder Neurological damage; eye disorder; cutaneous 8% of maternal sero- . . conversion in pregnancy Not known scars Rubella Eye and heart defects; 90% after serologically deafness; neurological confirmed infection of damage mother in first 10 weeks of pregnancy Toxoplasmosis Neurological damage; 30-40% after maternal eye disorder; deafness seroconversion in pregnancy without treatment Other maternal diseases: Neurological damage; Microcephaly in 8.5% of Phenylketonuria cardiac defects phenyketonuric infants with blood phenylalanine >1.2 nmol/L Insulin-dependent Cardiovascular and Major defects in 8% of diabetes mellitus central nervous system infants of affected women (CNS) damage; who did not receive special caudal regression care during early pregnancy Medications: Androgens and Anomalies of external Clitoridal hypertrophy and androgenic genitalia virilization of female infants compounds after first-trimester exposure at high doses; risks with other drugs not known but appear to be lower Anticonvulsants Spina bifida after 4% overall, but varies with valproate; oral clefts; cardiovascular defects number and nature of anticonvulsants used (continued)

36 TABLE 2-2 continued REDUCING THE IMPACT OF BIRTH DEFECTS Teratogen Main Defects Caused Estimated Risk Coumarin derivatives Nasal hypoplasia; Nasal hypoplasia or epiphyseal stippling; epiphyseal stippling in 8% neurological damage after use in first trimester; brain damage in 5% after use in second trimester Diethylstilbestrol Genital anomalies Testicular anomalies, epididymal cysts, or penile hypoplasia in up to 20% of males, and ridges in cervix and/or vagina in up to 40% of females exposed to a dose of 150 mg between 7 and 34 weeks' gestation Folic acid antagonists Craniofacial defects 40% after aminopterin in (aminopterin, first 10 weeks of pregnancy; methotrexate) not known for methotrexate Lithium Cardiac defects, 3% especially Ebstein's anomaly Retinoids Microtia-anotia; CNS, 20% after isotretinoin in cardioaortic, and first trimester thymic defects Thalidomide Reduction deformities 50% after use in first 8 of limbs weeks of pregnancy Recreational drugs: Cocaine Urinary tract defects Major defects in 5% of users of cocaine with or without other drugs Alcohol Neurological damage; 30% of infants of women cardiac and joint with manifest chronic defects alcoholism Environmental pollutants: Neurological damage 6% of infants in fishing Methylmercury village where seafood was contaminated Miscellaneous: Iodine deficiency Neurological damage; 40% of surviving infants in deafness iodine-deficient area whose mothers' blood total thyroxine was <25 ng/mL Ionizing radiation Neurological damage Microcephaly in 70% after estimated dose >1.5 gy from atomic bombs in first 18 weeks of pregnancy SOURCE: Adapted from Leck, 1994.

IMPACT AND PATTERNS OF O CCURRENCE Infectious Pathogens 37 Infections during pregnancy are common, and the majority of maternal infections do not affect the fetus. Those that do, however, can result in fetal loss or severe birth defects. Teratogenic pathogens may exert their effects immediately, or they may initiate complex processes that cause damage throughout gestation and into infancy (Afford and Pass, 1981; Hanshaw, 1985~. Although infections cause only a fraction of total birth defects, they represent an opportunity for reducing birth defects through prevention (Hanshaw, 1985~. A variety of agents can infect the fetus or newborn either in utero or intrapartum and cause birth defects and/or injury to developing organs- particularly the brain, eye, and ear with lifelong sequelae among survi- vors. The most important agents are rubella virus, cytomegalovirus, Toxo- plasma gondlii, and herpes simplex virus. Infectious pathogens, such as syphilis, can cause congenital infections that result in postpartum condi- tions (e.g., bone deformities, developmental disorders, blindness, deafness (Finelli et al., 1998) if left untreated. These are addressed in a companion report (Institute of Medicine, 20031. Specific diagnoses may be difficult because some agents (e.g., cytomegalovirus, Toxoplasma gondlii) produce similar clinical syndromes and because infection may be asymptomatic or not clinically obvious at birth. Laboratory diagnosis or confirmation of a clinically suspected infection may be difficult or impossible in some devel- oping-country settings. Infectious pathogens are distributed worldwide; prevalence data from developing countries are limited, however, because of the difficulties in diagnosis. Nonetheless, it is known that for many agents, the risk of mater- nal infection during pregnancy and therefore of fetal or neonatal infec- . . . . . . . tlon varies Wlt" ~ socioeconomic status, access to preventive ant curative health services (especially immunization), prevalence of sexually transmit- ted diseases (STDs), cultural practices, and geographic region. The follow- ing discussion of these disorders draws on the limited number of studies on infection-associated birth defects in developing countries and on developed country data for the symptoms and understanding of risk factors. Rubella Maternal infection with rubella virus in early gestation interferes with critical organ development in the fetus. The resulting birth defects blind- ness, deafness, cardiovascular anomalies, and mental retardation are re- ferred to collectively as congenital rubella syndrome (CRS). The prognosis for infants with severe CRS is poor. For those diagnosed during the first year, mortality is high, and most survivors are seriously impaired (Bos et al., 19951.

38 REDUCING THE IMPACT OF BIRTH DEFECTS Since 1969, vaccination against rubella has made CRS increasingly rare in most developed countries. Rubella remains endemic in many developing countries, however, as shown in Figure 2-3. Although it is a major cause of preventable hearing impairment and blindness, CRS is often not recognized or recorded (Tantivanich et al., 1980; Cutts and Vynnycky, 1999; Lawn et al., 2000; St. John and Benjamin, 2000~. The majority of all women of childbearing age have acquired immunity to rubella virus by exposure or vaccination (Banatvala, 1998), but there appears to be considerable vari- ability in maternal immunity, as well as in CRS incidence, among countries (see Table 2-3~. A mode! of rubella incidence predicts about 236,000 cases of CRS annually in nonepidemic years, mostly in developing countries; the number of cases may increase tenfold during epidemics (Salisbury and Savinykh, 1991; Banatvala, 1998~. In unimmunized populations, rubella epidemics occur on average 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 (WorId Health Organiza- tion, 2000) per 1,000 live births. These rates are similar to those reported , O'er' Rubella vacine used ~ . ,,; I'm, ~~ r - if ~N ~ \i ~ 'I'm FIGURE 2-3 Countries/areas with rubella vaccine in their national immunization program, April 2000. SOURCE: World Health Organization, 2000.

39 · - a, o ~ ~ o .= .- ~ o o Id - ~ An o ~ .~o ~ Id ¢ In - lo lo ~ ~ .= ~ 1 ~ ~ ~ ~ ~ \ ~ ~ ~ - ~ :: ~ ~ ~ ~ In ~^ _ am, ,, ~ a ~ ~ ~ ~ TO ~ ~ ~ · _ ~ ~ ~ ~ ~ ~ \~' ~ ~ I 0 ~ \ \ \ \ ~ ~ \ \ ~ \ \ I \ ~ ~ O A ~ ~ ~ ~ oo ~ ~ ~ ~ ~ . - ~ ~L, . ~ To ~ ~ _, == a ~ ~ =~°-^ O at, ~ ~ ~ ~ ~ ~ ~ ~ ~ a . ~ ~ . 4 j · ~ ~ i . ~ 'a ~ ~ L —~ - ~ ~ ~ ~ 5 ~ ~ ~ ~ ¢ ~ ~ =\ ~ 00 I u, I · ~ 00 ~ \e, ~ O ~ ~ . c<, . ~ ~ · ~ · ~ ~ . ~ O 3 ~ ~ 3 ~ ~ ·— ~ ·— ·— ILL ~ ·— ~ ~ o ~ ~, ~ ~ ~ ~, 0 _ ~ _ _ ~ ~ ~ ~ ~ ~ ° 0 ~ 0 0 ~ ~ ~ 0 ~ ^ i~ ^ ~ ~ ~ _ U. · _ ~ ~ ~ ~ ~ · - d ~ ~ ~ C<, ~ E~ td ~ ~ · - ~ O ~ ~ ~ ~ ~ ~ 0 ~r ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ _ o ¢~ ~ ~ O ~ E~ ~ o ~ ~ ~ 0 o . _ bC · ~^ ~ 0 ~ ~ ~ cd' ~ ~' ~ ~ ·~ ~ ~ ~= ~ ~ ~ ~ ~ ~ ~ ~ ~ - ~ o ~ ~ ~ ~ ~ ~ o u, - ~ O .s ~ 11 ~ bC O )

40 REDUCING THE IMPACT OF BIRTH DEFECTS for developed countries during the prevaccination era. Even higher rates are found in CRS prevalence studies with follow-up after 2 or more years, since this is the time when signs such as deafness or psychomotor retardation are more likely to be detected. Cytomegalovirus (CMV) CMV is the most common intrauterine infection and is estimated to affect 0.4-2.5 percent of live-born infants. Over 90 percent of the infected infants are asymptomatic at birth, but 5-17 percent of them will later develop sensorineural hearing loss, chorioretinitis, mental retardation, and neurological damage. Nearly 90 percent of the infants with symptoms at birth will develop severe abnormalities associated with damage to the cen- tral nervous system (CNS) or sensory organs. (Afford et al, 1990; Fowler et al., 1992; Stagno and Whitley, 1985~. Like other members of the herpes family, CMV can persist in a latent state following a primary infection. Despite maternal immunity, it can be reactivated during pregnancy and transmitted to the fetus, or reinfection can occur from a different strain of CMV (Bos et al., 19951. The infection is, however, generally less severe in the presence of maternal antibody (Stagno et al., 1984~. The average age of CMV infection in a population depends on the level of hygiene, which in turn is related to the level of development. In countries with high standards of hygiene, fewer women of childbearing age are im- mune to CMV, putting the fetus at greater risk. In studies from developing countries, almost all women of childbearing age have been found to be immune: 96 percent in South Korea (Sohn et al., 1992), 100 percent in Thailand (Taechowisan et al., 1997),99 percent in Turkey (Hize! et al., 1999),88 percent in the Gambia (Bello and Whittle, 1991), 100 percent in the Ivory Coast (Stagno et al., 1982), and 60-100 percent in South Africa (Stagno et al., 1984~. The percentages of neonates with CMV vary: 0.2-2.3 percent in South Africa (Stagno et al., 1984),1.4 percent in the Ivory Coast (Stagno et al., 1982), and 1 percent in South Korea (Sohn et al., 1992~. Toxoplasma gondii This infection is generally transmitted by oocysts present in soil or water that has been contaminated by the feces of infected cats or by tissue cysts that persist in the undercooked meat of infected animals (Cook et al., 2000; Dubey, 2000~. The seroprevalence of toxoplasmosis in women dur- ing pregnancy has been found to vary markedly in different populations: 12 percent in Thailand (Chintana et al., 1991), 14 percent in Indonesia (Ganda- husada, 1991), 25 percent in Egypt (Essawy et al., 1990), 35 percent in

IMPACT AND PATTERNS OF O CCURRENCE 41 Tanzania (Doehring et al., 1995), and 75-80 percent in Nigeria (Onadeko, 1996). The signs and symptoms of congenital toxoplasmosis include choriore- tinitis, anemia, jaundice, hepatomegaly, splenomegaly, intracranial calcifi- cations, hydrocephalus or microcephaly, and growth restriction. Long-term sequelae include mental retardation, seizures, severe visual impairment, blindness, and hearing impairment. Herpes simplex virus (HSV) Genital herpes is becoming a leading cause of genital ulcers in many developing countries (O'Farrell, 19991. Herpes simplex virus types 1 (HSV- 1) and 2 (HSV-2) can cause genital infection and be transmitted from mother to fetus or newborn. HSV infection in the newborn can be acquired in utero (rare), intrapartum (most common), and postnatally. The newborn is at greatest risk if the mother has a primary HSV infection at or near the time of delivery (transmission rates of 50 percent or more) (Brown et al., 19971. Unfortunately, many women are asymptomatic at the time of pri- mary infection. Neonatal HSV infection is a life-threatening illness that presents clinically as isolated CNS disease; disseminated disease with CNS involvement; or isolated skin, eye, and/or mouth infection. CNS damage, including microcephaly, hydranencephaly, and/or meningoencephalitis, can result. Therapy with intravenous acyclovir reduces the risk of death (0 percent for localized skin disease, 5 percent for encephalitis, 25 percent for disseminated disease), but morbidity remains high. While 95 percent of those with skin disease are normal at 2 years of age, only 40 percent of those surviving encephalitis and 60 percent of those surviving disseminated disease are normal at age two (Whitley at al., 19911. Genital herpes is increasingly being recognized as an important prob- lem in developing countries (Carey and Handsfield, 20001. Few studies of HSV during pregnancy have been conducted in developing countries, but maternal seroprevalences of 50 percent for HSV-1 and 20 percent for HSV- 2 have been reported in India (Kaur et al., 19991; in Eritrea, 97 percent of pregnant women were found to be seropositive for HSV-1 and 23 percent for HSV-2 (Ghebrekidan et al., 19991; in Costa Rica, 97 percent were seropositive for HSV-1 and 39 percent for HSV-2 (Oberie et al., 19891. In a large study of the seroepidemiology of HSV infections in many countries, Nahmias et al. (1990) reported that adult populations in several countries, including Rwanda, Zaire, Senegal, China, Taiwan, Haiti, Jamaica, and Costa Rica, had a prevalence of HSV-1 antibodies of 85 percent. Rates of HSV-2 antibodies among pregnant women varied from less than 10 percent in Japan, Italy, and Spain to 50 percent in Haiti. Nahmias et al. noted an increase in HSV-2 seroprevalence rates over time.

42 REDUCING THE IMPACT OF BIRTH DEFECTS Other Maternal Illnesses Insulin-dependent diabetes mellitus (IDDM) This affects about 0.5 percent of pregnancies in developed countries and is reported to be equally prevalent in several developing countries. Pregnant women with preexisting diabetes are at risk for having infants with CNS, cardiovascular, renal, and limb defects (Khoury et al., 1989; Loffredo et al., 2001). Such pregnancies also have higher-than-average rates of fetal loss and stillbirth. Phenylketonuria This is an autosomal recessive disorder carrying a significant risk that affected infants will also have disorder, a congenital malformation, or neu- rological impairment (see the earlier discussion under single-gene disor- ders). Improved outcomes have been reported for infants when their moth- ers maintain low-phenylalanine diets (Cunningham, 2000; Platt et al., 2000). Hyperthermia This involves a fever of 39°C or higher for at least 24 hours during the first 4 weeks of pregnancy. It increases the risk for NTDs and other birth defects Walter and Warkany, 1983; Warkany, 1986; Chambers et al., 1998; Graham et al., 1998~. It is not known whether these birth defects are due to the hyperthermia or the underlying cause of the fever. Maternal Nutrition Deficiencies in maternal nutrition, particularly of folate and iodine, during pregnancy can increase the risk of an infant's being born with a birth defect. Folic acid deficiency When this occurs before and during the early weeks of pregnancy, it has been shown by randomized controlled trials to be the predominant cause of NTDs (spine bifida, anencephaly, and encephalocele) (MRC Vita- min Study Research Group, 1991; Czeize! and Dudas, 1992~. The number of children born each year with spine bifida and anencephaly is estimated at 300,000 or more. Further discussion follows in the section in this chapter on NTDs.

IMPACT AND PATTERNS OF O CCURRENCE Iodine deficiency disorders (IDDs) 43 These occur worldwide and are among the most readily preventable causes of birth defects (Hollowell and Hannon, 1997; Maberly, 1998~. In 1990, it was estimated that 43 million people worldwide live with cretin- ism, mental retardation, and brain damage due to IDD (United Nations Children's Fund, 1998~. In endemic areas, where up to 100 percent of the population fails to consume adequate iodine (All, 1995; Wyss et al., 1996; Yusuf et al., 1996; Geelhoed, 1999; Kouame et al., 1998), nearly every developing fetus is affected by IDD (Mittal et al., 20001. Severe maternal iodine deficiency begins to affect the fetus in the second trimester of preg- nancy, and the resulting damage becomes irreversible at the end of that period (DeLong et al., 1985~. The spectrum of these disorders includes endemic cretinism, endemic goiter, and reduced intellectual ability. Cretins have severe mental retardation, with IQ usually below 30 (Boyages et al., 1987; Sankar et al., 1998~. They have broad CNS defects that include preservation of primitive reflexes, deafness, squint, a character- istic grin, and spasticity that affects the larger proximal limb muscles more than the distal extremities (DeLong et al., 1985~. They also have cartilage defects, bony deformities, and laxity in joints. If they are able to walk, it is with difficulty. The presence or absence of goiter, stunted growth and sexual development, and gross myxedema depends on the severity of the condition and the time lived with congenital hypothyroidism. Lifelong hy- pothyroidism in certain individuals substantially alters the clinical picture (Halpern et al., 19911. Endemic cretinism occurs in areas severely deficient in iodine and has been reported to affect 0.5-11 percent of the population in several countries (Wyss et al., 1996; Yusuf et al., 1996; Talil et al., 1997; Bellis et al., 1998; Kouame et al., 1998; Sankar et al., 1998; Geelhoed, 19991. A rural hospital study in Zaire that examined more than 3400 consecutive births found 5 percent of the neonates to be cretins (Smith et al., 1986~. Endemic goiter is the hallmark of iodine deficiency and has been used as an indicator of deficiency in a population when goiter rates in school-age children exceed 5 percent. Even after the introduction of iodized salt to a deficient population, goiters may persist for many years despite adequate iodine intake (WorId Health Organization, 20011. Goiter rates can ap- proach 100 percent in severely iodine-deficient populations, but a rate of 40-60 percent is more common. The presence or absence of goiter in an individual does not relate directly to the level of iodine deficiency, associ- ated perturbations of thyroid function, or other features of IDD (Maberly and Eastman, 19761. In populations with mild to moderately severe iodine deficiency, popu- lation cognitive performance distribution curves are shifted by as much as

44 REDUCING THE IMPACT OF BIRTH DEFECTS one standard deviation as compared with iodine-replete populations (Stan- bury, 1994~. A meta-analysis of 18 studies involving 2,214 individuals examined cognitive and neuromotor function (Bleichro~t et al., 1980~. The mean IQ scores in the iodine-deficient group were 13.5 points lower than in the control group. This would suggest that the widespread effect of iodine deficiency on brain function and learning ability has profound implications for the economic and manpower development of affected populations (Dunn, 1994~. Medications A number of therapeutic drugs have been implicated as teratogens. Teratogenicity is dependent on the timing of use in pregnancy, dose levels, genetic susceptibility, and other factors. The use of medications during pregnancy is of particular concern in the developing world because of the widespread over-the-counter availability of many drugs, as well as the large proportion of unplanned pregnancies and the fact that most women are unaware of their pregnancies during the first few weeks. Teratogenic medi- cations that are important in developing countries are reviewed below; additional drugs with proven teratogenic effects in humans are listed in Table 2-4. New drugs are rarely tested in pregnant women, so their descrip- tion includes a disclaimer such as "use in pregnancy is not recommended unless the potential benefits justify the potential risks to the fetus." Com- mon drugs initially thought to be teratogenic but subsequently proven safe include diazepam, oral contraceptives, spermicides, salicylates, and Ben- dectin (doxylamine plus pyridoxine) (Koren et al., 1998~. Alternative drugs that are not known to be teratogenic are listed in Table 2-5. Thalidomide This is the paradigm of teratogenic drugs. It was withdrawn from global markets in the early 1960s when it was determined that the seda- tive 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~. Today, because of its additional properties as an immunomodulator, thalidomide is once again available in many countries for indications including leprosy and HIV (Castilla et al., 1996; Diggle, 2001~. Access to thalidomide is likely to result in birth defects unless preventive measures are established to protect preg- nant women from exposure (Vanchieri, 1997; Annas and Elias, 19991. For example, 34 infants have been born with thalidomide embryopathy in the last 25 years in areas of South America where leprosy is endemic (Castilla et al., 19961.

IMPACT AND PATTERNS OF O CCURRENCE TABLE 2-4 Drugs with Proven Teratogenic Effects in Humansa Teratogenic Effect Central nervous system (CNS) and limb malformation Prolonged renal failure in neonates, decreased skull ossification, renal tubular dysgenesis Neonatal meconium ileus Fetal and neonatal goiter and hypo- thyroidism, aplasia cutis (with methimazole) Neural tube defects (NTDs) CNS malformations, secondary cancer Masculinization of female fetuses Vaginal carcinoma and other genitourinary defects in female and male offspring Neonatal hypoglycemia Ebstein's anomaly Moebius sequence Constriction of the ductus arteriosus,C necrotizing enterocolitis Facial and CNS defects Growth retardation, CNS defects Neonatal withdrawal syndrome when drug is taken in late pregnancy CNS, craniofacial, cardiovascular, and other defects Anomalies of teeth and bone Limb-shortening defects, internal organ defects Facial and CNS defects NTDs Skeletal and CNS defects, Dandy-Walker syndrome 45 Drug Aminopterin,b methotrexate Angiotensin-converting enzyme inhibitors Anticholinergic drugs Antithyroid drugs (propylthiouracil and methimazole) Carbamazepine Cyclophosphamide Danazol and other androgenic drugs Diethylstilbestrolb Hypoglycemic drugs Lithium Misoprostol Nonsteroidal anti-inflammatory drugs Paramethadioneb Phenytoin Psychoactive drugs (e.g., barbiturates, opioids, benzodiazepines) ,~ . . . . . . . ~ystem1c ret1no1c s 1soretlnoln and etretinate) Tetracycline Thalidomide Trimethadioneb Valproic acid Warfarin aOnly drugs that are teratogenic when used at clinically recommended doses are listed. The list includes all drugs proven to affect neonatal morphology or brain development and some of the toxic manifestations predicted on the basis of the pharmacologic actions of the drugs. bThe drug is not currently in clinical use. CSulindac probably does not have this effect. SOURCE: Briggs et al., 1994. Misoprosto! This is used for cervical ripening and induction of labor, also to induce early abortion (Gonzalez et al., 1998; Orioli and Castilla, 20001. The drug is not always effective for this purpose, and surviving newborns have exhib- ited several birth defects attributed to vascular disruption, including trans- verse limb reduction anomalies, constriction rings, Moebius sequence, hy-

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47 ~ s-^ ~ U. Cd ~ a hi' ~ ~ =0, ~ ' ° a a ~ ~ :5 ' O =~ ~~ · ~ a 5 .= Cat 5, ·, ~ At, ~ . it set s O. ~ 0 T ~ ~ ~i ~ ~ ~ i= ~ , -

48 REDUCING THE IMPACT OF BIRTH DEFECTS drocephalus, and arthrogryposis (Gonzalez et al., 1998; Orioli and Castilla, 20001. A multicenter, case-controlled study conducted in Brazil showed that 34 percent of mothers of infants with vascular disruption defects had taken misoprosto! during the prenatal period, compared with only 4 per- cent in a control group consisting of mothers of children with other birth defects (Vargas et al., 20001. Another Brazilian study of 15 patients with growth retardation, underdeveloped bones, joint rigidity, and short feet with equinovarus revealed that all their mothers had taken 400-4800 mi- crograms of misoprosto! between the eighth and twelfth weeks of preg- nancy (Coelho et al., 20001. Anticonvuisant drugs When used during pregnancy, these have been associated with congeni- tal anomalies. Phenobarbital, phenytoin, carbamazepine, and valproate have been implicated as causes of major malformations, including NTDs, micro- cephaly, growth restriction, and minor malformations of the face and fin- gers (Koren, 1998; Samren, 1999; Arpino et al., 2000; Adab et al., 2001; Holmes et al., 20011. These birth defects do not appear to be associated with maternal epilepsy itself (Holmes et al., 20011. A large retrospective cohort study has concluded that antiepileptic drugs used in polytherapy carry a higher risk of causing birth defects than those used in monotherapy (Samren et al., 19991. Research is under way to explore the effectiveness and risk of monotherapy for epilepsy in pregnant women (Adab et al., 2001). Anticoagulants When used during pregnancy, anticoagulants cause congenital disor- aers. Fetal exposure, particularly during the first trimester, to derivatives of coumarin such as Coumadin (warfarin) can cause nasal hypoplasia, stip- pling of bones, optic atrophy, microcephaly, and growth and mental retar- dation. Exposure after the first trimester has also been associated with facial anomalies and fetal and neonatal hemorrhage. Heparin is the pre- ferred anticoagulant for use during pregnancy because it does not cross the placenta (Hardman et al., 19961. Alcoho! and Recreational Drugs Alcoho! Heavy alcoho! use during pregnancy is associated with fetal alcoho! syndrome (FAS) and alcohol-related neurodevelopmental disorder (ARND)

IMPACT AND PATTERNS OF O CCURRENCE 49 in exposed children. FAS/ARND has been reported in up to 9 per 1,000 infants exposed to high alcohol levels during pregnancy (Sampson et al., 19971. FAS encompasses a constellation of physical abnormalities, includ- ing alterations in facial features and fetal growth reduction, as well as behavioral and cognitive effects (Institute of Medicine, 19961. With or without the recognized dysmorphologic pattern known as FAS, mental retardation is the most serious and constant effect of alcohol use during pregnancy. Research to measure the prevalence of FAS in South African school children is described in Box 2-3.

so Tobacco REDUCING THE IMPACT OF BIRTH DEFECTS Evidence for the role of smoking in birth defects is controversial. The well-established role of smoking in preterm births and intrauterine growth restriction is discussed in the companion to this report (Institute of Medi- cine, 20031. Environmental Pollutants Although teratogenic pollutants are known to be present in some developing-country settings and have been associated with birth defects in clinical studies, their impact in developing countries remains unknown. Common teratogens may include heavy metals such as organic mercury, pesticides such as DDT, solvents, and other toxic contaminants (Jacobson and Jacobson, 1996; Ramsay and Reynolds, 20001. This risk is poorly defined because most developing countries do not have systems to detect 1. · 1 1 1 .1 1 1 . exposures or resulting problems, nor do they have laws to protect against hazardous exposure. Research is needed to establish whether these pollut- ants contribute significantly to the occurrence of birth defects in different settings. Mercury contamination of the environment can be widespread and persistent (Institute of Medicine, 20001. Methy~mercury causes birth de- fects in the central nervous system and, to a lesser extent, in the liver and kidneys (Institute of Medicine, 20001. The chemical accumulates up the food chain and may be present at teratogenic levels in some fish popula- tions. Mass methy~mercury poisoning, which occurred in Japan in the 1950s (Friberg et al., 1971) and in Iraq in the 1970s (Marsh et al., 1987), resulted in severe neurological dysfunction and developmental abnormalities among children who were exposed in utero. The adverse effects included mental retardation, cerebral palsy, deafness, blindness, and dysarthria. Occupational exposure to environmental pollutants, both agricultural and industrial, can be teratogenic or fetotoxic. The risk posed by maternal occupational exposures to industrial pollutants is unknown, and male- mediated teratogenesis remains controversial (McDonald et al., 1989; Olshan et al., 19901. Ionizing Radiation Studies of atomic bomb survivors demonstrated that exposure to ioniz- ing radiation during gestation can damage the developing brain, particu- larly when exposure occurs 8 to 25 weeks after ovulation (Schull and Otake, 19991. Diagnostic radiography involves a low level of X-ray expo-

IMPACT AND PATTERNS OF O CCURRENCE 5 sure of the fetus so that, with protection, the risk of a birth defect is small (Fattibene et al., 1999; Fenig et al., 20011. 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 (environmen- tal) factors. These conditions are usually limited to a single organ system and include the following: NTDs, congenital heart disease, cleft lip and palate, talipes or clubfoot, and developmental dysplasia of the hip. These conditions were selected for discussion because of their documented disease burden in developing countries. Neural Tube Defects These encompass a range of congenital malformations that result from incomplete development of the brain and spinal cord or their protective coverings. The three major types are anencephaly, spine bifida, and encephalocele. Spina bifida is the incomplete closure of the neural tube, which is the predecessor of the spinal cord. The birth outcome varies with the location of the genetic defect and whether it affects the neural tube, skeletal compo- nents, 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 hydrocephalus, paralysis, incontinence, or skel- etal deformities depending on the location and nature of the defect. Al- though spine bifida has long been considered to be a lethal condition, surgery at birth saves some infants, but they may be significantly handi- capped (Shibuya and Murray, 1998; Gross et al., 1983; Hunt, 1990; Laurence 1974; McLaughlin et al., 19851. 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 condition causes significant mortality before and soon after birth. Encephalocele involves a protrusion of the brain and its covering mem- branes through the skull. This condition may or may not be lethal, but serious neurological deficits usually occur. Worldwide, NTDs are estimated to affect 300,000 or more infants each

52 REDUCING THE IMPACT OF BIRTH DEFECTS year (Murray and Lopez, 1998). The wide variation in birth prevalence of NTDs, demonstrated in Appendix A (Table A-9), can be explained by genetic and nutritional factors and in part by differences in the availability of prenatal screening and termination of affected pregnancies (Shibuya and Murray, 19981. Epidemiological studies show a strong association between NTDs and inadequate maternal consumption of folic acid during the peri- conceptional period (see the discussion of folic acid deficiency in Chapter 31. Mutations of the methylenetetrahydrofolate reductase gene in the ab- sence of a folate-rich diet are associated with elevated maternal plasma homocysteine and increased risk of NTDs in offspring (Wilcken, 1997; Van der Put et al, 19981. Congenital Heart Disease A malformation of the heart or large blood vessels near the heart is present at birth. This is the most common of the major birth defects, affecting 8 per 1,000 live births, and is a leading cause of birth defect- related deaths, despite improvements in diagnosis and surgical treatments over the last 40 years. The more serious symptoms and signs of congenital heart disease include cyanosis, pulmonary hypertension, growth retarda- tion, and syncope. Left untreated, these symptoms will, in most cases, prove fatal before age 20 (Cartmill et al., 1966; Rygg et al., 1971; Kirklin and Barrat-Boyes, 1993; Cohen et al., 20011. Today, echocardiography, avail- able in urban centers in developing countries, can provide a reliable ana- tomical diagnosis when clinical data suggest a cardiac defect. A variety of conditions maternal rubella infection, maternal diabetes, alcohol abuse, genetic abnormalities, and chromosomal disorders such as Down syndrome can result in congenital cardiac malformations. Lesions include ventricular septal defect, atrial septal defect, pulmonary stenosis, coarctation of the aorta, aortic stenosis, and tetralogy of Fallot. Prevalence data on congenital heart disease (both the general disease and specific lesions) in developing countries are given in Appendix A (Table A-101. Because congenital heart disease is often not recognizable at birth, studies have used a wide range of ascertainment methods (Shibuya and Murray, 19981. Cleft Lip and/or Cleft Palate These are congenital malformations involving a gap in the soft palate and roof of the mouth, sometimes extending through the upper lip. This condition occurs when the various parts of a lip or palate don't grow together to make a single lip or hard palate. It is usually correctable. Af-

IMPACT AND PATTERNS OF O CCURRENCE 53 fected infants have difficulty first with feeding, then with speech develop- ment, hearing, and tooth formation; stigmatization and discrimination pose lifelong problems. Malnutrition and infection resulting from cleft lip and/or palate can lead to severe illness and, in some cases, death (Shibuya and Murray, 19981. Half of all infants with cleft lip and/or palate have addi- tional birth defects, such as heart malformations, that co-occur as genetic syndromes (Shibuya and Murray, 19981. Birth prevalence rates for oral clefts from several countries are shown in Appendix A (Table A-ll); most lie between 1 and 2 per 1,000 live births. Several of the studies listed in the appendix identified environmental, ma- ternal, and birth-order risk factors for these congenital malformations (Chou~hury et al., 1989; Wu et al., 1995; Chuangsuwanich et al., 1998; Cooper et al., 20001. Talipes or Clubfoot This involves a spectrum of common abnormalities in ankle joints and in the bones, muscles, and ligaments of the foot. The main types of deformi- ties include abduction of the whole foot with planter inversion, external rotation of the foot, concave profile of the sole, convex profile of the sole, and medial deviation of the anterior third of the foot (Winter et al., 19881. Pathological changes resulting from the deformity vary among patients. In severe cases, bones may be smaller than normal, with displacement of the talocalcaneonavicular joint. When bones are normal in shape and size, the deformity is maintained by contracted muscles, tendons, and ligaments (Sinha, 19871. Transient deformities not requiring treatment are not con- sidered here. Left untreated, talipes prevents normal motion of the foot and pro- duces an awkward gait. If both feet are affected (about 50 percent of cases), the child is forced to walk on the balls of the feet or, when the feet are badly twisted, on the sides or even the tops of the feet. These surfaces often become infected and develop large, hard calluses. Over time, talipes causes arthritis and can hinder the growth of the entire leg. The birth prevalence of talipes in several populations is presented in Appendix A (Table A-121. The rate in most countries is 1.5 to 4 per 1,000 live births. Some 30-40 percent of infants with talipes have other severe congenital malformations, particularly spine bifida. The etiology of talipes is heterogeneous and complex, and involves the interplay of extrinsic in- trauterine compression (Dietz, 19851; intrinsic neurological deficit (Nadeem et al., 20001; and genetic anomalies, including major genes (Yang et al., 19871.

54 REDUCING THE IMPACT OF BIRTH DEFECTS Developmental Dysplasia of the Hip (DDH) A malformation of the hip joint in which the head of the femur is not correctly positioned in the acetabulum. The cause is unknown, but genetic factors may play a role. Problems range from the relatively rare congenital dislocation of the hip where the head of the femur is completely outside the acetabulum and the hip is very unstable to conditions where the displace- ment shortens one leg and causes limping, joint and knee problems, pain, and the degenerative changes of osteoarthrosis (Leek, 2000~. The prevalence reported for DDH varies widely (see Appendix A, Table A-13), due more to the criteria applied, rather than to actual differences among populations (Dunn et al., 1985; Herring, 1990; Bialik et al., 19991. However, two recent hospital-based studies conducted by experienced di- agnosticians using both manual and ultrasound methods one in Singapore (Any et al., 1997), the other in Israel (Bialik et al., 1999) reported birth prevalence rates for DDH of about 5 per 1,000 live births. Females out- number males five to one, presumably because of sexual differences in the shape of the acetabulum and the pelvis (Woolf and Turner, 1969; Simpson and Golbus, 1992~. The recurrence risk for DDH in siblings is 4 percent for males and 8 percent for females, rising to 10-15 percent if a parent is also affected (Simpson and Golbus, 1992~. Traditional practices of infant care appear to significantly influence natural prevalence rates for DDH. Considerably higher rates are found in communities where infants are swaddled or diapered with their thighs ex- tended, a position that separates the femur head from the acetabulum. Such practices are traditional in Japan, Turkey, and Saudi Arabia, as well as among Lapps and some Native American groups. A dramatic reduction in DDH prevalence occurred in a Japanese community when the traditional infant wrappings were abandoned (Yamamuro et al., 1984~. Low rates of DDH occur in regions of Africa, China, and other communities where infants are carried on their mothers' backs with their thighs flexed and abducted (Salter, 1968~. This position, which stabilizes the femoral head deep within the acetabulum, may correct many cases of congenital hip instability, preventing them from developing into dislocation (Edelson et al., 1984~. CONCLUSION Birth defects impose a severe disease burden worldwide: they affect all major body systems and cause fetal deaths, neonatal and childhood deaths, and severe and lifelong disabilities. And for many birth defects, the stigma associated with the condition isolates affected individuals and their families and creates substantial social, psychological, and economic hardship.

IMPACT AND PATTERNS OF O CCURRENCE 55 The patterns of occurrence of birth defects in developing countries reveal a wide range of causes and risk factors for a wide range of condi- tions. In the absence of basic preventive public health measures, birth de- fects occur with increased frequency: Down syndrome where family plan- ning services are deficient or underutilized; neural tube defects where periconceptional intake of folic acid is inadequate; iodine deficiency syn- drome where iodized salt is not available; congenital rubella where popula- tions are unvaccinated; cardiovascular and CNS damage where maternal control of insulin-dependent diabetes mellitus is poor; fetal alcohol syn- drome where alcohol abuse occurs; and other birth defects where pregnant women are exposed to teratogenic drugs and pollutants. Affordable, practical interventions are available to prevent some of the more common and severe birth defects. For populations where these par- ticularly cost-effective interventions are being used effectively, there are additional cost-effective ways to further reduce the impact of birth defects through improved prevention and expanded treatment. To implement these interventions cost-effectively, policy makers need information about the occurrence of specific birth defects and risk factors in their populations, and the clinical- and cost-effectiveness of specific interventions. REFERENCES Adab N. Winterbottom J. Tudur C, Williamson PR. 2001. Common antiepileptic drugs in pregnancy in women with epilepsy. Cockade Database of Systematic Reviews (2):1-14. Akinyanju OO. 1989. A profile of sickle cell disease in Nigeria. Annals of tI7e New York Academy of Sciences 565:126-136. Alford CA, Pass RF. 1981. Epidemiology of chronic congenital and perinatal infections of man. Clinics in Perinatology 8(3):397-414. Alford CA, Stagno S. Pass RF, Britt WJ. 1990. Congenital and perinatal cytomegalovirus infections. Review of Infectious Diseases 12(suppl 7):745-753. Al-Gazali LI, Sztriha L, Dawodu A, Bakir M, Varghese M, Varady E, Scorer J. Abdulrazzaq YM, Bener A, Padmanabhan R. 1999. Pattern of central nervous system anomalies in a population with a high rate of consanguineous marriages. Clinical Genetics 55(2):95- 102. All O. 1995. Iodine deficiency disorders: A public health challenge in developing countries. Nutrition 11(5 suppl):517-520. All ZA, Hull B. Lewis M. 1986. Neonatal manifestation of congenital rubella following an outbreak in Trinidad. Journal of Tropical Pediatrics 32(2):79-82. Allison AC, Clyde DF. 1961. Malaria in African children with deficient erythrocyte glucose- 6-phosphate dehydrogenase. British Medical Journal I: 1346-1349. Ang KC, Lee EH, Lee PY, Tan KL. 1997. An epidemiological study of developmental dyspla- sia of the hip in infants in Singapore. Annals of tile Academy of Medicine, Singapore 26(4):456-458. Angastiniotis M, Modell B. Englezos P. Boulyjenkov V. 1995. Prevention and control of haemoglobinopathies. Bulletin of tile World HealtI7 Organization 73(3):375-386. Annas GJ, Elias S. 1999. Thalidomide and the Titanic: Reconstructing the technology trag- edies of the twentieth century. American Journal of Public HealtI7 89(1):98-101.

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Each year more than 4 million children are born with birth defects. This book highlights the unprecedented opportunity to improve the lives of children and families in developing countries by preventing some birth defects and reducing the consequences of others. A number of developing countries with more comprehensive health care systems are making significant progress in the prevention and care of birth defects. In many other developing countries, however, policymakers have limited knowledge of the negative impact of birth defects and are largely unaware of the affordable and effective interventions available to reduce the impact of certain conditions. Reducing Birth Defects: Meeting the Challenge in the Developing World includes descriptions of successful programs and presents a plan of action to address critical gaps in the understanding, prevention, and treatment of birth defects in developing countries. This study also recommends capacity building, priority research, and institutional and global efforts to reduce the incidence and impact of birth defects in developing countries.

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