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

Chapter:3 Interventions to Reduce the Impact of Birth Defects

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Suggested Citation:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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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Page110
Suggested Citation:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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:"3 Interventions to Reduce the Impact of Birth Defects." 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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Interventions to Reduce the Impact of Birth Defects Impact of birth defects in developing countries can be reduced through a series of interventions and eventually a comprehensive pro- gram that encompasses prevention, education about reproductive health, diagnosis, treatment, and rehabilitation. Several interventions pre- sented in this chapter involve prevention of common birth defects and have been found to be affordable in even the poorest settings. These high priority interventions can be expanded as other health problems are resolved, as birth defects become a public health priority, and as additional resources become available. The health care provided to children and adults with birth defects should always be equitable with the care provided for other health conditions. In low-resource settings this may be very limited, but as the level of health care improves, the ability to diagnose and treat birth defects can be expanded and the quality of medical support for rehabilita- tion programs can be improved. Once health care has reduced infant mor- tality due to other causes, screening for genetic defects becomes cost-effec- tive and can further reduce the impact of birth defects. Although the number and severity of birth defects pose a challenge to countries with limited health resources, the process of reducing the impact of birth defects can be undertaken in three stages: 1. Introduction of low-cost preventive interventions. 2. Provision of improved treatment for children and adults with birth defects. 3. Introduction of screening to identify genetic birth defects that can be prevented or treated. 68

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 69 Developing countries have a wide range of priorities, capacities, and resources for health care services. Successful implementation of each inter- vention requires that it be matched to the local setting. At each stage of development, health care services also need national leadership and coordi- nation, surveillance to provide a sound evidence base for setting public health priorities, and monitoring of interventions to ensure their clinical- and cost-effectiveness. BASIC REPRODUCTIVE CARE Basic reproductive care, which includes family planning, and precon- ceptional, prenatal, and neonatal care, is the foundation for improving neonatal and infant mortality and reducing birth defects. As infant mortal- ity rates fall, birth rates tend to decline because parents become increasingly confident that the children they conceive will survive childhood. This trend is strongest where family planning is accessible and effective. Family Planning The primary goal of family planning is to provide couples with the knowledge they need to make well-informed decisions concerning whether, when, and under what circumstances to have children. Accomplishing this goal involves education and assistance in preventing unintended pregnan- cies. Planning for a family of the desired size and preventing additional births can substantially reduce the number of children born with birth defects simply by reducing the total number of births. In addition, couples who have an established genetic risk of producing children with birth de- fects can choose whether to have any (or more) children (WorId Health Organization, 19971. Preconceptional Care Maternal education, literacy, and overall socioeconomic status are pow- erful influences on the health of both mother and neonate (Bicego and Boerma, 1993; World Bank, 1993; Rao et al., 1996; van Ginneken et al., 19961. Where both the formal education and the health education of girls are limited, there is an especially acute need for preconceptional health care, which aims to ensure that women and their partners achieve an "op- timal state of physical and emotional health at the onset of pregnancy" (Wallace and Hurwitz, 19981. Preconceptional care identifies risk factors for adverse birth outcomes, including birth defects, and provides the means to minimize those risks.

70 REDUCING THE IMPACT OF BIRTH DEFECTS Identification of risk factors involves the following assessments (Moos, 19941: · Medical . history to identify preexisting medical conditions, such as 1nsulin-dependent diabetes mellitus, epilepsy, and heart disease, that may pose a threat to the mother and the developing fetus; medications used by the mother; and exposure to rubella and other infectious diseases. · Family history to identify birth defects in close family members. · Reproductive history to identify risk factors that have contributed to previous poor pregnancy outcomes, some of which can be addressed through preconceptional and prenatal care. _ T . · . · 1 /~-1 . 1 . · . 1 · l~utrltlonal profile to Determine the overall nutritional status anu intake of micronutrients, such as iodine and folic acid. · Life-style profile to determine the potential for maternal exposure to infectious agents or recreational drugs such as alcohol. · Maternal occupation should be evaluated for potential teratogenic exposures. Preconceptional care advises on how to prevent certain birth defects that originate during the first weeks of pregnancy often before a mother realizes she is pregnant. At 2 to 8 weeks' gestation, when embryonic cells are dividing rapidly and organ systems and body parts are beginning to differentiate, the embryo is particularly vulnerable to teratogens (Moos, 19941. For example, folic acid supplementation (discussed later in the chap- ter) is only effective in preventing neural tube defects (NTDs) when con- sumed during the periconceptional period. Prenatal Care An early prenatal visit permits the identification and review of risk factors for the pregnancy and prenatal diagnosis if the fetus is at high risk of having a birth defect. As noted above, this is too late for certain preventive measures such as increasing dietary consumption of folic acid to avoid NTDs. Neonatal Care Where possible, neonatal care should include a complete physical ex- amination at birth (or prior to discharge for those born in a clinic or hospital) to diagnose detectable conditions. Early diagnosis followed by timely treatment can minimize some conditions and reduce disability. In- fants with birth defects should receive the best care locally available. This will vary with local resources, the prevalence of specific birth defects, and the cost and effectiveness of potential interventions (Christianson et al.,

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 71 2000; World Health Organization, 1985, l999b; Alwan and Modell, 19971. Low-cost rehabilitation may be less effective than prevention of birth de- fects, but it can reduce dependence and provide a better quality of life for affected individuals and their families. Recommendation 1. Basic reproductive health care services an essen- tial component of primary health care in all countries should be used to reduce the impact of birth defects by providing: · Effective family planning, · Education for couples on avoidable risks for birth defects, · Effective preconceptional and prenatal care and educational cam- paigns to stress the importance of such care, and · Neonatal care that permits the early detection and best care lo- cally available for management of birth defects. LOW-COST PREVENTIVE STRATEGIES These low-cost interventions to prevent birth defects have been found to be affordable in even the poorest settings. They address some important risk factors and involve family planning, public health campaigns, fortification of staple foods, maternal and child health, and infectious disease control. Discouraging Pregnancy in Women Over 35 The simplest means of preventing Down syndrome and other chromo- somal disorders such as trisomies 13 and 18 is to decrease the number of pregnancies among women older than 35 years. This is accomplished by making family planning widely available and providing information about what Down syndrome is and how it is caused (WorId Health Organization, 1997, 2000a). This strategy was shown to be effective in Europe between 1950 and 1975 when family planning programs were expanded and the birth prevalence of Down syndrome decreased from 2.5 to 1.0 per 1,000 live births (Modell and Kuliev, 19901. Recommendation 2. Women should be discouraged from reproducing after age 35 to minimize the risk of chromosomal birth defects such as Down syndrome. Folic Acid Fortification The predominant cause of NTDs is folate deficiency in the early weeks of pregnancy (Oakley, 1993~. Randomized controlled trials in Europe

72 REDUCING THE IMPACT OF BIRTH DEFECTS showed that folic acid supplementation in early pregnancy reduced NTDs by 70 percent (MRC Vitamin Study Research Group, 1991) and 100 per- cent (Czeize! and Dudas, 19921. A randomized controlled trial from India was halted because of the ethical need to provide folic acid to all partici- pants once its effectiveness had been established. The findings of that study supported the conclusion that folic acid deficiency is the predominant cause of NTDs (Indian Council of Medical Research, 20001. In a large, non- randomized community intervention study in a high-prevalence area (4 to 5 NTDs per 1,000 births) of China, pregnant women received daily supple- ments of 400 micrograms of synthetic folic acid before and during the first 28 days of pregnancy. This prevented 85 percent of NTDs among pregnant women taking folic acid more than 80 percent of the time (Berry et al., 1999) (see Box 3-11. Although folic acid is present in leafy vegetables, legumes, and citrus fruits, it is unlikely that dietary advice alone can adequately increase con-

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 73 gumption of these foods by those at risk. The above studies led the United States to fortify cereal grains with synthetic folic acid to increase consump- tion of the nutrient by an average of 100 micrograms a day (Food and Drug Administration, 19961. Although this amount represents just one-quarter of the daily consumption recommended, it raised blood folate to levels that decreased NTDs by about 20 percent (Green, 2002; Oakley 2002a). The United Kingdom and Chile fortify at about twice the U.S. level. Since Chil- eans consume twice as much wheat as each of the other populations, the average woman in Chile is estimated to receive the recommended level of 400 micrograms of synthetic folic acid daily (Oakley, 2002a). Folic acid fortification is being introduced in several South and Central American countries, many of which already fortify wheat flour with other B vitamins. Folic acid is so inexpensive that the cost of the vitamin premixture hardly changes with its addition. In countries where folic acid fortification is not already under way, its cost is estimated at 0.1 percent of the total cost of flour. Fortification overcomes the logistical problems of supplementation in early pregnancy as well as taking a complete regimen. However, almost universal coverage for women of reproductive age is relatively inexpensive. Fortification is recommended at a level of 240 micrograms per 100 grams of a widely consumed staple food (Oakley, 2002b). Supplementation is useful where fortification is not possible or is below the recommended level (Committee on Medical Aspects of Food and Nutrition Policy, 20001. Recommendation 3. All women of reproductive age should routinely receive 400 micrograms of synthetic folic acid per day for the reduction of neural tube defects. This is best accomplished through fortification of widely consumed staple foods. Where fortification is not feasible or is incomplete, daily supplementation programs should be provided for women before and during pregnancy. Universal Salt Iodization The primary cause of iodine deficiency disorders (IDDs) is insufficient iodine in the diet. The adult requirement for iodine can be met with 100 to 150 micrograms daily, and an additional 50 micrograms daily during preg- nancy (Stanbury, 1998; World Health Organization, 20011. Correction of maternal iodine deficiency before conception is necessary to avoid adverse effects on the fetus. Measurement of urinary iodine is a convenient and reliable method for assessing iodine nutritional status in a community. This method is more accepted and considerably less expensive than the use of

74 REDUCING THE IMPACT OF BIRTH DEFECTS thyroid-stimulating hormone or other thyroid hormone measurements (Dunn et al., 1994; World Health Organization, 20011. Iodine deficiency may be exacerbated by goitrogens, which interfere with the incorporation of iodine into thyroxine (Geelhoed, 19991. The effects of goitrogens can be mitigated by ensuring a more-than-adequate intake of iodine; avoiding consumption of thiocyanate-containing vegetable products such as cassava; and cooking potentially goitrogenic foods to reduce the goitrogen content (Bourdoux et al., 19821. Soaking foods is also effective in reducing the goitrogen level, but vitamin A and other nutrients are also lost in this process. Vitamin A deficiency can be addressed with dietary supplements (Vanderpas et al., 1993). Iodine, a volatile trace element, is more abundant in the sea than on land. Except in certain geological regions (Li et al., 1989), iodine has been largely depleted from world soils (McClendon, 19391. Plants do not require iodine for healthy growth, and the amount of iodine in plants and animals generally reflects the low levels in soil. Thus to prevent iodine deficiency, most populations need supplementation (Hetze! and Maberly, 19861. The accepted strategy for eliminating iodine deficiency is universal salt iodization (Stanbury, 1998), which is among the most cost-effective health interventions (WorId Bank, 19931. However, since this estimate does not encompass an assessment of the full impact of IDDs, the actual cost is likely to be lower (WorId Health Organization, United Nations Children's Fund, International Council for the Control of Iodine Deficiency Disorders, 19991. The customary level of fortification is 25-50 milligrams of iodine per kilo- gram of salt (WorId Health Organization, 1996b). The fortified salt prod- uct costs only slightly more ($0.02-$0.06 per person annually) than the unfortified product. In populations with endemic cretinism and IDDs, iodized oil has been administered to entire populations as an emergency prophylactic and thera- peutic (Delange, 1996; Geelhoed, 19991. In a Central African population in remote Congo, for example, an intramuscular injection of iodized oil was found to control goiter and cretinism and protect iodine stores for a period of 1 to 5 years, which reduces concerns about compliance (Geelhoed, 19991. Iodization of drinking water and bread has also been shown to provide a safe and cost-effective alternative in some settings (EInager et al., 19971. National leaders at the 1990 World Summit for Children set the goal of virtually eliminating this deficiency by the year 2000. In 1990, less than 20 percent of household salt was iodized, and more than one- third of the worId's population was recognized as having inadequate dietary iodine. By 2002, more than 70 percent of household salt worId- wide was iodized. Annually, this supplementation protects about 85 million infants, but another 35 million infants remain unprotected (Ramalingaswami, 20001. Figure 3-1 shows the percentage of house-

75 i; :l If . - A ~ —-~t \1. - ~ ~ E ~ ~ ° ~ i o — UD g ~ Ct to to do '>-a .m to to Ct O IL ~ Z O >, Ct U. . o . o 1 U. ~ . 5- Ct O O O ~ as U. ~ O ~ U. U. O - O ~ O O C;, 5- ~ · ~ .= .. V O ~ U)

76 REDUCING THE IMPACT OF BIRTH DEFECTS holds worldwide that use iodized salt, and efforts are under way to reach those households by 2005. The rapid progress of the last decade has demonstrated the effective- ness of national "ownership" of the challenge (Ramalingaswami, 2000) and close collaboration among public, private, civic, and scientific groups to support the production of good-quality iodized salt, the delivery of only iodized salt, persistent market outreach to all parts of the country, periodic advocacy to sustain political commitment, and continued education to sus- tain public demand. Recommendation 4. A program of universal fortification of salt with 25-50 milligrams of iodine per kilogram of salt used for human and animal consumption should be adopted to prevent iodine deficiency disorders. Immunization Against Rubella Rubella infections are common worldwide and are strongly teratoge- nic. Vaccination programs in several, mostly developed, countries prevent virtually all cases of congenital rubella. Some countries have immunized all young children, some have immunized prepubescent females, and some have used a combined approach with measles-mumps-rubella (MMR) vaccine (Immunization Working Group, 2000; Massad et al., 19951. By 1996, 78 countries worldwide reported national rubella vaccination pro- grams. Included among these were 43 percent of Latin American, 12 per- cent of Eastern Mediterranean, 5 percent of South East Asian, and 11 percent of the Western Pacific populations. Notably absent were African countries (Robertson et al., 19971. The decision to introduce rubella vaccination into a country or region should be based on the susceptibility of women of childbearing age, the burden of disease due to congenital rubella syndrome (CRS), the strength of the measles immunization program, the infrastructure and resources for immunization, the record of injection safety, and other priority uses for limited health resources (WorId Health Organization, 2000b). In countries where more than 80 percent of the population is immunized for other childhood diseases, rubella should be included in the immunization pro- gram. In countries where immunization coverage is lower than 80 percent, overall coverage should be increased before introducing rubella immuniza- tion because vaccination can interrupt natural transmission during child- hood and actually increase the number of women who are not immune (Banatvala, 19981. A vaccination strategy developed and implemented in Brazil was able to eliminate CRS in 2 years (see Box 3-21.

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 77 The most rapid reduction in CRS has been achieved with mass cam- paigns for all women of childbearing age. Checking for rubella antibodies before conception allows those who test negative to be immunized and those who test positive to be reassured. The benefits are considerable, while the main risk is the inappropriate reassurance of women who have false- positive tests (Tookey et al., 19911. All evidence indicates that rubella virus vaccine does not pose a risk to the fetus, so prior screening for pregnancy is unnecessary (Tosefson, 2001; World Health Organization, 2000b). Vacci- nation of women of childbearing age against rubella has been shown to have a benefit-to-cost ratio of 11 to 1 in the United States (Hatziandreu et al., 1994) and a benefit-to-cost ratio of more than 1 in several developing- country studies (Hinman et al., 20021. Eradication of rubella is feasible because it infects only humans and the vaccine is highly immunogenic, highly protective, affordable in all but the poorest countries, and can be administered in conjunction with measles and rubella vaccines and as part of a standard immunization schedule at 9 months of age (Plotkin et al., 19991. Eradicating rubella has not, however, been recognized as a priority in low-income countries (Banatvala, 19981. Combining rubella and measles vaccines can significantly reduce the cost of rubella immunization (Cutts and Vynnycky, 19991. In Latin America and the Caribbean, for example, 20,000 or more infants are born with CRS each year, yet a one-time mass immunization of all females aged 5 to 39 years could control both rubella and CRS (Hinman et al., 19981. Surveillance of rubella and CRS following an eradication campaigns can be a challenge as rubella is often unreported and sometimes asymptom-

78 REDUCING THE IMPACT OF BIRTH DEFECTS atic. Rubella epidemics are monitored using immunoglobulin M (IgM) test- ing in serum and saliva samples (Perry et al., 19931. Simple hearing tests for infants would improve case ascertainment (Plotkin et al, 1999), while test- ing all infants with microcephaly, developmental delay, hearing loss, mi- crophthalmia, congenital cataracts, and congenital heart disease would cap- ture a more complete estimate of CRS incidence. Recommendation 5. Women should be vaccinated against rubella before they reach reproductive age to prevent congenital rubella syndrome. Preventing Other Congenital Infections Primary prevention of maternal infection with herpes simplex virus and Toxoplasma gondlii is the only way to prevent mother-to-child transmission of these agents. Herpes simplex virus (HSV) Where possible and safe, pregnant women with active genital herpes lesions at the time of delivery should deliver by cesarean section to decrease the risk of neonatal HSV. The risk is decreased to less than 10 percent if performed prior to the rupture of membranes (Nahmias and Schwahn, 19851. Toxoplasmosis Pregnant women can avoid exposure to Toxoplasma gondii by washing their hands after handling raw meat, cooking meat until well done, and avoiding contact with cat feces and soil, insects, or other material contami- nated with cat feces (Essawy et al., 19901. Limiting Alcohol Consumption Alcohol consumption during pregnancy causes fetal alcohol syndrome, which is the most common preventable cause of mental retardation (Vi~joen, 19991. A safe level of maternal alcohol use has not been established. The teratogenic risk of maternal binge drinking during pregnancy is uncertain, but studies suggest that a single heavy binge at a critical period of embry- onic development can damage the fetus (Gladstone et al., 19961. Since the earliest weeks of pregnancy are critical for central nervous system develop- ment, all women should be strongly advised to avoid (Institute of Medicine, 1996) or minimize alcohol consumption before conception as well as dur-

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 79 ing pregnancy. Where alcohol is recognized as an important public health problem, educational campaigns directed at schoolchildren, participants in family planning classes, and the general public should aim to increase pub- lic awareness of the risks of alcohol during pregnancy. Recommendation 6. Education programs and public health messages should course! women to limit or avoid alcohol consumption during pregnancy including during the early weeks. Avoiding Teratogenic Medications During Pregnancy Prevention of birth defects due to teratogenic medications such as anticonvuisants, anticoagulants, thalidomide, accutane, and misoprosto! requires awareness of the consequences of their use on the part of medical workers and women of childbearing age. Educational campaigns, health messages, and preconceptional counseling on the prevention of birth de- fects should include information on medications to be avoided during periconception and pregnancy. In some cases, as with heparin versus other anticoagulants (Hardman et al., 1996), alternative medications can be sub- stituted. Anticonvuisant monotherapy for epilepsy has been found to be associated with a lower rate of malformations than polytherapy (Adab et al., 2001, Kaneko et al., 19981. Recommendation 7. Education programs and public health messages should educate health care providers and women of childbearing age about the importance of avoiding locally available teratogenic medica- · ~ tlons ~ urlng pregnancy. As with teratogenic medications, public awareness of the risks for birth defects associated with environmental pollutants is an important means of prevention. However, individuals may be powerless to avoid chemical pol- lutants that permeate their home or workplace. Exposure to such terato- gens should be prevented through regulation of their manufacture, use, and disposal. Such reforms will require collaboration among the branches of government and, in some cases, international commitment. Recommendation 8. Ministries of public health, in collaboration with other government departments in developing countries, should estab- lish regulations to reduce occupational exposure to teratogens such as mercury and other pollutants and create programs to raise public awareness of the health risks, including birth defects, associated with these substances.

80 REDUCING THE IMPACT OF BIRTH DEFECTS Summing Up The burden imposed by birth defects justifies widespread implementa- tion of the highly cost-effective interventions recommended above. Success- ful implementation of these interventions will require resources for person- nel, training programs, and supplies of nutrients, vaccines, and medications. Recommendation 9. Where possible, cost-effective interventions to pre- vent birth defects should be provided through public health campaigns and the primary health care system. The resources necessary for their success, including staff, training, and adequate supplies of nutrients, medicines, and vaccines should be provided as well. PROVISION OF IMPROVED CARE The health care provided to children and adults with birth defects should always be comparable with the care provided for other medical conditions and the best possible for the resources available. In many set- tings this may be very basic, but even where health care resources are limited, affordable and effective options exist for the treatment and reha- bilitation of those with birth defects. Early diagnosis prenatal or neona- tal provides the best chance for effective treatment. Counseling of parents should also address future pregnancies and how the risk for a future preg- nancy to involve a birth defect can be lowered. Treatment An important aspect of reducing the impact of birth defects is access to treatment. Although some disorders cannot be treated cost-effectively or at all, others can be corrected partially or entirely by therapies that are clini- cally- and cost-effective. Treatments can be made available by screening for patients with treatable conditions, then referring them to secondary and tertiary centers. These opportunities are frequently overlooked by policy makers and health professionals in developing countries, and access to treatment in many countries is limited (Christianson, 2000; World Health Organization, 19991. Prenatal or early neonatal diagnosis can be important for scheduling surgery or initiating therapy before conditions become more severe or irre- versible. While few tertiary centers in low-income countries can undertake complex surgery such as cardiac procedures for children with congenital heart disease, simpler surgical procedures are generally available but with limited access. The setting of priorities for the development of surgical capacity should be based on the resources required, current health care

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 81 capacity, the availability and sustainability of technical expertise, and cost- effectiveness in comparison with other health care services. Each country must establish clear priorities for the provision of treat- ments based on the cost-effectiveness of specific therapies and surgeries as compared with other health care services. This process is complicated by the lack of evidence on the cost-effectiveness of many services, including neonatal surgery, even in developed countries (Stork et al., 20001. Long- term follow-up to estimate the lasting success of surgery and other therapies is complicated by the difficulty of identifying an outcome that is compa- rable for different surgeries and treatments. Moreover, generic quality-of- life measurements used for adults have to be adjusted to reflect children's understanding and perception. The following discussion presents therapies that are employed successfully in many developing countries. Talipes or clubfoot Infants with talipes include those whose deformity can be resolved through manipulation and passive stretching, and those who require sur- gery (Porter, 19871. In either case, early intervention is critical to correcting the condition and obtaining a foot that is supple, painless, plantigrade, and of normal shape and function. Serial manipulation, a gentle and gradual method of elongating the contracted tissues, should begin within a day or two of birth (Sinha, 1987; Alexander et al., 19991. By 12 weeks of age, the soft tissues of the infant foot are far less pliable, so only surgery can correct the condition (Sinha, 19871. For this reason, talipes can be considered an orthopedic emergency (Scott and Evans, 19971. The principles of surgical treatment for talipes have been recognized for nearly 150 years: surgery should be early; it should correct the deformity; and the correction should be maintained at first with a cast and later with a splint or brace worn at night (Porter, 19871. The surgical techniques employed depend on the severity of the condition, the age of the patient, and the health care setting (Alexander et al., 1999; Porter, 1987; Tellis, 19881. Early surgery may be appropriate for a child whose family is un- likely or unable to comply with routines for manipulation of the foot; however, the risk of injury during complex procedures increases signifi- cantly for very small feet (Turco, 19741. When manipulation fails, bone surgery can make the foot plantigrade, but this generally compromises mobility (Porter, 19871. Most of the treatment of talipes in Africa is provided by medical offic- ers without specialized training. In East Africa, for example, only 10 per- cent of children with talipes are likely to reach a specialist because of poor communications, travel expenses, and parental reluctance to leave family and crops. Patients who do reach surgeons often face delays in treatment

82 REDUCING THE IMPACT OF BIRTH DEFECTS due to the inadequate health care resources (Tellis, 19881. Efforts to over- come these challenges have met with variable success. A weekly "clubfoot clinic" established in a teaching hospital in Lusaka, Zambia, corrected 287 feet, 133 of them surgically over a 4-year period, with only eight relapses (Parekh, 19851. In this study, 95 percent of the patients attended the clinic regularly during treatment, and most returned for checkups even after full correction. In contrast, a program offered by a nonspecialist medical officer at a 78-bed rural mission hospital in Tanzania was considered unsuccessful because of poor parental compliance (Scott and Evans, 19971. Despite improvement in all cases, none of the 26 children attended over a sufficient period of time to be cured or referred for surgery. Other authors have also described low-cost, locally appropriate technologies for treating talipes (Sengupta, 1987; Eyre-Brook, 1986; Hadidi, 19741. Box 3-3 describes simple surgical techniques developed in Calcutta to correct talipes. Parental education on the etiology and treatment of talipes is key to overcoming major barriers to compliance: successful treatments are avail- able; surgery may be required; and after correction, periodic checkups should continue until the child's growth is complete. Families of infants undergoing manipulative treatment of the foot need to understand the importance of regular cast changing and manipulation, as well as how to care for the cast and perform neurovascular checks on the immobilized foot (Alexander et al.,

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 83 19991. They should be encouraged to promote normal growth and develop- ment, including sitting up and crawling, while the foot is immobilized (Kryzer, 1991; Alexander et al., 19991. Postcorrection follow-up for talipes could be incorporated into local community-based rehabilitation or maternal and child health programs (Scott and Evans, 19971. Cleft lip and/or cleft palate Early establishment of feeding is a priority for neonates with cleft lip and/or cleft palate. Prenatal detection of the condition, available in some urban areas, can help parents to prepare for feeding and other special care of their child (Bender, 20001. Surgical repair of the lip can be done at 3 months and palatal repair at 6 months of age. This surgery, which is simple and effective, is available in several developing-country settings through the services of visiting surgeons supported by international foundations such as Operation Smile (see Box 3-4) and Medical Group Mission Christian Medi- cal and Dental Society (Smith et al., 19911. As children with cleft lip and/or cleft palate grow, their condition can cause a variety of physical, functional, and social problems. These can be minimized when treatment is available and when families, teachers, and the

84 REDUCING THE IMPACT OF BIRTH DEFECTS community are informed about the cause and difficulties associated with the condition. Support and education are key components of ongoing care (Chapados, 20001. Comprehensive treatment, which is not accessible for most developing country populations, can include speech and language therapy, preventive and restorative dental care, orthodontics, secondary surgery, otolaryngology for hearing problems, and psychological counsel- ing (Cockell and Lees, 20001. Isolated cases of cleft lip and palate show strong familial aggregation with a significant genetic component (Christenson and Mitchell, 19961. The risk of recurrence is, however, generally low. Surgical repair is gener- ally effective (Czeize! and Hirschberg, 1997) and the isolated defect is not an indication for pregnancy termination (Czeize! and Hirschberg, 1997), but orofacial defects may be associated with congenital malformations of the limbs, spine, and cardiovascular system (Pilu et al., 19861. Fetal karyo- typing can detect associated chromosomal anomalies or syndromes (Bender, 2000; Cockell and Lees, 20011. Congenital heart disease (CHD) In developed countries, CHD is diagnosed by ultrasound and repaired during infancy, but most developing countries lack the infrastructure neces- sary to treat this condition. Researchers estimate that hundreds of thou- sands of children are born each year with surgically treatable CHD. Most are not treated and die as children or teenagers (Cartmill et al., 1966; Rygg et al. 1971; Kirklin and Barrat-Boyes, 19931. However, hundreds of these children have been assisted without charge in developed countries or by traveling surgical teams supported by charitable organizations. One such organization, the Save a Child's Heart Foundation, has also assisted some institutions in developing countries in the establishment of CHD treatment capabilities (see Box 3-5) (Cohen et al., 20011. Developmental dysplasia of the hip (DDH) Early diagnosis of DDH and simple, noninvasive postural treatments can prevent a severe and crippling condition. Without these early treat- ments, true dislocation of the hip requires a series of complicated surgeries and rehabilitations, the results of which are frequently unsatisfactory. The most widely used diagnostic screen for DDH, the manual Ortolani-Bariow (O-B) test, is often included in a routine neonatal clinical examination in developed countries (Leek, 20001. Its usefulness depends on the skill and experience of the pediatrician, physical therapist, or orthopedic surgeon in identifying unstable hips, particularly those most likely to degenerate into full dislocation (Medb0, 1961; Leck, 20001. Ultrasound provides a similar

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 85 detection rate but may have a higher false-positive rate in primary DDH screening. Clinical examinations in industrialized countries have been shown to detect approximately three-quarters of neonates whose hips are or will become dislocated. If the identified neonates are treated promptly by splint- ing, about two-thirds will not develop DDH (Leek, 20001. This estimate is, however, complicated by high levels of false-negative and false-positive results. Fewer false positives are likely if the O-B test is conducted at 6 weeks of age because many hips that appear dysplastic at birth stabilize without treatment by that time. Treatment appears to be equally effective at 6 weeks and can be undertaken successfully in children up to 2 years old (Kim et al., 1990), often through noninvasive methods (Ramsey et al., 1976; Mendes and Roffman, 1980; Kim et al., 19901. Early treatment maintains the thighs in a flexed and partly abducted position so that the

86 REDUCING THE IMPACT OF BIRTH DEFECTS head of each femur remains deep within the acetabulum, encouraging it to encompass the femoral head more completely. To maintain this position, the thighs are splinted for weeks to months (up to a year). Two widely used methods are the Paviik harness, which holds the legs in soft stirrups, and the von Rosen splint, a solid support. These splinting methods have not been compared through randomized trials, nor have they been developed for optimal performance (Leek, 20001. Either splint can cause ischemic or avascular necrosis of the femoral head, which is often accompanied by reduced femoral growth. This effect can be minimized by maintaining the hips in moderate, rather than extreme, abduction (Leek, 20001. Dislocated hips that fail to respond to early splinting and those detected and treated in older children can be managed with a range of surgical procedures, depend- ing on the child's age and the degree of dislocation (Kim et al., 19901. Oculocutaneous albinism For affected children, the symptoms of the disorder can be treated, and health education can improve the home care (and, eventually, self-care) of affected children and dispel misconceptions that surround the condition. Affected children are extremely sensitive to the sun and have poor vision. Sun protection is critical since those affected can be severely sun- burned from minute-long exposures, which over time make them vuiner- able to skin cancer. Covering the skin with long-sleeved shirts, long pants, and wide-brimmed hats helps protect from exposure to ultraviolet A (WA) radiation. Sunscreens with a sun protection factor (SPF) rating of greater than 25 should be used at all times (King et al., 19961. Vision problems, such as hyperopia, myopia, and astigmatism, require correction to obtain the best possible visual acuity (King et al., 19961. Nearly every respondent among 138 school children with albinism in rural Zimbabwe reported problems in school due to poor vision (Lund, 20011. Yet most of these children can function in a regular classroom, provided the teacher and school attend to their special vision needs (King et al., 19961. Adults with albinism frequently encounter social problems associated with their appearance, including difficulty in finding employment (Lund, 19981. A survey of attitudes toward people with albinism conducted in urban Soweto, South Africa, found that although they may be accepted in their community, people with albinism were regarded as abnormal and perhaps not fully human (Kromberg, 19921. Negative attitudes persist and are based on myths and superstitions concerning albinism, the most perva- sive being that people with the condition do not die normally, but "vanish." Treatment of the condition and education of the public about the medical cause should be used to dispel this and other myths, and allow affected individuals to be accepted (and to accept themselves).

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 87 Recommendation 10. Children and adults with birth defects should receive the best medical care that is available in their setting, including, where possible, medication and surgery. Treatment should be under- taken as early as possible and be provided through an organized refer- ral process. Rehabilitation Many infants with severe birth defects experience lifelong disability requiring long-term treatment or rehabilitation (Carey, 1992; World Health Organization, 1996a, 1999b). There are promising models of rehabilitation services for children with birth defects even in settings where professional resources are extremely limited. These models are based in communities: schools, hospitals and other institutions, and primary health care. The more comprehensive models are in the primary care system and are based on a national rehabilitation strategy. Although this report focuses on the care of infants and children with birth defects, it is important to recognize that rehabilitation programs are also needed for adults impaired by lifelong conditions. In many cases, appropriate education and rehabilitation for children and adults substantially increases their ability to function indepen- dently and contribute to family and community responsibilities. Community-based rehabilitation (CBR) CBR has been defined as a strategy in communities for the rehabilita- tion, equalization of opportunities, and social integration of people with disabilities (International Labor Organization, United Nations Educational, Scientific and Cultural Organization, and World Health Organization, 1994; United Nations Children's Fund and the Ministry of Education and Science, Spain, 19941. The strategy mobilizes local resources and enables people with disabilities and their communities to create their own solutions and programs for rehabilitation. It also addresses the isolation and stigma- tization experienced by people with disabilities and encourages those with disabilities to live lives that are as normal as possible and are integrated into society. Disabled children are encouraged, where possible, to attend public schools with the goal of their not being limited by different social expecta- tions or environmental constraints (Groce, 19991. The Jamaican program described in Box 3-6, is an example of how individuals with disabilities can be viewed as partners in national development. Since 1983, WHO has produced training manuals for CBR workers and promoted CBR as the most appropriate mode! of rehabilitation for people with disabilities, including those due to birth defects (WorId Health Organization, 1980, 1993; Helander et al., 19891. While the WHO ap-

88 REDUCING THE IMPACT OF BIRTH DEFECTS proach to CBR is largely home-based, mode! center-based approaches have also been developed (Werner, 19871. The advantages of the CBR approach are its accessibility to low-income families and its ability to work with low-cost, locally available resources. The disadvantages are the lack of skilled resources, funds, and volunteered time; the difficulty of monitoring the quality of services and effectiveness in reach- ing the desired outcomes; and the inadequate opportunities for ongoing train- ing and advancement of rehabilitation workers. Even with these drawbacks, CBR may be the most viable and cost-effective mode! for rehabilitative care in developing countries provided interventions are flexible, sensitive to cul- tural beliefs, appropriate to the country's current level of development, and compatible with local resources and development priorities.

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 89 School-based models Educational opportunities for children with disabilities are limited in low-income countries. When available, they range from highly segregated, specialized residential and day schools to special classes in regular schools to a fully mainstreamed or inclusive education. Little information is avail- able on the extent to which mainstreaming is practiced in low-income countries. Promotion of this approach began internationally following such agreements as the United Nations Educational, Scientific and Cultural Or- ganization (UNESCO) Declaration of Education for All, which stipulates that all countries have a responsibility to provide equal access to education for children with disabilities as an integral part of the education system (Haddad, 1990; UNESCO and Ministry of Education and Science, Spain 19941. CBR and inclusive education appear to be mutually reinforcing, since CBR programs attempt to place children in regular schools, and teach- ers derive support from CBR workers when they accept children with dis- abilities (Thorburn, 20001. Box 3-7 describes school-based programs and other activities of the Bangladesh Protibondhi Foundation. Reports from some low-income countries indicate that many schools do not have the facilities, trained teachers, or positive attitudes required to accommodate children with disabilities (Mariga and Phachaka, 19931. Given the already overcrowded environment of government schools in most low-income countries, a major commitment of resources is required to accommodate these children. Institution- and hospital-based models Institutional care and hospital-based services for children with birth de- fects are present in many low-income countries but serve only a small fraction of the children who need them. Rehabilitation specialists generally agree that institutional care should be discouraged because it promotes psychological dependence and prevents children from interacting with their peers and in- tegrating into society. Perhaps the strongest disadvantage, however, is the cost. The monthly cost per child in an institution for disabled children in Harare, for example, was US$80 in 1990, a cost that exceeded the monthly income of the majority of Zimbabwean families (House et al., 19901. Some institutions have supported community-based approaches, as de- scribed in Box 3-8. Institutions that previously offered long-term residential care have been converted to boarding schools for severely disabled children, who return to their families during school vacations. Institutions can also provide short-term rehabilitation for rural children who require surgery or the fitting of appliances. Hospital rehabilitation departments that tradition- ally focused on the short-term rehabilitation of patients with an acute

9o REDUCING THE IMPACT OF BIRTH DEFECTS disability, particularly those at the district and provincial levels, now pro- vide technical, administrative, and training support to community-based programs through outreach activities. Rehabilitation villages have been constructed in rural hospitals so that disabled children and their caregivers can be accommodated for group activities and workshops.

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 91 Primary health care mode! The most comprehensive CBR mode! is based in the primary health care system and is supported by a national strategy for rehabilitation of children and adults with disabilities including those from birth defects. Rehabilitation in Zimbabwe is an example of this mode! of care (see Box 3-81.

92 Psychosocial support REDUCING THE IMPACT OF BIRTH DEFECTS Birth defects have serious lifelong consequences for both the patient and the family. Those afflicted require psychological, emotional, and social support on a continuing basis; this support should include referral to and assistance from social services such as education and social welfare. Many birth defects lead to death in infancy or early childhood, so care of the patient may also include terminal or palliative care. Depending on the setting, care may be provided by a nurse, physician, or other health worker trained to provide appropriate support (see Box 3-6) (Christianson et al., 20001. These caregivers must provide the best locally available care for the patient and the family (World Health Organization, 1999; Christianson et al., 2000), including addressing their concerns and uncertainties. Patient and parent support groups can provide mutual assis- tance and support (World Health Organization, 19991. Recommendation 11. Parents of children with birth defects should be guided to organizations that provide rehabilitation for the child and psychosocial support for the child and family. Education policies at the national and local levels should ensure that all children, including those with birth defects, receive appropriate schooling. SCREENING FOR GENETIC DISORDERS Over the past four decades, infant mortality in developing countries has declined, though there is still room for considerable improvement (Table 3-11. Once countries have successfully used the basic strategies of reproduc- tive health care to reduce infant mortality, up to two-thirds of which is neonatal mortality (Hill, 1999), the more intractable causes of mortality and severe morbidity become the next challenge. Important among these are the more common genetic disorders for which screening becomes es- sential to further decrease infant mortality (World Health Organization, 2000a). Such programs are more demanding of resources and highly trained staff than are programs for basic reproductive health care; but, when intro- duced after basic reproductive health care services have reduced mortality, they too can be cost-effective. Screening programs were introduced in Cuba when the infant mortality rate (IMR), had been lowered to 19 per 1,000 live births (Heredero, 1992) and in Costa Rica (Saborio, 1992) at a similar IMR. Genetic screening of populations identifies clinically normal individuals who have genotypes associated with a birth defect or who are at high risk of producing offspring with a birth defect. It aims to identify as many affected

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 93 TABLE 3-1 Improving Infant Mortality Rates in Developing Countries (1960-1999) Total Infant Mortality Population, Rate per 1,000 1999 Live Births Country (thousands) 1960 1999 Afghanistan 21,923 215 165 Albania 3,113 112 29 Algeria 30,774 152 36 Angola 12,479 208 172 Argentina 36,577 60 19 Armenia 3,525 38 25 Azerbaijan 7,697 55 35 Bangladesh 126,947 149 58 Barbados 269 74 14 Belarus 10,274 37 23 Benin 5,937 176 99 Bolivia 8,142 152 64 Bosnia and Herzegovina 3,839 105 15 Brazil 167,988 115 34 Bulgaria 8,279 49 14 Burkina Faso 11,616 181 106 Burundi 6,565 151 106 Cambodia 10,945 86 Cameroon 14,693 151 95 Central African Republic 3,550 187 113 Chad 7,458 195 118 Chile 15,019 107 11 China 1,266,838 150 33 Colombia 41,564 82 26 Congo 2,864 143 81 Congo, Democratic Republic 50,335 175 128 Costa Rica 3,933 80 13 Cote d'lvoire 14,526 195 102 Croatia 4,477 70 8 Cuba 11,160 39 6 Czech Republic 10,262 22 5 Dominican Republic 8,364 102 43 Ecuador 12,411 107 27 Egypt 67,266 189 41 El Salvador 6,154 130 35 Eritrea 3,719 170 66 Ethiopia 61,095 180 118 Gabon 1,197 171 85 Georgia 5,006 52 19 Ghana 19,678 127 63 Guatemala 11,090 136 45 Guinea 7,360 215 115 Haiti 8,087 169 83 (continued)

94 TABLE 3-1 continued REDUCING THE IMPACT OF BIRTH DEFECTS Total Infant Mortality Population, Rate per 1,000 1999 Live Births Country (thousands) 1960 1999 Honduras 6,316 137 33 Hungary 10,076 51 9 India 998,056 146 70 Indonesia 209,255 128 38 Iran 66,796 164 37 Iraq 22,450 117 104 Jamaica 2,560 58 10 Jordan 6,482 97 29 Kazakhstan 16,269 55 35 Kenya 29,549 122 76 Korea, Democratic People's Republic 23,702 85 23 Korea, Republic of 46,480 90 5 Kyrgyzstan 4,669 135 55 Lao People's Democratic Republic 5,297 155 93 Latvia 2,389 35 17 Lebanon 3,236 65 28 Lesotho 2,108 137 93 Liberia 2,930 190 157 Libya 5,471 159 19 Lithuania 3,682 52 18 Madagascar 15,497 219 95 Malawi 10,640 205 132 Malaysia 21,830 73 8 Mali 10,960 293 143 Mauritania 2,598 180 120 Mexico 97,365 94 27 Moldova, Republic of 4,380 64 27 Mongolia 2,621 61 Morocco 27,867 132 45 Mozambique 19,286 180 127 Myanmar 45,059 169 79 Nepal 23,385 212 75 Nicaragua 4,938 130 38 Niger 10,400 211 162 Nigeria 108,945 123 112 Pakistan 152,331 139 84 Panama 2,812 58 21 Papua New Guinea 4,702 137 79 Paraguay 5,358 66 27 Peru 25,230 142 42 Philippines 74,454 80 31 Poland 38,740 62 9 Romania 22,402 69 21 Russian Federation 147,196 48 18 Rwanda 7,235 124 110

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 95 TABLE 3-1 continued Total Infant Mortality Population, Rate per 1,000 1999 Live Births Country (thousands) 1960 1999 Saudi Arabia 20,899 170 20 Senegal 9,240 173 68 Sierra Leone 4,717 220 182 Slovakia 5,382 33 9 Somalia 9,672 175 125 South Africa 39,900 89 54 Sri Lanka 18,639 83 17 Sudan 28,883 123 67 Syria 15,725 136 25 Tajikistan 6,104 95 54 Tanzania 32,793 142 90 TFYR (The Former Yugoslav Republic of) Macedonia 2,011 120 22 Thailand 60,856 103 26 Togo 4,512 158 80 Tunisia 9,460 170 24 Turkey 65,546 163 40 Turkmenistan 4,384 100 52 Uganda 21,143 133 83 Ukraine 50,658 41 17 Uruguay 3,313 48 15 Uzbekistan 23,942 84 45 Venezuela 23,706 56 20 Vietnam 78,705 147 31 Yemen 17,488 220 86 Yugoslavia 10,637 87 20 Zambia 8,976 126 112 Zimbabwe 8,976 97 60 SOURCE: United Nations Children's Fund, 2000b. individuals as possible, but screening alone does not detect all individuals at high risk. Diagnosis usually follows a positive screening test and it provides a high level of accuracy. Examples of screening programs include those for oc-thalassemia in Asian populations, p-thalassemia in Mediterranean popu- lations, sickle cell disorder (SCD) in African populations, glucose-6-phos- phate hydrogenate (G6PD) deficiency in female relatives of a patient with the deficiency, and chromosomal abnormalities in women over 35 years of age. Genetic screening programs can involve preconceptional detection of risk factors associated with birth defects, also prenatal and neonatal screen- ing and diagnosis of birth defects. The criteria for establishing screening

96 REDUCING THE IMPACT OF BIRTH DEFECTS programs for genetic clisorclers are presented in the next section, followed by a discussion of the important role of genetic counseling in any screening effort. The specific goals and methods of preconceptional, prenatal, and neonatal screening for birth defects follow, then ethical considerations of . . . . screening, c lagnosls, anc prevention or treatment. Criteria for Establishing Genetic Screening Programs for Genetic Disorders Screening programs need to be tailored to the health priorities of each community as cletermineci by epiclemiology, demographics, resources, and the capacity of health care services. The following prerequisites guicle the determination of which birth defects can benefit from genetic screening (Simpson and Golbus, 1992; Cuckle and Walci, 20001: · The target condition is serious and relatively common. Since incliviclu- als with less serious birth defects can live fulfilling lives, the conditions that are appropriate for screening are those that are serious or life threatening. · Screening takes place at the best possible time. While screening may be conclucteci in the preconceptional, prenatal, or neonatal periods, the earlier a diagnosis is macle, the more opportunities may be available to prevent a birth defect or minimize its severity. · The screening assay clearly distinguishes between individuals who have the condition and those who do not. Since each birth defect is rela- tively rare, the assay should have a low false-positive rate. · Effective and acceptable management strategies are available. Popu- lation screening and prenatal diagnosis for or- and p-thalassemia, sickle cell anemia, and phenylketonuria (PKU) are appropriate because there are man- agement strategies for each. · The program is cost-effective. Although the technology is available to screen for many clisorclers, not all screening is likely to be cost-effective in a given population or health care setting. Thalassemia p-Thalassemia major is easy to diagnose, and effective though costly- treatment is available. Blooci transfusions combined with iron chelating therapy allow many people with the clisorcler to survive into their twenties and thirties. A more expensive and higher-risk option stem cell transplant from bone marrow or cord blooci can cure the clisorcler but is not afforci- able in low-income populations. Without diagnosis and treatment, patients with p-thalassemia major usually clie early in chilc~hooci; thus, the popula- tion prevalence of p-thalassemia is a fraction of the birth prevalence, and

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 97 the cost of treating the few people who survive to adulthood is low. Where diagnosis and treatment for p-thalassemia are available, patients survive longer, the population prevalence increases, and national treatment costs rise. Screening and control programs have significantly reduced the birth prevalence of p-thalassemia in Greece (Loukopoulous, 1996), Iran (see Box 3-9), and Sardinia (Cao et al., 1991, 19961. A premarital screening program in the Aegean region of Turkey tested nearly 10,000 couples over 4 years and found a p-thalassemia trait preva- lence of 2.6 percent in that population. Prenatal screening of the same population identifies at-risk couples who are offered prenatal diagnosis

98 REDUCING THE IMPACT OF BIRTH DEFECTS and, in the case of pregnancies with p-thalassemia major, pregnancy termi- nation (Keskin et al., 20001. Hospital-based prenatal screening programs in Thailand (Taovisi~ha et al., 2000) identify pregnancies at risk for or- and p- thalassemias. At-risk couples are offered prenatal diagnosis and, if severe thalassemia is diagnosed, the option to terminate the pregnancy. Sickle cell disorder More than 60 percent of all births of children with SCD or other major hemoglobin disorders occur in Africa, the region with the most limited resources for addressing these conditions (Angastiniotis et al., 19951. Thus, while there are treatments for SCD, cost-effective measures to educate at- risk couples and communities about SCD and reduce the number of chil- dren born with sickle cell anemia (HbSS) appear to be important, but have not been recognized as a priority. To date, Cuba is the only country in Latin America (Angastiniotis et al., 1995) that has initiated a comprehensive control program for SCD; it is described in Box 3-10. As with thalassemia, primary prevention of SCD can be achieved through preconceptional genetic screening and counseling of couples at risk for having a child with the disease, while secondary prevention can be provided through prenatal screening and counseling, which may be fol- lowed by prenatal diagnosis and the possibility of terminating affected pregnancies. Where genetic screening is not available, couples who have given birth to a child with SCD should be advised on the risk for future pregnancies. Where screening for sickle cell trait and disease is undertaken, neonatal screening permits the early treatment of SCD. It also provides the opportu- nity to educate parents on the care of affected children and the risk for future pregnancies. The potential harm that could result from false-positive and false-negative results should be carefully considered. Treatments for SCD include measures to reduce the symptoms and severity of anemia and prevent potentially fatal infections (penicillan pro- phylaxis and pneumococcal vaccine), to which SCD patients are especially susceptible (Lees et al., 2000; Steensma et al., 20011. Hydroxyurea can prevent vaso-occlusive crises (Koren et al., 1999), but the drug is expensive (Charache et al., 1995; Kate, 2001; Davies and Oluhohungbe, 20021. Bone marrow transplantation is available in high-resource settings (Kate, 2001), but rarely in developing countries. Some homozygotes with high levels of fetal hemoglobin may need little more than long-term folate supplementa- tion, while others require aggressive supportive care, frequent hospitaliza- tions, pain relief, and transfusions (Steensma et al., 20011. Pulmonary symp- toms require immediate attention since acute chest syndrome is a major cause of death (Vichinsky et al., 19971.

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 99 In some developing countries, SCD goes largely undiagnosed and leads to high mortality during the first 5 years of life (Akinyanju, 1989; Angas- tiniotis et al., 19951. Under such circumstances, health education is a prior- ity, since there is no chance for prevention or treatment in populations where SCD is not recognized and diagnosed. Where treatment for SCD is unavailable such as in tribal areas of Maharashtra, India a combination of health education and genetic screening has been suggested as the most effective means of reducing the impact of SCD (Kate, 20011. Glucose-6-phosphate debydrogenase deficiency The primary effects of G6PD deficiency are hematological (Verjee, 1993), so most interventions focus on reducing the occurrence and severity

100 REDUCING THE IMPACT OF BIRTH DEFECTS of hemolytic crises. These episodes can be precipitated by infections such as hepatitis or pneumonia; exposure to certain chemicals and oxidative medi- cations, including some antimalarial drugs; and consumption of fava beans (Chatterjea, 1966; Meloni et al., 1992; Beutler, 1994; Verjee, 19931. Avoid- ing these triggers for hemolysis requires that affected persons be diagnosed and counseled. Occasionally those with the Mediterranean form of the deficiency and those in hemolytic crisis require a blood transfusion. Elevated bilirubin levels, elevated reticulocyte count, and low red blood cell count and hemoglobin levels are signs of G6PD deficiency. In the neonate, hyperbilirubinemia may be severe and, if left untreated, can cause bilirubin encephalopathy. Screening tests fluorescent spot test, ascorbate cyanide test, MTT staining test, methemoglobin reduction methods, and dye decolorization (Verjee, 1993) are quick, easy, inexpensive, and suit- able for large populations. The diagnosis is confirmed by enzyme assay (Melon), 1992), but the definitive assay requires laboratory equipment that is not usually available in the countries where G6PD deficiency is common. Cystic fibrosis Screening the family members of a patient with cystic fibrosis (CF) can detect the CF gene in 60-90 percent of carriers (Grody et al., 2001), which allows informed reproductive choices to be made (Frossard et al., 19991. An early diagnosis is key for prevention of CF since many high-risk couples have a second affected child before the diagnosis has been established for the first child (Rabbi-Bortolini et al., 19981. Prenatal screening programs have not become routine even in developed countries (Haddow et al., 19991. The most important diagnostic test for CF in developing countries is the sweat electrolytes test (Mahashur, 19931. Screening tests include DNA testing, fecal fat, upper gastrointestinal and small bowel series, and mea- surement of pancreatic function. In Latin America, CF is underdiagnosed because of high mortality rates from pulmonary and gastrointestinal dis- eases and limited access to the sweat test (Macri et al., 19911. Ideally, treatment of CF would involve a multidisciplinary team (physi- cian, physiotherapist, nutritionist, and social worker) to provide conven- tional therapy (antibiotics, pancreatic enzyme replacement by ingestion of capsules with meals, and nutritional support) and treatment for CF-associ- ated complications (Mahashur, 1993; Zar et al., 19981. Such an intensive approach is not available or cost-effective in many settings. Phenylketonuria Screening for PKU is done with the relatively inexpensive Guthrie test on fiIter paper blood specimens. The timing of the screening is critical, so the specimen should be obtained in the hospital of birth as close to dis-

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 101 charge as possible. Because second tests are unlikely to detect new cases, resources are best directed at improving the primary screening (Cunning- ham,20001. In countries where the incidence of PKU is relatively high, such as Estonia (Ounap et al., 1998), and Latvia (Lugovska et al., 1999) 1 per 6,010 and 1 per 8,700 respectively there are mass screening programs, while in countries, such as South Africa, where the incidence is low (Hitzeroth, 1995) 1 per 20,000 there are more pressing health priorities. The number of infants born at home and thus not diagnosed is undeter- mined. The mainstay of treatment is a phenylalanine-restricted diet. By limit- ing daily consumption to only 250-500 milligrams of phenylalanine per day, a positive nitrogen balance and safe plasma levels of phenylalanine can be maintained. The amino acid supplements, which are taken with vitamin and mineral supplements are not palatable, which makes compliance with the restricted diet difficult (Cunningham, 2000; Poustie and Rutherford, 20011. The diet should begin as soon after birth as possible and be contin- ued as long as the patient is able to comply. While a phenylalanine- restricted diet has been shown in nonrandomized studies to reduce blood phenylalanine levels and improve IQ and neuropsychological outcome, the evidence is inadequate for determining a safe upper level of phenylalanine and when, if ever, dietary restrictions can be relaxed (Poustie and Ruther- ford, 20011. Because early dietary treatment has proven successful, affected women now become potential mothers (Cunningham, 20001. Avoiding mental re- tardation and other problems in their offspring requires that they resume the restricted diet prior to and throughout pregnancy to avoid phenylala- nine levels that would be toxic to the fetus and cause severe mental retarda- tion, birth defects, heart disease, and low birth weight. Hemophilia A and B Because hemophilias A and B are relatively uncommon, prenatal screening should be restricted to families with a history of the disorder. A fetal blood sample can be used for diagnosis of genetic disorders of red cells, white cells, or platelets and for identification of clotting factor defi- ciencies. Amniocentesis, chorionic villus sampling, or a placental biopsy are used to obtain cells for cytogenetic or biochemical analysis and to isolate fetal DNA (Weatherall and Letsky, 20001. Male patients with severe hemophilia are often diagnosed shortly after birth because of an extensive cephalohematoma or profuse bleeding at circumcision. Neo- nates suspected of having hemophilia should receive screening tests for hemostasis, including a platelet count, bleeding time, and blood clotting ability (Handin, 19981.

102 REDUCING THE IMPACT OF BIRTH DEFECTS Treatment is complicated and expensive, which limits its usefulness for most developing countries. In Turkey, a program using intermediate con- centrates rather than high-purity concentrates or recombinants and a twice- weekly regimen (instead of three times a week) reduced the cost of therapy (Kavakli et al., 19971. A rehabilitation center in India has reported a pro- gram for preventing and treating acute hemarthrosis in which the patient is taught a series of exercises that facilitate absorption of the hematoma to improve joint range and strengthen muscles, which reduces the frequency of bleeding (Kale, 19991. Many centers have organized home care programs so that patients can administer their own factor VIII infusions with the onset of symptoms (Han- din, 20011. Local health clinics can give injections to hemophiliacs. Home and local care spare limited health personnel resources and solve problems of transportation and absenteeism from school and work. Hemophiliacs are at high risk for HIV/AIDS and hepatitis B if a safe supply of blood products is not maintained. An alternative may be to import blood products. Genetic Counseling Counseling, an integral component of screening for genetic risk, assists couples or mothers by educating them about genetic risks and reproductive choices, thereby allowing them to make free and informed decisions (Hogge and Hogge, 1996; Biesecker, 20011. Prior to screening, counselors describe the conditions that can be identified and the available screening tests, diag- nostic methods, and options for preventing or treating birth defects. The limitations of screening tests are explained, along with the goal of identify- ing high-risk pregnancies that may require invasive follow-up tests to ob- tain a diagnosis. Women or couples who do not see an advantage in having the diagnosis or do not wish to confront the options raised by the results of the screening process may decline to be screened. If they request screening, the counselor explains the test results and answers questions. When coun- seling those who had a positive screening test, the counselor provides infor- mation on the diagnosis, etiology, prognosis, and consequences; describes options for prevention; and responds to questions or concerns. Counselors must be able to obtain accurate information and communi- cate clearly and respectfully. Printed explanations can be used as a reference and to convey information to family and friends. The counselor should avoid judgments and provide factual knowledge that empowers women or couples to make their own decisions. Counseling those with a previous abnormal pregnancy can be particularly challenging because anxiety can interfere with the ability to understand and retain information. These cases may require extra time to review the genetic history and answer questions. Where possible, families need to be reassured that they could not have

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 103 prevented an abnormal pregnancy and to receive guidance on the risk for future pregnancies. When a birth defect does not carry a risk for future pregnancies, counseling can relieve much of the anxiety. With appropriate training, a variety of health care professionals may serve as genetic counselors. In some settings, primary care workers are well positioned to course! because they are known in the community, which can increase the trust and respect with which they are received (Christianson et al., 20001. Regardless of their previous medical qualifications, genetic coun- selors need to be trained and tested in the content and delivery of informa- tion. The content of each consultation should be documented and moni- tored. Genetic counselors provide an important linkage between health care and the social, religious, and legal underpinnings of society, which together determine the availability of reproductive choices. Preconceptional Screening Preconceptional screening has the advantage of identifying and coun- seling couples at high risk for producing a child with a birth defect before conception. The screening has three components: recording and evaluation of 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 and carriers of abnormal reces- sive genes who are at risk of passing a disorder to their children. Individuals at high risk can be screened and, if determined to be at risk, should receive counseling and other appropriate care (see Box 3-111. A genetic history explores whether a couple is at risk for inherited disorders or for chromosomal abnormalities or mutations that could result in birth defects. Maternal age over 35 years is the most common risk factor for chromosomal abnormalities. Paternal age over 40 years increases the risk of certain dominant mutations (McIntosh et al., 19951. Exposure to mutagenic agents should also be determined. Abnormal reproductive out- comes (repeated spontaneous abortions, stillbirths, and infants born with birth defects) among first-degree relatives (siblings, parents, offspring), second-degree relatives (uncles, aunts, nephews, nieces, and grandparents), and third-degree relatives (first cousins) are reviewed. Identification of sec- ond- and third-degree relatives with birth defects generally does not in- crease a couple's risk significantly unless the couple is consanguineous. The ethnic origin of each potential parent should be noted because of the higher risk for certain birth defects among particular groups. Genetic histories can be recorded efficiently using a questionnaire that requires only positive responses (Simpson and Golbus, 19921. Preconceptional screening of national populations or high-risk groups has been undertaken in countries where serious recessive birth defects are

104 REDUCING THE IMPACT OF BIRTH DEFECTS prevalent, a reliable test is available, and the condition is amenable to prevention. Conditions that are common in the developing world and ame- nable to prevention include thalassemia and SCD. National screening is performed in Greece, Iran (see Box 3-9), Sardinia, and Cyprus for p-thalas- semia and in Cuba for SCD (see Box 3-101. Family planning services pro- vide an ideal setting for genetic screening and the use of genetic histories for the preconceptional prevention of birth defects.

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 105 Prenatal Screening and Diagnosis Prenatal screening identifies pregnancies at high risk for genetic disor- ders but is not able to exclude the possibility of a birth defect. Prenatal diagnosis, which generally follows a positive result from prenatal screening, determines with more certainty the presence or absence of a birth defect. Prenatal screening programs can effectively address populations at high risk for Down syndrome, NTDs, and single-gene disorders (Baird, 19991. Screen- ing and diagnosis take place before 20 weeks' gestation to allow parents to consider the option of pregnancy termination in the case of severe birth defects or to plan the time and place of delivery in cases where surgery is necessary at birth. The following procedures are widely used in developed countries for diagnosis and are increasingly available in the larger cities of developing countries. Maternal serum screening Identification of those at risk for Down syndrome, NTDs, and other fetal abnormalities should involve noninvasive screening methods for those at low risk younger couples with no family history of these disorders. Elevated levels of oc-fetoprotein in maternal serum are associated with NTDs and fetal anomalies. This single screen can identify more than 90 percent of first-occurring NTDs in a family, missing only 10-15 percent of all cases (Ross and Elias, 1997), which are closed NTDs. Because elevated oc-feto- protein levels also occur in cases of fetal death, underestimates of gesta- tional age, or multiple gestations, an elevated result is often followed with a repeat test (before 18 weeks' gestation) and with ultrasonography. If these methods do not find a reason for the elevated oc-fetoprotein level, amnio- centesis can be used to obtain amniotic fluid for assays of oc-fetoprotein and acety~cholinesterase. In the US about 3-5 percent of the latter procedures lead to diagnosis of an NTD. Measuring levels of human chorionic gonadotropin, unconjugated es- triol, oc-fetoprotein, and sometimes inhibin A helps in the detection of Down Syndrome. The "quadruple screen" a noninvasive test (Ross and Elias, 1997; Wald et al., 2003), identifies women at elevated risk of carry- ing a fetus with Down syndrome. Only this selected group (rather than all) then undergoes the invasive procedures, amniocentesis or chorionic villus sampling, to obtain a definitive diagnosis. Fetal ultrasonography Ultrasound technology can be used to identify signs or markers indicat- ing increased risk of a birth defect (e.g., screening for nuchal translucency

106 REDUCING THE IMPACT OF BIRTH DEFECTS and Down syndrome) or to detect structural malformations in the fetus (e.g., diagnosis of open NTDs). For most high-risk couples, the report of normal ultrasound findings provides considerable relief. Screening for structural malformations is done at 18-20 weeks' gesta- tion, when fetal abnormalities are large enough to be recognized. Although ultrasonography can detect more than 200 different fetal abnormalities, its appropriate use is limited to those conditions that can be addressed with an effective intervention. Depending on the setting, these conditions may in- clude serious abnormalities that cause a severe disability for which termina- tion of pregnancy is generally agreed to be justified, fatal abnormalities in which termination of pregnancy avoids waiting until the end of an unpro- ductive pregnancy, and abnormalities where arrangements need to be made for treatment of the neonate immediately after birth. This option is offered only after appropriate, nondirective counseling. Ultrasound technology is not universally available for population screening because of its expense and requirement for trained staff, but it is increasingly available in the larger cities of developing countries. The qual- ity of screening varies widely with the experience of the operator and the resolution obtainable by the equipment. Ultrasound-based prenatal screen- ing programs need to be carefully planned and monitored to ensure they are appropriate, viable, and cost-effective. The basic requirements for a cost- effective program include well-maintained instruments, staff who are fully trained in the instrumentation, guidelines on the number and timing of ultrasound examinations, a protocol or checklist of conditions to be exam- ined, and guidelines on the level of screening for each condition. Screening services must also be adequately supported with counseling services and with diagnostic services for cytogenetic, biochemical, and molecular genetic analyses, all of which also have to be monitored for their cost and effective- ness. It is important to develop and refine pilot screening projects before implementing ultrasound screening nationwide. Well-planned screening programs are likely to be cost-effective since the treatment and rehabilita- tion of individuals with severe birth defects are expensive and since many couples choose to terminate a pregnancy if a severe birth defect is identified (Baird, 19991. Amniocentesis and chorionic villus sampling These sampling procedures provide cells of fetal origin that can used to identify a chromosomal condition by karyotyping or DNA analysis or a genetic disorder by enzymatic or DNA analysis. Amniocentesis involves the aspiration of amniotic fluid and is the most commonly used procedure. Chorionic villus sampling (CVS) involves aspiration of villi using a flexible cannula passed through the uterine cervix or a hollow needle inserted into

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 107 the maternal abdomen. Both procedures are guided by ultrasound. Amnio- centesis is usually undertaken in the fourteenth to sixteenth week of preg- nancy, while CVS can be performed from the beginning of the tenth week until the end of the twelfth week of gestation.) Both amniocentesis and CVS have very high detection rates for chromosomal abnormalities the princi- pal goal of such sampling. Since second-trimester amniocentesis is easier to perform than CVS, particularly for inexperienced operators, it is the more widely used procedure. CVS can, however, be performed earlier in the pregnancy (Gosden et al., 20001. Amniocentesis or CVS is typically offered for pregnancies at increased risk for chromosomal abnormalities risks that once were determined solely by advanced maternal age and previous adverse obstetric history but are now increasingly identified by abnormal maternal serum markers and ultra- sonographic evidence of early fetal abnormalities (Ross and Elias, 1997; Yang et al., 19991. Fetal karyotyping following amniocentesis is successful virtually 100 percent of the time, and the diagnosis is available in the sixteenth to nineteenth week of gestation. Because of the significant risk of maternal mortality and other major complications of abortion at this stage of pregnancy, early amniocentesis procedures have been developed with the aim of diagnosing severe birth defects prior to 15 weeks' gestation. Al- though these techniques make amniocentesis at 11 to 12 weeks' gestation possible, this approach is not generally recommended because it is associ- ated with a higher failure rate, greater fetal loss, and increased birth preva- lence of talipes compared with standard amniocentesis (Gosden et al., 20001. For single-gene disorders such as the thalassemias, SCD, and CF, diag- nostic testing of amniotic fluid or chorionic villi is appropriate where there is a family history of such disorders or as a follow-up for high-risk pregnan- . . .,. . . CleS 1C ent1~1ec in a screening test. Neonatal Screening Although neonatal screening generally plays a smaller role than prena- tal screening, it provides an important opportunity to identify birth defects early in the neonatal period and be able to initiate therapy or surgery early in life. Early, appropriate treatment can prevent or reduce some lethal or disabling sequelae of birth defects. For neonates born in hospitals, screen- ing should occur before they leave. Even when little can be done to help the infant, accurate diagnosis of birth defects can alert parents to the risks they , . . . may tace in tuture pregnancies. In Southeast Asian populations in which G6PD deficiency is common it can also be accompanied by neonatal jaundice and kernicterus. In these lA 10-week gestation corresponds to 8 embryonic weeks after conception.

108 REDUCING THE IMPACT OF BIRTH DEFECTS populations, early neonatal screening for G6PD deficiency is important. Affected infants are monitored for several weeks with regular tests of the bilirubin level (Weatherall and Letsky, 20001. For PKU, congenital hypothyroidism, and other inherited metabolic defects, neonatal screening is the only screening available and it allows early dietary intervention for PKU and thyroid replacement therapy for hypothyroidism, both of which are critical to avoid mental retardation. Neonatal diagnosis of congenital hip dislocation provides the best chance for correcting this disorder through noninvasive techniques. Ethical Considerations Prevention, diagnosis, and treatment of birth defects can all benefit from the application of genetic knowledge when appropriate consideration is given to the following principles (WorId Health Organization, 19971: · Respecting the autonomy of individuals and protecting those with diminished autonomy; · Giving the highest priority to the care and welfare of individuals; · Maximizing the benefits and minimizing the harm and cost to indi- viduals; and · Treating individuals with fairness and equity, and distributing the benefits and burdens of health care impartially. Women and couples have the right to be appropriately informed and counseled about the screening services provided, to choose whether to ac- cept them, and to receive continuing support independently of their choice. Before undergoing a screening test, they should be informed of the severity and frequency of occurrence of the birth defect being screened for, the detection rate for the test, the probability of being affected if the result is positive, the follow-up diagnostic test, and the choices available if the diag- nostic test is also positive. If one choice is to terminate the pregnancy, this should be made clear, because some women or couples may not wish to face that choice. There is agreement in many countries that pregnancy termination must not be offered for the purpose of gender selection (Wald et al., 20001. The entire population of a country or region should be offered the most effective and safe screening service possible, provided it is affordable and judged to be cost-effective compared with alternative screening methods. Priority should be given to genetic tests involving birth defects that impose the heaviest burdens on the population as a whole. In particular, efforts should be directed at the primary care level toward improving access to genetic screening where it has been judged to be cost-effective (World Health

INTERVENTIONS TO REDUCE THE IMPACT OF BIRTH DEFECTS 109 Organization, 19971. Access to diagnostic procedures that are expensive or hazardous should be limited to those for whom the risk for the birth defect justifies the expense and the risk involved in the diagnosis (Wald et al., 20001. A genetic screening service should have the resources to provide all components of screening: testing, patient information, staff education, coun- seling, diagnostic and treatment services, monitoring, and quality and cost control (Wald and Hackshaw, 20001. The results of genetic tests should be provided with supportive counsel- ing that does not direct women or couples toward either continuing or terminating a pregnancy when the fetus is afflicted with a severe genetic disorder. Genetic data should be used only to benefit members of a family or ethnic group it should never stigmatize or discriminate against them and should be treated as confidential at all times (WorId Health Organiza- tion, 19971. Summing Up Genetic screening services provide an opportunity to profoundly reduce the impact of birth defects in developing countries. Such services are, how- ever, expensive for countries with limited resources for health care because they require highly trained staff, sophisticated equipment, and the support of diagnostic and counseling services. Even after the initial high cost to establish such services, continued delivery of good quality services requires ongoing staff training and rigorous maintenance of the equipment. There is, however, a time for each country when more affordable interventions have substantially reduced infant and neonatal mortality due to more prevent- able conditions and birth defects become a priority. By that time treating birth defects can be taking up a substantial and increasing share of health costs and hospital beds, and genetic screening for common and severe conditions has been found, even by countries with limited resources, to be cost-effective relative to other health interventions. Examples of national genetic screening programs that have been dis- cussed in this chapter are found in Cyprus, Greece, Iran, and Sardinia for thalassemia, and in Costa Rica and Cuba for a wider set of locally prevalent genetic disorders. There are more examples of genetic screening programs that have been undertaken in regions of a country, such as the Northern Province of South Africa. Each country will have its own timing on the introduction of genetic screening programs, which is influenced by national and local priorities, the prevalence of preventable birth defects in the popu- lation, health care capacity, financial and human resources, and the ability to dedicate substantial additional resources. For many countries, this is likely to become important when other health interventions have reduced the infant mortality rate to the range of 20-40 per 1,000 live births.

110 REDUCING THE IMPACT OF BIRTH DEFECTS Recommendation 12. Countries with comprehensive systems of basic reproductive health care that have lowered infant mortality rates to the range of 20 to 40 per 1,000 can further reduce infant mortality by establishing genetic screening programs. These programs should ad- dress severe, locally prevalent conditions with clear screening and diag- nostic tests; effective, acceptable strategies for prevention or treatment; and be cost-effective. Counseling, with the goal of enabling individuals to make free and informed health care decisions, including the choice, where legal, to terminate a pregnancy in the case of a severe birth defect, should be integral to all screening and diagnostic programs. NATIONAL COORDINATION, SURVEILLANCE, AND MONITORING The impact of individual birth defects and of birth defects in the aggre- gate must be known with some accuracy if priority needs are to be identi- fied and addressed. Epidemiological data can establish the prevalence and health burden associated with birth defects and provide information for establishing priorities for interventions. Regular surveillance provides trends and monitors the clinical- and cost-effectiveness of interventions. The as- sessment of neonatal mortality due to birth defects is difficult and expen- sive, however, since most deliveries in developing countries take place at home, and infant deaths that occur during or shortly after childbirth are rarely recorded in official statistics. As a result, data on total infant mortal- ity and mortality due to birth defects vary widely and are almost certainly underestimates. Developing countries differ widely in their needs and resources for the establishment of data systems. Further, establishment of a monitoring sys- tem competes for limited resources with interventions to reduce birth de- fects. However, even relatively simple efforts to monitor the birth preva- lence of common birth defects (see Box 3-12), along with associated death and disability, can highlight priority areas and changes in those areas over time. This information is key to identifying priority interventions and to their success over time. Recommendation 13. Collection of epidemiological data on birth de- fects is necessary to understand the extent of the problem and identify intervention priorities. Depending on the infant mortality rate, the ca- pacity of the health care system, and the resources available, countries should incrementally develop the following: · National demographic data on neonatal and infant mortality and morbidity,

INTER VENTIONS TO RED UCE THE IMPA CT OF BIR TH DEFE CTS 1 1 1 · Data on causes of death, · Documentation of birth defects using standardized protocols for diagnosis, and · Ongoing monitoring of the common birth defects in a country or region. Many organizations and parts of government can contribute to the strengthening of health care in developing countries. National leadership

2 REDUCING THE IMPACT OF BIRTH DEFECTS and coordination of these organizations and capabilities can vastly improve the quality and equity of health care, including reproductive health care and care of birth defects. Recommendation 14. Each country should develop a strategy to reduce the impact of birth defects, a framework of activities by which this can be accomplished, and the commitment of health leaders to accomplish these goals. National programs of basic reproductive health should collect and in- terpret surveillance data, set uniform standards for the training and perfor- mance of health care providers, and foster communication among health care providers, researchers, and policy makers. Recommendation 15. Each country should strengthen its public health capacity for recognizing and implementing interventions that have proven effective in reducing the impact of birth defects. This includes monitoring and tuning interventions for clinical- and cost-effectiveness in the local setting. CONCLUSION Despite the existence of low-cost interventions for preventing and treat- ing a number of birth defects, the human, economic, and social burdens associated with these conditions remain high. Obstacles to improving care for birth defects include financial constraints; lack of knowledge on the part of health care workers; poor access to medical facilities; and issues sur- rounding ethnicity, language, religion, and culture. Governments must be educated on the cost-effectiveness of reducing the impact of birth defects through proven methods of prevention and care, which can be adapted to local resources and needs. Providing the best possible care for patients with birth defects begins with the recognition that such care may require signifi- cant financial commitment and that the care that can be provided will vary with the setting(WorI3 Health Organization, 1985, 1997, l999;Carey, 19921. Robust programs of basic reproductive health care and public health campaigns provide a framework for new efforts to reduce the impact of birth defects. Reducing the impact of birth defects in developing countries can be approached through a three-stage process. The first stage of the process involves low-cost interventions to prevent specific birth defects. The second stage addresses improved treatment and rehabilitation for those with birth defects. Although generally more costly than the first stage pre-

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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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