Community Genet 2002;5:61-69 PREVENTING CONGENITAL ANOMALIES IN DEVELOPING COUNTRIES Victor B.

Penchaszadeh Division of Medical Genetics Beth Israel Medical Center Albert Einstein College of Medicine First Ave & 16th Street New York, NY 10003, USA Tel. 1-212-420-4179, Fax 1-212-420-3440, E-Mail vpenchas@chpnet.org

Key words Birth defects, congenital anomalies, prevention, developing countries

ABSTRACT

INTRODUCTION This paper addresses needs and strategies for the prevention of congenital anomalies in developing countries. Numerous experiences indicate that the conditions of underdevelopment require preventive modalities of low cost and high impact, which may differ from those implemented in wealthier countries (Penchaszadeh, 1992; WHO, 1999; 2000). This paper will focus on structural congenital malformations detectable at birth, which are the bulk of birth defects in the third world. The prevention of genetic disorders in general in developing countries has been reviewed recently elsewhere (Penchaszadeh, 2000). The term developing applies to nations that are not part of the wealthy and industrialized world of Western Europe, United States, Canada and Japan. Thus, the developing world (also called third or less developed world, where most than 80% of the world population lives and 90% of births occur) includes Asia, Africa, Latin America and the Caribbean and Eastern Europe (although some would put this group in a separate category). While there is wide variations in almost every indicator, common denominators of most developing countries are a gross economic product significantly lower than that of the industrialized countriesXXX, deficient infrastructure and technology, scarcity of human resources and great inequalities between a majority of population living in poverty with deficient access to all types of services, and well-to-do elites with wealth and access to services and power similar to the rich in developed countries. Compared to industrialized countries, demographic and health characteristics of developing countries include high fertility, low life expectancy, high maternal and infant mortality due largely to preventable exogenous factors, and very little public attention to, and expenditures in health services and prevention (Penchaszadeh, 2000). It must be noted, however, that the socioeconomic and cultural variations between and within individual developing countries are so numerous that any generalization runs the risk of distorting and stereotyping a complex reality. Errors of morphogenesis leading to congenital anomalies have many recognized causes, including specific single-gene mutations, chromosome imbalances and the action of teratogenic agents. Most congenital anomalies, however, are of multifactorial origin, occurring by complex interactions between not yet well understood genetic and environmental factors. For many malformations, gradients of increasing birth prevalence with decreasing socioeconomic status have been documented, indicating the importance of environmental factors associated with poverty in their causation (Leck et al, 1968). However, and while geographic variations for individual anomalies exist, the global prevalence rates at birth of congenital anomalies are remarkably similar worldwide (ICBDMS, 1991). The causes of geographic variations in birth prevalence may reflect differing methods of detection and recording, or true differences in frequency due to dissimilar environmental exposures, genetic constitutions or the interaction of both. A commonly held but erroneous view is that congenital disorders are not a public health issue in developing countries. Contrary to this misconception, a number of developing countries are in fact experiencing an epidemiological transition, with significant declines in infant mortality rates, reduction of infections and malnutrition and

a relative increase of morbidity and mortality due to non-communicable diseases, including congenital anomalies (Penchaszadeh, 2000). It is a matter of debate what are the proper indicators, and cut-off values, to determine whether a country has reached the level at which public health concerns should include the prevention of congenital anomalies. A group convened by the World Health Organization (WHO, 1999) stated that programs for the prevention of birth defects should be implemented when infant mortality falls below 40 per thousand, essentially because it is at that stage that congenital malformations begin to make up a significant proportion of infant mortality. By the end of the 20th century, 69 of 142 developing countries, with a population of over 2.5 billion people, had infant mortality under 40 per thousand (UNICEF, 2001). However, no single health indicator by itself can determine the priority of preventing congenital anomalies in public health programs. More important, perhaps, is identifying low cost and high impact measures to attain that goal, as described below. I will first examine the birth prevalence of the main etiological categories of congenital anomalies and then analyze preventive strategies. PREVALENCE OF CONGENITAL ANOMALIES The birth prevalence of congenital anomalies in the developing world is underestimated by deficiencies in diagnostic capabilities and lack of reliability of medical records and health statistics. As a result, recorded diagnoses in vital statistics focus on overt acute illnesses, rather than on preexisting congenital conditions that increase vulnerability to infections and malnutrition (WHO, 1985). More reliable estimates of the prevalence at birth of congenital anomalies come from registries of congenital malformations in newborns (reviewed in: Penchaszadeh, 2000), which show that the prevalence of recognizable malformations among newborns is between 2-3%, that is similar to that found in the industrialized world (ICBDMS, 1991). Recorded rates in developing countries must be considered minimum estimates because of low diagnostic capacities and underreporting. Congenital anomalies of multifactorial origin Most congenital anomalies are of multifactorial causation, that is due to a combination of environmental and genetic factors. Geographical variations in prevalence reported by malformation registries may give clues to etiological factors when they represent true differences, as is the observed variation in prevalence rates of neural tube defects in different regions of the world. Neural tube defects indeed are particularly prevalent in China (Xiao, 1990), Mexico (Mutchinik, 1988), Central America (Saborio, 1992) and Chile (Nazer et al, 2001), probably because of a combination of nutritional deficiencies and exposure to environmental pollutants. Other examples are cleft lip and palate, which are more common among Amerindian and Asian populations (Xiao et al, 1988; ICBDMS, 1991), and microtia, frequent in the highlands of Ecuador, South America (Castilla & Orioli, 1986). In many instances, however, the meaning of differences in birth prevalence is confounded by varying diagnostic criteria and recording methodologies. Congenital anomalies due to chromosome abnormalities Maternal age-specific rates of Down syndrome in developing countries are similar to those reported in developed countries (WHO, 1985; Model & Boulyjenkov, 1988; Castilla & Lopez-Camelo, 1990; Venter et al, 1995; Xiao et al, 1988). Scarce cytogenetic laboratories limit existing data on the frequency of other chromosomal disorders. Some

data suggest, however, that the overall birth prevalence of chromosome disorders is higher in developing countries, resulting probably from the lack of family planning services and a higher proportion of births to women of advanced age (WHO, 1996; Castilla, 1996). Indeed, the percentage of births to women over 35 years old ranges form 11 to15% in different regions of the developing world, compared with 5-9% in industrialized countries (UNFPA, 1998). The very limited availability of, and access to prenatal diagnosis and the fact that in many developing countries abortion is illegal, further contribute to higher birth prevalence of chromosome abnormalities. Congenital anomalies due to identifiable environmental exposures. Pregnancies in developing countries tend to be exposed to potential teratogens to a higher degree than in industrialized nations (Schuler et al, 2002). This is because of a number of concomitant factors: (a) low socioeconomic and educational levels, (b) increased incidence of malnutrition, mineral and vitamin deficiencies, and intrauterine infections, (c) lack of environmental protection policies, high level of environmental pollution and unsafe working conditions during gestation, and (d) access to medicines without medical indication nor prescription (self-medication), and common use of home remedies of unknown composition. Intrauterine infections Among intrauterine infections, rubella is of note because of its prevalence, its high teratogenicity and the possibility of its eradication by immunization (Cutts et al, 1997). The number of new cases of congenital rubella syndrome in developing countries in 1996 has been estimated in 110,000 (Cutts & Wynnyck, 1997). Congenital syphilis continues to represent a significant burden in developing countries, in spite of efficient preventive methods (Murray & Lopez, 1996; McDermott et al, 1993). The current pandemic of HIV/AIDS is determining a very high prevalence of this condition among infants and children in the developing world, as drugs preventing maternal transmission are out of reach of most groups at risk because of economic and structural factors. While congenital malformations are not the hallmark of maternally transmitted AIDS, this condition not only fits the definition of a birth defect but it is overshadowing all other types of birth defects, particularly in Sub-Saharan Africa (World Bank, 1997). Prescription drugs In many developing countries drugs are usually available over the counter, and self-medication by patients is a common practice. Although most prescription medicines are not considered teratogenic, there are several situations in which overtly teratogenic substances are available to the population without proper gate-keepers or regulations. A recent study in Porto Alegre, Brazil, found that 22% of pregnant women of low socioeconomic status had used medications without medical indication, 22% smoked and 13% had an attempted abortion (Schuler et al, 2002). A case in point is thalidomide. After the tragedy between 1959 and 1964, the drug was withdrawn from the market in most countries. However, it continues to be used against leprosy in a majority of South American countries, where it is available through leprosy treatment centers and also occasionally from regular pharmacies. Unfortunately, drug regulations are much less stringent than in developed countries, and a number of cases of thalidomide embryopathy have recently been reported in the region (Castilla et al, 1996). It is possible that unrecognized thalidomide embryopathy is occurring in other regions of the underdeveloped world where leprosy is endemic. The situation may

worsen as the discovery of its anti-angiogenic properties is leading to new therapeutic applications for a variety of conditions (DAmato et al, 1994). Thus, through a combination of extended therapeutic applications, laxity of drug regulations and high frequency of unintended pregnancies, a stage may be set for a new thalidomide catastrophe (Castilla et al, 1996). Another example is misoprostol, a synthetic prostaglandin E -1 analogue used to prevent and treat gastrointestinal lesions induced by nonsteroidal anti-inflammatory drugs. The drug is contraindicated during pregnancy because it stimulates uterine contractions and cause vaginal bleeding. In fact, the combination of misoprostol and mifepristone is popular for the elective induction of abortion, particularly in developing countries where abortion is illegal. In Brazil, for example, misoprostol can be obtained over the counter and is used by 57 to 75% of women who attempt abortion in the first trimester of pregnancy (Schuler et al, 1992). However, since misoprostol fails to induce abortion in approximately 80% of the cases, most pregnancies exposed to the drug continue to term. Misoprostol is known to cause facial nerve paralysis, with or without limb defects, probably due to vascular disruption of the subclavian artery and an ischemia in the embryonic brain stem (Costa & Vessey, 1993; Coelho et al, 1993; Pastuszak et al, 1998). Although a prospective study indicated that the drug has a rather low teratogenic risk (Schuler et al, 1999), women using misoprostol for gastrointestinal indications should be warned not to become pregnant during its use. In a hypocrisy paradigmatic of undervelopment, the criminalization of abortion not only does not prevent abortions, but it instead leads women to the illegal use of an ineffective abortifacient which in addition can cause birth defects in their offspring. A small number of prescription medications are known to increase the risk of congenital anomalies in the exposed offspring, such as anti-epileptics, some antidepressants, some antibiotics, etc (Shepard, 1999??????? Alcohol Fetal exposure to alcohol is a well known cause of congenital anomalies and mental retardation. Less well known are the minimal levels of alcohol intake that are safe in pregnancy and the actual prevalence of fetal alcohol effects (FAE) and fetal alcohol syndrome (FAS) in particular populations. Studies in South Africa have shown that maternal alcohol consumption in pregnancy is very prevalent in some rural areas (Croxford & Viljoen, 1999), and the prevalence of FAS among school-aged children is the highest reported in the world (May et al, 2000). In these communities, FAS prevalence is correlated with maternal low educational level, alcohol consumption and smoking (Viljoen et al, 2001). Although no hard data exist on FAS and FAE in other developing countries, it is probably a problem of great magnitude. Iodine deficiency Iodine deficiency in pregnancy is a cause of preventable congenital hypothyroidism and mental and growth retardation and is quite prevalent in a number of less developed countries (Phaorah, 1993). Folic acid deficiency Intrauterine folic acid deficiency is a well known factor predisposing to neural tube defects and possibly other congenital anomalies (Czeizel & Duds, 1992). As mentioned above, neural tube defects have relative high prevalence in a number of

developing countries. However, although some cross sectional studies in developing countries have shown suboptimal levels of folic acid in women of reproductive age, its significance as cause of congenital anomalies is not yet clear (WHO, 2000) Congenital anomalies due to single gene mutations A small proportion of congenital anomalies are due to single gene mutations, usually in the form of syndromes of multiple congenital anomalies (WHO, 1996, 2000). Most these conditions are rare, although geographical clusters of unusually high frequency of specific single-gene congenital syndromes may occur due to demographic factors such as founder effects, genetic isolation or consanguinity and eventually pose a significant public health concern (WHO, 1996). PREVENTION OF CONGENITAL ANOMALIES The World Health Organization has recently made a number of recommendations to prevent congenital anomalies and genetic disorders, with particular attention to developing countries (WHO, 1999, 2000; Penchaszadeh et al, 2000). Latin American geneticists have also issued recommendations suited for this region, which is the most advanced of the third world in terms of health indicators and development of genetic services (Penchaszadeh & Beiguelman, 1998). These revolve around improving maternal health and nutrition, family planning, XXXXX. In this paper, I will discuss the status of two main types of programs for the prevention of congenital anomalies in developing countries: (a) primary prevention, and (b) prevention based on prenatal diagnosis and selective interruption of affected pregnancies. Further, I will comment on the role that genetic counseling Primary prevention of non-hereditary congenital anomalies The goal of primary prevention is to reduce the incidence of congenital anomalies through the removal of causative factors. The majority of identified causes of congenital anomalies are non-hereditary and the main preventive measures recommended and being tried in developing countries are: (a) expansion of rubella immunization, (b) access to family planning programs that include the encouragement to complete reproduction before 35 years of age, (c) periconceptional supplementation of folic acid, and (d) access to adequate prenatal care, including nutrition, control of maternal infections and avoidance of teratogens. Expansion of rubella immunization The congenital rubella syndrome has been eradicated in the United States by the near universal rubella vaccination as part of childhood immunization programs. By contrast, the burden of congenital rubella in developing countries has been estimated in at least 100,000 cases per year (Cutts & Wynnyck, 1997), but only 28% of all developing countries have rubella immunization programs in place, as compared with 92% of industrialized countries (Robertson et al, 1997). The worse off continent is Africa, where only one of 47 countries uses rubella vaccine. The implementation of immunization programs are a function of political will and appropriate funding. In addition, a minimum of infrastructure, cold chains and adequate organization at community levels are required. In Latin America and the Caribbean, the Pan American Health Organization (PAHO) has been promoting rubella vaccination as part of childhood immunization since the late 1990s. By January 2001, 44 of the 47 countries in the Americas had included rubella vaccine in their national childhood immunization programs. In addition, in order to reduce the risk of rubella infection in women of child-bearing age, a number of countries

in the Region have scheduled vaccination campaigns using rubella vaccine during the postpartum period. Cuba and Uruguay have been using measles-mumps-rubella vaccines for several years and have virtually eradicated congenital rubella syndrome (PAHO, 2001). Currently, efforts are directed at developing a congenital rubella syndrome surveillance system to monitor the effectiveness of the rubella immunization programs. This system will be based in part in the Latin American Collaborative Study of Congenital Malformations (ECLAMC), which is a congenital malformations surveillance system covering most countries of South America (Castilla & Lopez-Camelo, 1990). Eradication of congenital rubella syndrome is within reach in Latin America and the Caribbean by the end of this decade. In other regions of the developing world, the outlook is not as promising, due to scarcity of funds and infrastructure, conflicting priorities or lack of political will (Robertson et al, 1997). Folic acid supplementation It has been known since 1980 that periconceptional multivitamin intake reduces the risk of neural tube defects in the offspring (Smithels et al, 1980). Later studies identified that the key element was folic acid and that its protective effect only occurred when normal levels were present periconceptionally (MRC, 1991). Since most pregnancies are unplanned, the United States Public Health Service recommended that women capable of becoming pregnant should consume 400 ug of folic acid daily (CDC, 1992) and in 1996, the Food and Drug Administration mandated the fortification of all enriched grain products, like flour and pastas, with 140 ug per 100 g of grain. In other countries, like Australia and the Netherlands, it was recommended that women plan their pregnancies and consume 400 ug of folic acid while they attempt to become pregnant (Cornel & Erickson, 1997). Obviously this approach would be completely unrealistic in the developing world, where the overwhelming majority of pregnancies are unplanned. Recently, in a community-based intervention study in China, a daily dose of 400 ug of folic acid pills alone given periconceptionally was effective in determining a 85% reduction in neural tube defects in an area of high incidence and a 41% reduction in an area of low incidence (Berry et al, 1999). It is doubtful, however, that this type of strategy could be sustained beyond a well funded research project during a limited period of time. The only viable and sustainable preventive strategy is thus the fortification of food with folic acid. In 1999 the Ministry of Health of Chile, South America, issued a regulation requiring that as of January 2000, folic acid be added to the premix currently in use for wheat flour at a concentration of 2.2 mg/kg of flour. At this level, 100 g of the commonly consumed bread supplies 182 ug of folic acid, which according to the average level of bread consumption in the country, would supply 360 ug/day of folic acid (Nazer et al, 2001). This policy has received the support of the Pan American Health Organization, the March of Dimes and the CDC and plans are been implemented to monitor the effect of the policy on the prevalence of neural tube defects, taking advantage of a preexisting and ongoing register of congenital malformations (Nazer et al, 2001). In another Latin American example, in 1994 the Cuban government issued a policy of supplementation of multivitamins pills containing 400 ug of folic acid to all the adult population, after an epidemic of optic neuritis attributed to an ill-defined vitamin deficiency and possible food toxics (REF). In addition, as described below, since the mideighties Cuba has implemented a very successful program of prevention of neural tube

defects based on prenatal alpha-fetoprotein and ultrasound screening followed by the option of termination of affected pregnancies. Thus, the effectiveness of the folic acid supplementation policy in reducing the frequency of NTDs could not be assessed (Rodriguez et al, 1997). Family planning A number of experiences in developing countries attest to the importance of family planning as a basic human right of women and its positive role in reproductive health and the improvement of pregnancy outcomes (UNFPA, 1998). By reducing birth rate and fertility, family planning may contribute to a decline in birth prevalence of genetic congenital anomalies. It has been estimated that in many developing countries with high fertility, its reduction to 2-3 children per family could reduce the birth prevalence of genetic disorders by 40-50%. Further, when combined with encouragement to complete reproduction before age 35, family planning can contribute to a 50% reduction of Down syndrome (WHO, 2000). Unfortunately, these programs are opposed in many countries because of entrenched traditions and the conservative influence of Catholicism and Islam. In a number of Latin American countries, for example, the all powerful Catholic church has consistently opposed the access of women to contraceptive services. While these obstacles dont affect the wealthy, they do prevent access of women of low socioeconomic levels to family planning services. Health professionals interested in preventing congenital anomalies should ally with the increasingly assertive women rights movements in developing countries to make family planning services available and accessible to all that request them. Avoidance of potential teratogens in pregnancy This is an area in which traditions, socioeconomic factors and medical culture coalesce against the goal of avoiding exposure to teratogens. On the one hand, some cultures in developing countries resort to home remedies on unkown composition and teratogenic potential. On the other hand, in some developing countries pharmaceutical companies market their products directly to consumers, who can purchase most medications over the counter without medical prescription. Compounding these factors are lax environmental quality regulations and unhealthy working conditions which expose pregnant women to environmental pollutants (Schuler et al, 2002). Teratogen information services are a valid strategy to counter the above factors and prevent exposure to known teratogens. An example of such approach is the teratogen information service implemented since 1990 at the medical genetics department of the University Hospital of Porto Alegre, Brazil. Through public awareness campaigns directed at the public and obstetricians, questions and concerns are channeled to centralized telephone lines and consultations provided on the possible effects of exposures to drugs and other environmental substances (Schuler et al, 1993). This service has a national scope and is the first of its kind in Latin America, an experience that was later followed in other cities of Brazil, Argentina, Colombia and Paraguay (Schuler et al, 2002). While teratogen information services fulfill a very important educational function, it is difficult to assess objectively whether and to what extent they actually prevent teratogen exposures and reduce the birth prevalence of congenital anomalies. Prevention of congenital anomalies based on reproductive options The shortcomings and difficulties of primary prevention programs of congenital malformations of unknown or complex origin have led some developing countries to

follow the example of developed nations and implement mass prenatal screening followed by prenatal diagnosis by amniocentesis. Cuba, for example, has pioneered the routine use of maternal serum AFP and fetal ultrasound in all pregnancies in a multi-step strategy of diagnosis of fetal anomalies which includes genetic counseling and offer of amniocentesis and eventual voluntary termination of pregnancies with fetal anomalies. The MS-AFP assay technology used in Cuba was developed locally at very low cost (less than 0.50 US dollar per test), and the program covers 95% of all pregnancies (Heredero, 1992, 1998). In addition, all pregnancies of women over 38 years old are offered prenatal chromosome analysis by amniocentesis. When fetal chromosome abnormalities or severe malformations are detected, couples are counseled and given the option of pregnancy termination. In Havana City, between 1982 and 1993, 328,983 pregnancies (approximately 95% of all the total) were screened by MS-AFP. A total of 1,371 malformed fetuses were detected by amniotic fluid AFP or ultrasound, two-thirds of which had neural tube defects. In that 12-year period, the birth prevalence of NTDs in Havana City fell 90% (Rodriguez at el, 1997). Similarly, the strategy followed in China for the prevention of congenital anomalies at a population level applied tools developed in Western countries, particularly ultrasound technology to detect fetal malformations prenatally, followed by the option of pregnancy termination (Lo, 1985; Wang et al, 1991). EUGENICS ETHICS Contrary to widely held misconceptions, induced abortion is legal in numerous developing countries, such as China, South Africa, India and Cuba. In a number of Latin American countries, legal restrictions to abortion are been relaxed to allow interruption of pregnancies because of fetal anomalies. In fact, prenatal diagnosis of fetal anomalies by ultrasound and amniocentesis is available throughout Latin America in the private sector, albeit accessible only to those who can pay for it. This trend may slowly lead to an expansion to the use of prenatal diagnosis, particularly by ultrasound, to prevent births with congenital anomalies Secondary prevention Readers from developed countries may be appalled to learn that is not unusual in many developing countries that nobody examines newborns before discharge. Systematic clinical examination of newborns for congenital malformations can be a method of secondary prevention (minimization of medical consequences of a condition) through early detection of anomalies that may warrant medical or surgical intervention. Development of registries of congenital malformations Problems, successes and failures Primary care, political will, regionalization, preexisting programs: family planning, prenatal care, etc cost/effectiveness EUGENICS? ethics The Cuban experience demonstrates that a developing country of low income and scarce resources can accomplish goals of prevention and care of genetic diseases and birth defects, by the implementation of clear policies, political will and an adequate organization of resources. Conclusions References SIFILIS, neuritis optica, levels of folic acid, Viljoen 2001

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