Prevention of Neural Tube Defects by Periconceptional Use of Folic Acid

Abstract

After completing this article, readers should be able to:Birth defects are the leading cause of infant mortality and a major contributor to heightened morbidity in the United states. The basic definition of a birth defect is a structural abnormality present at birth. Infant mortality attributable to birth defects has not declined as rapidly as overall infant mortality; from 1968 to 1995, the proportion of infant mortality due to birth defects increased from 14.5% to 22.2%. It has been estimated that approximately 20% to 25% of all birth defects are due to gene mutations, 5% to 10% to chromosomal abnormalities, and another 5% to 10% to exposure to a known teratogenic agent (such as prescription drugs, chemicals, or radiation)or a maternal factor. Together, these percentages account for only 30% to 40% of birth defects, leaving the etiology of more than 50%unexplained. It has been speculated that environmental factors account for no more than 10% of all congenital anomalies. Genetic factors are responsible for 30% of pediatric hospital admissions.Birth defects rank somewhere between second and fifth among causes of death in children younger than 1 year of age; 3% to 4% of infants in their first year of life are diagnosed as having major birth defects. Of the 120,000 to 150,000 infants born with serious birth defects each year, approximately 6,000 die during their first 28 days of life and another 2,000 die before reaching their first birthdays.In an aggregate analysis of the expense of illness in the United States, congenital abnormalities as a group was estimated to cost$6.3 billion in 1980 or 1.4% of the total cost of illness. This estimate did not include nonmedical direct costs, such as special education and developmental services. Although recent advances in medical technology have increased the chances of survival for children who have birth defects and disabilities, the quality of life for most of these children remains compromised. The economic cost of medical conditions such as birth defects often is discussed without a full understanding of how these conditions affect the lives of infants and families.Because estimates of the cost per new case of birth defects represent the savings from preventing a case,an incidence-based approach enables assessment of the value of prevention strategies. This type of approach was used to estimate the cost of illness for some of the major, most clinically important structural birth defects in the United States. This report used data from a California birth defect monitoring program (adjusted to provide national estimates) and national data to estimate the costs of major structural birth defects occurring in the United States during 1992 (Table 1). The birth defects were selected based on their clinical significance and broad representation of the organ systemThese findings are subject to at least four limitations. First,California data used to estimate incidence rates and treatment costs may not be representative of the United States;total costs per case may vary from state to state. Second, the contribution of time and effort by family members to the provision of care were not estimated and may be substantial for some cases. Third, the psychological costs of these types of illness, which may exceed traditional human capital costs, were not included. For these and other reasons, the use of the human capital approach underestimates what the public is willing to pay to prevent these conditions. Finally, excess medical and educational costs probably were underestimated for some conditions because they could not be ascertained completely. If all of the approximately 120,000 to 150,000 infants born each year in the United States who have serious birth defects had been included in this analysis, the economic costs would have been higher.NTDs are among the most serious and common birth defects to cause infant mortality, morbidity, and disability in the United States. Each year, approximately 4,000 births that involve NTDs as well as other defects result in miscarriage or stillbirth. There are several forms of NTDs, and they vary widely in severity. The birth prevalence of these conditions has declined substantially over the past 60 years due to better medical care. NTDs are reported in 3.6 to 4.6/10,000 live births in the United States. These rates underestimate true incidence,however, because affected pregnancies may be spontaneously or electively aborted and because not all cases are detected and reported at birth. Population-based active surveillance programs that include prenatal diagnosis have reported NTD rates of 7.2 to 15.6/10,000 liveborn and stillborn infants. Women in the United States who have had a pregnancy resulting in an infant or fetus who has an NTD have a 2% to 3% risk for having another pregnancy resulting in a similarly affected infant or fetus.Spina bifida is an inclusive name for various conditions characterized by incomplete fusion of the vertebral arches with a protruding sac that contains meninges, spinal cord, or nerve roots that cause permanent damage to the spinal cord and spinal nerves. It is a complicated and common birth defect that can affect pregnancy without warning. Results of prenatal examinations suggest that affected fetuses exhibit leg movement until the third trimester but become paralyzed later in pregnancy, several months after the initial spinal cord defect occurs. The Centers for Disease Control and Prevention (CDC) estimates that 300,000 to 400,000 infants are born each year with spina bifida worldwide. In the United States,approximately 2,500 infants are born annually with spina bifida and anencephaly, and an estimated 1,500 fetuses affected by these birth defects are aborted.Based on 1992 cohort data, the estimated lifetime cost of spinal bifida is $294,000 per case. Spina bifida can range from mild (spina bifida occulta) to severe(myelomeningocele). Depending on the pattern and level of spinal cord involvement, the resultant deficit can include a lifelong handicap due to infectious complications, motor and sensory paraplegia, bladder and bowel incontinence, Arnold-Chiari malformations, and hydrocephalous.Unlike spina bifada, in which 80%to 90% of infants survive into adulthood, anencephaly is a lethal malformation characterized by the absence of the cranial vault and the cerebral hemisphere that usually results in stillbirth or death within hours or days. Fifty percent of anencephalic fetuses are aborted spontaneously, but if pregnancy goes to term, the infants quickly succumb,showing only slow, stereotyped movements and frequent decerebrate posturing. The incidence of anencephaly is 1/1,000 live births and is responsible for about 50% of all NTDs.Encephalocele is a rare congenital defect of the skull that results in herniation of meninges and brain tissue. It is seen most commonly in the occipital region, where it may be associated with other anomalies,such as brainstem and skull base deformities and hydrocephalous. The incidence of occipital encephalocele is 1/10,000 live births. Most encephaloceles are detected in children shortly after birth, and the outcome relates to the position of the defect and to the associated anomalies. The primitive nervous system begins as a flat neural plate 2 weeks after conception, which becomes indented by a longitudinal groove at 20 days,with neural folds on the flanks. These folds begin to fuse in the midline, forming a cylinder in the middle of the plate. In a zipper fashion, this dorsal closure is promulgated rostally and caudally, resulting in a tubular structure with an open anterior and posterior aperture. At 26 days, the anterior aperture closes,followed at 29 days by the posterior aperture. Factors necessary for formation of the neural tube are intrinsic in the neural ectoderm and adjacent mesoderm. A teratologic insult in embryogenesis timed to interfere with the closure of the anterior aperture will result in anencephalus. Failure of the posterior aperture to close results in an exposed spinal cord, which is recognized later as spina bifida. In broad terms, NTDs result from incomplete neurulation and refer to a wide spectrum of congenital malformations in which separations of the midline vertebral and cranial elements are the common feature,but they usually are taken to mean anencephalus, spina bifida, and encephalocele.Despite considerable progress having been made in understanding NTDs, they remain the most common serious birth defect, and the etiology of most cases still is unknown. It is accepted that there is a genetic-environmental interaction in the causation of NTDs. Genetic and epidemiologic studies have suggested high-risk groups: those who have a past history of NTDs; a maternal age of less than 20 or more than 35 years; parity (primipara and grand multipara); and low socioeconomic status with gross nutritional deficiency and inadequate antenatal care.Several clinical and epidemiologic studies have reported various teratogens that produce NTDs in offspring, including radiation;maternal hyperthermia such as prolonged high fever; exposure to heat and hot-tub use; hypo- and hypervitaminosis A; maternal viral infections such as rubella, toxoplasma, and cytomegalovirus; and drugs such as aminopterin, pyrimethamine,trimethoprim, triamterane,sulfasalazine, methotrexate, anticonvulsants(eg, valproic acid and carbamazepine),aliphatic nitrites, phenothiazines, cyclophosphamide,and cyanide. Teratogens cause NTDs by acting as folic acid antagonists or by being associated with inadequate folic acid availability to the embryo.A number of environmental agents also have been hypothesized as etiologic, particularly dietary agents such as soft water, blighted potatoes, nitrite-cured corn beef,canned peas treated with magnesium salts, effluent from factories, and zinc deficiency. However, none of these factors has been proved scientifically to be linked with NTDs.Certain occupations such as male painters, female agricultural workers, and male welders have been associated with an increased risk of NTDs in offspring. Also, several studies suggested that compared with women of normal weight,women who are extremely obese before pregnancy have a significantly increased risk of having an infant who has NTDs and several other malformations, such as central nervous system, great vessel, ventral wall, or other intestinal defects.Mildly elevated maternal plasma homocysteine (Hcy) levels recently have been observed in some pregnancies that resulted in NTDs and other birth defects. In the past 2 decades, research has shown mild hyperhomocysteinemia to be linked to an increased risk of premature atherosclerosis, pregnancies complicated by NTDs, early pregnancy loss, and venous thrombosis. Plasma Hcy is governed by both genetic and nutritional factors. A lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase genes, or a combination of the two can explain elevated Hcy levels in blood plasma. Genetic mutations were found on the first chromosome (677 C T and 1298 A–C) and can explain up to 50% of the protective effect of folic acid against NTDs. A personal or family history of a pregnancy affected by an NTD is associated with an increased risk of having an affected pregnancy, as is maternal type 1 diabetes, but about 90% to 95% of cases occur in the absence of any positive history. Infants of women who have type 1 diabetes have a 1% to 2% risk of NTDs. NTDs are seen more frequently in certain racial/ethnic groups, particularly Hispanics and Caucasians of European extraction,and are less common among Ashkenazi Jews, most Asians, and African-Americans. NTDs also appear to occur more frequently in association with fetal alcohol syndrome. Folic acid supplementation is not known to prevent NTDs or other teratogenic effects of alcohol on the embryo and fetuses of alcoholic women. The primary goal for such women is to avoid excessive alcohol ingestion during pregnancy. Women who have a folic acid deficiency because of intestinal disorders (such as celiac disease,small intestine malabsorption, or intestinal bypass) and those who have epilepsy and are using certain anticonvulsants may be at greater risk for having offspring who have NTDs. Infants of women treated with valproic acid and carbamazepine during pregnancy have an estimated 1% to 2% and 1% risk for spina bifida in offspring,respectively. It seems prudent to determine whether women who have epilepsy and are planning a pregnancy have a folic acid deficiency. It is not known, however, whether folic acid supplementation would decrease the risk of NTDs in the offspring of these women.Thirty years ago, it was suggested that maternal intake of certain vitamins during pregnancy affected the incidence of serious fetal malformations. Subsequent research has revealed that folate (folic acid), a B vitamin, plays a crucial role in the development of the central nervous system during the early weeks of gestation, which generally is before pregnancy is confirmed. In a significant number of embryos, an inadequate supply of folate at this time leads to failure of the primitive neural tube to close and differentiate normally, resulting in NTDs. Numerous studies have confirmed the importance of an adequate intake of folate during the weeks just before and after conception. Randomized placebo-controlled trials and nonrandomized controlled trials in pregnant women who had a prior pregnancy affected by an NTD have demonstrated that folic acid supplements substantially reduce the risk of recurrent NTDs.It has been suspected that diet has a role in the causation of NTDs. The possibility that folic acid might be involved was raised in 1964 by Hibbard. In 1980 and 1981, the results of two other interventional studies were published in which vitamin supplementation was instituted around the time of conception among women who already had had a child who had an NTD. In the first study, which was not randomized,participating women were given a mixture of eight vitamins that included folic acid (0.36 mg/d), with women who already were pregnant or who had declined to take part in the study serving as controls. The risk of recurrence in the supplemented group was about one-seventh that of the group who received no supplements. The second study was a small randomized trial of folic acid supplementation alone (4 mg/d). It yielded inconclusive results when analyzed according to randomly allocated treatment group (so avoiding bias), but when analyzed after transferring to the control group those women in the folic acid group who did not take their capsules (ie, ignoring the randomization and so introducing the possibility of bias), the supplemented women had a significantly lower risk.To avoid bias, an international multicenter, double-blind,randomized British Medical Research Council (MRC) prevention trial was initiated in July 1983. Conducted at 33 centers (17 in the United Kingdom and 16 in six other countries), it was designed to determine whether supplementation with 4 mg folic acid(one of the vitamins in the B group)or a mixture of seven other vitamins(A, D, B1, B2, B6, C, and nicotinamide) around the time of conception could prevent NTDs. A total of 1,817 women who had previous pregnancies affected by an NTD that was not associated with the autosomal recessive disorder were eligible for the study if they were planning another pregnancy and were not already taking vitamin supplements. Women who had epilepsy were excluded in case the folic acid supplementation adversely affected their treatment. The effect of both forms of supplementation was investigated by use of a factorial study design.The women were allocated randomly to one of four groups—folic acid, other vitamins, both, or neither. The four groups were similar with respect to age and the occurrence of previous pregnancies. Women were asked to take a single capsule each day from the date of randomization until 12 weeks of pregnancy (estimated from the first day of the last menstrual period). Of 1,817 women, 1,195 had a completed pregnancy in which the fetus or infant was known to have or not have an NTD. A total of 27 infants had known NTDs, with 6 in the folic acid groups and 21 in the two other groups. Sequential analysis showed a 72% protective effect(relative risk, 0.28; 95% confidence interval [CI], 0.12 to 0.71). The other vitamins showed no significant protective effect (relative risk, 0.80;95% CI, 0.32 to 1.72). There was no demonstrable harm from the folic acid supplementation, although the ability of the study to detect rare or slight adverse effects was limited. The study result is unlikely to be due to chance, and the randomized double-blind design excluded bias as an explanation. The results also demonstrate that folic acid, rather than any other vitamins, is responsible for the preventive effect.Another significant study was a randomized, double-blind, controlled trial from Hungary that enrolled 4,753 women planning pregnancy. Results documented that the first occurrences of NTDs could be prevented significantly by administering periconceptional multivitamin supplements daily that included 0.8 mg of folic acid. This study was extended to examine the effect of supplementation on other congenital abnormalities. Periconceptional administration of multivitamin supplements reduced NTDs by 50% and the incidence of other major genetic congenital abnormalities, such as cardiovascular anomalies, defects of the urinary tract, congenital hypertrophic pyloric stenosis, and congenital limb defects.Six observational studies of dietary folate or the use of folic acid and other vitamin supplements and NTDs and one nonrandomized folic acid supplementation study have been published. All but one showed an association, but all may have suffered from selection bias, and none could identify folic acid specifically as the responsible vitamin.Results of the British MRC randomized, controlled trial proved that folic acid can prevent spina bifida and anencephaly and provided critical scientific data on which to base public health policy for preventing these birth defects. Within weeks of publication of this study, the CDC developed and issued guidelines for women who had had a pregnancy affected by spina bifida or anencephaly. In September 1992, the United States Public Health Service(USPHS) issued the recommendation that all women of child-bearing age who are capable of becoming pregnant should be offered treatment with 0.4 mg of folic acid daily to reduce their risk of having an NTD-affected pregnancy. For women who already have had an NTD-affected pregnancy, the USPHS also recommends administration of 4.0 mg(4,000 mcg) of folic acid every day starting 1 to 3 months prior to the planned conception and continuing throughout the first 3 months of pregnancy.Research during the past 5 years makes it clear that people who do not take folic acid supplements are at increased risk for functional folate deficiency, which has been proven to cause spina bifida and anencephaly and has been associated with an increased risk for occlusive cardiovascular disease. The evidence that consumption of folic acid during the periconceptional period can reduce the number of NTDs has been accumulating for several years. Published data are available from randomized control trials, nonrandomized interventional trials, and observational studies (Table 2). Research on adverse effects from folic acid supplementation is limited. Evidence that folic acid supplements in daily doses of 1 to 5 mg can mask the hematologic manifestations of vitamin B12 deficiency, possibly delaying its diagnosis and treatment and thereby leading to permanent neurologic consequences, is limited to uncontrolled interventional studies and case reports. Hematologic improvement in pernicious anemia also has been reported in some patients receiving folic acid doses of less than 1 mg, but the response is not consistent, particularly at lower doses. Nevertheless, this has been advanced as one reason to avoid universal supplementation or food fortification with folic acid. However, it also has been argued that it is unreasonable to maintain anemia and ease the B12 deficiency diagnosis at the risk of an avoidable NTD. Limited evidence supports independent associations of low-normal folate and B12 levels and high Hcy levels with NTDs, suggesting that a causal mechanism for these defects may be an abnormality in methionine synthase, a folate- and B12-dependent enzyme. If these results are confirmed, supplementation with both folic acid and B12 may be appropriate to prevent NTDs. This could reduce the potential for adverse effects of folate supplementation in patients deficient in B12.None of the trials of healthy pregnant women reported serious adverse effects associated with folic acid supplementation. In the Hungarian trial, infants born to women who received a multivitamin,multimineral supplement with folic acid did not differ in mortality, somatic development, mental and behavioral development, and total serious or chronic disorders at 8 to 21 months(mean, 11 mo) of age from those born to women receiving only trace elements. The rate of atopic dermatitis, asthma, and wheezy bronchitis was significantly increased among those whose mothers received multivitamins (16 versus 5/1,000), but more affected infants in the supplemented group also had a family history of these disorders. This difference also may be a chance effect due to the large number of comparisons made. A group of 91 children born to women who had taken daily multivitamins containing 0.36 mg of folic acid to prevent NTD recurrences revealed no adverse effects on health, auditory, visual, growth,or developmental status at age 7 to 10 years compared with the general population. There were significant increases in neurotic traits, but whether this was attributable to folic acid or to other causes (eg,increased parental anxiety related to having had a previously affected pregnancy) is unknown.Most of the randomized and nonrandomized controlled trials showed that among women at high risk of having a child who had an NTD,those who received 4 mg/d of folic acid had approximately 70% fewer cases of NTD-affected offspring than those who received no supplements. Several interventional retrospective and case-control studies also support this conclusion,although the mechanism of this action is unclear. Approximately 30% of NTDs appear resistant to folic acid (as with the curly tail mutant mouse, a model of folate-resistant NTDs). The administration of inositol to the mouse can cure such defects, but this does not occur in humans. The molecular pathway by which this is achieved is thought to be by the upregulation of the retinoic acid receptor beta in the underlying hindgut endoderm, which corrects a proliferation defect.In mice, folate did not reduce NTDs, but methionine did. The curly tail mouse has been studied extensively to determine the agents that prevent NTDs in embryos. Prevention has been found with retinoic acid, inositol, hydroxyurea,mitomycin C, 5-fluorouracil, cytosine arabinoside, possibly riboflavin, vitamin C, and vitamin D2. No prevention was seen with folic acid, folinic acid, vitamin B6, vitamin B12, zinc,methionine, or thymidine.The mechanism of action of folic acid still is being investigated. Kirke et al suggested that there may be a metabolic block rather than a simple deficiency effect. Others have found that the Hcy level is significantly higher for mothers of infants who have NTDs during pregnancy than for vitamin B12-matched controls. Methionine synthase is a folate-dependant enzyme, and a defect in it would lead to increased levels of Hcy. Overcoming an abnormality in Hcy metabolism, particularly an abnormality of methionine synthase by folic acid supplementation,presently is favored. Methionine synthase is pivotal in methylation reactions to produce myelin basic protein and make tetrahydrofolate for DNA synthesis, either of which may be the responsible pathway for producing NTDs.The incidence of NTDs is declining throughout the world following the introduction of ultrasonographic examination and measurement of maternal serum alpha fetoprotein(MSAFP), amniotic fluid alpha fetoprotein (AFAFP), and amniotic fluid acetylcholinesterase (AFAChE). The latter two measurements are employed primarily as confirmatory tests and should not be regarded as part of the routine screening of women at risk of NTDs. Ultrasonography is used both as a screening test and as a follow-up test after positive results on MSAFP screening. All cases of anencephaly and approximately 65% of cases of spinal bifida could be identified by measurement of MSAFP and ultrasonography.The decline in the rates of NTDs in the United States began before the widespread availability of prenatal diagnostic services, suggesting the presence of a substantial environmental component in the etiology of these defects (eg, improved nutrition). Available data indicate that folic acid can help to avert NTDs when administered at doses of 4 mg/d to women who already have had an NTD-affected pregnancy. Results of the British MRC study suggest that the addition of other vitamins to the folic acid confers no added benefit in terms of NTDs. Based on the findings from several studies, folic acid supplementation at a dose of 4 mg/d beginning 1 to 3 months prior to conception and continuing through the first trimester is recommended for women planning pregnancy who have had a pregnancy previously affected by an NTD.However, results of controlled trials indicate that folic acid supplementation will not prevent all NTDs. The protective effect demonstrated in studies of lower-dose folic acid,measured by the reduction of NTD incidence, ranged from none to substantial. Therefore, it is reasonable to estimate that administration of low-dose (0.4 mg/d) folic acid supplementation to all women capable of pregnancy would reduce the incidence of NTDs in the United States.The use of periconceptional folic acid supplements does not preclude offering screening for NTDs,although the cost-effectiveness of such screening is likely to be reduced if there is a lower risk of occurrence. The possibility of reducing the number of cases of NTDs in the United States by 70% with the consumption of 3 cents worth of folic acid per day presents an important opportunity in public health. Efforts should be made to assure that all women capable of becoming pregnant consume 0.4 mg of folic acid daily to achieve this goal.Implementation of this recommendation presents a challenge because almost 50% of the pregnancies in the United States are unplanned. Furthermore, it is difficult, if not impossible, to achieve a daily intake of 0.4 mg of folate through diet alone. To derive the protective benefit of vitamin supplementation, women must begin to take supplements before conception occurs, a potentially less likely step if pregnancy occurs unexpectedly. Fortification of food is a “passive”public health intervention that can increase women’s intake of folic acid during the critical period of embryonic development. In February 1996, the USPHS announced that folic acid fortification of enriched cereal grain products (flour, bread,pasta, rice, and corn meal) would become mandatory as of January 1,1998. Fortification is expected to increase the daily intake of folic acid among women of reproductive age by about 100 mcg/d. Such fortification would prevent about 1,000 spina bifida and anencephaly birth defects each year and perhaps as many as 50,000 premature deaths each year from coronary heart disease.The most commonly cited potential risk of food fortification is the previously noted masking of megaloblastic anemia that often is associated with vitamin B12 deficiency,which might complicate the diagnosis and treatment of this problem,thereby increasing the potential for irreversible neurologic damage. Physicians should be aware of this possibility and remember that vitamin B12 deficiency, although occurring most commonly in the elderly, can occur at any age. Also, care should be taken to keep total folate consumption to less than 1 mg/d, except under the supervision of a physician.The recommended intake of folate in the periconceptional period may be achieved by advising women who could become pregnant to supplement a healthy, folate-rich diet with a daily vitamin pill;fortifying foods with folic acid; or combining these measures.Programs should be implemented to educate physicians, other health professionals, and the public about the value of folic acid supplementation in preventing NTDs. Ongoing surveillance programs should monitor the prevalence of NTDs in fetuses and newborns. Basic and clinical research into the mechanisms by which folic acid prevents NTDs should be encouraged. In addition, more clinical trials are needed to determine the effectiveness of folic acid in preventing the occurrence and recurrence of NTDs.