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~ 1 Periconceptional Vitamin Supplementation and Neural Tube Defects Very early in pregnancy, the developing embryo is susceptible to mal- formations from a varieUr of causes. Animal studies suggest that these causes may include certain maternal nutrient deficiencies or excesses if they occur during embryogenesis (i.e., during the first 2 months of gesta- tion). The implications of this for human nutrition are uncertain. Evidence that excessive intake of vitamin A may be teratogenic (i.e., may cause birth defects) is covered in Chapter 17. This chapter considers evidence relating to periconceptional micronutrient status and supplementation to neural tube defects. The periconceptional period is a term that lacks a tight definition. The subcommittee suggests that it be used to denote a period from 1 to 3 months before conception to week 6 of gestation. The critical period for the formation of the neural tube is from 17 to 30 days gestation. NEURAL TUBE DEFECTS Neural tube defects such as spine bifida have been linked by several investigators to periconceptional nutrient intake. The seriousness and the frequency with which neural tube defects occur warrant careful considera- tion of evidence from studies that address nutrition-related approaches for reducing their incidence. Occurrence Despite a recent decline in the occurrence rate, 2,500 to 3,000 in- fants are born with neural tube defects in the United States each year. It is 412
PERICONCEPIIONAL VITAMIN SUPPLEMENTATION 413 estimated that 30,000 living Americans have spine bifida. Many other cases of neural tube defects are aborted, stillborn, or die early in life. The magnitude of the problem on a worldwide basis is estimated at 300,000 to 400,000 births per year. Occurrence rates for neural tube defects vary widely according to geographic area, socioeconomic status, and ethnic background. Rates are relatively low in the United States, the highest rates being found in the Southeast and lowest rates in the West. In each area, rates are much lower for blacks than for whites. Marked changes in the occurrence rate of neural tube defects have been observed; the rate peaked in the middle of this century and has progressively declined over the past 40 years in North America and Western Europe. The risk of a recurrent neural tube defect, i.e., more than one affected child born to the same parents, is much greater than the risk of occurrence. Recurrence rates have been estimated to be as high as 2 to 10%, compared with an occurrence rate of <0.04% in a low-risk area. However, the absolute number of first occurrences to parents greatly exceeds that of recurrent events. Possible Causes Neural tube defects result from genetic-environmental interactions. The genetic component, which probably involves several genes, is complex and not well understood. The sum of epidemiologic and other evidence indicates a strong environmental component. The nature of the envi- ronmental factors, especially the supposed role of micronutrient nutrition and metabolism, has become the focus of intense scientific interest and debate. ~ reduce the risk of neural tube defects, periconceptional vi- tamin supplementation has been recommended, especially for all women who have had a previous pregnancy complicated by a neural tube defect (International Conference on Prepregnancy Nutrition, 1987) but also for all pregnant women (Holmes, 1988; International Conference on Prepreg- nancy Nutrition, 1987~. However, most researchers have been cautious about overinterpreting their data. Evidence of Effects of Nutrients The subcommittee examined evidence from studies in animal models and in humans addressing the possible value of folate and multivitamin supplementation commencing prior to conception. The human studies reported to date have involved laboratory assays, supplementation studies, and case-control studies, but no randomized controlled clinical trials.
414 Studies in Animal Models DIETARY INTAKE AND NUTRIENT SUPPLEMENTS Animal models provide some support for the hypothesis that vitamin deficiencies may be one etiologic factor in the multifactorial etiology of human neural tube defects (Kalter and Warkany, 1959~. However, folate deficiency produced neural tube defects in rats only when folate antagonists were given (Nelson et al., 1955~. The therapeutic use of the anticonvulsant drug valproic acid during pregnancy is associated with a 20-fold excess risk of neural tube defects (Lammer et al., 1987~. A similar teratogenic effect of valproic acid has been demonstrated in mice ([Lots et al., 1987~. When folinic acid, the metaboli- cally active form of folio acid, is administered, the rate of valproate-induced neural tube defects is reduced. A recent preliminary report indicates that valproate impairs the activity of the enzyme glutamate formyltransferase (EC 2.1.2.6), which catalyzes the conversion of tetrahydrofolate to folinic acid (Weaner and Nau, 1989~. These observations indicate that neural tube defects can result from disturbed folate metabolism. Laboratory Assays The results of laboratory assays suggest that maternal folate status may be abnormal in subjects whose offspring have neural tube defects. Smithells et al. (1976) observed significantly lower levels of red cell folate and white cell ascorbate during the first trimester in mothers who delivered an infant with a neural tube defect. Similarly, Yates et al. (1987) reported that mothers with an affected pregnancy had lower red cell folate levels than those of controls. Moreover, red cell folate levels were lowest in the group with three or more neural tube defect pregnancies. No differences were found for serum folate or for other serum vitamin measurements. Molloy et al. (1985) observed no difference in maternal serum folate or vitamin BE levels between those with neural tube defect pregnancies and controls. These observations suggest that a change in maternal folate metabolism may be associated with neural tube defect pregnancies, but they do not necessarily suggest that a low intake of folate was involved. Epidemiologic Observations Epidemiologic observations indicate that poor maternal nutrition could be important in the etiology of neural tube defects (Laurence et al., 1980~. These observations were not sufficiently detailed to indicate any specific nutrient deficiency.
PERICONCEPIIONAL VITAMIN SUPPLEMENTATION Penconcep~nal Vitamin Supplementation Studies 415 In 1981, Laurence and colleagues reported the outcome of a folate supplementation study (4 mg of folate per day) in South Wales. Subjects and controls were women who had a previous neural tube defect pregnancy. They reported a statistically significant higher incidence of recurrence rates in the placebo group, but only after the folate group was adjusted for noncompliers, as determined from blood analyses (Laurence et al., 1981~. The study group was very small (N = 111) with a total of six neural tube defects occurring in test and control groups combined. Smithells et al. (1983) reported the combined results of studies on two cohorts of women with previous neural tube defect pregnancies included in the United Kingdom Multicenter llial. The trial was a nonrandomized study of periconceptional multivitamin and mineral supplementation. The recurrence rate among subjects receiving the multivitamin preparation was 0.7% (3 out of 454) in comparison with a recurrence rate for the nonsupple- mented group of 4.8% (24 out of 519~. This apparent sevenfold protective effect is extremely unlikely to be attributable to chance. However, bias in this nonrandomized trial cannot be excluded (Wald and Polani, 1984), es- pecially since predictors of neural tube defects are still poorly understood. For example, willingness to collaborate in a study involving administration of a capsule three times a day for several months or the initiative to consult with a doctor prior to conception may be factors associated with a relatively low risk of a recurrent neural tube defect. The marked and unexplained decrease in the overall rate of recurrence during the study period has added further to the complexities of interpreting the data. The confusion and controversy associated with this study are a direct consequence of an inadequate design that did not include appropriate controls. Although the presumptive evidence for a beneficial effect of the multivitamin mineral preparation is quite strong, Smithells and colleagues have stated that "fur- ther studies are a prerequisite for policy decisions designed to reduce the occurrence of neural tube defects" (Smithells et al., 1983~. Case-Control and Cohort Studies of Periconceptional Multivitamin Use The results of three case-control studies and one cohort study of multivitamin or folate supplements or dietary folate intake in relation to the occurrence of neural tube defects were reported in 1988 and 1989. In one of these studies (Mulinare et al., 1988), the use of a folio acid- containing multivitamin during the periconceptional period was associated with a reduced prevalence of neural tube defects as compared with the prevalence among nonusers (0.9 compared with 3.3 per 1,000, respectively).
416 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS The precise composition of the multivitamin preparations in this study were not available; the mothers were interviewed between 2.5 and 16 years after the relevant pregnancy. The investigators emphasized that they could not exclude the possibility that a factor associated with the use of multivitamins rather than the vitamin intake per se was the real determinant of the observed decrease. Such factors might involve socioeconomic status, since poor women and women with relatively few years of formal education are not as likely to take multivitamins as their more advantaged counterparts (Block et al., 1988; Koplan et al., 1986~. Milunsky and colleagues (1989) reported that the use of folio acid- containing multivitamins during the first 6 weeks of pregnancy was associ- ated with a 73% reduction in the prevalence of neural tube defects. No protective effect of multivitamins without folate was observed, nor was there any apparent benefit of folate supplements started after 6 weeks of gestation. Among women not taking folate supplements, the prevalence of neural tube defects was lower among those with dietary folate intakes exceeding 100 Friday than among those with lower intakes. (The estimated mean daily folate intake of women aged 19 to 44 in the United States is approximately 220 fig iSubar et al., 1989; USDA, 19853~. The cohort in this study consisted of 23,500 women undergoing maternal serum a-fetoprotein screening or amniocentesis at approximately week 16 of gestation, 49 of whom had an affected fetus. Several biases are possible in the study. For example, some of the subjects knew the results of their screening before being interviewed. Furthermore, women who elected to take folate sup- plements before week 6 of gestation may have had characteristics different from those of women who did not take supplements or who started their supplements later in gestation. Bower and Stanley (1989) found a reduction in the occurrence of neural tube defects with increasing dietary intake of free folate during the first 6 weeks of pregnancy. Similar but weaker trends were seen when the effect of total folate intake was examined. These investigators concluded that dietary folate deficiency in early pregnancy is associated with the occurrence of neural tube defects but that confirmation is required before the issue of prevention can be addressed. In a large population-based case-control study conducted in California and Illinois, Mills et al. (1989) found no evidence of a protective effect from the use of a multivitamin preparation during the periconceptional period. Although these investigators attempted to minimize recall bias by using two control groups (one consisting of mothers who had delivered stillborn infants or infants with other abnormalities and one comprising women who had given birth to normal infants), the possibility of recall error or misclassification of multivitamin use cannot be discounted. Although the results of these studies are not consistent, they do,
PERICONCEPTIONAL VITAMIN SUPPLEMENTATION 417 however, point clearly to the need for more definitive studies of maternal vitamin intake, especially folate intake, in the periconceptional period. Limitations of the Evidence Data associating the periconceptional use of multivitamin or folate preparations with protection against neural tube defects are inconsistent. Although the findings of some key studies; e.g., the United Kingdom Multicenter filial (nonrandomized) (Smithells et al., 1983), the Centers for Disease Control case-control study (Mulinare et al., 1988), and the Boston cohort study (Milunsly et al., 1989), were very unlikely to be due to chance, factors other than periconceptional vitamin use cannot be excluded as possible explanations for the results. For example, there is evidence that the average diets consumed by women who take vitamin supplements have a higher nutrient density than the diets of nonusers (Kurinij et al., 1986~. Furthermore, dietary factors other than vitamins may provide protection. In animal models, maternal zinc deficiency has produced lesions sim- ilar to anencephaly (another type of neural tube defect) in humans, and neural tube defects are produced more readily by zinc deficiencies than by deficiency of any other micronutrient (Hurley, 1980~. Other evidence from studies in humans suggests that maternal zinc deficiency is potentially teratogenic, including neural tube defects as one of the adverse outcomes (see the review by Hambidge et al., 1975~. Well-designed randomized, prospective studies of periconceptional vi- tamin supplementation are needed to examine the putative protection against neural tube defects. I\vo major studies are in progress-one orga- nized by the Medical Research Council in the United Kingdom and the other in Hungary. Additional studies will be necessary. Although the daily administration of a multivitamin preparation may appear superficially to be simple, relatively inexpensive, safe, and possibly beneficial, there are persuasive reasons for caution. The quantities of vitamins in a standard multivitamin preparation are unlikely to be harmful, but the possibility of side effects cannot be overlooked. For example, inadvertent overuse of vitamins may damage the fetus. Furthermore, a recommendation to take multivitamins during the periconceptional period will divert attention from other factors that may be the true causative factors of neural tube defects. CONCLUSION The subcommittee concluded that the scientific evidence does not provide a sufficient basis for making recommendations concerning the periconceptional use of vitamins and minerals for the prevention of neural
418 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS tube defects. However, it recognizes the importance of the questions that have been raised and the critical need for adequate, carefully designed research to provide definitive answers as soon as possible. Meanwhile, since one or more nutritional factors are likely to play a role in the etiology of human neural tube defects, it would be desirable for women of childbearing age to follow dietary guidelines. Guidelines that encourage increased consumption of fruits, vegetables, whole grain breads and cereals, and legumes all of which are good sources of folate and other micronutrients- may be found in publications of both the public and private sector (e.g., ACS 1984; AHA [1988~; AICR [1985~; NCI [19873; NRC [19893; and USDA/DHHS [19853~. REFERENCES ACS (American Cancer Society). 1984. Nutrition and Cancer Cause and Prevention. American Cancer Society Special Report. American Cancer Society, New York 10 PP. AHA (American Heart Association). 1988. Dietary guidelines for healthy American adults: a statement for physicians and health professionals by the Nutrition Committee, American Heart Association. Circulation 77:721A-724~ AICR (American Institute for Cancer Research). 1985. Dietary Guidelines to Lower Cancer Risk. American Institute for Cancer Research, Washington, D.C. 14 pp. Block, G., C. Cox, J. Madans, G.B. Schreiber, L. Licitra, and N. Melia. 1988. Vitamin supplement use, by demographic characteristics. Am. J. Epidemiol. 127:297-309. Bower, C., and F.J. Stanley. 1989. Dietary folate as a risk factor for neural-tube defects: evidence from a case-control study in Western Australia. Med. J. Aust. 150:613-619. Hambidge, KM., KH. Neldner, and P.A. Walravens. 1975. Zinc, acrodermatitis entero- pathica, and congenital malformations. Lancet 1:577-578. Holmes, L.B. 1988. Does taking vitamins at the time of conception prevent neural tube defects? J. Am. Med. Assoc. 260:3181. Hurley, L-S. 1980. Trace elements II: manganese and zinc. Pp. 199-227 in Developmental Nutrition. Prentice-Hall, Englewood Cliffs, NJ. International Conference on Prepregnancy Nutrition. 1987. Report from the International Conference on Prepregnancy Nutrition. March of Dimes Birth Defects Foundation, White Plains, N.Y. 4 pp. Kalter, H., and J. Warkany. 1959. Experimental production of congenital malformations in mammals by metabolic procedure. Physiol. Rev. 39:69-115. Koplan, J.P., J.L~ Annest, P.M. Layde, and G.L. Rubin. 1986. Nutrient intake and supplementation in the United States (NHANES II). Am. J. Public Health 76:287-289. Kurinij, N., M.A. Klebanoff, and B.I. Graubard. 1986. Dieta~y supplement and food intake in women of childbearing age. J. Am. Diet. Assoc. 16:1536-1540. Lammer, EJ., L^E. Sever, and G.P. Oakley, Jr. 1987. Teratogen update: valproic acid. Teratology 35:465-473. Laurence, K.M., N. James, M. Miller, and H. Campbell. 1980. Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dieta~y counselling. Br. Med. J. 281:1592-1594. Laurence, KM., N. James, M.H. Miller, G.B. Tennant, and H. Campbell. 1981. Double- blind randomised controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. Br. Med. J. 282:1509-1511.
PERICONCEPIIONAL VITAMIN SUPPLEMENTATION 419 Mills, J.L., G.G. Rhoads, J.L. Simpson, G.C. Cunningham, M.R. Conley, M.R. Lassman, M.E. Walden, O.R. Depp, H.J. Hoffman, and the National Institute of Child Health and Human Development Neural lube Defects Study Group. 1989. The absence of a relation between the periconceptional use of vitamins and neural-tube defects. N. Engl. J. Med. 321:430435. Milunsky, A., H. Jick, S.S. Jick, C.L. Bruell, D.S. MacLaughlin, KJ. Rothman, and W. Willett. 1989. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. J. Am. Med. Assoc. 262:2847-2852. Molloy, A.M., P. Kirke, I. Hillary, D.G. Weir, and J.M. Scott. 1985. Maternal serum folate and vitamin B12 concentrations in pregnancies associated with neural tube defects. Arch. Dis. Child. 60:660-665. Mulinare, J., J.F. Cordero, J.D. Erickson, and R.J. Berry. 1988. Periconceptional use of multivitamins and the occurrence of neural tube defects. J. Am. Med. Assoc. 260:3141-3145. NCI (National Cancer Institute). 1987. Diet, Nutrition, and Cancer Prevention: A Guide to Food Choices. NIH Publ. No. 87-2878. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Senrices. U.S. Government Pnnting Office. Washington, D.C. 39 pp. Nelson, M.M., H.V. Wnght, C W. Asling, and H.M. Evans. 1955. Multiple congen~tal abnor- malities resulting from transitory deficiency of pteroylglutamic acid during gestation in the rat. J. Nutr. 56:349-370. NRC (National Research Council). 1989. Diet and Health: Implications for Reducing Chronic Disease Risk. Report of the Committee on Diet and Health, Food and Nutrit~on Board, Commission on Life Sciences. National Academy Press, Washington, D.C. 749 pp. Smithells, K.W., s. shepparo, ano c~. ~cuoran. l~rm. v~am~n acnc~enc~es ana neura~ rug'; defects. Arch. Dis. Child. 51:944-950. Smithells, R.W., N.C. Nevin, M.J. Seller, S. Sheppard, R. Harris, ~P. Read, D.W. Fielding, S. Walker, CJ. Schorah, and J. W~ld. 1983. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1:1027-1031. Subar, NF., G. Block, and L^D. James. 1989. Folate intake and food sources in the US population. Am. J. Clin. Nutr. 50:508-516. Trc~tz, M., C. Wegner, and H. Nau. 1987. Valproic acid-induced neural tube defects: reduction by folinic acid in the mouse. Life Sci. 41:103-110. USDA (U.S. Department of Agriculture). 1985. Nationwide Food Consumption Survey. Continuing Su~vey of Food Intakes by Individuals. Women 19-50 Years and Their Children 1-5 Years, 1 Day, 1985. Report No. 85-1. Nutrition Monitoring Division, Human Nutrition Information Senrice, U.S. Department of Agriculture, Hyattsville, Md. 102 pp. USDA/DHHS (U.S. Department of Agriculture/Department of Health and Human Se~vices). 1985. Nutrition and Your Health. Dieta~y Guidelines for Americans, 2nd ed. Home and Garden Bulletin No. 232. U.S. Department of Agriculture/Department of Health and Human Se~vices. Washington, D.C. 24 pp. Wald, N.J., and P.E. Polani. 1984. Neural-tube defects and vitamins: the need for a randomized clinical trial. Br. J. Obstet. Gynaecol. 91:516-523. Wegner, C.H.R., and H. Nau. 1989. Valproic acid-induced neural tube defects: disturbance of the folate metabolism in day 9 mouse embryo. Teratology 39:488 Yates, J.R.W., M.A. Ferguson-Smith, A. Shenkin, R. Guzman-Rodriguez, M. White, and B.J. Clark. 1987. Is disordered folate metabolism the basis for the genetic predispostion to neural tube defects? Clin. Genet. 31:279-287.
