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Periconceptional Use of Multivitamins and the Occurrence of Anencephaly and Spina Bifida

In 1988, CDC completed the analysis of data collected in 1982 and 1983 from a population-based case-control study to evaluate the association between periconceptional multivitamin use* and the occurrence of anencephaly or spina bifida (neural tube defects (NTDs)). Results of this study suggest that mothers who were periconceptional multivitamin users were at lower risk of having babies with NTDs than were mothers who did not use multivitamins (1). In 1982 and 1983, the Atlanta Birth Defects Case-Control (ABDCC) Study obtained information from parents of babies with serious malformations identified through the Metropolitan Atlanta Congenital Defects Program. Information was gathered also from a randomly selected group of parents of babies without birth defects from the same area identified through birth certificates. Mothers were questioned about a variety of maternal exposures, including multivitamin use, through a telephone interview (2,3). A total of 519 babies with NTDs and 4043 controls without birth defects were identified. The mothers of 347 NTD babies and 2829 matched controls completed interviews, for an overall 70% participation rate. Participation was higher for white mothers (74%) than for mothers of other races (57%). To assess possible maternal recall bias, a second control group, comprising ABDCC mothers whose babies had serious birth defects other than NTDs (n=3665), was used. In addition to the group of mothers defined as periconceptional multivitamin users, mothers who used multivitamins were classified into two additional groups: 1) early postconceptional multivitamin users (use during each of the first 3 months of pregnancy only) and 2) late postconceptional multivitamin users (use during the second and/or third months of pregnancy only). Mothers who said they used vitamins less than 3 times a week and mothers who reported no periconceptional vitamin use were considered nonusers of multivitamins. Fourteen percent of mothers reported periconceptional multivitamin use, 11% reported early postconceptional multivitamin use, 28% reported late postconceptional multivitamin use, 40% reported nonuse, 5% reported other vitamin use, and 2% were unknown. For mothers who were periconceptional multivitamin users, the risk of having babies with NTDs was lower than that for mothers who did not use multivitamins (odds ratio = 0.41, 95% CI = 0.26, 0.66) (Table 1). For mothers who were early or late postconceptional multivitamin users, the odds ratios were 0.75 and 0.86, respectively (Table 1). For anencephaly and spina bifida separately, odds ratios were less than 1.0, except for mothers of other races whose babies had anencephaly. These odds ratios for early and late postconceptional multivitamin use relative to no multivitamin use were 1.80 and 1.28, respectively. Neither of these associations was statistically significant. When periconceptional multivitamin use among mothers of babies with NTDs was compared with use among mothers of babies with all other types of major malformations, odds ratios were similar to those obtained using controls without birth defects. Reported by: Birth Defects and Genetic Diseases Br, Div of Birth Defects and Developmental Disabilities, Center for Environmental Health and Injury Control, CDC.

Editorial Note

Editorial Note: Severe congenital malformations occur in 2%-4% of all infants born in the United States. The cause of most of these defects is unknown. NTDs are among the more common severe congenital malformations. Approximately 3500 infants with anencephaly or spina bifida (1 case per 1000 live births) are born each year in the United States. The etiologies of NTDs are usually unknown. Women who previously have had NTD-affected infants are at increased risk of having similarly affected infants in subsequent pregnancies. Periconceptional multivitamin use by these women had been reported to reduce this risk (4), but no studies similar to that reported here had been done among women who have not previously had an NTD-affected infant. The CDC study is the first population-based investigation of the relationship between multivitamin use and birth defects in the United States. The findings suggest that women who have never had an NTD-affected child and who use periconceptional multivitamins are less likely to have an infant with an NTD. Methodologic concerns about case-control studies, such as the representativeness of a sample, call into question the strength of the conclusions about a multivitamin effect. In this study, periconceptional multivitamin users differed from nonusers in a number of demographic, health-related, and lifestyle characteristics. These include maternal age, education, alcohol use, and history of stillbirths or fetal deaths before the index birth, use of spermicides before the index birth, smoking any time during the periconceptional period, and a maternal history of chronic illness. Adjusting the data for these factors did not change results. However, it is not known whether the apparent protective effect of multivitamins for NTDs results directly from multivitamin use or from other characteristics of women who use multivitamins. Randomized clinical trials offer an opportunity to minimize the inherent weaknesses, such as selection and recall bias, of case-control studies. Such clinical trials among mothers of NTD-affected children in the United Kingdom and Egypt are being conducted to assess the effect of multivitamin use on the recurrence of NTDs. Recent laboratory data have increased interest in the mechanisms of folate metabolism and its possible relationship to NTDs. Studies have been done measuring red cell folate in women who had a history of two or more NTD pregnancies. Compared to a control group, mothers with an NTD-affected pregnancy had lower red cell folate levels. These studies suggest that maternal metabolic factors are involved in the etiology of NTDs (5,6), indicating that the mechanisms relating to these factors should be explored further. Evidence is insufficient to recommend periconceptional multivitamin use in the United States to prevent NTDs. The question of whether multivitamin use affects the risk of NTDs can be answered best by randomized clinical trials of proper design and size and through clinical and biochemical studies.


  1. Mulinare J, Cordero JF, Erickson JD, Berry RJ. Periconceptional use of multivitamins and the occurrence of neural tube defects. JAMA 1988;260:3141-5. 2.Erickson JD, Mulinare J, McClain PW, et al. Vietnam veterans' risks for fathering babies with birth defects. JAMA 1984;252:903-12. 3.CDC. Vietnam veterans' risks for fathering babies with birth defects. Atlanta: US Department of Health and Human Services, Public Health Service, 1984. 4.Smithells RW, Nevin NC, Seller MJ, et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;1:1027-31. 5.Yates JR, Ferguson-Smith MA, Shenkin A, Guzman-Rodriguez R, White M, Clark BJ. Is disordered folate metabolism the basis for the genetic predisposition to neural tube defects? Clin Genet 1987;31:279-87. 6.Trotz M, Wegner C, Nau H. Valproic acid-induced neural tube defects: reduction by folinic acid in the mouse. Life Sci 1987;41:103-10. *Periconceptional multivitamin use was defined as regular multivitamin or prenatal vitamin use during every month of a 6-month periconceptional period (i.e., 3 months before conception through the first 3 months of pregnancy).

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