Prevention of the First Occurrence of Neural-Tube Defects by Periconceptional Vitamin Supplementation
24 Dec 1992-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 327, Iss: 26, pp 1832-1835
TL;DR: A randomized, controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects.
Abstract: Background. The risk of recurrent neural-tube defects is decreased in women who take folic acid or multivitamins containing folic acid during the periconceptional period. The extent to which such supplementation can reduce the first occurrence of defects is not known. Methods. We conducted a randomized, controlled trial of periconceptional multivitamin supplementation to test the efficacy of this treatment in reducing the incidence of a first occurrence of neural-tube defects. Women planning a pregnancy (in most cases their first) were randomly assigned to receive a single tablet of a vitamin supplement (containing 12 vitamins, including 0.8 mg of folic acid; 4 minerals; and 3 trace elements) or a trace-element supplement (containing copper, manganese, zinc, and a very low dose of vitamin C) daily for at least one month before conception and until the date of the second missed menstrual period or later. Results. Pregnancy was confirmed in 4753 women. The outcome of the pregnancy (whether the fetu...
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TL;DR: Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
Abstract: Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
3,646 citations
TL;DR: The data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity by the 677(C-->T) mutation, and can be an additional genetic risk factor for N TDs.
Abstract: Summary Recently, we showed that homozygosity for the common 677(C→T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A→C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an Mbo II recognition site and has an allele frequency of .33. This 1298(A→C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P P P n = 86) of the NTD patients compared with 20% ( n = 403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9–4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C→T) mutation, and can be an additional genetic risk factor for NTDs.
1,598 citations
TL;DR: Evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 μg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy, and identified 102 and 173 women with neural-tube defects.
Abstract: Background Periconceptional use of multivitamins containing folic acid can reduce a woman's risk of having a baby with a neural-tube defect. Methods As part of a public health campaign conducted from 1993 to 1995 in an area of China with high rates of neural-tube defects (the northern region) and one with low rates (the southern region), we evaluated the outcomes of pregnancy in women who were asked to take a pill containing 400 μg of folic acid alone daily from the time of their premarital examination until the end of their first trimester of pregnancy. Results Among the fetuses or infants of 130,142 women who took folic acid at any time before or during pregnancy and 117,689 women who had not taken folic acid, we identified 102 and 173, respectively, with neural-tube defects. Among the fetuses or infants of women who registered before their last menstrual period and who did not take any folic acid, the rates of neural-tube defects were 4.8 per 1000 pregnancies of at least 20 weeks' gestation in the nort...
1,254 citations
TL;DR: The risk for spina bifida associated with C677T homozygosity may depend on nutritional status or on the genotype of other folate-related genes (e.g., cystathionine-beta-synthase and methionine synthase reductase).
Abstract: The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. C677T homozygosity in infants is associated with a moderately increased risk for spina bifida (pooled odds ratio = 1.8; 95% confidence interval: 1.4, 2.2). Maternal C677T homozygosity also appears to be a moderate risk factor (pooled odds ratio = 2.0; 95% confidence interval: 1.5, 2.8). The A 1298C allele combined with the C677T allele also could be associated with an increased risk for spina bifida. Some data suggest that the risk for spina bifida associated with C677T homozygosity may depend on nutritional status (e.g., blood folate levels, intake of vitamins) or on the genotype of other folate-related genes (e.g., cystathionine-beta-synthase and methionine synthase reductase). Studies of the C677T allele in relation to oral clefts, Down syndrome, and fetal anticonvulsant syndrome either have yielded conflicting results or have not been yet replicated.
1,042 citations
Cites background from "Prevention of the First Occurrence ..."
...Folic acid, if taken daily in a sufficient amount during pregnancy, can reduce the occurrence of neural tube defects by as much as 50-85 percent (81-83)....
[...]
TL;DR: A 19% reduction in NTD birth prevalence occurred following folic acid fortification of the US food supply, however, factors other than fortification may have contributed to this decline.
Abstract: ContextDaily consumption of 400 µg of folic acid before conception and
during early pregnancy dramatically reduces the occurrence of neural tube
defects (NTDs). Before food fortification, however, only an estimated 29%
of US reproductive-aged women were taking a supplement containing 400 µg
of folic acid daily. The US Food and Drug Administration authorized addition
of folic acid to enriched grain products in March 1996, with compliance mandatory
by January 1998.ObjectiveTo evaluate the impact of food fortification with folic acid on NTD
birth prevalence.Design, Setting, and PopulationNational study of birth certificate data for live births to women in
45 US states and Washington, DC, between January 1990 and December 1999.Main Outcome MeasureBirth certificate reports of spina bifida and anencephaly before fortification
(October 1995 through December 1996) compared with after mandatory fortification
(October 1998 through December 1999).ResultsThe birth prevalence of NTDs reported on birth certificates decreased
from 37.8 per 100 000 live births before fortification to 30.5 per 100 000
live births conceived after mandatory folic acid fortification, representing
a 19% decline (prevalence ratio [PR], 0.81; 95% confidence interval [CI],
0.75-0.87). During the same period, NTD birth prevalence declined from 53.4
per 100 000 to 46.5 per 100 000 (PR, 0.87; 95% CI, 0.64-1.18) for
women who received only third-trimester or no prenatal care.ConclusionsA 19% reduction in NTD birth prevalence occurred following folic acid
fortification of the US food supply. However, factors other than fortification
may have contributed to this decline.
1,021 citations
References
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TL;DR: It is concluded that folic acid supplementation might be a cheap, safe, and effective method of primary prevention of neural-tube defects but that this must be confirmed in a large, multicentre trial.
Abstract: A randomized controlled double-blind trial was undertaken in south Wales to prevent the recurrence of neural-tube defects in women who had had one child with a neural-tube defect. Sixty women were allocated before conception to take 4 mg of folic acid a day before and during early pregnancy and 44 complied with these instructions. Fifty-one women were allocated to placebo treatment. There were no recurrences among the compliant mothers but two among the non-compliers and four among the women in the placebo group. Thus there were no recurrences among those who received supplementation and six among those who did not; this difference is significant (p = 0.04). It is concluded that folic acid supplementation might be a cheap, safe, and effective method of primary prevention of neural-tube defects but that this must be confirmed in a large, multicentre trial.
612 citations
TL;DR: Women who had previously given birth to one or more infants with a neural-tube defect were recruited into a trial of periconceptional multivitamin supplementation and found no difference in the number of infants/fetuses with an NTD.
560 citations
TL;DR: The hypothesis that the dietary intake of folate in early pregnancy protects against the occurrence of isolated neural‐tube defects in infants is supported, and trends were seen when total folate intake was the exposure variable.
Abstract: A population-based case-control study was conducted to test the hypothesis that the risk of the occurrence of neural-tube defects in infants with no other birth defects (isolated neural-tube defects) is associated inversely with the maternal dietary intake of free and/or total folate in early pregnancy. Information was collected from the mothers of 77 case subjects with isolated neural-tube defects who were born in Western Australia from 1982 to 1984, from the mothers of 77 control subjects with birth defects other than neural-tube defects (control group 1) and from the mothers of 154 control subjects with no birth defects (control group 2). The case and control subjects were matched individually by the date of the mother's last menstrual period. Odds ratios were adjusted for a number of potentially-confounding variables, such as the country of birth of the parents, paternal social class, previous pregnancy outcome, interval between index and previous pregnancy and pregnancy order. Crude and adjusted odds ratios showed a protective effect of an increasing intake of free folate in the first six weeks of pregnancy. Adjusted odds ratios, with reference to the lowest quartile of intake, (and their 95% confidence intervals) were 0.72 (0.25-2.08), 0.37 (0.11-1.23) and 0.31 (0.10-0.97) for quartiles 2-4 when control group 1 was used, and 0.44 (0.17-1.13), 0.34 (0.13-0.90) and 0.16 (0.06-0.49) when control group 2 was used. Similar, but weaker, trends were seen when total folate intake was the exposure variable. These findings support the hypothesis that the dietary intake of folate in early pregnancy protects against the occurrence of isolated neural-tube defects in infants. Measures of postpartum dietary folate and of postpartum serum and red-cell folate levels showed no association with the occurrence of neural-tube defects in infants.
329 citations
TL;DR: It is concluded that the periconceptional use of multivitamins or folate-containing supplements by American women does not decrease the risk of having an infant with a neural-tube defect.
Abstract: Whether taking multivitamins or folate around the time of conception can reduce a woman's risk of having a child with a neural-tube defect is controversial. To investigate this question, we examined the periconceptional use of vitamin supplements by women who had a conceptus with a neural-tube defect (n = 571), women who had had a stillbirth or a conceptus with another malformation (n = 546), and women who had had a normal conceptus (n = 573). Women with conceptuses with neural-tube defects were identified either prenatally or postnatally and were matched to control mothers for gestational age. To minimize recall bias, we interviewed nearly all the women within five months of the diagnosis of a birth defect or the birth of the infant (mean, 84 days); information on vitamin use was obtained by an interviewer who was unaware of the outcome of pregnancy. The rate of periconceptional multivitamin use among the mothers of infants with neural-tube defects (15.8 percent) was not significantly different from the rate among mothers in either the abnormal or the normal control group (14.1 percent and 15.9 percent, respectively). After adjustment for potential confounding factors, the odds ratio for having an infant with a neural-tube defect among women classified as having had full supplementation with multivitamins was 0.95 as compared with the mothers of the abnormal infants (95 percent confidence interval, 0.78 to 1.14) and 1.00 as compared with the mothers of normal infants (95 percent confidence interval, 0.83 to 1.20). There were no differences among the groups in the use of folate supplements. The adjusted odds ratio for having an infant with a neural-tube defect among those receiving the recommended daily allowance of folate was 0.97 as compared with the mothers of abnormal infants (95 percent confidence interval, 0.79 to 1.18) and 0.98 as compared with the mothers of normal infants (95 percent confidence interval, 0.80 to 1.20). We conclude that the periconceptional use of multivitamins or folate-containing supplements by American women does not decrease the risk of having an infant with a neural-tube defect.
224 citations
TL;DR: The results suggest that folic acid supplementation might be an effective method of primary prevention of neural tube defects.
Abstract: Folic acid (5 mg) was given daily, for not less than one menstrual period before conception and until the tenth week of pregnancy, to 81 women (FS) with a history of a previous neural tube defect (NTD) birth. There was no NTD recurrence among this group or among the offspring of a further 20 women (PS) whose folic acid supplementation fell short of the full regime. In another 114 women who became pregnant without folic acid supplementation (US), there were four NTD recurrences (3.5 per cent). Our results suggest that folic acid supplementation might be an effective method of primary prevention of neural tube defects.
185 citations