Correspondence
Neural-Tube Defects
N Engl J Med 2000; 342:1135-1137April 13, 2000
- Article
To the Editor:
Botto et al. (Nov. 11 issue)1 fail to represent fairly the work of Smithells and associates2 and the subsequent delayed response by public health authorities to the important discovery that folic acid supplementation prevents a substantial percentage of neural-tube defects. Botto et al. claim that because Smithells and colleagues “had not been permitted to randomly assign the use of the multivitamin among participants in their study, their finding did not lead to any public health action” until the results of randomized studies were published a decade later. In fact, Smithells and colleagues had earlier reported the association between low folate levels and neural-tube defects found in the late 1970s,3 and the study cited by Botto et al., published in 1983,2 was the second by that group of authors to demonstrate convincingly that folate supplementation reduced the frequency of neural-tube defects.
Many physicians and scientists argued then that such data were sufficient to justify advocating folic acid supplementation for pregnant women, in view of the large potential benefits and almost immeasurably small risk of such supplementation, but these arguments were repeatedly ignored by public health authorities until well into the 1990s. By that time, numerous studies had confirmed what Smithells and colleagues had long ago proved. Botto et al. estimate that about 300,000 newborns worldwide are affected with neural-tube defects each year. It is a tragedy that for over a decade, scores of thousands of infants every year were born with neural-tube defects that could have been prevented if the international public health authorities had acted instead of advocating delay. This story should not be presented to the medical or general public as a triumph in which “never before has progress been so fast and substantive.”
3 ReferencesJoseph D. Schulman, M.D.
Genetics & IVF Institute, Fairfax, VA 220311
Botto LD ,Moore CA ,Khoury MJ ,Erickson JD . Neural-tube defects. N Engl J Med 1999;341:1509-1519
Full Text | Web of Science | Medline2
Smithells RW ,Nevin NC ,Seller MJ , et al. Further experience of vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;1:1027-1031
CrossRef | Web of Science | Medline3
Smithells RW ,Sheppard S ,Schorah CJ , et al. Possible prevention of neural-tube defects by periconceptional vitamin supplementation. Lancet 1980;16:339-340
CrossRef
To the Editor:
We congratulate Berry and his colleagues for their ambitious and important study of folic acid and neural-tube defects in two regions of China (Nov. 11 issue).1 However, the authors of this report, as well as Botto et al. in their accompanying review article, neglected to note that the specific dose of 400 μg of folic acid was found by our group in 1993 to reduce significantly the risk of neural-tube defects.2
Our case–control study, conducted in the United States and Canada, examined the most common patterns of folic acid intake, including the daily intake of the 400-μg dose contained in multivitamins, among the relevant population — women of childbearing age. Indeed, our findings provided direct evidence in support of the recommendation of the Public Health Service that women take 400 μg of folic acid daily.3 In addition, we found that the group of women who began supplementation after the first missed menstrual period did not have a reduction in risk, whereas the women whose supplementation began before that time did. The study in China had a unique strength in that its design allowed the investigators to examine the effect of folic acid as a single component, unconfounded by the effects of other nutrients.
3 ReferencesMartha M. Werler, Sc.D.
Allen A. Mitchell, M.D.
Boston University School of Public Health, Brookline, MA 024461
Berry RJ ,Li Z ,Erickson JD , et al. Prevention of neural-tube defects with folic acid in China. N Engl J Med 1999;341:1485-1490
Full Text | Web of Science | Medline2
Werler MM ,Shapiro S ,Mitchell AA . Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 1993;269:1257-1261
CrossRef | Web of Science | Medline3
Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Morb Mortal Wkly Rep 1992;41:1-7
Medline
To the Editor:
The informative review of neural-tube defects by Botto et al. discusses at some length the association between prenatal vitamin supplementation, especially with folic acid, and a diminished frequency of such congenital malformations in newborns. The authors review the potential biochemical mechanisms that could explain this observation, which they imply are attributable solely to a direct antiteratogenic effect of supplementation. They do not mention, however, other associations that might be pertinent, at least in part, to the reduction in the number of birth defects. In a Hungarian study of the incidence of birth defects, including neural-tube defects,1 a study by the British Medical Research Council on supplementation and the recurrence of neural-tube defects,2 and a prospective study from the California Department of Health Services,3 there was about a 15 percent increase in the frequency of recognized spontaneous abortion above the expected rate.1,2 The mechanisms responsible for this increase are unknown. If the increase was not attributable to an unlikely chance, it may have resulted in part from the postponement of what would otherwise have been an unrecognized miscarriage to a time at which pregnancy (and thus loss of the fetus) was recognized.4 Or it may have been caused by some direct abortifacient effect. If the latter were responsible, then “terathanasia” (i.e., selective death of embryos with birth defects) may account, at least in part, for the reduction in the number of birth defects among infants born to women who took folic acid supplements.4
4 ReferencesErnest B. Hook, M.D.
University of California, Berkeley, CA 94720-73601
Czeizel AE ,Dudas I ,Metneki J . Pregnancy outcomes in a randomised controlled trial of periconceptional multivitamin supplementation: final report. Arch Gynecol Obstet 1994;255:131-139
CrossRef | Web of Science | Medline2
Hook EB . Terathanasia, folic acid, and birth defects. Lancet 1997;350:1323-1324
CrossRef | Web of Science | Medline3
Windham GC ,Shaw GM ,Todoroff K ,Swan SH . Miscarriage and use of multi-vitamins or folic acid. Am J Med Genet 2000;90:261-262
CrossRef | Web of Science | Medline4
Hook EB ,Czeizel AE . Can terathanasia explain the protective effect of folic-acid supplementation on birth defects? Lancet 1997;350:513-515
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Schulman suggests that the public health response to the work of Smithells and associates should not have awaited the results of randomized trials, which took an additional 10 years. The debate — whether or not to wait for randomized trials — is not new and arose in nearly identical terms in response to the publication of the studies by Smithells and his colleagues, with vocal proponents and opponents.1,2 Medical and public health decisions should be based on the best evidence, and randomized trials can provide such evidence. However, if the scientific community decides that randomized trials are critically important, then the community should carefully evaluate and support them. One should not forget that the review board twice denied Smithells and his associates permission to conduct their studies as randomized trials. Although we cannot be certain, a major public health intervention — fortification of flour — probably would not have occurred in the United States without the findings of the randomized trials.
Dr. Schulman also suggests that, unlike the members of the public health community, medical professionals did not need the results of randomized trials to be convinced about the effectiveness of folic acid and that during the 1980s and 1990s some medical professionals did recommend that their patients take folic acid when planning a pregnancy. However, according to a survey conducted in the United States in 1998, only 13 percent of women interviewed said that their doctors had told them about the benefits of folic acid3 — nearly two decades after the brilliant and groundbreaking studies of Smithells and his associates and six years after the randomized trials were conducted.
Knowledge is indeed crucial, but it is only the beginning. Collaborative efforts undertaken by the medical and public health communities are critical for making primary prevention of neural-tube defects a reality.
3 ReferencesLorenzo D. Botto, M.D.
J. David Erickson, D.D.S., Ph.D.
Joseph Mulinare, M.D., M.S.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 30341-37241
Edwards JH . Vitamin supplementation and neural tube defects. Lancet 1982;1:275-276
CrossRef | Web of Science | Medline2
Chalmers TC ,Sacks H . Vitamin supplements to prevent neural tube defects. Lancet 1982;1:748-748
CrossRef | Web of Science | Medline3
Knowledge and use of folic acid by women of childbearing age -- United States, 1995 and 1998
Medline
Author/Editor Response
Hook asserts that the British trial on the recurrence of neural-tube defects, the Hungarian trial on the incidence of such defects, and the recently published study from California support his hypothesis that folic acid prevents neural-tube defects by inducing miscarriages. Although all three studies show a small increase in the rate of miscarriage among women who took multivitamins or folic acid, it is not clear whether this is real or whether it represents the statistical fluctuations that emerge when a data set is examined in many different ways.1 Some analyses show borderline statistical significance; most do not.1,2 The results of the California study, which show an increased risk of miscarriage among women who consumed four or more alcoholic drinks a week and took multivitamins containing folic acid and a decreased risk among women who smoked 10 or more cigarettes a day and took multivitamins containing folic acid, are interesting but do not answer the questions surrounding this issue.
Although it is clear that folic acid prevents neural-tube defects, the mechanism of this protective effect is unknown; however, the analyses to date offer little support for the hypothesis that folic acid prevents neural-tube defects by inducing miscarriage. In fact, a recent review suggests that folic acid has the opposite effect: women with low levels of folic acid have increased rates of miscarriage (pooled odds ratio, 3.4; 95 percent confidence interval, 1.2 to 9.9).3 The actual effect of folic acid on the risk of miscarriage can be addressed only by prospective studies that are able to compare accurately the incidence of the diagnosis of both pregnancy and miscarriage among women who are using folic acid with the incidence among women who are not. Women of reproductive age should continue to follow the recommendation of the Public Health Service to take 400 μg of folic acid every day.
3 ReferencesRobert J. Berry, M.D., M.P.H.T.M.
Jacqueline Gindler, M.D.
Lorenzo Botto, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 30341-37241
Burn J ,Fisk NM . Terathanasia, folic acid, and birth defects. Lancet 1997;350:1322-1323
CrossRef | Web of Science | Medline2
Wald N ,Hackshaw A . Folic acid and prevention of neural-tube defects. Lancet 1997;350:665-665
CrossRef | Web of Science | Medline3
Ray JG ,Laskin CA . Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review. Placenta 1999;20:519-529
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Benoit Bailey. (2003) Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women?. Birth Defects Research Part A: Clinical and Molecular Teratology 67:2, 133-140
CrossRef2
Jacqueline Gindler, Zhu Li, RJ Berry, Jun-chi Zheng, Adolfo Correa, Xia-mei Sun, Lee-Yang Wong, Ling-chun Cheng, J David Erickson, Yu Wang, Qiao-ling Tong. (2001) Folic acid supplements during pregnancy and risk of miscarriage. The Lancet 358:9284, 796-800
CrossRef
