1154 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
3 9
Smithells RW, Ankers C, Carver ME, Lennon D,
Schorah CJ, Sheppard S. Maternal nutrition in early preg-
nancy. Br J Nutr 1977;38:497–506.
4
Smithells RW, Sheppard S, Schorah CJ. Vitamin deficien-
cies and neural tube defects. Arch Dis Child 1976;51:
944–50.
5
Hibbard ED, Smithells RW. Folic acid metabolism and
human embryopathy. Lancet 1965;i:1254.
6 central nervous system. II. Maternal reproductive history
Pritchard JA, Scott DE, Whalley PJ, Haling RF, Jr. Infants
of mothers with megaloblastic anemia due to folate defi-
ciency. J Am Med Soc 1970;211:1982–4.
7 Sheppard PM. Spina bifida and anencephaly: miscarriage
Laurence KM, James N, Miller M, Campbell H. Increased
risk of recurrence of pregnancies complicated by fetal
neural tube defects in mothers receiving poor diets, and
possible benefit of dietary counselling. Br Med J 1980;281:
1592–4.
8
Smithells RW, Sheppard S, Schorah CJ et al. Possible pre-
vention of neural tube defects by periconceptional vita-
min supplementation. Lancet 1980;i:339–40.
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2011; all rights reserved.
Commentary: A brief history of folic acid
in the prevention of neural tube defects
Nicholas J Wald FRS
Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of
London, Charterhouse Square, London EC1M 6BQ, UK. E-mail: n.j.wald@qmul.ac.uk
Accepted 23 March 2011
In the 1960s, Richard Smithells and Elizabeth
Hibbard1 noticed that women who had given birth to
children with serious birth defects, notably neural tube
defects, were likely to have an abnormal formimino-
glutamic acid (FIGLU) excretion test indicative of
impaired folate status than women with unaffected
children. These observations encouraged Smithells to
organize a multi-centre intervention study in which
vitamin supplementation around the time of concep-
tion was given to women who had had a previous
pregnancy with a neural tube defect. Participating
women were given a multivitamin consisting of
eight vitamins that included folic acid (0.36 mg/day),
and women who were already pregnant or had
declined to take part in the study served as controls.
The risk of the recurrence of an unaffected pregnancy
in supplemented women was about one-seventh that
Wynn V. Vitamins and oral contraceptive use. Lancet
1975;i:561–4.
10
Gal I, Sharman IM, Pryse-Davies J. Vitamin A in relation
to human congenital malformations. Adv Terator 1972;5:
143–59.
11
Nevin NC. Letter: Recurrence risk of neural tube defects.
Lancet 1980;i:1301–2.
12
Record RG, McKeown T. Congenital malformations of the
and familial incidence. Br J Soc Med 1950;4:26–50.
13
Clarke CA, Hobson D, McKendrick OM, Rogers SC,
Downloaded from https://academic.oup.com/ije/article/40/5/1154/660590 by Ohio Northern University user on 12 April 2023
as possible cause. Br Med J 1975;iv:743–6.
14
James WH. Birth ranks of spontaneous abortions in sib-
ships of children affected by anencephaly or spina bifida.
Br Med J 1978;i:72–3.
15
Seller MJ, Embury S, Polani PE, Adinolfi M. Neural tube
defects in curly-tail mice. II. Effect of maternal adminis-
tration of vitamin A. Proc R Soc Lond[Biol] 1979;206:
95–107.
International Journal of Epidemiology 2011;40:1154–1156
doi:10.1093/ije/dyr131
in the unsupplemented women. In 1980, the results
suggested that folic acid, or another vitamin supple-
ment, might reduce the risk of a recurrence.2
The lower recurrence rate in the supplemented
women was unlikely to have arisen by chance. Two
explanations were possible. One explanation was that
folic acid or one of the other seven vitamins prevented
some cases of neural tube defects. The second explan-
ation was that women who chose to take the
multivitamins represented a more health conscious
group, with a healthier diet, who had a low risk
of having a further affected pregnancy. It was likely
that such selection was operating because women
who took the supplement were, on average, of
higher socio-economic status than those who did
not. Also, more women whose preceding pregnancy
did not end in a spontaneous abortion took the
 PREVENTION OF NEURAL TUBE DEFECTS BY FOLIC ACID
supplements than did women who did not have such
a history, and absence of a spontaneous abortion in
the preceding pregnancy is associated with a lower
risk of having a fetal neural tube defect recurrence.
Despite these sources of potential selection bias, there
could still have been a genuine preventive effect. If
this were so, the magnitude of such an effect would
need to be estimated, and it would need to be deter-
mined whether the responsible component was folic
acid or one of the other vitamins.
The issue could only be resolved by performing a
large trial in which, to avoid bias, women would be
randomly allocated to various groups, including a
control group that did not receive the extra vitamins.
Smithells’ work led to such a trial. With the collabora-
tion of many colleagues I led ‘MRC Vitamin Study’
trial which was launched in July 1983, with the aim
of recruiting women known to be at high risk through
having had a previous affected pregnancy. It was the
intention to obtain information on the outcome of at
least 2000 pregnancies unless a sufficiently clear
result emerged sooner. By April 1991, sufficiently con-
clusive results had emerged to warrant ending the
trial early.3 There was a 72% protective effect of
using folic acid daily in an intention-to-treat analysis
and an 83% protective effect in an on-treatment
analysis. There was no evidence that the other seven
vitamins in the formulation used by Smithells and his
colleagues had any effect.
It was perhaps surprising that a vitamin deficiency
in economically developed countries was an import-
ant cause of a common severe malformation. The
early work of Hibbard and Smithells and the subse-
quent work of Smithells et al.2,4 prompted the re-
search that led to the clear result in the MRC
Vitamin Study, published in 1991. The results were
consistent with those previously published by
Laurence et al.5 and those published in 1992 by
Czeizel et al.6
The MRC Vitamin Study had a difficult inception.
Critics claimed that the trial was unethical even
though there was uncertainty over whether any vita-
mins, let alone folic acid, could prevent neural tube
defects.7 It is to the credit of Sir James Gowans, the
then Secretary of the MRC, that he recognized the
need for the trial and stewarded it through a barrage
of hostile press and political commentary.
The MRC Vitamin Study showed that about 80% of
neural tube defects could be prevented by taking 4 mg
folic acid immediately before pregnancy. Subsequent
work8 showed that this achieved a greater degree of
protection than with 0.4 mg (400 mg) indicating that
all women planning a pregnancy should take a 4 mg
pill daily (or the more readily available 5 mg), not
0.4 mg as currently recommended. This would mean
recommending the same dose for women in general
as for women who have already had a neural tube
defect pregnancy, for whom 4 mg is already the stand-
ard dose.
1155
What remains disappointing is that Britain has
failed to introduce mandatory fortification of flour
with folic acid, as has been done in the USA and
about 60 other countries (http://www.sph.emory.
edu/wheatflour/globalmap). Expert advisory commit-
tees have recommended fortification but the UK
Government has not acted. Indeed no European
Union country has done so. There may be a system-
atic failure in the ability to translate research in
preventive medicine into public health practice.
Downloaded from https://academic.oup.com/ije/article/40/5/1154/660590 by Ohio Northern University user on 12 April 2023
There is a need for a UK or European Public
Health Agency with powers comparable with those
available to the US Public Health Service, to regulate
on such issues. In the 1990s, on the advice of
Godfrey Oakley (Director of the Division of Birth
Defects and Developmental Disabilities at the
Centers for Disease Control and Prevention) and
the support of the wider medical community (espe-
cially the March of Dimes), the Food and Drug
Administration’s regulations resulted in 1998 in the
USA being the first country9 to introduce mandatory
fortification of flour and other grains with folic acid
to help prevent neural tube defects. Smithells,
who died in 2002, was delighted that his lifelong
work led to the opportunity to prevent most cases
of serious birth defects, but he would have been sad-
dened that his own country had done so little in
delivering the benefits of British research to its
own population.
Conflict of interest: None declared.
Funding
None
References
1
Hibbard ED, Smithells RW. Folic acid metabolism and
human embryopathy. Lancet 1965;i:1254.
2
Smithells RW, Shephard S, Schorah CJ et al. Possible pre-
vention of neural-tube defects by periconceptional vita-
min supplementation. Lancet 1980;i:339–40.
3
MRC Vitamin Study Research Group. Prevention of
neural tube defects: results of the Medical Research
Council Vitamin Study. Lancet 1991;338:131–37.
4
Smithells RW, Sheppard S, Schorah C et al. Apparent
prevention of neural tube defects by periconceptional
vitamin supplementation. Arch Dis Child 1981;56:
911–18. Reprinted Int J Epidemiol 2011;40:1146–54.
5
Laurence KM, James N, Miller MH, Tennant GB,
Campbell H. Increased risk of recurrence of pregnancies
complicated by fetal neural tube defects in mothers
receiving poor diets, and possible benefit of dietary coun-
selling. BMJ 1980;281:1592–94.
6
Czeizel AE, Dudas I. Prevention of the first occurrence of
neural-tube defects by periconceptual vitamin supple-
mentation. N Engl J Med 1992;327:1832–35.
1156 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
7 9
Wald NJ, Polani PE. Neural-tube defects and vitamins:
the need for a randomized clinical trial. BJOG 1984;91:
516–23.
8
Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the
effect of folic acid. Lancet 2001;358:2069–73.
Published by Oxford University Press on behalf of the International Epidemiological Association
ß The Author 2011; all rights reserved.
Commentary: From controversy and
procrastination to primary prevention
Chris Schorah
Department of Clinical Sciences, University of Leeds, Leeds, UK
Correspondence to: 30 Gasgoigne Avenue, Barwick in Elmet, Leeds LS15 4LW, UK. E-mail: schorah.mail@virgin.net
Accepted 5 May 2011
Looking back 30 years towards the origins of a con-
troversy, we should perhaps begin with the one in-
controvertible outcome. The findings reported in the
1981 publication by Smithells et al.1 reprinted here
were correct; the ‘apparent’ prevention of neural tube
defects (NTDs) with periconceptional vitamin supple-
ments was to become ‘actual’ prevention.2 But it was
a long days journey into light and the article, which is
the subject of this commentary, was but a halfway
house, even if a significant one.
It had begun as little more than the chasing of a
dream, something that may be well nigh impossible
today with funding much more limited than it was in
the 1960s. Dick Smithells had become interested in
the idea that poor diet, and possibly defective folate
metabolism [There are many different naturally oc-
curring and metabolically interlinked forms of folate.
Folic acid (pteroylmonoglutamate) does not occur in
food, but is the form of folate in the supplements
used in the studies referred to here.], could play a
role in the causation of NTD.3 His vision was to see
if this could lead to a simple cost-effective prevention
strategy. This was not just a flight of fancy: there
were already epidemiological straws in the wind to
support the idea that undernutrition could be in-
volved. The Dutch Hunger Winter of 1944–45 had re-
sulted in an increase in the prevalence of NTD, but
only if exposure to famine had occurred during early
pregnancy, when the malformations arise.4 Socio-
economic disadvantage was also closely linked to
Crandall BF, Corson VL, Evans MI, Goldberg JD,
Knight G, Salafsky IS. American College of Medical
Genetics statement on folic acid: fortification and supple-
mentation. Am J Med Genet 1998;78:381.
International Journal of Epidemiology 2011;40:1156–1158
doi:10.1093/ije/dyr133
Downloaded from https://academic.oup.com/ije/article/40/5/1154/660590 by Ohio Northern University user on 12 April 2023
the condition, but this could implicate other factors
in addition to undernutrition.
When Smithells was appointed to the Chair of
Paediatrics in Leeds, he began an observational study
focussed on assessing nutritional parameters in the
first trimester of pregnancy, close to the time NTD
occurs in the fetus. The biochemical findings of that
study showed that women who had NTD-affected
fetuses had mean concentrations of red cell folic
acid and leucocyte vitamin C significantly lower than
those in the total population.5 Serum vitamin B12
levels were also found to be significantly lower.6
The epidemiological evidence, the findings of the
Leeds pregnancy study and the biological plausibility
of folate deficiency being implicated in poor cell div-
ision, and hence malformations, all pointed to the pos-
sibility that inadequate vitamin supply could be
involved in the aetiology of NTD. This prompted us
to undertake a multivitamin intervention study and,
unintentionally, to begin the controversy.
In the circumstances, a double-blind randomized
placebo study was warranted and the article reprinted
here indicates that this was our original intention.
However, ethics committee’s decisions and their re-
quirements prevented this. With hindsight, we
should have pressed for our intention and avoided
the apologetics that were required to support the find-
ings of the study.1 But we did not and decided to
supplement all women at recurrence risk who came
to us intending to conceive. Our controls were women