Periconceptional Folic Acid and Food Fortification in the Prevention of Neural Tube Defects (SAC Opinion Paper 4)

Scientific Advisory Committee Opinion Paper 4

This paper is available as a pdf:

1. Background

Neural tube defects (NTDs), which comprise open spina bifida, anencephaly and encephalocele, complicate 1.5/1000 pregnancies in the UK,1 and represent the first congenital malformations to be preventable through public health measures. The effect of periconceptional folic acid on reducing the incidence of both occurrence and recurrence of NTDs has been confirmed in quality randomised controlled trials.2,3

The use of supplements requires a conscious effort on the part of women anticipating a pregnancy, as adequate folic acid is needed at the time of embryogenesis. Prophylaxis commenced after pregnancy has been diagnosed is therefore unlikely to prevent these serious handicapping malformations. Despite public health campaigns, only around one third of women take folic acid supplements preconceptionally. Because many women do not plan a pregnancy, in particular those at nutritional risk because of poor dietary habits and/or socio-economic status, the only reasonable approach to maintaining adequate periconceptional levels of folic acid would appear to be through food fortification. In the USA all cereal-based products have been fortified since 1998.

The RCOG via its Scientific Advisory Committee in 1997 has previously advocated mandatory food fortification in the UK, such as through bread flour. This opinion was supported by the Report of the Committee on Medical Aspects of Food and Nutrition Policy (COMA).4 Since that publication the source of advice to the Department of Health has become the Food Standards Agency (FSA), which held a stakeholders meeting in March 2002 at which the RCOG viewpoint was reiterated. In May 2002, the FSA decided against recommending mandatory folic acid fortification.5 This opinion paper reviews the background to this decision, which conflicts with the RCOG's position. Its controversial nature is evident in leading articles published elsewhere.6

2. Evidence that folate supplementation prevents NTDs

2.1 Diet and congenital malformations

Smithells et al first noted the relationship between diet, social class and congenital malformations in the 1970s.7 In demonstrating a social class gradient in levels of red cell folate, leucocyte vitamin C and erythrocyte riboflavin, they noted that congenital CNS malformations including NTDs were more common in women of lower socio-economic status who also had lower first trimester levels of red cell folate and leucocyte vitamin C.

2.2 Prevention of NTD with periconceptional multivitamins

Smithells' suggested that low serum levels of vitamins represented poor diet and that periconceptional multivitamin supplementation might prevent some congenital anomalies including NTDs. Accordingly he undertook a non-randomised non-placebo controlled trial using contemporaneous controls. Women with a pregnancy previously affected with NTD were offered multivitamin supplementation, which included 360µg folic acid; those compliant with the mutivitamin regime had a 75% lower risk of NTD recurrence.8

2.3 Prevention of NTD with folic acid

The Smithells' trial was controversial, in particular because of the absence of a placebo controlled double blind approach. In response, the Medical Research Council (MRC) undertook a placebo controlled study using a factorial design with four arms, multivitamins with folic acid (4mg/day), multivitamins alone, folic acid alone (4mg/day), and placebo. The aim was to test in women with a previous NTD pregnancy whether there was a genuine preventative effect, and if so, whether folic acid alone was the active ingredient or whether multivitamins were having the positive effect. In 1991, this study showed that NTDs could be reduced by about 75%, and that this was due to folic acid supplements not multivitamins without folic acid.9

In 1992, Czeizel et al published the results of a randomised trial of multivitamins (including 800g/day folic acid), in women discontinuing contraception to become pregnant.3 The 2104 women taking the multivitamins with folic acid had a lower rate of congenital malformations overall and no NTDs, compared to 6 NTDs in the 2052 placebo treated women, the expected occurrence rate.

A Department of Health (DH) Expert Advisory Group then recommended that women with a history of NTD take 4mg (usually prescribed as 5mg tablets) of folic acid preconceptionally and for the first eight weeks of pregnancy.10 To prevent the first occurrence of NTD, they recommended a folic acid supplement of 400µg per day for all women planning a pregnancy.

3. Public health measures

3.1 UK Health Education Initiative
The DH contracted the then Health Education Authority (HEA) to publicise their 1992 advice that all women who were planning a pregnancy, or might become pregnant, should consume more folate rich foods and take a daily supplement of 400µg of folic acid continued for up to 12 weeks after conception.11 The prescription was at first available only through GPs, but then became cheaper to purchase through retail outlets including pharmacies and supermarkets. The basis of this recommendation was that natural sources of folate were not meeting DH recommended intakes for pregnancy. The work of Doyle and others in London for instance showed that among women with inadequate diet who gave birth to low birthweight babies, the daily folate intake was 162µg per day compared to 331µg per day in those judged to have an adequate diet.12 This compares with a reference nutrient intake (RNI) from COMA of 300µg per day for adults in the UK with a 400µg supplement before and during early pregnancy. It became obvious that women most at risk of NTD were unlikely to obtain adequate amounts of natural folate from food and they should be encouraged to take a periconceptional folic acid supplement. As a result of the HEA campaign (1995-98) and other publicity, this recommendation was taken up to a considerable extent by women planning a pregnancy. However, numerous surveys showed that although most women have heard of the need for periconceptional folic acid, and took it at some stage during early pregnancy, only a minority commence supplementation preconceptionally. For instance, a survey published in 2002, found that only 43% of women in Northampton consumed folate supplements before a planned conception. Those who failed to comply were particularly women under the age of 21, women who smoked and women from lower income groups. Unsupplemented women had on average an intake of 237µg of folate per day with 25% being below the RNI for pregnancy.13 This supports the view that groups at high risk for NTD are unlikely to benefit from public health advice to take periconceptional folic acid supplements.

3.2 Relationship of folic acid status to NTD risk
Scott's group in Dublin analysed antenatal booking samples to report a dose response relationship between maternal red cell (and plasma) folate and NTD risk which occurred in 6.6/1000 women with values below 150µg/l, falling to 0.8/1000 with booking red cell folate levels 400µg/l.14 In a population with an overall NTD risk of 1.9/1000 births, they suggested that an intervention which raised the periconceptional red cell folate level of all pregnant women above 400µg/l would be responsible for a reduction of about 50-60% in NTD risk. Subsequently, they compared five regimes in a randomised study:

  • folic acid 400µg/day
  • folic acid fortified foods contributing an extra 400µg/day
  • foods containing natural folates equivalent to an additional 400µg/day
  • dietary advice to improve natural folate intake and
  • controls.

Increases in red cell folate associated with each intervention respectively were 141, 173, 28, 53 and 9µg/l. These results suggested that only folic acid supplementation or food fortification was likely to be effective in achieving therapeutically beneficial levels of red cell folate.15

Next, they investigated the level of fortification needed to achieve a red cell folate concentration 400µg/l. Supplementation with 100µg, 200µg, or 400µg daily resulted in median post treatment concentrations of 375µg/l, 475µg/l and 571µg/l respectively, compared to no increase in red cell folate in the placebo group. They concluded that a fortification programme delivering 400µg folic acid daily would protect against NTDs, but at the expense of unnecessarily high exposure for many people. Delivery of 200µg daily would still be effective against NTD (estimated reduction 41% compared to 47% on 400µg/day) but safer for the general population. Based on projections from the positive folate balance in the group that received 100µg daily, this dose if taken continually as in fortified foods would also produce an important decrease in NTDs.16 For reference, the COMA report recommended universal folic acid fortification of flour at 240µg/100g, which they estimated would lead to an average total folate intake of 405µg/day and increase average folic acid levels of women aged 16-45 years by 201µg/day.4

Wald et al undertook a meta analysis 13 studies of folic acid supplementation to find a linear increase in serum (not red cell) folate concentrations of 0.94µg/ml for every 100µg/day increase in daily folic acid intake.17 They suggested that the COMA recommendation of 240µg/day would only reduce NTDs by about 20%, compared to a reduction of 85% if women took a 5mg supplement. Notwithstanding this, there have been no randomised studies of high dose folic acid in the prevention of NTD occurrence.

4. Biological plausibility of folic acid prevention of NTD

Interpretation of studies of micronutrient effects on early pregnancy outcomes requires clear separation of the concepts of replenishment in the face of nutritional deficiency (poor diet, malabsorption etc.) from the pharmacological effects of supraphysiological levels of a particular nutrient in certain circumstances e.g. a congenital enzyme deficiency requiring an increase in substrate to overcome adverse effects of the defect.

There is increasing recognition of the importance of the 677 cytosine→thymine (677 C→T) mutation of the 5, 10-methylene-tetrahydrofolate reductase gene (MTHFR). This results in circa 50% decreased activity and increased thermolability of the enzyme with about a 25% increase in homocysteine concentrations, even when folate intakes are adequate. This mutation is common, and has been implicated in the aetiology of NTDs. Whitehead et al first showed that the homozygous mutation (677C→T) was found more frequently in individuals with NTDs compared to controls (odds ratio 3.47, CI 1.28-9.41).18 Another study detected the homozygous mutation (677C→T) in 5% of a control population compared to 16% of mothers of NTD pregnancies, 10% of fathers of NTD pregnancies and 13% of children with NTDs.19 Although this enzyme defect, which can be overcome by folic acid supplementation leading to reduced plasma homocysteine levels, is involved in the aetiology of preventable NTD, it is found in only a small minority of affected individuals. A recent review confirmed the likely role of MTHFR, but was unable to find evidence of similar effects for polymorphisms of methionine synthase or cystathionine Β synthase.20 Given the relatively low prevalence in affected pregnancies, screening for 677C→T is only likely to have a marginal effect on NTD reduction.

Experimental studies have suggested number of potential mechanisms for folate-induced reduction in NTDs.20 Hyperhomocysteinaemia, either of dietary or metabolic origin (i.e. MTHFR homozygosity), could exert a teratogenic effect through its ability to act as an N-methyl-D-aspartate receptor (NMDA) blocker in early embryonic neural ectoderm,20 although increasing homocysteine levels in rodents does not cause NTDs.21 Alternatively folate deficiency could have a direct effect on neural epithelium, which unlike most embryonic cells, express very high levels of folate receptor message22. However, neither folate deficiency in murine pregnancy nor rat embryo culture under folate deficient conditions induces NTDs.23,24 Notwithstanding this, folic acid is effective in preventing NTDs in a range of mouse models (Cart 1 knockout, splotch mutant, the crooked tail mouse, and the Cited2 knockout).25-28 There is evidence for a defect of folate metabolism in only one of these (splotch), suggesting that folic acid may be preventive in the mouse models not by correcting a folate deficiency but by exerting a pharmacological effect, perhaps on cell proliferation or cell death. With all these actual and potential mechanisms, there is clear experimental support for one or more defects causing NTDs, which are remediable by folic acid fortification or supplementation.

4.1 Amniotic fluid homocysteine levels in NTD
Amniotic fluid homocysteine concentration in one study was not significantly elevated in NTD pregnancies with an abnormal fetal genotype, (either homo- or heterozygous 677C→T mutation), although there was a non-significant trend. In embryos with a normal genotype, 32% had raised amniotic fluid homocysteine compared to 10% in controls.29 These observations are compatible with a unifying hypothesis relating increased risk of NTDs to hyperhomocysteinaemia, which may be secondary to MTHFR mutations in some cases and dietary folate deficiency in others. This latter suggestion is compatible with major geographical variation in NTD incidence seen in epidemiological studies until the 1990s.1 Low socio-economic status and poor diet, particularly deficient in fruit and vegetables, is seen in women in the high risk group for NTD in the UK population.12

4.2 Is terathanasia the explanation?
Because fetuses with structural malformations and aneuploidies frequently result in miscarriage, Hook and Czeizel suggested that the reduction in NTD and other congenital defects seen in their study might be explained by a small increase (1.8%) in spontaneous miscarriage in the folic acid/multivitamin supplemented group.30 In other words, folic acid might not prevent formation of NTDs but instead influence how many affected pregnancies produced a potentially viable infant. In this light, untreated women with the homozygous form of cystathionine B synthetase deficiency, an inborn error of metabolism resulting in markedly elevated homocysteine and mental retardation, have a fetal loss rate of around 50%.

If terathanasia were the mechanism, it might be unacceptable to some members the general population. However, there was no evidence for terathanasia in the UK MRC study2, and analysis of the large Chinese study addressing this question found no excess of miscarriage amongst women taking folic acid before and during the first trimester compared to controls (9.0% versus 9.3%).31 Further the association between low folic acid levels and an increased risk of spontaneous abortion appears confined to chromosomally abnormal pregnancies.32 Notwithstanding this, there are no studies of sub-clinical miscarriage in relation to folate supplementation. Finally, animal studies showing that folic acid corrects neurulation in genetically predisposed embryos, suggests that it acts by true primary prevention.

5. Food fortification benefits, risks and optimal dosage

Fortification of wheat flour has been accepted and put into practice in a number of countries, including the USA, Canada and Chile. Following statutory fortification of all enriched cereal grain products since January 1998 in the USA, red cell folate levels rose from an average of 181ng/ml to 315ng/ml. The birth prevalence of NTDs fell 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).33 In Canada, folic acid fortification was associated with a more dramatic 48% decline in the early mid-trimester prevalence of NTDs, from 113 to 58 per 100 000 pregnancies (PR 0.52; 95% CI 0.40-0.67).34

Increasing evidence implicates hyperhomocystinaemia in adult cardiovascular disease. Interestingly the fall in US adults with raised plasma homocysteine levels from 18.7 mmol/l to 9.8 mmol/l35 was associated with 25 000 fewer deaths from strokes and ischaemic heart disease following fortification, a decrease of 3.4%.6 Meta-analysis of prospective studies of individuals with no history of cardiovascular disease suggests that a 25% reduction in plasma homocysteine levels would result in a 11% lower risk of ischaemic heart disease and a 19% lower risk of stroke.36 Although not the primary rationale, a reduction in cardiovascular disease may prove a widespread population benefit of food fortification to prevent NTDs.

The Scientific Advisory Committee maintains its support for COMA's recommendation that bread flour in the UK be fortified at the rate of 240µg/100g of food consumed. Objections to food fortification can be addressed under four headings as follows:

5.1 Freedom of choice
The first objection pursued vigorously by the Consumer's Association in lobbying the FSA was that the universal fortification removes freedom of choice and instead they favoured voluntary fortification with appropriate labelling, already widespread for example in breakfast cereals. The difficulty with the choice approach is that those most likely to benefit from fortified foods would be least likely to exercise such choice Food in the UK is already fortified under government regulation, for instance calcium, iron, thiamine and niacin is compulsorily added to all but wholemeal wheat flour, and vitamins A and D to margarine.4 Freedom of choice could be catered for by providing some appropriately-labelled types of bread without folic acid, but these should be at the premium end of the market.

5.2 Risk of masked B12 deficiency in the elderly
The second objection to fortification is the risk of masking Vitamin B12 deficiency in the elderly, leading to irreversible neurological damage in the form of sub-acute combined degeneration of the cord. The COMA panel were of the view that this was only likely to happen with folate intakes >1mg/day, which at the level of fortification proposed, would be reached in <2% of the UK population over 50 years.4 There is no evidence of harm at the levels recommended by COMA, and if there were, suitable approaches to this problem might be to introduce B12 fortification as well as folic acid fortification, or to screen elderly populations for B12 status. It is important to note that folate deficiency is also widespread in the elderly, and that correcting hyperhomocysteinaemia through folic acid fortification might reduce considerably deaths from coronary heart disease and stroke.36

5.3 Inappropriate mass medication
The third objection to food fortification is that millions of members of the public would be taking compulsory treatment from which only a few might benefit. Although high risk groups for NTD might be identified by screening for folate cycle polymorphism carriers who are hyperhomocysteinaemic, unfortunately such screening and targeted supplementation will only have a small impact on NTD prevalence. Although there is a genetic influence, environmental factors are also important, particularly in the West of the British Isles. It has also been argued that mass fortification would have less effect in the UK than other countries, since the vast majority of pregnancies affected by spina bifida are now detected antenatally and undergo termination. Indeed, based on 1998 figures, fortification at the level suggested in the COMA report would have prevented the birth of only 74 babies with NTDs.4 Such argument underplays the considerable parental emotional and physical sequelae of termination for fetal abnormality.

6. Folic acid supplementation and twinning

A fourth objection to folic acid fortification is that there may be a relationship between folic acid intake and twinning. The MTHFR 677C→T mutation is heterogenously distributed in different geographical populations, being least common where dichorionic twinning is most common (i.e. almost 0% in Africa), of intermediate frequency in European populations and with frequencies of up to 20% in Far Eastern populations where twinning rates are as low as 6/1000 deliveries. A German study found the MTHFR T allele more frequently in mothers of singletons compared to twins (odds ratio 2.28, CI 1.18-4.66).37 It is thus theoretically possible that hyperhomocysteinaemia associated with the MTHFR 677C→T mutation reduces twin births and that folic acid supplementation might lead to an increase in twinning. In support of this, Lumley et al suggested that the three randomised studies,2,38 although individually not significant, were nevertheless each compatible with a 40% increase in surviving twin pregnancies or an additional 5.7 twin gestations per 1000 confinements.39 Ericson et al used the Swedish Medical Births Registry to report an odds ratio, after controlling for infertility, of 1.45 (CI 1.06-1.98) for dizygotic twinning in women who used early pregnancy folic acid supplements.40 They speculated that if 30% of the population took folic acid supplements, this would result in 45 fewer infants with NTDs per 100 000 women but an extra 225 twin births. Both papers concluded that the resultant increase in perinatal mortality and morbidity secondary to increased twinning as a result of widespread folic acid fortification might outweigh any benefit from reduced NTD incidence. However not all studies showed a trend to increased twining,41 and in particular a large scale cohort study from China involving almost a quarter of a million women found if anything a lower incidence of twins in folate supplemented conceptions compared to controls (ratio 0 91; 95% CI 0 82-1 00).42 Furthermore, a recent large study in Australian and Dutch women, as yet published only in abstract form, found no excess of allele sharing amongst dizygotic twins that would be expected if MTHFR variants contributed to variation in dizygotic twinning.43

In conclusion, there is no consistent effect of periconceptional folic acid supplementation or fortification on twinning in the available studies. The evidence suggesting twinning is not strong; even in Lumley et al's meta-analysis, the pooled relative risk was not significant (1.40, CI 0.93-2.11)39 while Ericson et al's study was based on recall with fewer than 1% of the population reporting preconceptional folic acid use.40 Better prospective information may become available from countries, which have already introduced food fortification, although it may prove difficult to exclude the effect of increasing use of assisted reproduction techniques in national datasets from the USA for instance. Until such time, there is no evidence of harm from folic acid fortification, and the evidence of likely benefit is strong.

7. Conclusions

Good quality scientific studies have shown that a major handicapping congenital malformation can be prevented in high-risk groups either by supplementation or fortification with folic acid. Health Education strategies have failed to ensure that a majority of women take folic acid supplements preconceptionally. In particular, women in the UK who are most at risk and thus most likely to benefit from supplementation are also those least likely to be aware of it or to use it. Food fortification in the USA and Canada has resulted in a sizeable reduction in NTD incidence. There is no evidence of harm from this strategy, and considerable evidence of benefit. On this basis, the Committee continues to recommend to the FSA and the DH that statutory fortification of bread flour should be introduced at the level suggested in the COMA report.

References

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  40. Ericson A, Kallen B, Aberg A. Use of multivitamins and folic acid in early pregnancy and multiple births in Sweden. Twin Res 2001;4:63-6.
  41. Mathews F, Yudkin P, Neil A. Folates in the periconceptional period: are women getting enough? Br J Obstet Gynaecol 1998;105:954-9.
  42. Li Z, Gindler J, Wang H, Berry RJ, Li S, Correa A et al. Folic acid supplements during early pregnancy and likelihood: a population-based cohort study. Lancet 2003;361:380-4.
  43. Montgomery G, Duffy D, Marley K, Zhao Z, Marsh A, Boomsma D et al. The segregation distortion of MTHFR haplotypes is not increased in DZ twinning. Am J Hum Genet 2002;71:363.

This opinion paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Mr R B Fraser FRCOG, Sheffield; and Professor N M Fisk FRCOG, London.
and peer reviewed by:

Dr A J Copp, Institute of Child Health, London; Professor R J Lilford FRCOG, Birmingham; Professor J M Scott, Department of Biochemistry, Trinity College, Dublin; Professor N J Wald FRCOG, London; Professor D R R Williams, epidemiologist, University of Wales, Swansea; and Dr S Wilson, Department of Primary Care and General Practice, University of Birmingham.

The final version is the responsibility of the Scientific Advisory Committee of the RCOG.

Date published: 01/04/2003

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