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Objective: In 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in the UK from 1998 as it had been in the USA., Design: Estimates of NTD prevalence, the preventive effect of folic acid and the proportion of women taking folic acid supplements before pregnancy were used to predict the number of NTD pregnancies that would have been prevented if folic acid fortification had been implemented., Setting: Eight congenital anomaly registers in England and Wales., Main Outcome Measures: The prevalence of pregnancies with an NTD in the UK and the number of these pregnancies that would have been prevented if folic acid fortification had been implemented., Results: From 1991 to 2012, the prevalence of NTD pregnancies was 1.28 (95% CI 1.24 to 1.31) per 1000 total births (19% live births, 81% terminations and 0.5% stillbirths and fetal deaths ≥20 weeks' gestation). If the USA levels of folic acid fortification from 1998 onwards had been adopted in the UK, an estimated 2014 fewer NTD pregnancies would have occurred., Conclusions: Failure to implement folic acid fortification in the UK has caused, and continues to cause, avoidable terminations of pregnancy, stillbirths, neonatal deaths and permanent serious disability in surviving children., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Folic acid is known to prevent neural-tube defects (NTDs) but the size of the effect for a given dose is unclear. We aimed to quantify such an effect., Methods: We used published data from 13 studies of folic acid supplementation on serum folate concentrations and results from a large cohort study of the risk of NTDs according to serum folate, to measure the preventive effect of specified increases in intake of folic acid., Findings: Serum folate concentrations increase by 0.94 ng/mL (95% CI 0.77-1.10) for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, and about double that in people aged 40-65. Every doubling of serum folate concentration roughly halves the risk of an NTD. These two effects can be combined to predict the reduction in risk according to intake of extra folic acid and background serum folate concentration. Such results predict that the preventive effect is greater in women with low serum folate than in those with higher concentrations. The results have also been used to predict direct observations from large randomised trials and the effect of food fortification. From a typical western background serum folate of 5 ng/mL, about 0.2 mg/day (the US level of folic acid fortification) would be expected to reduce NTDs by about 20%; a similar effect can be expected from the current British recommendation (0.24 mg/day). An increase of 0.4 mg/day would reduce risk by about 36%, of 1 mg/day by 57%, and taking a 5-mg tablet daily would reduce risk by about 85%., Interpretation: Folic acid fortification levels should be increased. Additionally women planning a pregnancy should take 5 mg folic acid tablets daily, instead of the 0.4 mg dose presently recommended.

Background: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear., Methods: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued., Results: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical., Conclusions: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

Objective: To determine the relation between blood folic acid and serum vitamin B12 in neural tube defect pregnancies using data from the MRC Vitamin Study and a literature review of all studies., Design: Stored blood samples collected as part of a randomised trial of vitamin supplementation in the prevention of neural tube defects were retrieved from affected pregnancies (cases) and unaffected pregnancies (controls). Four controls were matched with each case by centre, maternal age and duration of storage of the blood sample. The samples had been collected from women at entry to the trial, immediately before the women became pregnant, and at around 12 weeks of pregnancy. Our results were combined with those already published from other studies to obtain an overall assessment of blood folic acid and vitamin B12 in relation to neural tube defects., Setting: Blood samples were collected as part of the MRC Vitamin Study. The collaborating centres were in the United Kingdom, Hungary, Israel, Australia, Canada and Russia., Participants: Twenty-seven women with neural tube defect pregnancies and 108 matched controls with unaffected pregnancies., Results: Serum and red cell folic acid and serum vitamin B12 levels were lower in the cases than in controls at each of the three occasions when blood samples were collected, but no comparison was significant (P > 0.05). A systematic review of all studies from the literature showed that on average, during the 1st trimester of pregnancy, serum folic acid was 0.6 ng/ml lower in neural tube defect pregnancies (P < 0.01), red cell folic acid was 77 ng/ml lower (P < 0.001) and serum vitamin B12 was 38 ng/l lower (P < 0.001). A logistic regression showed no association between serum B12 and neural tube defects after allowing for serum folic acid., Conclusion: our results are consistent with other evidence that folic acid and vitamin B12 levels are lower in women with neural tube defect pregnancies and consistent with evidence from randomised trials which showed that folic acid is protective.

Fortification of flour with folic acid is simple, economical and safe. Failure to take appropriate regulatory action will mean that tens of thousands of women in Europe will needlessly continue to have pregnancies with neural tube defects.

The results of the MRC Vitamin Study have established the specific role of folic acid in the prevention of neural tube defects. Folic acid supplementation (4 mg/day) at the time of conception reduced the recurrence rate by about 70%. Evidence from observational studies and the Hungarian randomized trial (that used 0.4-0.8 mg/day supplemental folic acid) indicates that a similar level of prevention can be achieved among women who have not already had an affected pregnancy and that this may be achieved with a lower dose of folic acid. The medical implications of these results are important. (1) Women planning a pregnancy should take folic acid supplements. (2) Because a large proportion of pregnancies are unplanned and many of those that are planned will occur in women who will not have taken folic acid supplements, a complementary general public health strategy is needed, based on dietary advice and food fortification designed to achieve the benefit with adequate safety. (3) Any public health prevention strategy needs to be monitored for efficacy and possible harm. (4) Research is needed on the dose-response relationship between folic acid and neural tube defect prevention and the mechanism of action.