Folic acid fortification: A public health success story

By Dr. Stuart MacLeod

In the aftermath of the thalidomide tragedy, and despite growing awareness of the teratogenic effects of drugs taken during pregnancy, surprisingly little attention was paid at that time to other nutritional or biochemical exposures that might harm (or benefit) embryonic development.

That changed in 1991, when the U.K.’s MRC Vitamin Study Research Group published a report showing that folic acid supplementation given around the time of conception reduced the risk of serious neural tube defects ^[1]. That recognition was followed in 1995 with the publication of a CPS statement entitled “Periconceptional use of folic acid for reduction of the risk of neural tube defects”. By 1998, Canada and the United States had introduced legislation requiring mandatory fortification of some cereal products with folic acid. Considerable scientific debate went into determining the ideal concentration of folic acid in flour needed to achieve a dose high enough for a daily intake of up to 1 mg without exceeding that limit. There was concern that a daily adult intake greater than 1 mg might obscure a diagnosis of pernicious anemia.

In 2007 a large, pan-Canadian, multi-disciplinary team reported that the incidence of neural tube defects had diminished from 1.58 per 1000 births before fortification to 0.86 per 1000 births after mandatory fortification policy was implemented ^[2]. Their results covered seven provinces and showed a decrease proportional to the pre-fortification baseline rate in each province. The observed reduction in rate was greater for spina bifida (53%) than for anencephaly (38%) and encephalocele (31%).

One lesson was especially clear: The issues determining optimal practice are too important to be left to independent analysis by an array of subspecialists, some with very narrow interests, acting in isolation. What had succeeded was a coordinated “bridging” approach that embraced input from at least a dozen disciplines, including obstetrics, fetal-maternal medicine, paediatrics, nutritional science, medical genetics, embryology, neurology, neuropathology, clinical biochemistry, teratology, pharmacology, and toxicology. Validation of optimal obstetrical therapeutics cannot be achieved by any single discipline. The marriage of basic science to clinical understanding and to health policy decision-making was critical.

In view of this success story, it is perhaps surprising that we have not seen more parallel developments. While the policy initiative of the mid-1990s has been shown to yield important benefits, further progress in the application of science to pregnancy has remained slow in many respects. Above all, this sequence of events demonstrated the importance of carefully designed clinical epidemiology studies to monitor the effectiveness of nutritional policy initiatives, just as would be expected with other therapeutic interventions. The 2007 report clearly closed the loop from scientific discovery to improved outcomes. Astonishingly, and despite the exemplary validation process in this case, only 80 countries to date have adopted policies on folic acid fortification. The U.K., where the underlying scientific justification originated, belatedly introduced a mandatory policy on September 20, 2021 ^[3].

There are three main conclusions that can be drawn from the history of the past 30 years regarding periconceptional folic acid impact in pregnancy and the reduced incidence of neural tube defects.

1) It is possible to engender sound public health policy on the basis of careful scientific observation. In this case, early reports from the UK-MRC Vitamin Study Research Group led to policies on fortification in fairly short order in Canada and the United States.

2) The appropriate application of clinical investigation—with careful design based on epidemiological principles—serves to confirm the efficacy and benefits of innovative public health policy. In this case, the benefit of folic acid fortification mandates was demonstrated within 10 years and, to date, this result has driven the adoption of parallel policy in 80 countries ^[3].

3) The study of folic acid periconceptionally and during pregnancy, and the promulgation of policies encouraging folic acid fortification at levels likely to be beneficial without toxicity to the adult population, has been exemplary. Subsequent analysis of this policy’s outcomes has conclusively demonstrated the critical importance of an integrated, multi-disciplinary approach.

The folic acid story illustrates an ideal of what may be achieved by marrying sound science with astute policy-making. If we are truly committed to improving our collective efforts at evidence-based policy decisions, we must do everything possible to increase the training opportunities that will allow young physicians to work at the interface of molecular biology, basic biomedical research, clinical care, and evaluative science. In 2022 there is no more important challenge than the need for such a reorientation in our post-graduate clinical training system.

Dr. Stuart MacLeod is a retired clinical pharmacologist and emeritus professor in paediatrics at the University of British Columbia. He chaired the CPS Drug Therapy and Hazardous Substances Committee from 1996-2001 and has published extensively on optimal drug therapies for children and youth, safe medication use, and pharmacogenomics.

References

1. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991;338(8760):131-37.

2. De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 2007;357(2):135-42.

3. Haggarty, P. UK introduces folic acid fortification of flour to prevent neural tube defects. Lancet 2021;398(10307):1199-1201.

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