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Prof. K. N. Saraswathy

Professor of Biological Anthropology

Department of Anthropology, University of Delhi


Folic acid supplementation is a part of routine antenatal care in India wherein a dose of 5mg (5000μg) of folic acid once a day is given to all pregnant women during the first trimester. This has been associated with a reduced risk of occurrence of Neural tube defects (NTDs). Although folic acid supplementation is deemed necessary and safe for pregnant women and reduces pregnancy complications, the untold story of indiscriminate folic acid supplementation is now raising concern over its safety. Let’s understand the importance of folate during pregnancy, a brief history of folic acid supplementation and recent concerns with respect to the folic acid supplementation program in India.

Folate is one of the important micronutrients which cannot be adequately synthesized by the human body and must be acquired from the environment for the healthy functioning of the body. The importance of folate in the human system can be understood from the role that it plays in the maintenance of one-carbon metabolism. Folate (Vitamin B9), along with cobalamin (Vitamin B12), pyridoxine (Vitamin B6) etc., act as a critical co-factor in the one-carbon metabolic pathway (OCMP). This pathway in turn plays an important role in the synthesis of DNA, polyamines, amino acids, creatine, and phospholipids. It also participates in key metabolic reactions and production of methyl groups for epigenetic mechanisms (DNA methylation reaction.)

Owing to its wide array of functions, maternal bioavailability of folate during pregnancy becomes crucial for healthy embryonic and foetal development as well as foetal epigenetic programming via OCMP. It is suggested that higher amounts of folate are required during pregnancy due to the rapid rate of cellular and tissue growth for the development of the foetus; thus, maternal folate deficiency during this period is suspected to have detrimental and irreversible effects on the growing foetus. In fact, several studies in the last five decades have associated folate deficiency during pregnancy with various pregnancy complications including Neural tube defects (NTDs). NTD, which refers to congenital malformations of the spine, spinal cord or cranium resulting from the failure of normal neural tube closure during early pregnancy. This is a common pregnancy complication and is known to have affected 300,000 neonates each year, worldwide, during the 1990s.

Due to the heavy burden of NTDs, a need for suitable public health intervention was felt in the latter decades of the twentieth century. Clinical trials during the 1980s and 1990s conclusively showed that periconceptional folic acid intake resulted in the decreased prevalence of NTDs. Consequently, pre-and periconceptional folic acid supplementation during pregnancy became a standard intervention in many countries. Initially, a prophylactic dose of 300 μg (0.3 mg) per day throughout pregnancy was suggested in 1968 by the World Health Organization (WHO, 2012). This supplemental dose was increased to 400 μg (0.4 mg) of folic acid per day in 1998 following the publication of several studies supporting the periconceptional use of folic acid in the prevention of NTDs.

Folic acid supplementation has indeed reduced the prevalence of NTDs worldwide; however, recent studies have raised important questions pertaining to folate overdose and toxicity. Nutritional requirements of populations depend on their genetic architecture as well as biocultural environments. The major source of folate is a vegetarian diet, whereas B12 is readily available in a non-vegetarian diet. As a matter of fact, western countries are predominantly non-vegetarian, while a large percentage of Indians, particularly women practice vegetarianism. By implication, western populations are folate deficient but B12 replete; however, the opposite trend is seen in the Indian populations. In India, folate deficiency has been reported in 1.2% to 26.3% of periconceptional women but B12 deficiency is up to 74% in pregnant women. Yet, despite the low prevalence of folate deficiency in India, pregnant women are given 5000 μg/day of folic acid supplement, which is 5 times higher than its tolerable upper limit of 1000 μg/day and 12.5 times higher than WHO recommended limit of 0.4 mg.

This additional supplementation being given to pregnant women was typically considered safe due to its water-soluble characteristic. However, emerging evidence has demonstrated that this high intake of folic acid is likely to create an imbalance both in terms of exacerbating vitamin B12 deficiency and aberrant methylation patterns. Numerous studies have shown an association of high folic acid intake with a higher risk of cancers such as breast cancer. A study on mouse models revealed adverse foetal outcomes, i.e., foetal anomalies because of extra intake of folic acid. Animal experiments have also indicated that excess folic acid compounds induce a cancer-causing reaction, that is, hypermethylation in the DNA of cancer cells. Thus, the epigenetic alterations caused due to high intake of folic acid may have an evolutionary significance as well. Another point of concern is the timing of starting the folic acid supplementation. The majority of the pregnant women in India seek antenatal care only after the first month post-conception by when the neural tube is already been closed, hence the purpose of supplementing with folic acid to prevent Neural Tube Defects gets defeated.

In fact, in our series of collaborative studies with Lady Harding Medical College spanning across a decade, we have observed folate deficiency to be almost in negligible frequency among both pregnant and non-pregnant women in their reproductive ages. Interestingly, homocysteine (one of the metabolites of OCMP and an inflammatory marker) was found to be significantly higher among women with pregnancy complications such as preeclampsia (PE), recurrent miscarriages (RM) and preterm premature rupture of membranes (PPROM) as compared to their respective controls. The deficiency of vitamin B12, another important cofactor, was found to be a significant risk factor for RM. It is pertinent to highlight here that despite the folate repletion, high levels of homocysteine were rampant among cases and was significantly associated with preeclampsia, RM, and PPROM. These observations point towards the ineffectiveness of folic acid supplementation in reducing homocysteine levels. Thus, folate repletion doesn’t appear to prevent pregnancy complications; neither independently nor by reducing homocysteine levels. Further, a huge imbalance in terms of high folate and low B12 among pregnant females of north India was also observed and reported, which may put them at increased risk for other pregnancy complications like GDM.

From this discussion it can be inferred that folic acid supplementation in the absence of its deficiency has not demonstrated health benefits, rather may have detrimental outcomes. It also highlights the importance of population specific anthropological research in health science and policymaking. However, perhaps the biggest takeaway from this discussion is that it is time for us (health scientists and policymakers) to realize that indiscriminate supplementation of folate or for that matter any nutrient may have risks associated with them. These supplements tend to disturb physiological pathways, not just the ones that they are acting in but also others, and hence may have unanticipated effects on the human system, be it in the short or long term. Therefore, before implementing any such health intervention, population-specific genetic and biocultural studies must be taken up and supplementation or fortification programs should be only for the targeted individuals.

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