Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial

Re: Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial

Impairment of endothelial function has been demonstrated in preeclampsia and proposed to play a central pathobiological role.1 Furthermore, homocysteine has been implicated in the initiation of vascular endothelial dysfunction by a mechanism involving reactive oxygen species, shown to be increased in pregnancies of women with preeclampsia.2 Daily supplementation with folic acid lowers homocysteine levels in a dose-dependent manner.3 4

Based on this rationale, in an international multicentric randomized clinical trial, Wen and colleagues investigated the effect of folic acid supplementation as early as 8-16 weeks of gestation for prevention of pre-eclampsia in high risk pregnancies. Despite the intervention with a relatively high dose (4.0 mg/day), the authors found the supplementation ineffective in prevention of preeclampsia under the study conditions.5 Conventionally, observational studies and clinical trials investigating the role of nutrients in preeclampsia have focused on a single nutrient, e.g., folate, vitamin D, Omega-3 (n-3) fatty acids, calcium, to name a few.6 A recent meta-analysis on cohorts and trials of folic acid supplementation in pregnancy and the risk of preeclampsia suggests that folic acid during pregnancy could substantially lower preeclampsia risk, if taken with multivitamins but not alone.7 This report raises the question whether an interaction of the folic acid metabolic pathway with other nutrient metabolic pathways might be involved in the pathobiology of preeclampsia and potentially be a reason for the null report by Wen and colleagues, among other methodological trial considerations. For instance, the roles of vitamins B12 and B6 in the metabolism of homocysteine has been demonstrated.8 9 Another micronutrient often deficient during pregnancy is vitamin D. There is evidence on the inverse relationship between 25-hydroxyvitamin D (25OHD) deficiency and homocysteine levels through modulation of gene expression of enzymes involved in homocysteine metabolism.10 11 More specifically, homocysteine is cleared from the serum by the cystathionine β-synthase (CBS) enzyme through the trans-sulfuration pathway where Vitamin D (1,25-dihydroxyvitamin D3) is found to be a major catalyst.12 Serum folate is also shown to be linked with vitamin D receptor (VDR) methylation.13

Investigation of an individual micro or macronutrient in relation to the complex pathobiology of preeclampsia should be accompanied by collection of information on the other potential interacting dietary components and maternal factors in pregnancy. More extensively, we agree with Dodd and colleagues’ statement that “there is a need for well-powered prospective intervention studies to evaluate the role of healthy dietary patterns in pregnancy and their impact on maternal and infant health outcomes”.14

Hooman Mirzakhani, MD, PhD, MMSc1; Scott T. Weiss, MD, MS1,2

1 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
2 Partners Center for Personalized Medicine, Partners Health Care, Boston, MA, USA

Email for correspondence
Hooman Mirzakhani
hmirzakhani@bwh.harvard.edu

Reference:

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