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

BMJ 2018; 362 doi: (Published 12 September 2018) Cite this as: BMJ 2018;362:k3478

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Why is the search for pre-eclampsia prevention so elusive?

Rapid Response:

Folic Acid and Preeclampsia: Is there an Invisible Accomplice?

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


1. Chambers JC, Fusi L, Malik IS, et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285(12):1607-12.

2. McDowell IF, Lang D. Homocysteine and endothelial dysfunction: a link with cardiovascular disease. J Nutr 2000;130(2S Suppl):369S-72S. doi: 10.1093/jn/130.2.369S

3. Homocysteine Lowering Trialists C. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 2005;82(4):806-12. doi: 10.1093/ajcn/82.4.806

4. Study of the Effectiveness of Additional Reductions in C, Homocysteine Collaborative G, Armitage JM, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 2010;303(24):2486-94. doi: 10.1001/jama.2010.840

5. Wen SW, White RR, Rybak N, et al. Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial. BMJ 2018;362:k3478. doi: 10.1136/bmj.k3478

6. Roberts JM, Balk JL, Bodnar LM, et al. Nutrient involvement in preeclampsia. J Nutr 2003;133(5 Suppl 2):1684S-92S. doi: 10.1093/jn/133.5.1684S

7. Liu C, Liu C, Wang Q, et al. Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis. Arch Gynecol Obstet 2018;298(4):697-704. doi: 10.1007/s00404-018-4823-4

8. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354(15):1567-77. doi: 10.1056/NEJMoa060900

9. Strain JJ, Dowey L, Ward M, et al. B-vitamins, homocysteine metabolism and CVD. Proc Nutr Soc 2004;63(4):597-603.

10. Amer M, Qayyum R. The relationship between 25-hydroxyvitamin D and homocysteine in asymptomatic adults. J Clin Endocrinol Metab 2014;99(2):633-8. doi: 10.1210/jc.2013-3262

11. Pham TM, Ekwaru JP, Mastroeni SS, et al. The Effect of Serum 25-Hydroxyvitamin D on Elevated Homocysteine Concentrations in Participants of a Preventive Health Program. PLoS One 2016;11(8):e0161368. doi: 10.1371/journal.pone.0161368

12. Kriebitzsch C, Verlinden L, Eelen G, et al. 1,25-dihydroxyvitamin D3 influences cellular homocysteine levels in murine preosteoblastic MC3T3-E1 cells by direct regulation of cystathionine beta-synthase. J Bone Miner Res 2011;26(12):2991-3000. doi: 10.1002/jbmr.493

13. Beckett E, Duesing K, Martin C, et al. Relationship between methylation status of vitamin D-related genes, vitamin D levels, and methyl-donor biochemistry. Journal of Nutrition & Intermediary Metabolism 2016;6:8-15. doi: doi:10.1016/j.jnim.2016.04.010

14. Dodd JM, O'Brien C, Grivell RM. Preventing pre-eclampsia - are dietary factors the key? BMC Med 2014;12:176. doi: 10.1186/s12916-014-0176-4

Competing interests: No competing interests

03 December 2018
Hooman Mirzakhani
Scott T. Weiss
Brigham and Women's Hospital, Harvard Medical School
Channing Division of Network Medicine; 181 Longwood Ave., Boston, MA 02115