Folic Acid and Pregnancy: Research Review

Folic acid, also known as vitamin B-9, is naturally found in many foods. It is added to prenatal vitamins and many fortified foods such as cereal. Folic acid is a crucial nutrient during early pregnancy and can help reduce the risk of birth defects.

Physiology

As a quick reminder, MTHFR induces a reaction, using 5, 10 me-THF, that will mostly produce 5-m THF (methylated folate), a substrate required to synthetize methionine from homocysteine and this is the only form of folate used in the central nervous system (CNS).

Hyperhomocysteinemia is observed in approximately 5% of the general population and is associated with increased risk for many inflammatory disorders including auto immune disorders (Rheumatoid Arthritis, Diabetes, Multiple Sclerosis, Systemic Lupus erythematosus, Grave disease), birth defects and adverse pregnancy outcomes (pre-eclampsia, placental abruption, spontaneous abortion, low birth weight), as well as vascular and neurodegenerative diseases. Homocysteine is at the epicenter of oxidative stress and DNA methylation errors.

Published clinical data

Numerous studies showed that a compromised folate status in pregnant women is associated with recurrent spontaneous abortion (miscarriage)^1-2 and fetal neural tube defects³. Elevated serum homocysteine concentration is an important problem causing birth defects⁴, pre-eclampsia^5-7, placental abruption⁸, low birth weight and other maternal or fetal complications⁹.

Low folate and high homocysteine are associated with the occurrence of congenital heart disease (CHD)^10-11.

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References

1. Gupta S, Agarwal A, Banerjee J, Alvarez JG. The role of oxidative stress in spontaneous abortion and recurrent pregnancy loss: a systematic review. Obstet Gynecol Surv. 2007 May; 62(5):335-47; quiz 353-4. Review. PubMed PMID: 17425812.
2. Xu Y, Ban Y, Ran L, Yu Y, Zhai S, Sun Z, Zhang J, Zhang M, Hong T, Liu R, Ren L, Hu L. Relationship between unexplained recurrent pregnancy loss and 5,10-methylenetetrahydrofolate reductase) polymorphisms. Fertil Steril. 2019 Mar;111(3):597-603.
3. Pereza N, Ostojić S, Kapović M, Peterlin B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril. 2017 Jan;107(1):150-159.e2.
4. Cai CQ, Fang YL, Shu JB, Zhao LS, Zhang RP, Cao LR, Wang YZ, Zhi XF, Cui HL, Shi OY, Liu W. Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway. Ital J Pediatr. 2019 Mar 14;45(1):37.
5. Zhang Y, He X, Xiong X, Chuan J, Zhong L, Chen G, Yu D. The association between maternal methylenetetrahydrofolate reductase C677T and A1298C polymorphism and birth defects and adverse pregnancy outcomes. Prenat Diagn. 2019 Jan;39(1):3-9.
6. Chaudhry SH, Taljaard M, MacFarlane AJ, Gaudet LM, Smith GN, Rodger M, Rennicks White R, Walker MC, Wen SW. The role of maternal homocysteine concentration in placenta-mediated complications: findings from the Ottawa and Kingston birth cohort. BMC Pregnancy Childbirth. 2019 Feb 19;19(1):75.
7. Brenner B, Aharon A. Thrombophilia and adverse pregnancy outcome. Clin Perinatol. 2007 Dec; 34(4):527-41, v. Review. PubMed PMID: 18063103.
8. Den Heijer M, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 334, 1996, 759-762.
9. Enciso M, Sarasa J, Xanthopoulou L, Bristow S, Bowles M, Fragouli E, Delhanty J, Wells D. Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy. Hum Genet. 2016 May;135(5):555-68.
10. Hall J, Solehdin F: Folic acid for the prevention of congenital anomalies. Eur J Pediatr 1998; 157:445-450.
11. 18- Leclerc D, Rozen R: [Molecular genetics of MTHFR: polymorphisms are not all benign]. Med Sci (Paris) 2007; 23:297-302.