Do high levels of folic acid in women’s blood impact the outcome of IVF?

Of significant scientific and practical interest is the relationship between the blood plasma levels of folic acid at preconception and the outcome of pregnancy. A phase III clinical trial on the efficacy and safety of the biosimilar follitropin alfa has recently been completed within the ongoing assisted reproductive technology (ART) programs. The results confirmed the therapeutic equivalence of the investigational agent to the reference drug. In this trial, women with tubal infertility or male factor infertility were included. The study did not include women with endometriosis and polycystic ovary syndrome. A total of 118 patients were recruited; of those, 110 were randomized; then the 110 women underwent hormonal stimulation and 98 of them underwent embryo transfer. Blood samples were taken within a period not exceeding 28 days before the start of the stimulation; the samples were analyzed for folic acid (FA), trace elements and hormones. The results were grouped by quartiles (Q) according to the levels of FA in the blood serum: Q1 – 2.9–10.7 ng/ml, Q2 – 10.8–20.5 ng/ml, Q3 – 20.6–32.9 ng/ml, and Q4 ≥ 33.0 ng/ml. In addition, group distribution was also made according to the WHO recommendations: possible FA deficiency – 3.0–5.9 ng/ml, normal – 6.0–20.0 ng/ml, and elevated levels – more than 20 ng/ml. A significant decrease in the number of fertilized oocytes, clinical pregnancies and live births in Q4 (increased FA) compared with Q1 was found. Also, in women with high levels of FA, the number of aspirated oocytes was significantly lower than that in women with normal or decreased FA levels. We also found a significant inverse relationship between the number of aspirated oocytes and the levels of estradiol and serum FA. Plasma FA levels > 20 ng/ml detected prior to the IVF procedure may be associated with a low number of aspirated oocytes, and FA levels > 33 ng/ml – with a reduced number of fertilized oocytes, clinical pregnancies and live births. Thus, the excessive content of FA in the body can contribute to a worse outcome of IVF programs.

1. Milunsky A., Jick H., Jick S.S. et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA. 1989;262(20):2847–52. DOI: 10.1001/jama.262.20.2847.

2. Ray J.G., Meier C., Vermeulen M.J. et al. Association of neural tube defects and folic acid food fortification in Canada. Lancet. 2002;360(9350):2047–8. DOI: 10.1016/S0140-6736(02)11994-5.

3. Rosenquist T.H., Ratashak S.A., Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci U S A. 1996;93(26):15227–32. DOI: 10.1073/pnas.93.26.15227.

4. Blinov D.V., Zimovina U.V., Dzhobava E.M. Management of magnesium deficiency in pregnant women: pharmacoepidemiological study. [Vedenie beremennyh s deficitom magniya: farmakoepidemiologicheskoe issledovanie]. FARMAKOEKONOMIKA. Sovremennaya farmakoekonomika i farmakoepidemiologiya. 2014;7(2):23–32. (In Russ.).

5. Malek L., Umberger W., Makrides M., Zhou S.J. Poor adherence to folic acid and iodine supplement recommendations in preconception and pregnancy: a cross‐sectional analysis. Aust N Z J Public Health. 2016;40(5):424–9. DOI: 10.1111/1753-6405.12552.

6. Navarrete-Muñoz E.M., Valera-Gran D., García de la Hera M. et al. Use of high doses of folic acid supplements in pregnant women in Spain: an INMA cohort study. BMJ Open. 2015;5(11):e009202. DOI: 10.1136/bmjopen-2015-009202.

7. Study to compare efficacy and safety of Primapur and Gonal-f in women for assisted reproductive treatment. Available at: https://clinicaltrials.gov/ct2/show/NCT03088137.

8. Podkorytov A.B., Zhilyaev O.V., Polzikov M.A. A pen injector for selfadministration of follitropin alpha solution with a minimal dose increment of 5 IU. [Shpric-ruchka dlya samostoyatel’nogo vvedeniya rastvora follitropina al’fa s minimal’nym shagom ustanavlivaemoj dozy 5 ME]. Akusherstvo, ginekologiya i reproduktsiya. 2017;11(4):35–42. (In Russ.). DOI: 10.17749/2313-7347.2017.11.4.035-042.

9. Vorobiev I.I., Semikhin A.S., Golovina E.O. The novel biosimilar of follitropin alfa to be manufactured in Russia starting from 2017. [Proizvodstvo novogo bioanalogovogo follitropina al’fa v Rossii – eto uzhe real’nost’ v 2017 godu]. Akusherstvo, ginekologiya i reproduktsiya. 2017;11(3):116–26. (In Russ.). DOI: 10.17749/2313-7347.2017.11.3.

10. Barakhoeva Z.B., Vovk L.A., Zorina I.V.et al. Major results of a phase III comparative multicenter study on the follitropin alfa biosimilar (Primapur®) and the original follitropin alfa (Gonal-f®). [Osnovnye rezul’taty sravnitel’nogo mnogocentrovogo issledovaniya III fazy bioanalogovogo follitropina al’fa (Primapur®) i original’nogo follitropina al’fa (Gonal-f®)]. Akusherstvo, ginekologiya i reproduktsiya. 2018;12(3):5–16. (In Russ.). DOI: 10.17749/2313-7347.2018.12.3.005-016.

11. Polzikov M., Barakhoeva Z., Yakovenko S. et al. A multicenter, randomized study comparing the efficacy of follitropin alpha biosimilar and the original follitropin alpha. Hum Reprod. 2019;34(Suppl 1):439.

12. Orlova N.A., Kovnir S.V., Khodak Y.A. et al. High-level expression of biologically active human follicle stimulating hormone in the Chinese hamster ovary cell line by a pair of tricistronic and monocistronic vectors. PLoS One. 2019;14(7):e0219434. DOI: 10.1371/journal.pone.0219434.

13. Barakhoeva Z., Vovk L., Fetisova Yu. et al. A multicenter, randomized, phase III study comparing the efficacy and safety of follitropin alpha biosimilar and the original follitropin alpha. Eur J Obstet Gynecol Reprod Biol. 2019;241:6–12. DOI: 10.1016/j.ejogrb.2019.07.032.

14. Committee for Medicinal Products for Human Use. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human follicle stimulating hormone (r-hFSH). EMA/597110/2012. London: European Medicines Agency, 2013. 7 p. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-clinical-development-similarbiological-medicinal-products-containing_en.pdf.

15. Guidelines for the examination of medicines. Vol. IV. [Rukovodstvo po ekspertize lekarstvennyh sredstv. Tom IV]. Moskva: Poligraf-Plyus, 2014. 172 s. (In Russ.).

16. Nohr E.A., Olsen J., Bech B.H. et al. Periconceptional intake of vitamins and fetal death: a cohort study on multivitamins and folate. Int J Epidemiol. 2014;43(1):174–84. DOI: 10.1093/ije/dyt214.

17. Primapur. Instructions for medical use. LP-005826. State Register of Medicinal Products. [Primapur. Instrukciya po medicinskomu primeneniyu. LP-005826. Gosudarstvennyj Reestr Lekarstvennyh Sredstv]. Available at: http://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=6e4af9ad-ad10-4e7b-b8f0-948e4bb80fbb&t=.

18. WHO. Serum and red blood cell folate concentrations for assessing folate status in populations. Vitamin and Mineral Nutrition Information System. Geneva: World Health Organization, 2015. 7 р. Available at: https://apps.who.int/iris/bitstream/handle/10665/162114/WHO_NMH_NHD_EPG_15.01.pdf?sequence=1.

19. 19. Twigt J.M., Hammiche F., Sinclair K.D. et al. Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation. J Clin Endocrinol Metab. 2011;96(2):E322–9. DOI: 10.1210/jc.2010-1282.

20. Murto T., Skoog Svanberg A., Yngve A. et al. Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility. Reprod Biomed Online. 2014;28(6):766–72. DOI: 10.1016/j.rbmo.2014.01.017.

21. Centers for Disease Control and Prevention (CDC). Spina bifida and anencephaly before and after folic acid mandate, United States, 1995–1996 and 1999–2000. MMWR Morb Mortal Wkly Rep. 2004;53(17):362–5.

22. Human Vitamin and Mineral Requirements. World Health Organization, Food and Agriculture Organization of the United Nations. WHO, 2001. 303 p. Available at: http://www.fao.org/3/a-y2809e.pdf.

23. Food and Nutrition Board. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC: National Academies Press, 1998. Available at: https://www.ncbi.nlm.nih.gov/books/NBK114310.