Does folic acid reduce congenital anomalies and adverse pregnancy outcomes in women received long-term low dose methotrexate?

Authors

  • Ahmed M. Farag Department of Obstetrics and Gynecology, Faculty of Medicine Zagazig University, Zagazig, Egypt
  • Safaa A. Ibrahim Department of Obstetrics and Gynecology, Faculty of Medicine Zagazig University, Zagazig, Egypt

DOI:

https://doi.org/10.18203/2320-1770.ijrcog20195996

Keywords:

Congenital abnormality, Fetal outcomes, Folic acid, Maternal, Methotrexate, Pregnancy

Abstract

Background: Methotrexate (MTX) which is folic acid antagonist is used to treat many diseases, including rheumatic, inflammatory, autoimmune disorders or malignancies; it is also used for the medical treatment of ectopic pregnancy and termination of pregnancy. The objective of this study was to assess the impact of folic acid in preventing congenital anomalies (CAs) in the fetus of pregnant that take long-term low dose methotrexate.

Methods: The study included 1569 with history of low dose methotrexate therapy <25 mg/week that stopped one month before pregnancy, they were divided into 3 groups; Group 1 comprised 272 pregnant women, Group 2 comprised 367 pregnant women both groups take folic acid 4-5 weeks preconception and for the first 12-13 weeks gestation, the dose in the 1st group was 0.4 mg/day while in 2nd Group 4 mg/day, Group 3 comprised of 930 pregnant disease-matched with no folic acid. Group 4 comprised of 1015 pregnant no underlying autoimmune and no folic acid intake.

Results: The overall rate of CAs and cardiovascular CAs were higher in fetuses of Group 3 (OR: 1.7; 95% CI: 1.1-2.7) and (OR: 2.7; 95% CI: 1.4-5.2) respectively compared to the overall rate of CAs and cardiovascular CAs in other groups. Other adverse outcomes as abortion, preterm delivery, preeclampsia, placenta abruption, PROM, low birth weight, admission to NICU, IUGR and IUFD were higher in Group 3 and 4 than in Group 1 and 2. There were no significant differences in umbilical arterial PH. The Apgar scores <7 at 1, 5 min and gestational age at delivery were higher in Group 1 and 2 than Group 3 and 4.

Conclusions: There was a certain reduction in methotrexate teratogenic effect on the fetuses with folic acid intake during pregnancy, these pregnancies might benefit from taking of folic acid in high doses before conception and during the first trimester of pregnancy and improvement in fetal and maternal outcomes but the explanation of this effect requires further study.

References

Bawle EV, Conard, JV, Weiss L. Adult and two children with fetal methotrexate syndrome. Teratol. 1998;57:51-5.

Goffman D, Cole DS, Bobby P, Garry DJ. Failed methotrexate termination of pregnancy: a case report. J Perinatol. 2006;26:645-7.

Adam MP, Manning MA, Beck AE, Kwan A, Enns GM, Clericuzio C, Hoyme HE. Methotrexate/misoprostol embryopathy: report of four cases resulting from failed medical abortion. Am J Med Gen Part A. 2003;123(1):72-8.

Chapa JB, Hibbard JU, Weber EM, Abramowicz JS, Verp MS. Prenatal diagnosis of methotrexate embryopathy. Obstet Gynecol. 2003;101:1104-7.

Feldkamp M, Carey JC. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratol. 1993;47:533-9.

Lloyd ME, Carr M, McElhatton P, Hall GM, Hughes RA. The effects of methotrexate on pregnancy, fertility and lactation. QJM. 1999;92:551-63.

Charache S, Condit PT, Humphreys SR. Studies on the folic acid vitamins. IV. The persistence of amethopterin in mammalian tissues. Cancer. 1960;13:236-40.

McEvoy GK. AHFS drug information. Bethesda: American Society of Health-System Pharmacists. Methotrexate. 1996;751-9.

Hackmon R, Sakaguchi S, Koren G. Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy. Can Fam Physician. 2011;57:37-9.

Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr. 2000;71:962-8.

Bergen NE, Jaddoe VW, Timmermans S, Hofman A, Lindemans J, Russcher H, et al. Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: The generation R study. BJOG. 2012;119:739-51.

Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365:785-99.

Steegers E, von Dadelszen P, Duvekot J, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376:631-44.

Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long-term mortality of mothers and fathers after pre-eclampsia: population-based cohort study. BMJ. 2001;323:1213-6.

Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P, et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ. 2003;326:845.

Haukkamaa L, Salminen M, Laivuori H, Leinonen H, Hiilesmaa V, Kaaja R. Risk for subsequent coronary artery disease after preeclampsia. Am J Cardiol. 2004;93:805-8.

Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335:974-7.

Chang HH, Larson J, Blencowe H, Spong CY, Howson CP, Cairns-Smith S, et al. On behalf of the born too soon preterm prevention analysis group: preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet. 2013;381:223-34.

Yi Y, Lindemann M, Collins A, Snowball C. Economic burden of neural tube defects and impact of prevention with folic acid: a literature review. Eur J Pediatr. 2011;170:1391-400.

March of Dimes, The partnership of maternal, newborn and child health, save the children, World Health Organization: Born too soon: the global action report on preterm birth. Geneva: World Health Organization; 2012.

Bhutta ZA, Das JK, Rizvi A, Gaffey MF, Walker N, Horton S, et al. Lancet Interventions Review Group, Maternal and Child Nutrition Study Group: Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382:452-77.

Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992;327:1832-5.

Czeizel AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet. 1996;62:179-83.

Czeizel AE, Dobo M, Vargha P. Hungarian cohort-controlled trial of periconceptional multivitamin supplementation shows reduction in certain congenital abnormalities. Birth Defects Res (PartA). 2004;70:853-61.

Czeizel AE, Medvecki E. No difference in the occurrence of multi malformed offspring after periconceptional multivitamin supplementation. Obstet Gynecol. 2003;102:1255-61.

Czeizel AE. Specified critical period of different congenital abnormalities: a new approach for human teratological studies. Congenit Anom. 2008;48:103-9.

Czeizel AE, Puhó E, Bánhidy F. No association between periconceptional multivitamin supplementation and risk of multiple congenital abnormalities. A population-based case-control study. Am J Med Genet Part A. 2006;140A:2469-77.

Manning, SM, Jennings R, Madsen JR. Pathophysiology, prevention, and potential treatments of neural tube defects. Mental Retard Develop Disable Res Rev. 2000;6:6-14.

MRC vitamin study research group. Prevention of neural tube defects: results of the medical research council vitamin study. The Lancet. 1991;338(8760):131-7.

Khoury JM, Shaw GM, Moore CA, Lammer EJ, Mulinare J. Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? Data from two population-based case-control studies. Am J Med Gen. 1996;61:30-6.

Medical research council vitamin study research group. Prevention of neural tube defects: results of medical research council vitamin study. Lancet. 1991;338:131-7.

Lewis DP, Van Dyke DC, Stumbo PJ, Berg MJ. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-17.

Moore CA, Li S, Li Z, Hong SX, Gu HQ, Berry RJ, et al. Elevated rate of severe neural tube defects in a high-prevalence area in northern China. Am J Med Gen. 1997;73:113-8.

Berry RJ, Li Z, Erickson D, Li S, Moore CA, Wang H, et al. Prevention of neural tube defects with folic acid in China. N Eng J Med. 1999;341:1485-90.

Kadir R, Sabin C, Whitlow B, Brockbank E, Economides D. Neural tube defects and periconceptional folic acid in England and Wales: retrospective study. Br Med J. 1999;319:92-3.

Wen SW, Guo Y, Rodger M, White RR, Yang Q, Smith GN, et al. Folic acid supplementation in pregnancy and the risk of pre-eclampsia-a cohort study. PLoS One. 2016;11(2):e0149818.

Shahraki AD, Dehkordi NZ, Lotfizadeh M. Comparison of high dose and low dose folic acid supplementation on prevalence, onset and severity of preeclampsia. Adv Biomed Res. 2016;5:192.

Hernández-Díaz S, Werler MM, Louik C, Mitchell AA. Risk of gestational hypertension in relation to folic acid supplementation during pregnancy. Am J Epidemiol. 2002;156(9and1):806-12.

Li Z, Ye R, Zhang L, Li H, Liu J, Ren A. Folic acid supplementation during early pregnancy and the risk of gestational hypertension and preeclampsia. Hyper. 2013;61:873-9.

Liu X, Lv L, Zhang H, Zhao N, Qiu J, He X, et al. Folic acid supplementation, dietary folate intake and risk of preterm birth in China. Eur J Nut. 2016;394-015-0959-1.

Bukowski R, Malone FD, Porter FT, Nyberg DA, Comstock CH, Hankins GD, et al. Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study. Plos Med. 2009;6(5):1000061.

Wang Y, Cao Z, Peng Z, Xin X, Zhang Y, Yang Y, et al. Folic acid supplementation, preconception body mass index, and preterm delivery: findings from the preconception cohort data in a Chinese rural population. BMC Preg Childbirth. 2015;15:336.

Saccone G, Berghella V. Folic acid supplementation in pregnancy to prevent preterm birth: a systematic review and meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2016;1:42.

Martinussen KP, Bracken MB, Triche EW, Jacobsen GW, Risnes KR. Folic acid supplementation in early pregnancy and the risk of preeclampsia, small for gestational age offspring and preterm delivery. Eur J Obstet Gynecol Reprod Biol. 2015;195:94-9.

Nilsen RM, Vollset SE, Rasmussen SA, Ueland PM, Daltveit AK. Folic acid and multivitamin supplement use and risk of placental abruption: a population-based registry study. Am J Epidemiol. 2008;167:867-74.

Charles DH, Ness AR, Campbell D, Smith GD, Whitley E, Hall MH. Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review. Paediatr Perinat Epidemiol. 2005;19:112-24.

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Published

2019-12-26

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Original Research Articles