Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study

Published:November 05, 2009DOI:



      Periconceptional folic acid or multivitamin supplementation is recommended for prospective pregnant women to prevent neural-tube defects. The question is whether it is worth continuing these supplementations after the first trimester of pregnancy or not. Thus the possible fetal growth promoting and/or preterm birth reducing effect of vitamin supplements in the second and mainly in the third trimester was studied.

      Study design

      Comparison of birth outcomes of singletons born to primiparous pregnant women with prospectively and medically recorded vitamin supplement in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980–1996 contained 6293, 169, and 311 primiparae with folic acid alone, multivitamins and folic acid + multivitamin supplementation, respectively, and their data were compared to the data of 7319 pregnant women without folic acid and folic acid-containing multivitamin supplementation as reference.


      Mean gestational age was 0.3 week longer and mean birth weight was by 37 g higher in the group of folic acid alone, than in the reference group (39.2 weeks; 3216 g). The rate of preterm births (7.6%) was significantly lower compared with the reference sample (11.8%), but the rate of low birth weight newborns did not show significant reduction. Folic acid alone in the third trimester associated with 0.6 week longer gestational age and a more significant reduction in the rate of preterm births (4.8%).


      Minor increase in mean birth weight after high dose of folic acid supplementation during pregnancy would not be expected to result in too large babies; however, the significant reduction in the rate of preterm births may have great public health benefit.


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        • Smithells R.W.
        • Sheppard S.
        • Wild J.
        • Schorah C.J.
        Prevention of neural tube defect recurrences in Yorkshire: final report.
        Lancet. 1982; 1: 498-499
        • MRC Vitamin Study Research Group
        Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.
        Lancet. 1991; 338: 131-137
        • Czeizel A.E.
        • Dudas I.
        Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation.
        N Engl J Med. 1992; 327: 1832-1835
        • Berry R.
        • Li Z.
        • Erickson J.D.
        • et al.
        Prevention of neural-tube defects with folic acid in China.
        N Engl J Med. 1999; 341: 1485-1490
        • Cziezel A.E.
        • Tóth M.
        • Rockenbauer M.
        A case-control analysis of folic acid supplementation during pregnancy.
        Teratology. 1996; (53_): 345-351
        • Czeizel A.E.
        • Vargha P.
        Periconceptional folic acid/multivitamin supplementation and twin pregnancy.
        Am J Obstet Gynecol. 2004; 191: 790-794
        • Mohammed K.
        Routine folate supplementation in pregnancy.
        in: Enkin M.W. Keirse M.J.C.N. Renfreq M.J. Nielson J.P. Pregnancy and Childbirth Module. Cochrane Database Syst Rev Review. 1993 ([No. 03158, April])
        • Haider B.A.
        • Bhutta Z.A.
        Multiple-micronutrients supplementation for women during pregnancy.
        Cochrane Database Syst Rev. 2006; 18: CD004905
        • Czeizel A.E.
        • Rockenbauer M.
        • Siffel Cs.
        • Varga E.
        Description and mission evaluation of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980–1996.
        Teratology. 2001; 63: 176-185
        • Czeizel A.E.
        The first 25 years of the Hungarian Congenital Abnormality Registry.
        Teratology. 1997; 55: 299-305
        • Czeizel A.E.
        • Petik D.
        • Vargha P.
        Validation studies of drug exposures in pregnant women.
        Pharmacoepid Drug Safety. 2003; 12: 409-416
        • Puho H.E.
        • Métneki J.
        • Czeizel A.E.
        Maternal employment status and isolated orofacial clefts in Hungary.
        Cent Eur J Publ Health. 2004; 13: 144-148
        • Bjerkedahl T.
        • Czeizel A.E.R.
        • Hosmer D.W.
        Birth weight of single livebirths and weight specific early neonatal mortality in Hungary and Norway.
        Paediat Perinat Epidemiol. 1989; 3: 129-140
        • Goldenberg R.L.
        • Culhane J.F.
        • Iams J.D.
        • Romero R.
        Epidemiology of preterm birth.
        Lancet. 2008; 371: 75-84
        • Scholl T.O.
        • Hediger M.L.
        • Schall J.I.
        • et al.
        Dietary and serum folate: their influence on the outcome of pregnancy.
        Am J Clin Nutr. 1996; 63: 520-525
        • McPartlin J.
        • Halligan A.
        • Scott J.M.
        • Darling M.
        • Weir D.G.
        Accelerated folate breakdown in pregnancy.
        Lancet. 1993; 341: 148-149
        • Cikot R.J.L.M.
        • Steegers-Theunissen R.P.M.
        • Thomas C.M.G.
        • et al.
        Longitudinal vitamin and homocysteine levels in normal pregnancy.
        Br J Nutr. 2001; 85: 49-58
        • Czeizel A.E.
        • Petik D.
        • Puho H.E.
        Smoking and alcohol drinking during pregnancy. The reliability of retrospective maternal self-reported information.
        Cent Eur J Publ Health. 2004; 12: 179-183
        • Adams J.
        Statement of the Public Affairs Committee of the Teratology Society on the importance of smoking cessation during pregnancy.
        Birth Defects Res (Part A). 2003; 67: 895-899
        • Siega-Riz A.M.
        • Savitz S.A.
        • Zeisel S.H.
        • et al.
        Second trimester folate status and preterm birth.
        Am J Obstet Gynecol. 2000; 191: 851-857
        • Vollset S.E.
        • Refsum H.
        • Irgens L.M.
        • et al.
        Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: The Hordaland Homocysteine Study.
        Am J Clin Nutr. 2000; 71: 962-968
        • Ronnenberg A.G.
        • Goldman M.B.
        • Chen D.
        • et al.
        Preconception homocysteine and B vitamin status and birth outcomes in Chinese women.
        Am J Clin Nutr. 2002; 76: 1385-1391
        • Catov J.M.
        • Bodnar L.M.
        • Ness R.B.
        • et al.
        Association of periconceptional use and risk of preterm or small-for-gestational-age births.
        Am J Epidemiol. 2007; 166: 296-303
        • Smits L.J.M.
        • Essed G.G.M.
        Short pregnancy intervals and unfavorable pregnancy outcomes: role of folate depletion.
        Lancet. 2001; 358: 2074-2077
        • Bukowski R.
        • Malone F.D.
        • Porter F.F.
        • et al.
        Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.
        PLoS Med. 2009; 6: e10000061
        • Eskes T.K.A.B.
        Vascular disease in women. Folate and homocysteine.
        in: Massaro E.J. Rogers J.M. Folate and Human Development. Humana Press, Totowa, NJ2002: 299-328
        • van der Molen E.F.
        • Verbruggen B.
        • Nokalova I.
        • et al.
        Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy.
        Br J Obstet Gynaecol. 2000; 107: 785-791
        • Ferguson S.E.
        • Smith G.N.
        • Walker M.C.
        Maternal plasma homocysteine levels in women with preterm premature rupture of membranes.
        Med Hypotheses. 2001; 56: 85-90
        • Johnson W.G.
        • Scholl T.O.
        • Spychala J.R.
        • et al.
        Common dihydrofolate reductase 19-base deletion allele: a novel risk factors for preterm delivery.
        Am J Clin Nutr. 2005; 81: 664-668