title: Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes.
abstract: BACKGROUND
  During pregnancy, fetal growth causes an increase in the total number of rapidly dividing cells, which leads to increased requirements for folate. Inadequate folate intake leads to a decrease in serum folate concentration, resulting in a decrease in erythrocyte folate concentration, a rise in homocysteine concentration, and megaloblastic changes in the bone marrow and other tissues with rapidly dividing cells
  
  
  OBJECTIVE
  To assess the effectiveness of oral folic acid supplementation alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes.
  
  
  METHODS
  We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2012) and we contacted major organisations working in micronutrient supplementation, including UNICEF Nutrition Section, World Health Organization (WHO) Maternal and Reproductive Health, WHO Nutrition Division, and National Center on Birth defects and Developmnetal Disabilities, US Centers for Disease Control and Prevention (CDC).
  
  
  METHODS
  All randomised, cluster-randomised and cross-over controlled trials evaluating supplementation of folic acid alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) in pregnancy.
  
  
  METHODS
  Two review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy.
  
  
  RESULTS
  Thirty-one trials involving 17,771 women are included in this review. This review found that folic acid supplementation has no impact on pregnancy outcomes such as preterm birth (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.38; three studies, 2959 participants), and stillbirths/neonatal deaths (RR 1.33, 95% CI 0.96 to 1.85; three studies, 3110 participants). However, improvements were seen in the mean birthweight (mean difference (MD) 135.75, 95% CI 47.85 to 223.68). On the other hand, the review found no impact on improving pre-delivery anaemia (average RR 0.62, 95% CI 0.35 to 1.10; eight studies, 4149 participants; random-effects), mean pre-delivery haemoglobin level (MD -0.03, 95% CI -0.25 to 0.19; 12 studies, 1806 participants), mean pre-delivery serum folate levels (standardised mean difference (SMD) 2.03, 95% CI 0.80 to 3.27; eight studies, 1250 participants; random-effects), and mean pre-delivery red cell folate levels (SMD 1.59, 95% CI -0.07 to 3.26; four studies, 427 participants; random-effects). However, a significant reduction was seen in the incidence of megaloblastic anaemia (RR 0.21, 95% CI 0.11 to 0.38, four studies, 3839 participants).
  
  
  CONCLUSIONS
  We found no conclusive evidence of benefit of folic acid supplementation during pregnancy on pregnancy outcomes.
authors.affiliation: Division of Women and Child Health, Aga Khan University Hospital, Karachi, Pakistan. zulfiqar.bhutta@aku.edu
authors.forename: Zohra S
authors.initials: ZS
authors.lastname: Lassi
authors.forename: Rehana A
authors.initials: RA
authors.lastname: Salam
authors.forename: Batool A
authors.initials: BA
authors.lastname: Haider
authors.forename: Zulfiqar A
authors.initials: ZA
authors.lastname: Bhutta
mesh_terms: D000740:Anemia / Q000097:blood / Q000517:prevention & control; D001724:Birth Weight; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006441:Hemoglobin A / Q000032:analysis; D006801:Humans; D008429:Maternal Welfare; D018977:Micronutrients / Q000008:administration & dosage*; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000097:blood / Q000517:prevention & control; D011256:Pregnancy Outcome; D047928:Premature Birth / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic; D050497:Stillbirth; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D018977:Micronutrients; D014803:Vitamin B Complex; D006441:Hemoglobin A; D005492:Folic Acid
references.citation: J Clin Periodontol. 1982 May;9(3):275-80
references.pmid: 7047579
references.citation: Br Med J. 1968 May 18;2(5602):390-4
references.pmid: 5648998
references.citation: Lancet. 1993 Jan 16;341(8838):148-9
references.pmid: 8093747
references.citation: Eur J Obstet Gynecol Reprod Biol. 1995 Jul;61(1):31-7
references.pmid: 8549845
references.citation: Pediatrics. 1996 Nov;98(5):911-7
references.pmid: 8909485
references.citation: J R Coll Gen Pract. 1976 Mar;26(164):228-30
references.pmid: 1263177
references.citation: Am J Clin Nutr. 1992 Aug;56(2):365-70
references.pmid: 1636615
references.citation: Eur J Obstet Gynecol Reprod Biol. 1999 Dec;87(2):111-3; discussion 103-4
references.pmid: 10597956
references.citation: BMJ. 2003 Mar 15;326(7389):571
references.pmid: 12637400
references.citation: Int J Gynaecol Obstet. 2009 Jul;106(1):3-7
references.pmid: 19368922
references.citation: Southeast Asian J Trop Med Public Health. 1983 Sep;14(3):317-23
references.pmid: 6658501
references.citation: J Nutr. 1998 Feb;128(2):204-8
references.pmid: 9446844
references.citation: Am J Clin Nutr. 1994 Feb;59(2 Suppl):511S-515S; discussion 515S-516S
references.pmid: 8304289
references.citation: Am J Clin Nutr. 1974 Apr;27(4):339-44
references.pmid: 4817634
references.citation: J Nutr. 2008 Oct;138(10):1946-50
references.pmid: 18806105
references.citation: Gynecol Obstet Invest. 1981;12(6):294-304
references.pmid: 7297938
references.citation: Br J Obstet Gynaecol. 1981 Jun;88(6):601-6
references.pmid: 7248217
references.citation: J Obstet Gynaecol Br Commonw. 1972 Mar;79(3):222-5
references.pmid: 5016319
references.citation: Ann Trop Med Parasitol. 1986 Apr;80(2):211-33
references.pmid: 3530158
references.citation: Eur J Clin Nutr. 1995 Aug;49(8):613-22
references.pmid: 7588512
references.citation: Am J Clin Nutr. 2006 Apr;83(4):788-94
references.pmid: 16600929
references.citation: Br Med J. 1965 Feb 20;1(5433):480-5
references.pmid: 14238675
references.citation: J Obstet Gynaecol Br Commonw. 1971 Sep;78(9):781-5
references.pmid: 5097161
references.citation: J Pediatr Gastroenterol Nutr. 1983 Nov;2(4):622-8
references.pmid: 6685760
references.citation: BJOG. 2000 Sep;107(9):1149-54
references.pmid: 11002960
references.citation: J Clin Pathol. 1970 Jul;23(5):379-91
references.pmid: 5476865
references.citation: Hum Nutr Clin Nutr. 1986 Jan;40(1):3-13
references.pmid: 3957708
references.citation: Lancet. 2001 Dec 15;358(9298):2074-7
references.pmid: 11755634
references.citation: Pregnancy Hypertens. 2012 Jul;2(3):198
references.pmid: 26105254
references.citation: Obstet Gynecol. 1992 May;79(5 ( Pt 1)):719-22
references.pmid: 1565355
references.citation: J Clin Periodontol. 1980 Oct;7(5):402-14
references.pmid: 7007454
references.citation: Br J Nutr. 2006 Jul;96(1):182-90
references.pmid: 16870008
references.citation: Food Nutr Bull. 2008 Jun;29(2 Suppl):S238-44
references.pmid: 18709899
references.citation: J Obstet Gynaecol Br Commonw. 1972 Oct;79(10):916-20
references.pmid: 5085832
references.citation: Adv Exp Med Biol. 2005;569:109-13
references.pmid: 16137113
references.citation: Am J Clin Nutr. 1975 May;28(5):465-70
references.pmid: 1130304
references.citation: Acta Obstet Gynecol Scand Suppl. 1997;165:71-5
references.pmid: 9219461
references.citation: Saudi Med J. 2009 Jan;30(1):88-97
references.pmid: 19139780
references.citation: Acta Obstet Gynecol Scand. 1969;48(3):339-48
references.pmid: 4905774
references.citation: J Obstet Gynaecol Br Commonw. 1968 Feb;75(2):133-7
references.pmid: 5641006
references.citation: BMJ. 2004 Dec 11;329(7479):1375-6
references.pmid: 15591563
references.citation: Dev Pharmacol Ther. 1982;4 Suppl:58-65
references.pmid: 7128394
references.citation: Am J Clin Nutr. 2000 May;71(5 Suppl):1295S-303S
references.pmid: 10799405
references.citation: Trop Geogr Med. 1977 Mar;29(1):24-8
references.pmid: 883006
references.citation: Br J Nutr. 2001 May;85 Suppl 2:S115-24
references.pmid: 11509099
references.citation: Am J Clin Nutr. 2008 Aug;88(2):253-4
references.pmid: 18689357
references.citation: Eur J Clin Nutr. 2012 Feb;66(2):261-8
references.pmid: 22085869
references.citation: J Nutr. 2006 May;136(5):1389-94
references.pmid: 16614435
references.citation: N Engl J Med. 1992 Dec 24;327(26):1832-5
references.pmid: 1307234
references.citation: Br Med J. 1960 Aug 27;2(5199):636-40
references.pmid: 13850046
references.citation: Br J Nutr. 2010 Jun;103(11):1648-56
references.pmid: 20211038
references.citation: Am J Clin Nutr. 1997 Feb;65(2):572-3
references.pmid: 9022548
references.citation: Ann Chir Gynaecol Fenn. 1968;57(3):382-6
references.pmid: 5710676
references.citation: Sangre (Barc). 1989 Feb;34(1):24-7
references.pmid: 2711281
references.citation: Thromb Res. 2004;114(1):25-7
references.pmid: 15262481
references.citation: J Nutr. 2011 Oct;141(10):1912-7
references.pmid: 21865563
references.citation: Am J Clin Nutr. 2007 May;85(5):1392-400
references.pmid: 17490978
references.citation: Am J Med Genet. 1996 Mar 15;62(2):179-83
references.pmid: 8882400
references.citation: Br J Obstet Gynaecol. 1985 Oct;92 Suppl 5:1-119
references.pmid: 4052352
references.citation: Isr J Med Sci. 1976 Dec;12(12):1410-7
references.pmid: 138664
references.citation: Paediatr Perinat Epidemiol. 2005 Mar;19(2):112-24
references.pmid: 15787886
references.citation: J Nutr. 2003 Nov;133(11):3492-8
references.pmid: 14608063
references.citation: Epidemiology. 1995 May;6(3):212-8
references.pmid: 7619925
references.citation: Am J Epidemiol. 2009 Nov 1;170(9):1127-36
references.pmid: 19778983
references.citation: Lancet. 1962 Nov 17;2(7264):1015-8
references.pmid: 14025595
references.citation: Br J Haematol. 1967 Jul;13(4):503-9
references.pmid: 6029952
references.citation: Am J Clin Nutr. 2006 May;83(5):993-1016
references.pmid: 16685040
references.citation: Lancet. 1995 Aug 12;346(8972):393-6
references.pmid: 7623568
references.citation: Ann Hum Genet. 1998 Sep;62(Pt 5):379-96
references.pmid: 10088035
references.citation: Acta Obstet Gynecol Scand. 1967;46(S7):71-85
references.pmid: 4865965
references.citation: Am J Clin Nutr. 1970 Jun;23(6):725-30
references.pmid: 5431038
references.citation: Cochrane Database Syst Rev. 2006 Oct 18;(4):CD004905
references.pmid: 17054223
references.citation: Am J Clin Nutr. 2009 Jul;90(1):132-40
references.pmid: 19474130
references.citation: JAMA. 1993 Dec 8;270(22):2693-8
references.pmid: 8133587
references.citation: Geburtshilfe Frauenheilkd. 1980 Mar;40(3):253-8
references.pmid: 7364189
references.citation: Med J Aust. 1971 Jul 3;2(1):17-21
references.pmid: 4937681
references.citation: Hypertension. 2004 Jun;43(6):1279-82
references.pmid: 15096466
references.citation: J Nutr. 2001 Jul;131(7):1928-37
references.pmid: 11435509
references.citation: Minerva Ginecol. 1992 Jan-Feb;44(1-2):33-7
references.pmid: 1508382
references.citation: Br J Obstet Gynaecol. 1976 Feb;83(2):132-6
references.pmid: 1032813
references.citation: Br Med J. 1968 Nov 9;4(5627):356-60
references.pmid: 5683581
references.citation: Schweiz Med Wochenschr. 1977 Dec 31;107(52):1943-7
references.pmid: 563620
references.citation: Schweiz Med Wochenschr. 1974 Mar 9;104(10):351-6
references.pmid: 4818631
references.citation: J Nutr. 2009 Aug;139(8):1575-81
references.pmid: 19549749
references.citation: JAMA. 2010 Dec 22;304(24):2716-23
references.pmid: 21177506
references.citation: Am J Clin Nutr. 1965 Jun;16:472-9
references.pmid: 14297280
references.citation: Br Med J. 1966 Dec 24;2(5529):1568-71
references.pmid: 5926263
references.citation: J Infect Dis. 2008 Nov 15;198(10):1550-3
references.pmid: 18831691
references.citation: Am J Clin Nutr. 2003 Dec;78(6):1194-202
references.pmid: 14668283
references.citation: J Obstet Gynaecol Br Commonw. 1968 Apr;75(4):425-32
references.pmid: 5653282
references.citation: Cochrane Database Syst Rev. 2010 Oct 06;(10):CD007950
references.pmid: 20927767
references.citation: Arch Gynecol Obstet. 2007 Feb;275(2):121-4
references.pmid: 16941105
references.citation: Am J Clin Nutr. 2011 Dec;94(6 Suppl):1880S-1888S
references.pmid: 21849596
references.citation: Acta Obstet Gynecol Scand. 1979;58(4):343-6
references.pmid: 525266
references.citation: Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004736
references.pmid: 16856058
references.citation: Am J Obstet Gynecol. 1971 Sep;111(1):13-6
references.pmid: 5096349
references.citation: Food Nutr Bull. 2009 Dec;30(4 Suppl):S480-7
references.pmid: 20120789
references.citation: PLoS Med. 2009 May 5;6(5):e1000061
references.pmid: 19434228
references.citation: Acta Obstet Gynecol Scand. 1969;48(3):349-56
references.pmid: 5370775
references.citation: Ann Pediatr (Paris). 1982 Apr;29(4):276-80
references.pmid: 7092073
references.citation: Am J Obstet Gynecol. 1975 Jun 1;122(3):332-6
references.pmid: 1130456
references.citation: Lancet. 1991 Jul 20;338(8760):131-7
references.pmid: 1677062
references.citation: BMJ. 2008 Nov 07;337:a2001
references.pmid: 18996930
references.citation: Br J Obstet Gynaecol. 1979 May;86(5):364-70
references.pmid: 465384
references.citation: PLoS Clin Trials. 2006 Oct 20;1(6):e28
references.pmid: 17053829
references.citation: J Obstet Gynaecol Br Commonw. 1971 Sep;78(9):769-75
references.pmid: 5097159
references.citation: Br Med J. 1970 Jan 3;1(5687):16-7
references.pmid: 5460838
references.citation: J Obstet Gynaecol Br Commonw. 1966 Dec;73(6):934-9
references.pmid: 5927784
references.citation: BMJ. 1993 Jun 19;306(6893):1645-8
references.pmid: 8324432
references.citation: Arch Dis Child. 2008 Aug;93(8):660-4
references.pmid: 18644934