Effects and safety of periconceptional folate supplementation for preventing birth defects

Abstract

Background It has been reported that neural tube defects can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear. Objectives This review updates and expands a previous Cochrane Review assessing the effects of periconceptional supplementation with folic acid to reduce neural tube defects (NTDs). We examined whether folate supplementation before and during early pregnancy can reduce neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (July 2010). Additionally, we searched the international clinical trials registry platform and contacted relevant organisations to identify ongoing and unpublished studies. Selection criteria We included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity. Data collection and analysis We assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion, one author extracted data and a second checked for accuracy. Main results Five trials involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs) were included. Overall, the results are consistent in showing a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.32, 95% CI 0.17 to 0.60). There is no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. There were no included trials assessing the effects of this intervention on maternal blood folate or anaemia at term. We found no evidence of short-term side effects. Authors’ conclusions Folic acid, alone or in combination with vitamins and minerals, prevents NTDs but does not have a clear effect on other birth defects.

Scientific Opinion on the substantiation of a health claim related to increasing maternal folate status by supplemental folate intake and reduced risk of neural tube defects pursuant to Article 14 of Regulation (EC) No 1924/2006

“…This consensus is in line with a recent systematic review and meta-analysis (De-Regil et al, 2010) which included six randomised and quasi-randomised trials (Laurence et al, 1981;MRC Vitamin Study Research Group, 1991;Czeizel and Dudas, 1992;Kirke et al, 1992;Czeizel et al, 1994;Indian Council of Medical Research, 2000) in women who became or were <12 weeks pregnant at the time of the intervention and in which supplemental folic acid was administered vs. no treatment, placebo or other micronutrients without folic acid on the risk of occurrence or reoccurrence of NTD. These studies evaluated a total 3 066 births in the intervention and 3 039 births in the control groups, with 12 occurrences of NTD in the intervention and 45 occurrences in the control arms.…”

Scientific Opinion on the substantiation of a health claim related to increasing maternal folate status by supplemental folate intake and reduced risk of neural tube defects pursuant to Article 14 of Regulation (EC) No 1924/2006

“…This consensus is in line with a recent systematic review and meta-analysis (De-Regil et al, 2010) which included six randomised and quasi-randomised trials (Laurence et al, 1981;MRC Vitamin Study Research Group, 1991;Czeizel and Dudas, 1992;Kirke et al, 1992;Czeizel et al, 1994;Indian Council of Medical Research, 2000) in women who became or were <12 weeks pregnant at the time of the intervention and in which supplemental folic acid was administered vs. no treatment, placebo or other micronutrients without folic acid on the risk of occurrence or reoccurrence of NTD. These studies evaluated a total 3 066 births in the intervention and 3 039 births in the control groups, with 12 occurrences of NTD in the intervention and 45 occurrences in the control arms.…”

Women's Awareness of Periconceptional Use of Folic Acid before and after Their Antenatal Visits

“…Although there has been a significant overall mean reduction of 32% in the prevalence of NTDs in the UK over a 10-year period up to 1999, 13 the expectations of a 72% reduction estimated by a Cochrane review of five clinical trials had not been met. 14 The contributory factors for these are the high number of unplanned pregnancy (25% in our study compared to 38% in Bitzer et al's study), low percentage of women (40% in this study) knowing that they should take folic acid at least one month before pregnancy, and lack of compliance to daily dose (about 30% in this study compared to 37-44% in Bitzer et al's study.) 12 Preconceptional counseling about the value of folic acid should be integrated in the school sex education and into family planning consultation either at the Primary Care Team or the dedicated family planning services.…”

Birth prevalence and determinants of neural tube defects among newborns in Ethiopia: A systematic review and meta-analysis

“…The meta-analysis result showed that women who took folic acid supplementation at any time within the pregnancy period were 71% less likely to have newborns with neural tube defects than their counterparts. The finding is supported by studies that indicate folic acid supplementation during the periconceptional period reduces the risk of neural tube defects [ 68 – 70 ]. Folate-preventable NTDs are high due to inadequate counselling about the benefits of folic acid for the prevention of congenital malformation and a lack of periconceptional folic acid supplementation.…”

Scientific Opinion on the substantiation of a health claim related to increasing maternal folate status by supplemental folate intake and reduced risk of neural tube defects pursuant to Article 14 of Regulation (EC) No 1924/2006

“…This consensus is in line with a recent systematic review and meta-analysis (De-Regil et al, 2010) which included six randomised and quasi-randomised trials (Laurence et al, 1981;MRC Vitamin Study Research Group, 1991;Czeizel and Dudas, 1992;Kirke et al, 1992;Czeizel et al, 1994;Indian Council of Medical Research, 2000) in women who became or were <12 weeks pregnant at the time of the intervention and in which supplemental folic acid was administered vs. no treatment, placebo or other micronutrients without folic acid on the risk of occurrence or reoccurrence of NTD. These studies evaluated a total 3 066 births in the intervention and 3 039 births in the control groups, with 12 occurrences of NTD in the intervention and 45 occurrences in the control arms.…”

Women's Awareness of Periconceptional Use of Folic Acid before and after Their Antenatal Visits

“…Although there has been a significant overall mean reduction of 32% in the prevalence of NTDs in the UK over a 10-year period up to 1999, 13 the expectations of a 72% reduction estimated by a Cochrane review of five clinical trials had not been met. 14 The contributory factors for these are the high number of unplanned pregnancy (25% in our study compared to 38% in Bitzer et al's study), low percentage of women (40% in this study) knowing that they should take folic acid at least one month before pregnancy, and lack of compliance to daily dose (about 30% in this study compared to 37-44% in Bitzer et al's study.) 12 Preconceptional counseling about the value of folic acid should be integrated in the school sex education and into family planning consultation either at the Primary Care Team or the dedicated family planning services.…”

Birth prevalence and determinants of neural tube defects among newborns in Ethiopia: A systematic review and meta-analysis

“…The meta-analysis result showed that women who took folic acid supplementation at any time within the pregnancy period were 71% less likely to have newborns with neural tube defects than their counterparts. The finding is supported by studies that indicate folic acid supplementation during the periconceptional period reduces the risk of neural tube defects [ 68 – 70 ]. Folate-preventable NTDs are high due to inadequate counselling about the benefits of folic acid for the prevention of congenital malformation and a lack of periconceptional folic acid supplementation.…”

Scientific Opinion on the substantiation of a health claim related to increasing maternal folate status by supplemental folate intake and reduced risk of neural tube defects pursuant to Article 14 of Regulation (EC) No 1924/2006

“…This consensus is in line with a recent systematic review and meta-analysis (De-Regil et al, 2010) which included six randomised and quasi-randomised trials (Laurence et al, 1981;MRC Vitamin Study Research Group, 1991;Czeizel and Dudas, 1992;Kirke et al, 1992;Czeizel et al, 1994;Indian Council of Medical Research, 2000) in women who became or were <12 weeks pregnant at the time of the intervention and in which supplemental folic acid was administered vs. no treatment, placebo or other micronutrients without folic acid on the risk of occurrence or reoccurrence of NTD. These studies evaluated a total 3 066 births in the intervention and 3 039 births in the control groups, with 12 occurrences of NTD in the intervention and 45 occurrences in the control arms.…”

Women's Awareness of Periconceptional Use of Folic Acid before and after Their Antenatal Visits

“…Although there has been a significant overall mean reduction of 32% in the prevalence of NTDs in the UK over a 10-year period up to 1999, 13 the expectations of a 72% reduction estimated by a Cochrane review of five clinical trials had not been met. 14 The contributory factors for these are the high number of unplanned pregnancy (25% in our study compared to 38% in Bitzer et al's study), low percentage of women (40% in this study) knowing that they should take folic acid at least one month before pregnancy, and lack of compliance to daily dose (about 30% in this study compared to 37-44% in Bitzer et al's study.) 12 Preconceptional counseling about the value of folic acid should be integrated in the school sex education and into family planning consultation either at the Primary Care Team or the dedicated family planning services.…”

Birth prevalence and determinants of neural tube defects among newborns in Ethiopia: A systematic review and meta-analysis

“…The meta-analysis result showed that women who took folic acid supplementation at any time within the pregnancy period were 71% less likely to have newborns with neural tube defects than their counterparts. The finding is supported by studies that indicate folic acid supplementation during the periconceptional period reduces the risk of neural tube defects [ 68 – 70 ]. Folate-preventable NTDs are high due to inadequate counselling about the benefits of folic acid for the prevention of congenital malformation and a lack of periconceptional folic acid supplementation.…”