Health Professionals:

Research on Folic Acid

Several studies have associated use of folic acid or folic acid-containing multivitamins with reduced risk for other birth defects. However, studies show mixed results.

Heart Defects

Several studies have examined the association between maternal use of multivitamins or folic acid and the reduced risk for heart defects in infants.

A randomized controlled trial conducted in Hungary found that women taking multivitamins containing 800 micrograms folic acid during the periconceptional period had a 58% reduced risk of having a child with a cardiovascular defect (Czeizel et al. 1998). A population-based case-control study conducted in Atlanta reported that the use of multivitamin supplements periconceptionally reduced the risk for heart defects by 24% (Botto et al. 2000). A population-based case-control study in California reported a 47% risk reduction for women consuming folic acid-containing supplements after controlling for confounders including maternal race/ethnicity, age, and education (Shaw et al. 1995). Several studies have found no association between periconceptional folic acid (Scanlon et al. 1998) or multivitamin (Werler et al. 1999) use and reduced risk for heart defects.

Because multivitamins contain vitamins and minerals other than folic acid there is no direct evidence that folic acid is responsible for the risk reduction seen in the before-mentioned studies. However, there is indirect evidence. A large case-control study reported that women taking folate antagonist medications (dihydrofolate reductase inhibitors) and not taking a multivitamin containing folic acid had an almost 8-fold increased risk of having a baby with a heart defect. This elevated risk was reduced to 1.5-fold (not statistically significant) in women taking a folic acid-containing multivitamin supplement concurrently with these medications (Hernandez-Diaz et al. 2000).

A 10-year case control study conducted in the northern Netherlands supported the hypothesis that periconceptional folic acid intake reduces congenital heart defect (CHD) risk in infants. Intake of at least 400 micrograms per day of folic acid from folic acid supplements or multivitamins was associated with approximately a 20% reduction in the prevalence of any type of CHD compared to non-users (van Beynum et al. 2010). To examine the potential effects of fortification on CHD incidence, a time trend analysis was conducted that included 1,324,440 births in Quebec in 1990-2005. Prior to mandatory folic acid fortification there was no change in the birth prevalence of severe CHD, but in the 7 years after fortification there was a significant 6% decrease in CHD per year, providing additional support that folic acid has preventive effects on CHD (Ionescu-Ittu et al. 2009). A similar large population-based cohort study in Canada reported that the rates of most subtypes of CHD decreased significantly when comparing pre-folic acid fortification (i.e., prior to 1998) to post-folic acid fortification (Liu et al. 2016a).

A meta-analysis of 20 case-control studies conducted in Chinese, American, and Dutch populations reported that folic acid supplementation during pregnancy was associated with a reduction in CHD risk in Chinese and European women, but not in American women (Xu et al. 2016). A major limitation of this study was that the researchers were not able to analyze for the effects of folic acid dose, timing of folic acid initiation, and duration of supplement intake.

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Orofacial Defects

The orofacial defects discussed here include cleft lip with and without cleft palate (CLP) and cleft palate alone (CP).

A population based case-control study in Norway investigated the association of facial clefts with maternal intake of folic acid supplements, multivitamins, and dietary folate. The results indicated that folic acid supplementation during early pregnancy (>400 micrograms/day) was associated with a 39% reduced risk of CLP. Independent of supplements, diets rich in foods that are high in folate attenuated the risk reduction somewhat to 25%. The lowest risk of cleft lip was among women who consumed folate rich diets and also took folic acid supplements and multivitamins at the same time. Folic acid was not associated with reduced risk for CP (Wilcox et al. 2007).
Several other case-control studies report a significant association between periconceptional intake of multivitamins and CLP (Shaw et al. 1995, Itikala et al. 2001). Risk reduction in both studies was approximately 50% when multivitamins were taken periconceptionally.

A multicenter case-control study in the US reported a 60% lower risk for CP in women taking multivitamins before and during early pregnancy (Werler et al. 1999). In this study, no risk reduction was observed for CLP.

A case-control study from the Netherlands reported that folic acid intake as part of a multivitamin or single tablet supplement was associated with a 47% reduced risk for CLP in offspring when the supplement was taken beginning 4 weeks before and through 8 weeks after conception (van Rooij et al. 2004). In this study, highest risk reduction was observed in mothers who concurrently took supplemental folic acid and had dietary folate intakes greater than 200 micrograms/day.

A comparison of two Hungarian datasets reported that high intake of folic acid (generally 6 milligrams/day during the critical palate formation period) was associated with reducing the risk for CLP by 18% and CP by 24%, but no significant risk reduction was associated with a lower dose of folic acid (800 micrograms/day) (Czeizel et al. 1999).

A meta-analysis (5 prospective and 12 case control studies) investigating folic acid consumption during pregnancy and risk of oral clefts supported the hypothesis that taking a folic acid-containing supplement during pregnancy is associated with a protective effective against the development of oral clefts. Specifically, data from the case control studies revealed that study participants who took folic acid-containing supplements during pregnancy were 33% less likely to have a child with any oral cleft, 29% less likely to have a child with CLP, and 20% less likely to have a child with CP. The data from the prospective studies revealed that those who took supplements during pregnancy were 45% less likely to have a child with any oral cleft and 49% less likely to have a child with CLP (Badovinac et al. 2007).

In a non-randomized intervention study, women supplemented with multivitamins plus 10 milligrams of folic acid on a daily basis had a significantly reduced risk for a recurrence of CLP (Tolarova 1982).

A randomized controlled trial in Hungary found no association between periconceptional use of multivitamins containing 800 micrograms of folic acid and risk for orofacial clefts (Czeizel 1993). A retrospective population-based study in Canada reported no change in the prevalence of orofacial clefts following folic acid fortification of cereal grain products (Ray et al. 2003).

A study in central California comparing the incidence of live births and stillbirths pre- and post-folic acid fortification from 1989-2010 reported that trends in the reduction of the incidence of orofacial clefts, cleft lip with/without palate, and cleft palate was more marked post-fortification compared to pre-fortification (Yang et al. 2016).  

A Cochrane Collaboration review evaluated randomized or quasi-randomized trials relating to the intake of periconceptional folic acid alone or folic acid plus other vitamins and minerals on the risk for a developing several different birth defects. The analysis included data from 5 trials and concluded that supplementation had no significant effect on the risk for cleft palate or cleft lip (De-Regil et al. 2015).

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Urinary Tract Defects

Case-control studies have reported that women in Washington State taking multivitamins before and during the first trimester had an 86% reduced risk for having a baby with a urinary tract defect (Li et al. 1995). A randomized controlled trial conducted in Hungary found an almost 80% reduced risk for urinary tract defects in the infants of women taking a multivitamin with 800 micrograms folic acid during the periconceptional period compared with women consuming a trace element supplement (Czeizel 1996). However, a subsequent cohort-controlled trial in Hungary failed to find a significant risk reduction for infants of women who took a multivitamin compared to unsupplemented women (Czeizel et al. 2004).

A retrospective case-control study including 562 children with congenital anomalies of the kidney or urinary tract (CAKUT) reported that the maternal use of folic acid supplements one month before conception through the eighth week after conception was associated with a 30% increased risk for CAKUT, while use of multivitamins containing folic acid during the same time period was associated with a 50% decreased risk for CAKUT (Groen In 't Woud et al. 2016).

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Limb Defects

A Hungarian randomized controlled trial reported an 80% risk reduction with periconceptional multivitamin use, but the results were not statistically significant (Czeizel 1998). A Hungarian cohort-controlled trial failed to find an association between multivitamin use and reduced risk for limb deficiencies (Czeizel et al. 2004). Similarly, three case-control studies reported null findings (Shaw et al. 1995, Werler et al. 1999, Czeizel 1995).

A case-control study in Western Australia found no evidence that folate intake during the periconceptional period was an important factor in the prevention of birth defects other than neural tube defects (Bower et al 2006).

Data from the 1997-2003 National Birth Defects Prevention Study indicated that use of a supplement containing folic acid was not associated with transverse or longitudinal limb deficiencies; however, lower intakes of certain nutrients, particularly folate and riboflavin may be associated with an increased risk for these limb deficiencies.

A single study (the Atlanta Birth Defects Case-Control Study) reported a significant 53% reduced risk for limb deficiencies in women taking a multivitamin 3 months prior to and 3 months following conception (Yang et al. 1997).

Data from the Canadian-based Alberta Congenital Anomalies Surveillance System reported no significant difference in the rates of upper or lower limb deformities when comparing data from before (1992-1996) and after (1999-2003) folic acid fortification (Godwin et al. 2008).

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