Research on Folic Acid
Several studies have associated folic acid or multivitamin use with reduced risk for other birth 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).
Risk reduction appears to be strongest for ventricular septal defects and some conotruncal defects (Botto et al. 2003). However, 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 concurrently taking a multivitamin supplement with folic acid and these medications (Hernandez-Diaz et al. 2000).
More recently published evidence support a role for folic acid in congenital heart defect (CHD) risk reduction. A 10 year case control study conducted in the northern Netherlands supported the hypothesis that periconceptional folic acid intake reduces CHD risk in infants. Intake of at least 400 micrograms per day of folic acid through 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).
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 measured 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 ug/day) was associated with a 39% reduced risk of CLP. Independent of supplements, diets rich in high folate containing foods attenuated the risk reduction somewhat to 25%. The lowest risk of cleft lip was among women who had folate rich diets and also took folic acid supplements and multivitamins. 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 isolated CLP (Shaw et al. 1995) and CLP (Itikalaet al. 2001). Risk reduction in both studies was approximately 50% when multivitamins were taken periconceptionally.
A multicenter U.S. case-control study 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 a higher 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 analyzed folic acid consumption during pregnancy and risk of oral clefts using five prospective studies and 12 case control studies. The results support the hypothesis that there is a protective effective of folic acid-containing supplement intake during pregnancy on the risk of oral clefts. Specifically, the data from the case control studies revealed that those 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).
These studies suggest that the protective effect of folic acid may be dose dependent.
A randomized controlled trial in Hungary found no association between periconceptional use of multivitamins containing 800 milligrams 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 review of the main studies on the effects of folic acid and orofacial defects reports that some studies have reported preventive effects, but the evidence is inconsistent and several questions such as dose and prevention of recurrence versus occurrence remain unanswered. (Wehby and Murray 2010).
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).
Studies are less supportive of a role for folic acid in reducing the risk for limb deficiencies.
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).
Folic acid or multivitamins may also play a role in reducing the risk for other birth defects, including those of the heart, urinary tract, and some orofacial defects. Data are less supportive of a role for folic acid in reducing the risk for limb defects.