Health Professionals:

Research on Folic Acid

Several studies have reported associations between folic acid intake and other pregnancy outcomes.

Preterm Birth

Lower folate intake (equal to or less than 240 micrograms/day) and lower serum folate at week 28 of gestation was associated with a higher risk for preterm delivery and low birth weight (Scholl et al. 1996). One study reported that dietary folate intake equal to or less than 500 micrograms/day or low serum or red blood cell folate concentrations during the second trimester resulted in a significantly higher risk for pre-term delivery (Relative Risk 1.7-1.8) (Siega-Riz et al. 2004).

An observational study including almost 6 million California infants compared adverse pregnancy outcomes prior to and after folic acid fortification of cereal grain foods. Fortification coincided with small but statistically significant reductions in babies born with low or very low birth weights (6-9% reduction) or preterm delivery (4% reduction) (Shaw et al. 2004).

A large population based study in Hungary examined the effect of vitamin supplementation in the second and third trimesters on pregnancy outcomes, including fetal growth and preterm birth (Czeizel et al. 2010). Folic acid intake in the third trimester was associated with a 0.6 week longer gestational age and a more significant reduction in the rate of pre-term births. Overall, the results indicate a significant reduction in preterm births after supplementation of folic acid in the second and third trimester of pregnancy.

A cohort study analyzing data from 34,480 low-risk pregnancies in the US showed that compared to women who did not take a folic acid supplement prior to conception, the risk of spontaneous preterm delivery between 20 and 28 weeks was 70% lower in women who took folic acid supplements for a year or longer before pregnancy (Bukowski et al. 2009). This study also reported that long term folate supplementation reduced the risk of preterm birth between 28 and 32 weeks by over 50%, but supplementation had no effect on preterm birth past 32 weeks. This study supports the association between long term folate supplementation and the reduced risk of early pre-term birth.

A systematic review and meta-analysis of cohort studies that investigated the effect of folic acid supplementation on the risk of preterm births and small for gestational age births reported that when folic acid was taken after conception there was a 32% reduced risk for preterm birth (Zhang et al. 2016). When folic acid was taken prior to conception, there was no significant effect on preterm birth. A review and meta-analysis of 5 randomized controlled trials reported that compared to controls folic acid supplementation during pregnancy was not effective in preventing preterm birth under 37 weeks gestation (Saccone and Berghella 2016). Other studies failed to confirm an association between folate status and risk for preterm birth (Ronnenberg et al. 2002), including a large randomized controlled trial (Czeizel et al. 1994b).

A prospective cohort study that included over 240,000 pregnant women in the Jiaxing Birth Cohort from Southeast China during 1999-2012 reported that pre-conceptional folic acid use was associated with lower risk of preterm birth compared to non-use (Zheng et al. 2016). Similarly, a study of over 10,000 women from Lanzhou, China between 2010 and 2012 reported that folic acid supplement use during pre-conception and/or pregnancy and of more than 12 weeks duration was associated with a 33% reduced risk for preterm birth (Liu et al. 2016b).

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Multiple Births

There has been speculation that folic acid supplementation during the periconceptional period is associated with an increased risk for multiple births.

A Hungarian randomized controlled trial described a significant increase in multiple births in women taking a multivitamin containing 800 micrograms of folic acid compared to women taking trace elements (Czeizel et al. 1994a). A subsequent study in Sweden found >70% increased risk for twin births with the use of folic acid periconceptionally (Kallen 2004). A systematic review of data published from 1994-2006 found a non-significant but persistent association between the intake of folic acid from supplementation or fortification, and twinning (Muggli and Halliday 2007).

An analysis of the Medical Research Council's intervention cohort combined with an observational study in the United Kingdom reported no increase in multiple births with folic acid supplementation (Mathews et al. 1999). The strongest data come from a non-randomized intervention study in >240,000 Chinese women. Women taking 400 micrograms of folic acid on a daily basis before and during pregnancy did not have a higher risk for twin pregnancies compared to women not taking folic acid (Li et al. 2003).

Observational studies that evaluated multiple birth rates before and after folic acid fortification include three studies finding no difference in the number of multiple births before and after fortification (Lawrence et al. 2004, Shaw et al. 2003, Waller et al. 2003) and one study reporting an increase in multiple births but only in women >30 years of age, which could possibly be explained by the use of assisted reproductive technologies (ART) in this age group (Kucik 2004).

Studies of multiple births can be highly confounded by the use of ART and the use of these technologies should be accounted for in studies (Berry et al. 2005). A Norwegian study reported no association between folate use and twin pregnancies after exclusion of pregnancies associated with ART (Vollset et al. 2005).

A study using United States birth and fetal death records to investigate whether twinning rates have increased since folic acid fortification revealed that twin gestation rates in women under age 20 years who were not using fertility treatments increased after fortification with folic acid, but only by a small amount. The authors concluded that the pattern of increase was not consistent with a fortification effect and that fortification was not the likely cause of the increase (Signore et al. 2005). A comprehensive evidence review conducted for the U.S. Preventive Services Task Force concluded that there was no consistent evidence that folic acid supplementation was associated with increased risk for twinning (Viswanathan et al. 2017).

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Miscarriage

The Hungarian randomized controlled trial observed a small but significant increase in miscarriages in women taking a daily multivitamin with 800 micrograms of folic acid compared to women taking a trace element tablet (Hook & Czeizel 1997). However, the Medical Research Council's randomized study (Wald & Hackshaw 2001) and the China folic acid intervention study (Gindler et al. 2001) failed to confirm such an association.

An observational study in California reported a small increase in miscarriages by women taking folic acid, but this increase was not statistically significant (Windham et al. 2000). On the contrary, other studies report an association between low folate status and increased risk for miscarriage (Nelen et al. 2000, George et al. 2002).

A Cochrane systematic review of clinical trials concluded that, based on 6 studies related to folic acid, there was no evidence of any difference in the risk of total fetal loss, early or late miscarriage, or stillbirth between women who took folic acid with or without multivitamins and/or iron compared with women who did not take folic acid (Balogun et al. 2016). Preliminary data from a large population-based cohort study that included over 1.5 million Chinese women reported that compared to women who did not take folic acid supplements before and during pregnancy, women who took folic acid supplements had a 41% to 47% lower odds for having a miscarriage (He et al. 2016). Reduced odds for miscarriage varied depending on when folic acid supplementation was started (i.e., just before pregnancy or 3 months before the last menstrual period).

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