Folic acid supplements before conception and in early pregnancy (up to 12 weeks) for the prevention of birth defects

Folic acid is a synthetic form of folate used in supplements and fortified foods (like wheat and maize flour) to reduce the occurrence of neural tube defects (NTDs). These include spina bifida (or cleft spine), where there is an opening in one or more of the bones (vertebrae) of the spinal column, and anencephaly where the head (cephalic) end of the neural tube fails to close. Supplementation with folic acid is internationally recommended to women from the moment they are trying to conceive until 12 weeks of pregnancy. Another option recommended by the World Health Organization (WHO) is that women of reproductive age take weekly iron and folic acid supplements, especially in populations where the prevalence of anaemia is above 20%. Supplementation may also reduce other birth defects such as cleft lip with or without cleft palate and congenital cardiovascular defects. Recently, 5-methyl-tetrahydrofolate (5-MTHF) has been proposed as an alternative to folic acid supplementation. This is because most dietary folate and folic acid are metabolised to 5-MTHF. Some women have gene characteristics which reduce folate concentration in blood.

This review confirms that folic acid supplementation prevents the first and second time occurrence of NTDs and shows there is not enough evidence to determine if folic acid prevents other birth defects. Information about the safety of other current and alternative supplementation schemes and any possible effects on other outcomes for mothers and babies is also lacking. This review of five trials, involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs), shows the protective effect of daily folic acid supplementation in doses ranging from 0.36 mg (360 µg) to 4 mg (4000 µg) a day, with and without other vitamins and minerals, before conception and up to 12 weeks of pregnancy, for preventing the recurrence of these diseases. There were insufficient data to evaluate the effects on other outcomes such as cleft lip and palate. More research is needed on different types of supplementation programmes and the use of different types of supplements (such as 5-methyl-tetrahydrofolate -5-MTHF), particularly in countries where folic acid fortification of staple foods like wheat or maize flour is not mandatory and where the prevalence of NTDs is still high.

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.

Read the full abstract...

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.


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 strategy: 

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.