Weekly iron–folic acid supplements containing 2.8 mg folic acid are associated with a lower risk of neural tube defects than the current practice of 0.4 mg: a randomised controlled trial in Malaysia
What this study found
Weekly 2.8 mg folic acid with iron produced a much larger improvement in folate status than 0.4 mg folic acid or no folic acid. At 16 weeks, mean RBC folate rose to 851±208 nmol/L in the 2.8 mg group versus 554±146 nmol/L with 0.4 mg and 466±158 nmol/L with 0 mg, and 68% of the 2.8 mg group exceeded the RBC folate threshold associated with low NTD risk versus 8% and 3%, respectively. The relative risk for achieving RBC folate above 748 nmol/L was 16.0 (6.1 to 42.3) for 2.8 mg versus 0 mg and 7.3 (3.9 to 13.7) for 2.8 mg versus 0.4 mg at 16 weeks, with similar superiority at 20 weeks. The…
- Study & population
- Randomized controlled trial in 331 nonpregnant women of reproductive age in Malaysia, recruited at Universiti Putra Malaysia, who were not intending pregnancy and were not taking folic acid supplements at baseline.
- Intervention
- Weekly tablets containing 60 mg iron as ferrous fumarate plus folic acid at 0.4 mg or 2.8 mg were compared with a 0 mg folic acid control, taken once at the clinic and then once weekly on the same day for 16 weeks.
- Key limitation
- Follow-up was short and outcomes were biomarker based rather than clinical NTD events, so the trial cannot directly measure pregnancy or birth outcomes.
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Open PDFOriginal abstract
Introduction Weekly iron–folic acid (IFA) supplements are recommended for all menstruating women in countries where anaemia prevalence is >20%. Anaemia caused by folate deficiency is low worldwide, and the need to include folic acid is in question. Including folic acid might reduce the risk of a neural tube defect (NTD) should a woman become pregnant. Most weekly supplements contain 0.4 mg folic acid; however, WHO recommends 2.8 mg because it is seven times the daily dose effective in reducing NTDs. There is a reluctance to switch to supplements containing 2.8 mg of folic acid because of a lack of evidence that this dose would prevent NTDs. Our aim was to investigate the effect of two doses of folic acid, compared with placebo, on red blood cell (RBC) folate, a biomarker of NTD risk. Methods We conducted a three-arm double-blind efficacy trial in Malaysia. Non-pregnant women (n=331) were randomised to receive 60 mg iron and either 0, 0.4, or 2.8 mg folic acid once weekly for 16 weeks. Results At 16 weeks, women receiving 0.4 mg and 2.8 mg folic acid per week had a higher mean RBC folate than those receiving 0 mg (mean difference (95% CI) 84 (54 to 113) and 355 (316 to 394) nmol/L, respectively). Women receiving 2.8 mg folic acid had a 271 (234 to 309) nmol/L greater mean RBC folate than those receiving 0.4 mg. Moreover, women in the 2.8 mg group were seven times (RR 7.3, 95% CI 3.9 to 13.7; p<0.0001) more likely to achieve an RBC folate >748 nmol/L, a concentration associated with a low risk of NTD, compared with the 0.4 mg group. Conclusion Weekly IFA supplements containing 2.8 mg folic acid increases RBC folate more than those containing 0.4 mg. Increased availability and access to the 2.8 mg formulation is needed. Trail registration number This trial is registered with the Australian New Zealand Clinical Trial Registry (ACTRN12619000818134).