Article Text

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
  1. Kaitlyn L I Samson1,2,
  2. Su Peng Loh3,
  3. Siew Siew Lee3,
  4. Dian C Sulistyoningrum4,5,
  5. Geok Lin Khor3,
  6. Zalilah Binti Mohd Shariff3,
  7. Irmi Zarina Ismai3,
  8. Lisa N Yelland4,6,
  9. Shalem Leemaqz4,
  10. Maria Makrides4,5,
  11. Jennifer A Hutcheon2,7,
  12. Marion L Roche8,
  13. Crystal D Karakochuk1,2,
  14. Timothy J Green4,5
  1. 1Food, Nutrition, and Health, The University of British Columbia, Vancouver, British Columbia, Canada
  2. 2Healthy Starts, British Columbia Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
  3. 3Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
  4. 4SAHMRI Women and Kids, South Australia Health and Medical Research Institute, Adelaide, South Australia, Australia
  5. 5School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
  6. 6School of Public Health, The University of Adelaide, Adelaide, South Australia, Australia
  7. 7Obstetrics and Gynaecology, The University of British Columbia, Vancouver, British Columbia, Canada
  8. 8Nutrition International, Ottawa, Ontario, Canada
  1. Correspondence to Professor Timothy J Green;{at}


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).

  • nutrition
  • randomised control trial
  • anaemia
  • prevention strategies
  • neural tube defects
  • folic acid

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

Statistics from

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • Handling editor Sanni Yaya

  • Contributors MLR, CDK and TJG conceived the trial and proposed the initial trial design. KLIS, SPL, GLK, ZBMS, IZI, MM, MLR, CDK and TJG revised and finalised the protocol; LNY, SL and JAH advised on sample size calculations, trial design and analysis; statistical analyses were completed by LNY; KLIS, SPL, SSL, DCS and IZI were responsible for organisation and conduct of the study; KLIS, SSL and DCS collected data. KLIS, DCS and TJG conducted the blood folate analyses; KLIS, CDK and TJG drafted the manuscript, all authors reviewed the manuscript and approved the final submission.

  • Funding This trial was supported by a grant in aid from Nutrition International (grant 10-1798-SOUAUS-02). The funder was involved with designing the trial and reviewed the manuscript before submission. The funder had no role in data collection, analysis or interpretation. Nutrition International is a not-for-profit organisation governed by a dedicated international Board of Directors and led by an internationally recognised team of technical experts, programme designers, advocates, analysts, evaluators, implementers, educators, resource managers and nutrition champions.

  • Competing interests MM reports being on the Scientific Board of Trajan Nutrition, outside the submitted work. LNY reports grants from Australian National Health and Medical Research Council, during the conduct of the study. MLR is an employee of the sponsor.

  • Patient consent for publication Not required.

  • Ethics approval Ethical approval was received from the Ethics Committee for Research Involving Human Subjects of Universiti Putra Malaysia (JKEUPM-2018–255) and The University of British Columbia Clinical Research Ethics Board (H18-00768).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on request. Deidentified data will be made available 12 months after publication. Person(s) requesting the data must provide a methodologically sound research proposal which will reviewed by the trial steering committee. If approved, a signed data access agreement will be required before the data is released. Please contact the corresponding author for access to the data.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.