Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006

Evelyne E Muggli and Jane L Halliday
Med J Aust 2007; 186 (5): 243-248.


Objective: To assess the evidence of an association between periconceptional folic acid (FA) supplementation or fortification of foods with FA and the risk of twinning, using the Food Standards Australia New Zealand (FSANZ) framework for assessing evidence when substantiating nutrition, health and related claims on foods.

Data sources: The Cochrane Library Database, MEDLINE, MEDLINE in Process, EMBASE, PubMed National Library of Medicine, and CINAHL were searched to identify systematic reviews and primary intervention and observational studies published from 1 July 1994 to 7 July 2006.

Study selection: One prospective and five retrospective cohort studies that assessed the rate of twinning in populations exposed to FA through supplementation, and six retrospective registry-based cohort studies examining twinning rates after fortification of foods with FA.

Data extraction: Two reviewers appraised eligible studies and evaluated data independently.

Data synthesis: The best maximal risk estimates of twinning after FA supplementation were an adjusted odds ratio (adjOR) of 1.26 (95% CI, 0.91–1.73) for preconceptional supplementation and dizygotic twinning and an adjOR of 1.02 (95% CI, 0.85–1.24) for overall twinning. Data from four FA fortification studies in the United States that allowed for calculation of an annual percentage increase showed a maximal annual increase in twinning rates of 4.6%.

Conclusions: Overall, under the FSANZ framework, there is possible evidence for a relationship between periconceptional FA intake and increased twinning. To support this tentative relationship, more well designed, long-term follow-up studies are needed in places where fortification with FA has been introduced, focusing on dose–response and obtaining accurate data on infertility treatments.

  • Evelyne E Muggli1
  • Jane L Halliday2

  • Public Health Genetics, Murdoch Childrens Research Institute, Melbourne, VIC.



This review was undertaken with financial support from Food Standards Australia New Zealand. We would like to thank Lucy Perez for her help with the Spanish–English translation of the article by Nazer et al.

Competing interests:

Jane Halliday has been a member of the Flour Fortification Initiative Australia and New Zealand.

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