An Australian study suggests that mandatory folic acid fortification may have unintended consequences, linking excess folate to rising gestational diabetes and calling for urgent policy reassessment.
Study: Maternal Folate Excess, Placental Hormones, and Gestational Diabetes Mellitus: Findings from Prospective Cohorts Before and After Mandatory Folic Acid Food Fortification. Image Credit: Pixel-Shot / Shutterstock
In a recent study in the journal Nutrients, researchers in Australia investigated the potential associations between folic acid, a commonly used food fortification in Australia, and the alarming surge in gestational diabetes currently observed in the country. The study leveraged a “natural experiment” comprising two large groups of pregnant women (n = 2,464; SCOPE and STOP cohorts) before and after Australia mandated folic acid food fortification.
Study findings revealed that post-fortification, gestational diabetes mellitus (GDM) rates tripled, maternal folate stores rose by 259%, and levels of key placental hormones were altered in ways that may affect glucose metabolism. These findings suggest that widespread maternal folate excess may be associated with the Australian GDM epidemic.
Background
Gestational diabetes mellitus (GDM) is a form of high blood sugar that develops specifically during pregnancy and can pose severe health risks to both the mother and her unborn child. Australia currently faces an unprecedented surge in GDM incidence, with reports estimating a rise from only 5.6% in 2010 to 19.3% in 2022.
While factors like rising maternal age and obesity are known contributors to GDM, their prevalence fails to account for the steepness of this trajectory, leading scientists to seek other potential environmental drivers and modifiable risk factors. Folic acid, the synthetic form of vitamin B9 (folate), and a known crucial requirement for normal foetal neural tube development, presents an unlikely prime candidate.
To ensure adequate vitamin B9 intake, Australia implemented a mandatory folic acid (FA) fortification program for bread-making flour (2009). This policy, combined with a sharp increase in the use of high-dose prenatal supplements, has successfully reduced Australia’s previous folate deficiency.
However, a growing body of observational and animal evidence suggests that the overconsumption of folic acid may trigger gestational complications, including GDM. Validating these accounts would help inform future public health policy within the nation, potentially reducing the risk faced by millions of mothers and children.
About the study
The present study aims to meet this knowledge requirement by leveraging a “unique natural experiment” comparing two large prospective cohorts of pregnant women recruited from the same hospital, one before and one after Australia’s 2009 folic acid fortification mandate.
Data for the pre-fortification group were obtained from the Screening for Pregnancy Endpoints (SCOPE) cohort, comprising 1,164 women recruited between 2005 and 2008. Analytically identical data from the Screening Tests to identify poor Outcomes of Pregnancy (STOP) cohort (1,300 participants), recruited between 2015 and 2018, were used to synthesize the post-fortification group dataset. Long-term folate data (RCF) for the pre-fortification period were not available from SCOPE and were instead derived from a separate contemporaneous cohort at the same hospital using identical protocols.
Data collection included blood samples (collected during early pregnancy) for serum folate and red cell folate (RCF) levels as representatives of recent intake and long-term folate stores, respectively. Key placental hormones involved in glucose regulation (e.g., human placental lactogen [hPL], placental growth hormone [GH2]) were also estimated.
The study’s primary outcome of interest was the rate of GDM, which was diagnosed using the same criteria for both cohorts to ensure a valid comparison. Between-group comparisons were conducted within a meta-analytic framework, utilizing log-binomial regression with inverse probability weighting models.
Study findings
Log-binomial regression with inverse probability weighting revealed a dramatic shift in both GDM rates and folate levels between the STOP and SCOPE participants. GDM incidence was observed to triple from 5.0% (SCOPE) to 15.2% in post-fortification STOP, mirrored by an unprecedented surge in maternal folate levels. Long-term folate stores, measured by RCF, were 259% higher in the post-fortification group (p < 0.0001).
Most alarmingly, between-group comparisons revealed that the proportion of women with RCF levels above the established clinical reference range increased from 0.5% before fortification to 57.6% afterward, indicating a nationwide scenario of folate excess. Serum folate was also 18% higher in the post-fortification group. However, serum folate concentrations alone were not significantly associated with the risk of GDM, whereas excess RBC folate was.
Subsequent analysis directly linked this folate excess to the risk of GDM. In the post-fortification cohort, women with excess RCF had 48% more GDM cases than women with normal RCF levels (p = 0.03). For every 500 nmol/L increase in RCF, the risk of developing GDM was observed to rise by 34% (p = 0.04).
Finally, the study found that women in the post-fortification era had significantly higher concentrations of placental hormones, including a 29% increase in hPL and a 13% increase in GH2. The authors noted that these hormones influenced the risk of GDM in opposite directions (hPL potentially protective, GH2 adverse), and while this suggests a plausible biological pathway, the combined mediation effect was not statistically significant.
Conclusions
The present study provides evidence of associations between Australia’s publicly successful folic acid fortification program of 2009 and its current GDM epidemic. Its findings suggest that high folate levels may alter placental hormone production, potentially disrupting the mother’s ability to regulate blood sugar during pregnancy.
While folic acid supplementation in early pregnancy remains essential, this research underscores the need to reassess current fortification and high-dose supplementation policies. Future public health policy in Australia should prioritize establishing an upper safe limit for folate intake during pregnancy, as it is crucial to balance the prevention of congenital disabilities with the protection of maternal metabolic health.
Journal reference:
Jankovic-Karasoulos, T., Smith, M. D., Leemaqz, S., Mittinty, M., Williamson, J., McCullough, D., Arthurs, A. L., Dekker, G. A., & Roberts, C. T. (2025). Maternal Folate Excess, Placental Hormones, and Gestational Diabetes Mellitus: Findings from Prospective Cohorts Before and After Mandatory Folic Acid Food Fortification. Nutrients, 17(17), 2863. DOI – 10.3390/nu17172863. https://www.mdpi.com/2072-6643/17/17/2863