Maternal Folate Excess, Placental Hormones, and Gestational Diabetes Mellitus: Findings from Prospective Cohorts Before and After Mandatory Folic Acid Food Fortification

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dc.contributor.authorJankovic-Karasoulos, T.
dc.contributor.authorSmith, M.D.
dc.contributor.authorLeemaqz, S.
dc.contributor.authorMittinty, M.
dc.contributor.authorWilliamson, J.
dc.contributor.authorMcCullough, D.
dc.contributor.authorArthurs, A.L.
dc.contributor.authorDekker, G.A.
dc.contributor.authorRoberts, C.T.
dc.date.issued2025
dc.description.abstractBackground/Objectives: Gestational diabetes mellitus (GDM) prevalence in Australia has increased from 5.6% (2010) to 19.3% (2022), coinciding with the introduction of mandatory folic acid (FA) food fortification and increased supplementation. Animal studies show that high FA intake in pregnancy impairs maternal glucose regulation, but the underlying mechanisms are unknown. We investigated whether fortification has altered maternal folate status to increase GDM risk, and whether key hormones that regulate maternal glucose homeostasis are affected following FA fortification. Methods: Serum folate, red cell folate (RCF), prolactin (PRL), human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early pregnancy samples from women enrolled in prospective cohorts: SCOPE (N = 1164; pre-fortification) and STOP (N = 1300; post-fortification). Associations with GDM were assessed. Results: Compared to pre-fortification, women post-fortification had a higher GDM incidence (5.0% vs. 15.2%), serum folate (↑ 18%), RCF (↑ 259%), hPL (↑ 29%), and GH2 (↑ 13%) concentrations. RCF concentrations above the clinical reference range were found in 57.6% of women post-fortification. Causal mediation analysis suggests that higher RCF contributed to increased GDM risk. Women with RCF excess had 48% more GDM cases, and higher PRL (↑ 24.2%) and hPL (↑ 12.7%) levels compared to those within the reference range. Conclusions: Maternal folate excess is likely contributing to the rising prevalence of GDM in Australia. These findings highlight the need to evaluate excess FA/folate safety in pregnancy, particularly in countries with mandatory fortification. Placental hormones may represent a mechanistic link between excess folate and GDM, warranting further investigation.
dc.description.statementofresponsibilityTanja Jankovic-Karasoulos, Melanie D. Smith, Shalem Leemaqz, Murthy Mittinty, Jessica Williamson, Dylan McCullough, Anya L. Arthurs, Gustaaf A. Dekker, and Claire T. Roberts
dc.identifier.citationNutrients, 2025; 17(17):2863-1-2863-16
dc.identifier.doi10.3390/nu17172863
dc.identifier.issn2072-6643
dc.identifier.issn2072-6643
dc.identifier.orcidJankovic-Karasoulos, T. [0000-0003-4293-359X]
dc.identifier.orcidLeemaqz, S. [0000-0003-4616-8426]
dc.identifier.orcidMittinty, M. [0000-0001-8778-9793]
dc.identifier.orcidArthurs, A.L. [0000-0002-4382-0610]
dc.identifier.orcidDekker, G.A. [0000-0002-7362-6683]
dc.identifier.orcidRoberts, C.T. [0000-0002-9250-2192]
dc.identifier.urihttps://hdl.handle.net/2440/148079
dc.language.isoen
dc.publisherMDPI AG
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1174971
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1161079
dc.rights© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
dc.source.urihttps://doi.org/10.3390/nu17172863
dc.subjectmicronutrient supplementation; one-carbon metabolism; maternal metabolic health; hyperglycemia in pregnancy; pregnancy complications; placental endocrine function
dc.subject.meshHumans
dc.subject.meshDiabetes, Gestational
dc.subject.meshFolic Acid
dc.subject.meshProlactin
dc.subject.meshPlacental Hormones
dc.subject.meshPlacental Lactogen
dc.subject.meshProspective Studies
dc.subject.meshPregnancy
dc.subject.meshFood, Fortified
dc.subject.meshAdult
dc.subject.meshAustralia
dc.subject.meshFemale
dc.titleMaternal Folate Excess, Placental Hormones, and Gestational Diabetes Mellitus: Findings from Prospective Cohorts Before and After Mandatory Folic Acid Food Fortification
dc.typeJournal article
pubs.publication-statusPublished online

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