Poster Presentation ESA-SRB-ANZOS 2025 in conjunction with ENSA

Mandatory folic acid fortification and supplementation alters one-carbon metabolites in pregnant women: implications for gestational diabetes mellitus (128697)

Jessica Williamson 1 , Melanie Smith 1 , Rakccha Chhetri 1 , Anya Arthurs 1 , Shalem Leemaqz 1 , Dylan McCullough 1 , Murthy Mittinty 1 , Gustaaf Dekker 2 , Randi Heimdal 3 , Adrian McCann 3 , Tanja Jankovic-Karasoulos 1 , Claire Roberts 1
  1. Flinders University, Bedford Park, South Australia, Australia
  2. Women and Children's Division, Lyell McEwin Hospital, Elizabeth Vale, South Australia, Australia
  3. BeVital, Bergen, Norway

Background: Folate is essential in pregnancy. Australia has implemented folic acid (FA; synthetic folate) food fortification policies and supplementation guidelines. Many pregnant women now exceed recommended FA intake, which is increasingly associated with gestational diabetes mellitus (GDM). Both folate and FA act in one-carbon metabolism (1CM)  though FA has limited capacity to be metabolised. We hypothesise fortification and supplementation increase folate status beyond metabolism thresholds, increasing unmetabolised FA (UMFA), with downstream implications for related one-carbon metabolites, and pregnancy outcomes.

Objective: Characterise maternal folate and related one-carbon biomarkers with respect to FA-fortification, supplementation dose and GDM.  

Methods: Maternal serum (12-15 weeks’ gestation) was collected from women pre- (2005-2008, n=861) and post-FA fortification (2015-2018, n=1216). Folate, UMFA, B12, homocysteine, cysteine and methionine were measured using HPLC (BeVital, Norway). Relative GDM risk was adjusted for age, BMI, ethnicity, smoking and socioeconomic index.

Results: Folate (25%), B12 (7%) and UMFA (72%) increased post-fortification (all p<0.001). UMFA also increased with high-dose FA supplementation (≥800 µg; 63.1% p=0.01). Homocysteine and cysteine (both 10%  p<0.001) increased post-fortification but homocysteine:cysteine ratio was unchanged and methionine (4% p<0.001) decreased.

GDM increased from 5% (pre-fortification) to 15% (post-fortification). One-carbon metabolites associated with GDM in SCOPE only. UMFA was not associated with GDM. Folate (13% p=0.003) increased GDM risk. Homocysteine (17%, p=0.04) and homocysteine:cysteine ratio (68%, p=0.01) decreased risk. Methionine was not associated with GDM.

Interpretation: FA intake now exceeds metabolic capacity, resulting in detectable circulating UMFA. Post-fortification, homocysteine is shunted to the transsulphuration pathway, seemingly at the expense of the methionine pathway. In GDM, homocysteine:cysteine ratio is reduced, which may be a compensatory response, increasing antioxidant capacity to reduce GDM-associated oxidative stress. No metabolites associated with GDM post-fortification, but incidence tripled. High and chronic FA exposure impacts 1CM in individual women differently placing some at increased risk for GDM.