Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Excess maternal folate levels dysregulate placental hormone secretion in vivo and in vitro: a novel mechanism linking folic acid and gestational diabetes mellitus (#477)

Jessica Williamson 1 , Anya Arthurs 1 , Melanie Smith 1 , Tayla Albertini 1 , Dylan McCullough 1 , Shalem Leemaqz 1 , Murthy Mittinty 1 , Shahid Ullah 1 , Gustaaf Dekker 2 3 , Claire T Roberts 1 , Tanja Jankovic-Karasoulos 1
  1. College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
  2. Women's and Children's Health, University of Adelaide, Adelaide, South Australia, Australia
  3. Women and Children's Division, Lyell McEwin Hospital, Elizabeth Vale, South Australia, Australia

Folic acid (FA) food fortification and increased periconceptional FA supplementation have increased maternal folate status (1). High FA intake and maternal folate are associated with increased risk of developing gestational diabetes mellitus (GDM) (2). We hypothesise that the mechanism of FA action involves placental hormone dysregulation of maternal insulin resistance.

Maternal folate, human placental lactogen (hPL) and placental growth hormone (GH2) were measured in early-gestation blood samples taken pre- (2005-2008, n=1164) and post- (2015-2018, n=1300) FA fortification. Furthermore, early to mid-gestation (n=66, 6-16 weeks’) human placental explants were treated in vitro with increasing doses of FA (0 nM (deficiency), 40 nM (adequate), 2000 nM (physiological excess)) to establish direct effects on placental hormone (hPL and GH2) secretion and folate receptor 1 (FOLR1) expression.

GDM incidence increased from 5% pre- to 15.2% post- FA fortification. Compared to pre-fortification, women post-fortification had higher serum folate (18%, p<0.001), red cell folate (RCF; 259%, p<0.001), hPL (29%, p<0.0001) and GH2 (13%, p=0.01). RCF increased GDM risk (RR: 1.34 95% CI: 1.01-1.78, p=0.04). In vitro, compared to adequate treatment, FA deficiency resulted in higher hPL (29%, p<0.005), whilst FA excess increased placental secretion of hPL (24%, p<0.05) and GH2 (26%, p<0.05). A similar U-shaped response was seen with FOLR1, where increased expression was measured in response to FA deficiency (40%, p=0.04) and excess (54%, p=0.0004) compared to adequate FA.

Excess FA dysregulates placental hormones that regulate maternal insulin resistance in vivo and in vitro, providing a novel mechanism linking FA and GDM. Interestingly, we provide evidence that the effects of excess FA parallel those of deficiency, suggesting FA metabolism is dysregulated in high-FA conditions, increasing concerns about excess intake in pregnancy. Given nearly 20% of Australian pregnancies are now affected by GDM, it is imperative to understand its pathogenesis.

  1. Jankovic-Karasoulos T, Smith MD, Leemaqz S, Williamson J, McCullough D, Arthurs AL, et al. Elevated Maternal Folate Status and Changes in Maternal Prolactin, Placental Lactogen and Placental Growth Hormone Following Folic Acid Food Fortification: Evidence from Two Prospective Pregnancy Cohorts. Nutrients. 2023;15(7):1553
  2. Williamson JM, Arthurs AL, Smith MD, Roberts CT, Jankovic-Karasoulos T. High Folate, Perturbed One-Carbon Metabolism and Gestational Diabetes Mellitus. Nutrients. 2022;14(19)