Background: Folate is essential in pregnancy. Australia mandated folic acid (FA; synthetic folate) food fortification in 2009. Excess folate is now more common than deficiency and associates with GDM. Both folate and FA act in one-carbon metabolism (1CM).
Objective: Characterise maternal one-carbon metabolites with respect to FA-fortification and GDM.
Methods: Early gestation maternal serum was collected pre- (SCOPE; 2005-2008, n=861) and post-FA fortification (STOP; 2015-2018, n=1216). Folate, unmetabolised FA (UMFA), B12, homocysteine, cysteine and methionine were measured using HPLC and mass spectrometry (BeVital, Norway). GDM was diagnosed using 2014 WHO thresholds. Relative risk for GDM was adjusted for age, BMI, ethnicity, smoking status and socioeconomic index.
Results: Folate metabolites (25%; p<0.001), UMFA (72% p<0.001) and B12 (7% p<0.001) increased post-fortification. Unexpectedly, homocysteine and cysteine (both 10% p<0.001) were also higher. Post-fortification cysteine) increased but homocysteine:cysteine ratio was unchanged while methionine (4% p<0.001) decreased.
GDM increased from 5% (SCOPE) to 15% (STOP). Folate metabolites (13% p=0.003) increased GDM in SCOPE only but UMFA did not. Homocysteine (17%, p=0.04) and homocysteine:cysteine ratio (68%, p=0.01) were associated with decreased GDM but methionine was not.
Interpretation: Altered 1CM is observed between cohorts. Post-fortification, homocysteine is shunted to the transsulphuration pathway, apparently at the expense of its remethylation to methionine. In GDM, homocysteine:cysteine ratio decreased, highlighting a potential compensatory mechanism, increasing antioxidant capacity to combat GDM-associated oxidative stress. In the context of high FA consumption, folate no longer associates with GDM, although incidence tripled, suggesting additional interactions between chronic FA exposure and GDM.