Association of maternal vitamin B(12) and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study)

AIMS/HYPOTHESIS: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B(12) and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B(12) and folate levels with the risk of GDM status at 26–28 weeks of gestation. METHODS: This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. RESULTS: GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B(12) insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B(12) levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26–28 weeks. B(12) was negatively associated with fasting plasma glucose (1 SD: −0.06 mmol/l; 95% CI −0.04, −0.08; p < 0.0001) and 2 h plasma glucose levels (−0.07 mmol/l; 95% CI −0.02, −0.12; p = 0.004). Higher B(12) was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic β: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B(12) status). Although no interactions were observed for B(12) and folate (as continuous variables) with glucose levels and GDM risk, a low B(12)–high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). CONCLUSIONS/INTERPRETATION: B(12) insufficiency and folate excess were common in early pregnancy. Low B(12) and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B(12) and folate levels on subsequent hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008824. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05510-7.