First-Trimester Folate and Vitamin B₁₂ Status and Maternal Complications in An Indian Pregnancy Cohort

Background: Folate supplementation during pregnancy is essential for preventing neural tube defects (NTDs). However, in populations with high folic acid exposure and prevalent vitamin B₁₂ deficiency, evidence is limited on whether micronutrient imbalance influences maternal pregnancy complications. We examined the independent, joint, and context-dependent associations of first-trimester folate, vitamin B₁₂, and homocysteine with maternal complications.<br><br>Methods: In this prospective cohort study, 1,005 pregnant women were recruited during the first trimester from a tertiary-care public hospital in Delhi, India (2023-2025). Serum folate, vitamin B₁₂, and plasma homocysteine were measured at baseline. Of the enrolled women, 582 with complete outcome data were included in analyses. Outcomes included gestational diabetes mellitus (GDM), gestational hypertension (GHTN), intrahepatic cholestasis of pregnancy (IHCP), premature rupture of membranes (PROM), and miscarriage. Multivariable regression, joint exposure, and moderation analyses evaluated context-dependent associations, including interactions with vitamin B₁₂, maternal age, and first-trimester body mass index.<br><br>Findings: Higher first-trimester folate concentrations were associated with increased odds of GHTN (odds ratio [OR] 2·31, 95% CI 1·17-4·58). Women with concurrent high folate and low vitamin B₁₂ had higher odds of overall maternal complications (OR 2·17, 1·13-4·15) and GHTN (OR 2·62, 1·22-5·62). Associations with GDM (OR 1·62, 0·98-2·65) and IHCP (OR 1·79, 0·95-3·37) were directionally similar but did not reach statistical significance. Plasma homocysteine was independently associated with miscarriage (OR 1·64, 1·04-2·58). Folate-related associations were stronger at lower vitamin B₁₂ concentrations and higher maternal BMI.<br><br>Interpretation: First-trimester folate status may be associated with maternal pregnancy complications in a context-dependent manner, particularly in the presence of vitamin B₁₂ deficiency and metabolic vulnerability. While folic acid supplementation remains essential for NTD prevention, optimisation of antenatal folic acid dosing and attention to micronutrient balance may merit consideration in populations with high baseline folate exposure and prevalent vitamin B₁₂ deficiency.