Low maternal red blood cell 5-methyltetrahydrofolate levels in early pregnancy are associated with increased risk of birth defects: A prospective cohort study.

BACKGROUND AND AIMS: Reduced maternal folate status is widely accepted as a major causative factor for neural tube defects, but its association with other birth defects remains unclear. This study aimed to evaluate the association between maternal 5-methyltetrahydrofolate (5-MTHF) levels and the risk of birth defects. METHODS: This prospective cohort study was conducted in a large obstetrics and gynecology hospital in Beijing, China. Pregnant women were recruited in their first trimester between December 2020 and November 2021, with baseline characteristics and blood samples collected at enrollment. Participants were followed until 42 days postpartum. After excluding those with missing baseline information, non-singleton pregnancies, loss to follow-up, or undetermined birth defect status, 6578 women were included in the primary analysis. Maternal red blood cell (RBC) and plasma 5-MTHF concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary outcome was structural birth defects and chromosomal abnormalities in offspring, including live births, stillbirths, and pregnancy terminations due to fetal abnormalities. Causality was assessed using two-sample Mendelian randomization. RESULTS: Among all participants (median gestational age at recruitment, 8.5 weeks), 355 (5.4%) offspring were diagnosed with birth defects. Maternal RBC but not plasma 5-MTHF concentrations were significantly lower in women with affected offspring. Subcategory analysis revealed a negative association between RBC 5-MTHF and the risk of congenital heart defects, eye, ear, face, and neck defects, musculoskeletal system defects, and chromosomal abnormalities. The incidence of birth defects decreased from the cohort-wide rate of 5.4% to 4.4% when RBC 5-MTHF levels exceeded 700 nmol/L, representing a relative risk reduction (RRR) of 18%. Two-sample Mendelian randomization based on the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism indicated potential causality. CONCLUSION: Low early-pregnancy RBC 5-MTHF levels were associated with an increased risk of birth defects.