Paternal homocysteine concentrations and prenatal growth outcomes in early and late gestation: the Rotterdam Periconception Cohort (Predict Study)

Background: In animal models, derangements in paternal one‑carbon metabolism, giving rise to elevated serum total homocysteine (tHcy) concentrations, can impair sperm DNA integrity and chromatin methylation signatures, with consequences for embryonic gene expression, (neuro)development and growth. We hypothesize that, in humans, elevated serum tHcy similarly impairs prenatal development. Methods: In a prospective periconception cohort, 881 pregnant women (<10 weeks of gestation) and their partners were enrolled from 2010 to 2022. Inclusion required paternal serum tHcy measurement in the first trimester. First trimester crown-rump length (CRL) and embryonic volume (EV) measurements were assessed on longitudinal three-dimensional ultrasound scans using virtual reality. Estimates of second trimester fetal biometry and birth outcomes were extracted from medical records. Associations between paternal tHcy and prenatal growth trajectories were assessed using linear mixed and piecewise regression models, adjusting for confounders. Results: Paternal tHcy concentrations were on average two-fold higher than those of female partners, with men more frequently exhibiting hyperhomocysteinemia. In piecewise regression models, paternal tHcy ≥15 μmol/L compared to <15 μmol/L was associated with decreased first trimester CRL (Δ slope coefficient −0.016, P = 0.019). The association persisted for fetal transcerebellar diameter (Δ slope coefficient −0.060, P = 0.002), abdominal circumference (Δ slope coefficient −0.393, P = 0.022), femur length (Δ slope coefficient −0.115, P = 0.005) and estimated fetal weight (Δ slope coefficient −2.703, P = 0.003). No associations were found with birth weight or adverse birth outcomes. Conclusions: Paternal tHcy may serve as a potential biomarker for prenatal growth. In preconception care, the benefit of assessing paternal tHcy concentrations and promoting multivitamin use warrants further investigation.