The Role of Maternal Homocysteine Concentration in Pregnancy Complications: A Systematic Review and Meta-Analysis

Background: Adverse pregnancy outcomes such as preeclampsia (PE), preterm birth, low birth weight (LBW), small for gestational age (SGA), and stillbirth are major contributors to maternal and neonatal morbidity and mortality. Elevated maternal homocysteine (Hcy) levels, influenced by genetic, dietary, and lifestyle factors, have been increasingly associated with placental dysfunction and adverse pregnancy outcomes. This review aims to evaluate the link between hyperhomocysteinemia and pregnancy complications to inform clinical practice. Methods: A comprehensive search of PubMed, Scopus, Web of Science, and Cochrane Central Library was conducted up to December 2024. Observational studies assessing maternal Hcy levels in relation to pregnancy complications were included. Heterogeneity was measured using the I² statistic, and a random-effects model using the DerSimonian-Laird method was applied to account for study variability. Effect sizes were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results: Thirteen studies were included in this meta-analysis. Elevated maternal Hcy was significantly associated with: PE (OR: 2.49; 95% CI: 1.41-4.40; I² = 96.03%; n = 9), preterm birth (OR: 4.01; 95% CI: 1.84-8.72; I² = 91.08%; n = 6), fetal loss (OR: 1.76; 95% CI: 1.22-2.52; I² = 41.47%; n = 6), SGA (OR: 1.69; 95% CI: 1.35-2.11; I² = 0.00%; n = 3), and LBW (OR: 2.46; 95% CI: 1.37-4.43; I² = 77.71%; n = 3). Conclusions: This review highlights a significant association between elevated maternal Hcy levels and various pregnancy complications. However, given the substantial heterogeneity and reliance on observational evidence, these findings should be interpreted with caution. Future well-designed prospective cohort studies with standardized definitions of hyperhomocysteinemia, consistent timing of exposure assessment across pregnancy trimesters, and adjustment for key confounders are needed to better clarify these associations and underlying mechanisms.