Association Between Maternal Hyperhomocysteinemia and Preterm Prelabor Rupture of Membranes: A Case-Control Study

Background: Preterm prelabor rupture of membranes (PPROM) precedes approximately one-third of preterm births and is a major contributor to perinatal morbidity and mortality, particularly in low- and middle-income countries. The structural integrity of the fetal membranes depends on a collagen-rich extracellular matrix; therefore, metabolic disturbances that promote oxidative stress and impair collagen synthesis, cross-linking, or remodeling may increase susceptibility to membrane rupture. Hyperhomocysteinemia, which is often associated with folate and vitamin B12 insufficiency, is a biologically plausible contributor. Objective: To determine the association between maternal hyperhomocysteinemia and preterm prelabor rupture of membranes (PPROM). Methods: This case-control study was conducted at Dhaka Medical College Hospital, Bangladesh, from July 2023 through June 2024. Sixty-six women with spontaneous PPROM at 24+0–36+6 weeks and 66 gestational-age-comparable controls with intact membranes were enrolled. Fasting serum homocysteine was measured on an automated analyzer. Hyperhomocysteinemia was defined as >8.60 µmol/L (24–28 weeks) or >11.17 µmol/L (29–36 weeks). Groups were compared using t/Mann–Whitney and chi-square tests; crude odds ratios (ORs) with 95% confidence intervals (CIs) were derived from 2×2 tables. Results: Cases and controls were similar in age, gestational age, parity, and body mass index, but poor socioeconomic status and absent first-trimester folic acid were more frequent among cases (folic acid non-use: OR 4.60, 95% CI 2.08–10.28). Elevated homocysteine was strongly associated with PPROM at 24–28 weeks (76.5% vs 16.7%; OR 16.25, 95% CI 2.45–100.0) and at 29–36 weeks (53.1% vs 16.7%; OR 5.65, 95% CI 2.02–16.31). Mean concentrations were more than double in cases in both strata (11.55±4.57 vs 5.11±3.42 µmol/L at 24–28 weeks and 11.34±3.96 vs 5.72±3.90 µmol/L at 29–36 weeks; p=0.001 for all comparisons). Conclusion: Maternal hyperhomocysteinemia was consistently associated with PPROM across gestation, supporting homocysteine as a potentially modifiable biomarker warranting prospective, confounder-adjusted evaluation.