Time-Threshold Dose-Response Relationship Between Duration of Premature Rupture of Membranes and Maternal, Neonatal, and Laboratory Evidence of Infection: A Systematic Review and Meta-Analysis.

Objective: To identify the continuous dose-response relationship between the duration of premature rupture of membranes (PROM) and the probability of neonatal and maternal infectious morbidity. Methods: This meta-analysis and systematic review synthesise data from 15 studies worldwide involving more than 70,000 mother-neonate pairs. A two-step random-effects model of PROM duration as a continuous dose, using restricted cubic splines, was used to estimate specific risk thresholds. Results: The analysis established a progressive, non-linear escalation of risk. The onset of statistical risks at 16 hours is the early-onset pneumonia (Adjusted OR 1.86, 95% CI: 1.152.99). At the age of 18 hours, the incidence of culture-proven sepsis in neonates was 4.0%, and the odds ratio for maternal fever was significantly higher (AOR 36.6). The analysis of the ROC curves revealed a critical mathematical pivot point at 37 hours, after which complications escalate exponentially. Latency greater than 48 hours was the most significant independent predictor of culture-proven sepsis, with an increased risk of 8.2 (p < 0.001). Histologic chorioamnionitis was detected in 39% of mothers, and in many cases, they are clinically silent. Considerable heterogeneity (I2 > 60%) was mainly caused by gestational age disparities in cohorts of extremely preterm and term babies. Conclusion: PROM latency risk is not a threat but accelerates with time. Although 18 hours will be an acceptable early warning level, the range of 37 to 48 hours is a high-risk period that needs aggressive treatment. International guidelines need to be reviewed to reflect this non-linear trend, especially regarding pregnancy, where the risks of delivery are low compared to the rising risk of latency.