Born at higher risk: persistent male excess risk of cerebral palsy from extreme prematurity to term: a systematic review and meta-analysis

Abstract Male sex is recognized as a risk factor for cerebral palsy (CP), but the magnitude and consistency of this association across gestational ages remain unclear. To quantify sex-specific CP risk across gestational age categories and assess whether male excess risk varies by gestational age or temporal period, we conducted a systematic review and meta-analysis following PRISMA guidelines. Studies reporting sex-specific CP prevalence stratified by gestational age were included. Random-effects meta-analyses were performed stratified by gestational age (< 28 weeks, ≤ 31 weeks, 32–36 weeks, ≥ 37 weeks). Meta-regression assessed trends across gestational ages and temporal changes. Twenty-two studies comprising 47 comparisons, 15,734 CP cases and over 6.5 million births were included. Males showed consistently elevated CP risk across all gestational ages. Pooled risk ratios were: ≤31 weeks 1.27 (95% CI: 1.16–1.39, p < 0.001; I²=34.6%, high certainty), 32–36 weeks 1.12 (95% CI: 1.00-1.26, p = 0.05; I²=0.0%, moderate certainty), and ≥ 37 weeks 1.25 (95% CI: 1.18–1.32, p < 0.001; I²=37.8%, high certainty). Overall pooled RR was 1.22 (95% CI: 1.17–1.28, p < 0.001; I²=36.3%, high certainty). Meta-regression found no significant relationship between gestational age and male excess risk (β=-0.0007, p = 0.863, moderate certainty), indicating consistent male predominance across the gestational age spectrum. Finally, meta-regression, using span-weighted year of birth covariates (defined as the arithmetic mean of the first and last calendar year of the study cohort period, representing the temporal midpoint of birth exposure within each study and the study period duration, defined as the total span in years), showed that the male-to-female risk ratio for cerebral palsy in both preterm (< 37 weeks; 32 comparisons, omnibus Wald test = 5.07, p = 0.013, low certainty), very preterm (≤ 31 weeks; 24 comparisons, omnibus Wald test = 4.41, p = 0.02, moderate certainty) and extremely preterm (< 28 weeks, 7 comparisons, omnibus Wald test = 13.2, p = 0.0014,moderate certainty) infants is decreasing in more recent birth cohorts. Male sex confers 22–27% increased CP risk across all gestational ages. While this excess risk remains relatively constant across the gestational age spectrum, there is evidence of narrowing sex-specific differences among very preterm infants in recent years, possibly reflecting improvements in prenatal and neonatal care that differentially benefit males.