Association between Endotype of Prematurity and Mortality: A Systematic Review, Meta-Analysis, and Meta-Regression

Preterm birth represents the leading cause of neonatal mortality. Pathophysiological pathways, or endotypes, leading to prematurity can be clustered into infection/inflammation and dysfunctional placentation. We aimed to perform a systematic review and meta-analysis exploring the association between these endotypes and risk of mortality during first hospital admission Methods: PROSPERO ID: CRD42020184843. PubMed and Embase were searched for observational studies examining infants with gestational age (GA) ≤34 weeks. Chorioamnionitis represented the infectious-inflammatory endotype, while dysfunctional placentation proxies were hypertensive disorders of pregnancy (HDP) and small for GA (SGA)/intrauterine growth restriction (IUGR). A random-effects model was used to calculate odds ratios (ORs) and 95% confidence intervals. Heterogeneity was studied using random-effects meta-regression analysis.

Of 4,322 potentially relevant studies, 150 (612,580 infants) were included. Meta-analysis showed positive mortality odds for chorioamnionitis (OR: 1.43, 95% confidence interval: 1.25-1.62) and SGA/IUGR (OR: 1.68, 95% confidence interval: 1.38-2.04) but negative mortality odds for HDP (OR 0.74, 95% confidence interval: 0.64-0.86). Chorioamnionitis was associated with a lower GA, while HDP and SGA/IUGR were associated with a higher GA. Meta-regression showed a significant correlation between these differences in GA and mortality odds.

Our data suggest that the infectious/inflammatory endotype of prematurity has a greater overall impact on mortality risk as it is the most frequent endotype in the lower GAs. However, when the endotype of placental dysfunction is severe enough to induce growth restriction, it is strongly associated with higher mortality rates even though newborns are more mature.