Funisitis increases the risk of death or cerebral palsy in extremely preterm infants

The relationship between histological chorioamnionitis (inflammation of fetal membranes) and funisitis (inflammation of umbilical cord), both commonly associated with preterm birth, with subsequent development of cerebral palsy remains controversial.

To determine if extremely preterm infants (<27 weeks) exposed to histological chorioamnionitis or funisitis are at a higher risk of death or cerebral palsy compared to those without these exposures.

Multicenter cohort study of prospectively collected data of preterm infants in the National Institute of Child Health and Development Neonatal Research Network. Infants born 2012 to 2019 who were 22 to 26^6/7 weeks of gestation, received active treatment, and had placental pathology available were included. Because preterm birth, as measured by gestational age, lies on the causal pathway for cerebral palsy, we used mediation analysis to evaluate whether the indirect mediated effect of gestational age on death or cerebral palsy contributed to the relationships of histological chorioamnionitis and funisitis with death or cerebral palsy.

The primary outcome was the composite outcome of death or cerebral palsy defined by the Amiel-Tison standardized exam and Gross Motor Function Classification System ≥1 at 22 to 26 months corrected age.

A total of 6949 infants met the eligibility criteria. Of these, 3971 (57%) infants had histological chorioamnionitis, and 2978 (43%) did not have histological chorioamnionitis. About 90% (6248/6949) of infants had follow-up and complete cerebral palsy data. Similarly, 1057 (28%) infants had funisitis, and 2689 (72%) did not have funisitis. Of these, primary outcome data were available for 87% (3267/3746) infants. On multivariable analysis, histological chorioamnionitis was not associated with death or cerebral palsy (relative risk: 0.98 [95% confidence interval: 0.91, 1.05]). Exposure to funisitis was associated with a higher risk of death or cerebral palsy (relative risk: 1.09 [1.01, 1.21]) that was primarily mediated by preterm birth. There was a higher risk of cerebral palsy among surviving infants exposed to funisitis (relative risk: 1.23 [1.04, 1.51]) compared to those without funisitis. This association was partially (40%) mediated by preterm birth (relative risk: 1.08 [1.05, 1.12]), but the major effect (60%) appears to be a direct adverse effect of funisitis exposure on cerebral palsy development (relative risk: 1.13 [0.97, 1.40]).

Funisitis was associated with an increased risk of the combined outcome of death or cerebral palsy. In surviving infants, the direct adverse effects of funisitis appear to lead to cerebral palsy, independent of preterm birth.