Causal Relationship between Funisitis and Congenital Cerebral Palsy in Preterm Infants: A Direct or Indirect Effect?

Abstract

Background: Premature delivery is the leading risk factor for congenital cerebral palsy (CCP). Intrauterine infection, leading to an inflammatory state, may link preterm birth and CCP. We evaluated the strength of the association between intrauterine infection and CCP, and determined if the effects of funisitis are directly or indirectly mediated. Methods: Using the U.S. Collaborative Perinatal Project (CPP) data (1959-1976), we performed a multivariate pathway analysis to evaluate the direct effects of funisitis on CPP, and the mediating effects of selected variables including Apgar score, severe infection during the neonatal period, and more specifically, gestational age. Findings: analysis was based on data from 4067 preterm singletons, with no evidence of central nervous system malformation. Infants were classified into 3 birth groups: extremely preterm (gestational age, 23-27 weeks), early preterm (28-33 weeks), and late preterm (34-36 weeks). size of the total, direct, and indirect effects of funisitis on CCP, and the 95% confidence interval (CI), were as follows: extremely preterm, 0·67 (95% CI, 0·49-0·80), 0·68 (95% CI, 0·45-0·84), and -0·01 (95% CI, - 0·17-0·14), respectively; and early preterm, 0·52 (95% CI, 0·44-0·59), 0·52 (95% CI, 0·44-0·60), and 0·00 (95% CI, -0·02-0·02), respectively. In the late preterm group, the direct effect of funisitis remained the dominant: total effect, 0·32 (95% CI, 0·27 to 0·37); direct effect, 0·30 (95% CI, 0·25 to 0·35); and indirect effect, 0·02 (95 % CI, 0·01 to 0·04). Interpretation: In preterm birth, especially in extremely preterm birth, intrauterine inflammation is an important risk factor for CCP and exerts a direct effect on the developing brain. Funding Statement: National Natural Science Foundation of China (NO. 81470201) and the Shanghai municipal health and family planning commission foundation of China (NO. 201740195). Declaration of Interests: authors have indicated they have no potential conflicts of interest to disclose. Ethics Approval Statement: authors state: The CPP study data have been de-identified and is publicly available. As such, ethics clearance was not required for the study.