Association Between Fetal Vascular Malperfusion and Cerebral Palsy in Preterm Births

Background: Placental histopathology is an underutilized source of information about pregnancy and the in-utero environment. Recent research has focused on understanding how inflammatory responses and vascular malperfusion may affect neurobehavioral outcomes associated with extreme prematurity. However, existing studies are small and reflect little consensus.

Objectives: We aimed to determine if placental inflammatory responses and vascular malperfusion are associated with greater odds of cerebral palsy (CP) or autism.

Design/Methods: This is a retrospective case-control study of children born preterm (≤30 weeks gestation) at an urban quaternary care center from 2012-2023. Included infants had an available placental pathology report and at least one visit at the associated pediatric hospital. Excluded were infants with grade III/IV intraventricular hemorrhage, major congenital malformations, or chromosomal anomalies, and multiple gestations with monochorionic placentation. Placental histopathologic examinations were conducted per the Amsterdam criteria. We evaluated chronic placental inflammation (CPI), maternal/fetal inflammatory response (MIR, FIR), and maternal/fetal vascular malperfusion (MVM, FVM) in association with the co-primary outcomes of CP and autism, as identified by International Classification of Diseases, Ninth or Tenth Revision (ICD-9 or 10) diagnosis codes in the electronic medical record. Generalized estimating equation regression models were used to calculate odds ratios adjusted for gestational age at delivery, infant sex, and parity.

Results: 631 of 1030 infants were eligible. Median gestational age was 28 weeks+0 days (IQR 26+2, 29+1). Self-reported race was 26.1% Black, 5.4% Asian, 0.8% American Indian or Alaska Native; 0.8% Native Hawaiian or Other Pacific Islander; 22.5% other or unknown. We identified 23 (3.6%) children with diagnosis of CP and 21 (3.3%) with diagnosis of autism. The presence of FVM was positively associated with CP (3/31, 9.7% vs 20/600, 3.3%), with 6.4 times higher adjusted odds of CP (95% CI 1.5, 27.1). CPI, MIR, FIR, and MVM were not associated with autism. Autism was not reported in any of the 31 infants with FVM.

Conclusions: FVM is associated with greater odds of CP postnatally. FVM on placental histopathology may inform parental counseling on neurodevelopmental outcomes after a preterm birth. We are completing a retrospective chart review to confirm this association and the absence of association between FVM and autism.