Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on MRI in very preterm infants

Abstract

Background

The independent risk for neurodevelopmental impairments attributed to chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury identified on magnetic resonance imaging (MRI) at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by post neonatal intensive care unit (NICU) environmental factors to more clearly investigate this relationship.

Objective

To determine whether preterm infants born with moderate to severe acute histological chorioamnionitis would have a higher MRI-determined global brain abnormality score, independent of early premature birth, as compared to preterm infants with no/mild chorioamnionitis.

Study Design

Prospective multicenter cohort study involving infants born very preterm at or before 32 weeks gestational age with acute moderate to severe histological chorioamnionitis, graded using standard histologic criteria. Brain abnormalities were diagnosed and scored using a well-characterized, standardized scoring system captured using a high-resolution 3 Tesla MRI research magnet. In secondary analyses, total brain volume and four MRI metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and associated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histological chorioamnionitis and brain abnormality score using mediation analysis.

Results

Of 353 very preterm infants, 297 infants had mild or no chorioamnionitis (controls), and 56 were diagnosed with moderate to severe acute histological chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histological chorioamnionitis exposed infants than in controls (median, 4 vs 7, p <0.001). Infants with acute histological chorioamnionitis had significantly lower brain tissue volume (p=0.03) and sulcal depth (p=0.04), while other morphometric indices did not differ statistically. On multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histological chorioamnionitis and brain abnormality score (ß=2.84 [1.51, 4.16], p<0.001), total brain volume, and sulcal depth. Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders. Mediation analyses demonstrated that 50% of brain abnormalities resulted indirectly from premature birth and the remaining 50% from a direct effect of moderate to severe acute histological chorioamnionitis as compared to preterm infants with no/mild chorioamnionitis. Examining gestational age as a mediator, funisitis did not exert a significant direct effect on brain abnormalities, after the significant indirect effects of preterm birth were accounted for.

Conclusion

Acute histological chorioamnionitis increases the risk of brain injury and/or delayed maturation, both directly and indirectly by inducing premature birth.