Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on magnetic resonance imaging 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 at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by postdelivery neonatal intensive care unit environmental factors to investigate this relationship more clearly.

Objective: This study aimed to determine whether preterm infants born with moderate to severe acute histologic chorioamnionitis would have a higher magnetic resonance imaging-determined global brain abnormality score, independent of early premature birth, when compared with preterm infants with no or mild chorioamnionitis.

Study design: This was a prospective, multicenter cohort study involving infants born very prematurely ≤32 weeks' gestational age with acute moderate to severe histologic 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 magnetic resonance imaging research magnet. In secondary analyses, total brain volume and 4 magnetic resonance imaging metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and correlated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histologic 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 histologic chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histologic chorioamnionitis-exposed infants than in the controls (median, 4 vs 7; P<.001). Infants with acute histologic chorioamnionitis had significantly lower brain tissue volume (P=.03) and sulcal depth (P=.04), whereas other morphometric indices did not differ statistically. In the multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histologic chorioamnionitis and brain abnormality scores (β=2.84; 1.51-4.16; P<.001), total brain volume (P=.03), and sulcal depth (P=.02). Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders (P=.005). Mediation analyses demonstrated that 50% of brain abnormalities was an indirect consequence of premature birth, and the remaining 50% was a direct effect of moderate to severe acute histologic chorioamnionitis when compared with preterm infants with no or mild chorioamnionitis exposure. 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 histologic chorioamnionitis increases the risk for brain injury and delayed maturation, both directly and indirectly, by inducing premature birth.

Keywords: brain score; cerebellum; cerebral palsy; chorioamnionitis; chorionic vasculitis; funisitis; grey matter; inflammation; magnetic resonance imaging; neurodevelopment; preterm; white matter injury.

Conflict of interest statement

Conflict of Interest: None declared

Copyright © 2022 Elsevier Inc. All rights reserved.

Figures

Figure 1:

Representative brain MR images of regional injury. A) Axial T1 weighted image demonstrating abnormal signal of the posterior limb of the internal capsule due to delayed myelination (arrow) and dilatated right lateral ventricles; B) Axial T2 imaging demonstrating bilateral frontal white matter cystic areas (arrows). Dark T2 signal is consistent with associated hemorrhage. The posterior horns of the lateral ventricles demonstrate a squared off configuration supporting white matter volume loss. C) Sagittal T1 image show punctate hyperintense white matter lesions (arrows). D) Axial susceptibility weighted imaging showing multiple foci of dark signal in the right and left cerebellar hemispheres consistent with hemorrhage. E) Axial T2 imaging demonstrating right frontal porencephalic cyst (solid arrow). There is also dark T2 signal at the right caudothalamic groove (dotted arrow) consistent with signal abnormality/germinal hemorrhage. Ex vacuo dilatation of the right lateral ventricle is also present. F) Axial susceptibility weighted imaging showing multiple foci of dark signal abnormality, consistent with hemorrhage, in the right temporal, right occipital and left occipital cortex. G) 2-dimensional measurement of the deep nuclear gray matter on a single axial T2 image at the level at which the caudate heads, lentiform nuclei, and thalami are largest size. H) Transcerebellar diameter (red line) and left and right lateral ventricular diameters (black lines) are measured on a single coronal T2 image at the level of the ventricular atrium. I) Interhemispheric distance (red line) and biparietal width (black) are measured on a single coronal T2 image using the cochlear and basilar truncus as landmarks.

Figure 2.

Mediation model. This model demonstrates that acute maternal moderate-severe histologic chorioamnionitis is significantly associated with brain MRI abnormalities on term-equivalent age MRI (the total effect) and this total effect is the product of both a direct effect (green arrow) and indirect effect (blue arrows) through acute chorioamnionitis’ effect on increased risk of preterm birth. Thus, preterm birth/gestational age is a mediator in the pathway between acute chorioamnionitis and brain abnormalities on MRI at term.