Abstract
RationaleChorioamnionitis and antenatal glucocorticoids are common exposures for preterm infants and can affect the fetal brain, contributing to cognitive and motor deficits in preterm infants. The effects of antenatal glucocorticoids on the brain in the setting of chorioamnionitis are unknown. We hypothesized that antenatal glucocorticoids would modulate inflammation in the brain and prevent hippocampal and white matter injury after intra-amniotic lipopolysaccharide (LPS) exposure.MethodsTime-mated ewes received saline (control), an intra-amniotic injection of 10 mg LPS at 106d GA or 113d GA, maternal intra-muscular betamethasone (0.5 mg/kg maternal weight) alone at 113d GA, betamethasone at 106d GA before LPS or betamethasone at 113d GA after LPS. Animals were delivered at 120d GA (term=150d). Brain structure volumes were measured on T2-weighted MRI images. The subcortical white matter (SCWM), periventricular white matter (PVWM) and hippocampus were analyzed for microglia, astrocytes, apoptosis, proliferation, myelin and pre-synaptic vesicles.ResultsLPS and/or betamethasone exposure at different time-points during gestation did not alter brain structure volumes on MRI. Betamethasone alone did not alter any of the measurements. Intra-amniotic LPS at 106d or 113d GA induced inflammation as indicated by increased microglial and astrocyte recruitment which was paralleled by increased apoptosis and hypomyelination in the SCWM and decreased synaptophysin density in the hippocampus. Betamethasone before the LPS exposure at 113d GA prevented microglial activation and the decrease in synaptophysin. Betamethasone after LPS exposure increased microglial infiltration and apoptosis.ConclusionIntra-uterine LPS exposure for 7d or 14d before delivery induced inflammation and injury in the fetal white matter and hippocampus. Antenatal glucocorticoids aggravated the inflammatory changes in the brain caused by pre-existing intra-amniotic inflammation. Antenatal glucocorticoids prior to LPS reduced the effects of intra-uterine inflammation on the brain. The timing of glucocorticoid administration in the setting of chorioamnionitis can alter outcomes for the fetal brain.
Highlights
Preterm birth is associated with chorioamnionitis, an infection/inflammation of the amniotic fluid and placental membranes, which is present in up to 60% of early gestation preterm births [1,2]
Gavilanes et al showed that a single intraamniotic bolus of LPS resulted in microglial activation, astrocyte proliferation and increased apoptosis in the ovine fetal brain, which were associated with functional changes in EEG after preterm birth [24]
Brain inflammation was investigated by measuring the area fraction (%) of IBA1 and GFAP as markers for microglial and astrocyte infiltration respectively, in the fetal hippocampus, subcortical white matter and periventricular white matter
Summary
Preterm birth (before 37 weeks of gestation) is associated with chorioamnionitis, an infection/inflammation of the amniotic fluid and placental membranes, which is present in up to 60% of early gestation preterm births [1,2]. Exposure to intra-uterine inflammation is associated with adverse effects on fetal lung [3,4], gut [5,6] and brain [7] development and increases the risk for complications in postnatal life [8]. Administration of antenatal glucocorticoids to induce fetal lung maturation has become standard of care for mothers at risk of preterm delivery, irrespective of the cause of preterm birth [9,10]. Gavilanes et al showed that a single intraamniotic bolus of LPS resulted in microglial activation, astrocyte proliferation and increased apoptosis in the ovine fetal brain, which were associated with functional changes in EEG after preterm birth [24]
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