Acquired neuropathology and its associations with key patterns of placental pathology

Perinatal brain injury is a major cause of neurodevelopmental disability worldwide. Placental pathology has been implicated as a likely cause of injury to the developing central nervous system (CNS). This study aims to elucidate the associations of multiple placental pathologies and CNS injury, including more subtle brain pathologies associated with adverse neurologic outcomes. Sixty-five subjects that underwent complete post-mortem neuropathologic examination and placental examination were selected for inclusion. Gross images, autopsy reports, and histologic sections from the CNS and placenta underwent blinded reviewed by experts in perinatal neuropathology and placental pathology, respectively. Immunostains useful in highlighting CNS lesions not apparent on routine histologic sections were performed. Placental pathology was classified according to the Amsterdam criteria, and all placental and CNS abnormalities were documented. A previously undescribed association between white matter injury and fetal vascular malperfusion was seen, likely due to improved detection of injury on immunohistochemical stains. Amniotic fluid infection was associated with acute neuronal injury in the cortex and cerebellum as well as subarachnoid hemorrhage. Hippocampal injury had the strongest association with high-grade chronic inflammation, and maternal vascular malperfusion showed higher relative frequencies of acute neuronal injury in the basal ganglia, brainstem, and spinal cord. To our knowledge, this is the first study to standardize placental pathology according to the Amsterdam consensus criteria, separate out injury across multiple CNS regions with independent assessment of these regions, and to utilize immunohistochemistry to improve detection of white matter injury. Different patterns of placental pathology were associated with different types of CNS injury, indicating neuronal injury and white matter injury may be influenced by distinct placental pathologies. Elucidating the placental contributions to these acquired CNS pathologies in stillborns is crucial for understanding long-term adverse neurodevelopmental outcomes associated with perinatal brain injury.