Histologic chorioamnionitis and risk of neurodevelopmental impairment at age 10 years among extremely preterm infants born before 28 weeks of gestation

Background: Extremely preterm infants whose placenta had histologic evidence of chorioamnionitis have early brain dysfunction, but little is known about neurologic development at 10 years of age. Objective: We investigated the association between histologic chorioamnionitis and neurodevelopmental impairment at 10 years among children born 2 standard deviations below the mean), and epilepsy at the age of 10 years by blinded evaluators using validated measures. Multivariable logistic regression with generalized estimating equations was used. Results: Among 805 placentas, 43% (347/805) had histologic chorioamnionitis by moderate or advanced maternal stage, 36% (286/805) by severe maternal grade, 18% (132/737) by moderate or advanced fetal stage, and 1% (10/737) by severe fetal grade. The frequencies of impairments were 11% (88/767) for cerebral palsy, 7% (56/773) for autism spectrum disorder, 15% (120/788) for cognitive impairment, and 7% (52/763) for epilepsy. After adjustment for maternal age, body mass index, race, insurance status, maternal education, tobacco use, infant sex, and multiple gestations, the adjusted odds ratio for the association between histologic chorioamnionitis and cerebral palsy years was increased with advanced maternal stage (adjusted odds ratio, 2.5; 95% confidence interval, 1.6–3.9), severe maternal grade (adjusted odds ratio, 2.0; 95% confidence interval, 1.2–3.4), moderate fetal stage (adjusted odds ratio, 2.20; 95% confidence interval, 2.1–2.2), and mild or moderate fetal grade (adjusted odds ratio, 1.5; 95% confidence interval, 1.0–2.2). Similarly, the adjusted odds ratio for the association between histologic chorioamnionitis and epilepsy was increased with advanced maternal stage (adjusted odds ratio, 1.5; 95% confidence interval, 1.3–1.6) and severe fetal grade (adjusted odds ratio, 5.9; 95% confidence interval, 1.9–17.8). In addition, the adjusted odds ratio for the association between histologic chorioamnionitis and autism spectrum disorder was increased with mild or moderate fetal grade (adjusted odds ratio, 1.7; 95% confidence interval, 1.0–2.9). Histologic chorioamnionitis was not associated with cognitive impairment. These findings held after adjustment for gestational age at delivery. In contrast to histologic chorioamnionitis, a clinical diagnosis of chorioamnionitis was not associated with neurodevelopmental impairment. Conclusion: Histologic chorioamnionitis may be associated with some forms of neurodevelopmental impairment at 10 years of life among infants born <28 weeks’ gestation

Prenatal Metal Exposure Alters the Placental Proteome in a Sex-Dependent Manner in Extremely Low Gestational Age Newborns: Links to Gestational Age

Prenatal exposure to toxic metals is associated with altered placental function and adverse infant and child health outcomes. Adverse outcomes include those that are observed at the time of birth, such as low birthweight, as well as those that arise later in life, such as neurological impairment. It is often the case that these adverse outcomes show sex-specific responses in relation to toxicant exposures. While the precise molecular mechanisms linking in utero toxic metal exposures with later-in-life health are unknown, placental inflammation is posited to play a critical role. Here, we sought to understand whether in utero metal exposure is associated with alterations in the expression of the placental proteome by identifying metal associated proteins (MAPs). Within the Extremely Low Gestational Age Newborns (ELGAN) cohort (n = 230), placental and umbilical cord tissue samples were collected at birth. Arsenic (As), cadmium (Cd), lead (Pb), selenium (Se), and manganese (Mn) concentrations were measured in umbilical cord tissue samples via ICP-MS/MS. Protein expression was examined in placental samples using an LC-MS/MS-based, global, untargeted proteomics analysis measuring more than 3400 proteins. MAPs were then evaluated for associations with pregnancy and neonatal outcomes, including placental weight and gestational age. We hypothesized that metal levels would be positively associated with the altered expression of inflammation/immune-associated pathways and that sex-specific patterns of metal-associated placental protein expression would be observed. Sex-specific analyses identified 89 unique MAPs expressed in female placentas and 41 unique MAPs expressed in male placentas. Notably, many of the female-associated MAPs are known to be involved in immune-related processes, while the male-associated MAPs are associated with intracellular transport and cell localization. Further, several MAPs were significantly associated with gestational age in males and females and placental weight in males. These data highlight the linkage between prenatal metal exposure and an altered placental proteome, with implications for altering the trajectory of fetal development