Early life stress and LPS interact to modify the mouse cortical transcriptome in the neonatal period

Introduction: Preterm birth (PTB) is closely associated with atypical cerebral cortical development and cognitive impairment. Early exposure to extrauterine life often results in atypical environmental and biological experiences that co-occur, including early life stress (ELS) and systemic inflammation. Understanding how these experiences interact to shape cortical development is an essential prerequisite to developing therapeutic interventions that will work in the complex postnatal environment of the preterm infant. Here, we studied the effects of a murine model of infection and ELS on the neonatal cortex transcriptome. Methods: We used a mouse model of infection (1 ​mg/kg LPS at postnatal day (P)3) +/− ELS (modified maternal separation; MMS on days P4–P6) at timepoints with neurodevelopmental relevance to PTB. We used 4 groups: control, LPS, MMS and LPS ​+ ​MMS. Cortices were dissected at P6 for 3′RNA sequencing. Results: LPS exposure resulted in reduced weight gain and increased expression of inflammation-associated genes in the brain. More genes were differentially expressed following LPS (15) and MMS (29) than with LPS ​+ ​MMS (8). There was significant overlap between the LPS and MMS datasets, particularly amongst upregulated genes, and when comparing LPS and MMS datasets with LPS ​+ ​MMS. Gene Ontology terms related to the extracellular matrix and cytokine response were enriched following MMS, but not following LPS or LPS ​+ ​MMS. 26 Reactome pathways were enriched in the LPS group, none of which were enriched in the LPS ​+ ​MMS group. Finally, a rank-rank hypergeometric overlap test showed similarities, particularly in upregulated genes, in the LPS and MMS conditions, indicating shared mechanisms. Conclusion: LPS and MMS interact to modify the cortical transcriptome in the neonatal period. This has important implications for understanding the neural basis of atypical cortical development associated with early exposure to extrauterine life

Preterm birth is associated with immune dysregulation which persists in infants exposed to histologic chorioamnionitis

IntroductionPreterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not.PopulationFor objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available.MethodsPlacental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.ResultsThe umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.ConclusionPreterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life

Hidden in plain sight:Using administrative data to conduct a longitudinal cohort study of children exposed to opioids in pregnancy

Objectives: Children of women who use substances are difficult to research at a population-level using traditional research methods due to the complexity of their lives. Resultingly, we have little robust evidence on their outcomes. This study developed an administrative data cohort of children exposed to opioids and explored health outcomes.Methods: Using data from birth records, antenatal records, prescription data, hospital/psychiatric hospital admissions, and drug and alcohol service data, we identified 6,408 children (born 2009-2019) in Scotland who were exposed to opioids through illicit use and/or medication assisted treatment (i.e. methadone/buprenorphine). A control group (n. 19,089) of children not exposed to opioids were matched on age of mother and Scottish Index of Multiple Deprivation. Data were described and linear and logistic regression models were used to examine the relationship between risk factors (such as drug and alcohol use in pregnancy, gestation at booking and at birth), and key early outcomes.Results: Although the majority of women had their substance use recorded in antenatal records, 28.9\% did not, demonstrating the importance of using multiple administrative datasets to form the cohort. Children in the cohort were more likely to experience a range of adverse outcomes including being born early (17\% born prematurely, compared with 6.5\% in control group), having a below normal Apgar score (the scoring system used to assess newborns shortly after birth) (2.9\% in cohort vs. 1.5\% in controls), having significantly lower birthweight, length and head circumference, and more likely to be removed from their mother prior hospital discharge. Differences between the cohorts remained after controlling for other risk factors including alcohol use, and gestation.Conclusion: This feasibility study brought together a cohort of children usually excluded from traditional forms of research. The research demonstrated early differences in outcomes between exposed children and others from similar socio-economic groups. The next stage of this research is exploring health and development outcomes in the preschool period