Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury

Abstract

Exposure to prenatal inflammation is a known risk factor for long term neurobehavioral disorders including cerebral palsy, schizophrenia, and autism. Models of systemic inflammation during pregnancy have demonstrated an association with an immune response an adverse neurobehavioral outcomes for the exposed fetus. Yet, the most common route for an inflammatory exposure to a fetus is from intrauterine inflammation as occurs with chorioamnionitis. The aims of this study were to assess the effect of intrauterine inflammation on fetal and neonatal brain development and to determine if the gestational age of exposure altered the maternal or fetal response to inflammation. CD‐1 timed pregnant mice on embryonic day 15 (E15) and E18.5 were utilized for this study. Dams were randomized to receive intrauterine infusion of lipopolysaccharide (LPS, 50 μg/dam) or normal saline. Different experimental groups were used to assess both acute and long‐term outcomes. For each gestational age and each treatment group, fetal brains, amniotic fluid, maternal serum and placentas were collected 6 h after intrauterine infusion. Rates of preterm birth, maternal morbidity and litter size were assessed. IL6 levels were assayed in maternal serum and amniotic fluid. An immune response was determined in the fetal brains and placentas by QPCR. Cortical cultures were performed to assess for fetal neuronal injury. Gene expression changes in postnatal day 7 brains from exposed and unexposed pups were determined. In the preterm period, low dose LPS resulted in a 30% preterm birth rate. Litter sizes were not different between the groups at either gestational age. IL6 levels were not significantly increased in maternal serum at either gestational time period. Low dose LPS increased IL6 levels in the amniotic fluid from exposed dams in the term but not preterm period. Regardless of gestational age of exposure, low dose intrauterine LPS activated an immune response in the placenta and fetal brain. Exposure to intrauterine LPS significantly decreased dendritic counts in cortical cultures from both the preterm and term period. Exposure to intrauterine inflammation altered gene expression patterns in the postnatal brain; this effect was dependent on gestational age of exposure. In conclusion, intrauterine inflammation, even in the absence of preterm parturition, can evoke fetal brain injury as evidence by alterations in cytokine expression and neuronal injury. Despite an absent or limited maternal immune response in low dose intrauterine inflammation, the immune system in the placenta is activated which is likely sufficient to induce a fetal immune response and subsequent brain injury. Changes in the fetal brain lead to changes in gene expression patterns into the neonatal period. Subclinical intrauterine inflammation can lead to fetal brain injury and is likely to be mechanistically associated with long term adverse outcomes for exposed offspring.

Maternal inflammation modulates infant immune response patterns to viral lung challenge in a murine model

“…In particular, the absence of basal IL-1β responses in our present study contrast with the marked IL-1β elevations in neonatal brains following exposure to intrauterine LPS reported by Elovitz et al (12). These differences may reflect the more direct fetal effects of intrauterine inflammation compared to the generalized maternal exposure in our studies.…”

“…Previous studies have shown a potentiating effect of intrauterine LPS on inflammatory cytokines in fetal and neonatal brains (12). In the present study, basal brain interleukin (IL)-1β mRNA expression was similar in LPS-exposed and control neonates, and SeV infection only moderately increased IL-1β expression in both groups (Figure 4).…”

Clinical chorioamnionitis at term: the amniotic fluid fatty acyl lipidome

“…Clinical chorioamnionitis and puerperal endomyometritis are the leading causes of infection-related complications in pregnant women. In addition to the maternal morbidity associated with clinical chorioamnionitis and puerperal infections, neonates born to mothers with clinical chorioamnionitis at term (TCC) are at increased risk for long-term complications, notably cerebral palsy (11)(12)(13).…”

Inhibition of Cxcr 1 and 2 Delays Preterm Delivery and Reduces Neonatal Mortality in a Mouse Model of Chorioamnionitis

“…Control groups (Negative control group): Dams received either saline injections (100 ul) on GD15 (n=5), or no injections (n=5). Term delivery was defined as delivery after 19 days of gestation (27). All the animals were observed until spontaneous delivery.…”

“…An intraperitoneal E. Coli LPS model was used to induce pretenn delivery in mice to model systemic inflammation with chorioamni onitis. A high dose of LPS (50llglmouse) was chosen based on our findings and previous studies using various doses ofLPS (20,21,27,30), in order to ensure consistent pretenn delivery (90% pretenn delivery) . The dams in the LPS group that delivered prematurely delivered within 24 h after LPS injection compared to the dams A .. .~.…”