Maternal Glucose Supplementation in a Murine Model of Chorioamnionitis Alleviates Dysregulation of Autophagy in Fetal Brain.

Fetal brain injury induced by intrauterine inflammation is a major risk factor for adverse neurological outcomes, including cerebral palsy, cognitive dysfunction, and behavioral disabilities. There are no adequate therapies for neuronal protection to reduce fetal brain injury, especially new strategies that may apply promptly and conveniently. In this study, we explored the effect of maternal glucose administration in a mouse model of intrauterine inflammation at term. Our results demonstrated that maternal glucose supplementation significantly increased survival birth rate and improved the neurobehavioral performance of pups exposed to intrauterine inflammation. Furthermore, we demonstrated that maternal glucose administration improved myelination and oligodendrocyte development in offspring exposed to intrauterine inflammation. Though the maternal blood glucose concentration was temporally prevented from decrease induced by intrauterine inflammation, the glucose concentration in fetal brain was not recovered by maternal glucose supplementation. The adenosine triphosphate (ATP) level and autophagy in fetal brain were regulated by maternal glucose supplementation, which may prevent dysregulation of cellular metabolism. Our study is the first to provide evidence for the role of maternal glucose supplementation in the cell survival of fetal brain during intrauterine inflammation and further support the possible medication with maternal glucose treatment.

Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury.

Preterm birth is a major risk factor for adverse neurological outcomes in ex-preterm children, including motor, cognitive, and behavioral disabilities. N-acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes.

Randomized clinical trial between hourly titrated and 2 hourly static oral misoprostol solution for induction of labor.

BACKGROUND: Misoprostol is an effective agent for the induction of labor. Existing guidelines recommend oral misoprostol solution 25 µg every 2 hours. However, more research is required to optimize the use of oral misoprostol solution for the induction of labor. OBJECTIVE: The purpose of this study was to compare efficacy and safety of hourly titrated-dose oral misoprostol solution with static-dose oral misoprostol solution every 2 hours for labor induction. STUDY DESIGN: In this randomized controlled study, oral misoprostol solution was administered as (1) 20 µg hourly (≤4 doses) that was increased in the absence of regular uterine contractions to 40 µg hourly (≤4 doses) and then to 60 µg hourly (≤16 doses) or (2) 25 µg every 2 hours until active labor began (≤12 doses). A sample size of 146 women was planned with the use of a projected 95% rate for the primary endpoint (vaginal delivery within 24 hours) for hourly titrated-dose misoprostol and 80% rate for static-dose misoprostol every 2 hours. Safety outcomes included maternal morbidity and adverse neonatal outcomes. RESULTS: From December 2013 to July 2015, 146 women were assigned randomly to treatment. Demographic and clinical factors were similar between groups, except for age. Vaginal delivery was achieved within 24 hours in 47 women (64.4%) who received hourly titrated-doses of misoprostol solution and 48 women (65.8%) who received 2-hourly static-dose misoprostol solution (P=1.00). Rates of vaginal delivery within 24 hours did not differ significantly between treatment groups for women who were nulliparous (P=1.00) or who had postterm pregnancies (P=.66), a Bishop score of ≤3 (P=.84), or oxytocin augmentation (P=.83). Cesarean deliveries were performed within 24 hours in 9 women who received hourly titrated-dose misoprostol solution and 2 women who received 2-hourly static-dose misoprostol solution (P=.056). Pyrexia and meconium-stained liquor occurred more frequently with the hourly titrated-dose regimen. CONCLUSION: The static-dose oral misoprostol solution every 2 hours has similar efficacy as hourly titrated-dose misoprostol solution but with fewer side-effects and lower complication rates.

Peri-Implantation Hormonal Milieu: Elucidating Mechanisms of Adverse Neurodevelopmental Outcomes.

While live births resulting from assisted reproductive technology (ART) exceed 1% of total births annually, the effect of ART on fetal development is not well understood. Data have demonstrated that IVF leads to alterations in DNA methylation and gene expression in the placenta that may have long-term effects on health and disease. Studies have linked adverse neurodevelopmental outcomes to ART, although human studies are inconclusive. In order to isolate the peri-implantation environment and its effects on brain development, we utilized a mouse model with and without superovulation and examined the effect of adult behavior as well as adult cortical neuronal density. Adult offspring of superovulated dams showed increased anxiety-like behavior compared to offspring of naturally mated dams (P < .05). There was no difference in memory and learning tests between the 2 groups. The adult brains from offspring of superovulated recipients had fewer neurons per field compared to naturally mated control offspring (P < .05). In order to examine potential pathways leading to these changes, we measured messenger RNA and microRNA (miRNA) expression in fetal brains at E18.5. Microarray analysis found that miRNAs miR-122, miR-144, and miR-211, involved in regulation of neuronal migration and differentiation, were downregulated in brains of offspring exposed to a superovulated environment(P < .05). There was also altered expression of genes involved in neuronal development. These results suggest that the peri-implantation environment can affect neurodevelopment and can lead to behavioral changes in adulthood. Human studies with long-term follow-up of children from ART are necessary to further investigate the influence of ART on the offspring.