Dataset Information

Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection.

ABSTRACT: BackgroundIntrauterine infection is a significant cause of early preterm birth. We have developed a fetal-neonatal model in the rhesus macaque to determine the impact of chronic intrauterine infection with Ureaplasma parvum on early neonatal reflexes and brain development.MethodsTime-mated, pregnant rhesus macaques were randomized to be inoculated with U. parvum (serovar 1; 105?c.f.u.) or control media at ~120 days' gestational age (dGA). Neonates were delivered by elective hysterotomy at 135-147?dGA (term=167d), stabilized, and cared for in our nonhuman primate neonatal intensive care unit. Neonatal reflex behaviors were assessed from birth, and fetal and postnatal brain magnetic resonance imaging (MRI) was performed.ResultsA total of 13 preterm and 5 term macaque infants were included in the study. Ten preterm infants survived to 6 months of age. U. parvum-infected preterm neonates required more intensive respiratory support than did control infants. MRI studies suggested a potential perturbation of brain growth and white matter maturation with exposure to intra-amniotic infection.ConclusionWe have demonstrated the feasibility of longitudinal fetal-neonatal studies in the preterm rhesus macaque after chronic intrauterine infection. Future studies will examine long-term neurobehavioral outcomes, cognitive development, neuropathology, and in vivo brain imaging to determine the safety of antenatal antibiotic treatment for intrauterine infection.

SUBMITTER: Kelleher MA

PROVIDER: S-EPMC5552412 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection.

Kelleher Meredith A MA Liu Zheng Z Wang Xiaojie X Kroenke Christopher D CD Houser Lisa A LA Dozier Brandy L BL Martin Lauren D LD Waites Ken B KB McEvoy Cindy C Schelonka Robert L RL Grigsby Peta L PL

Pediatric research 20170524 2

BackgroundIntrauterine infection is a significant cause of early preterm birth. We have developed a fetal-neonatal model in the rhesus macaque to determine the impact of chronic intrauterine infection with Ureaplasma parvum on early neonatal reflexes and brain development.MethodsTime-mated, pregnant rhesus macaques were randomized to be inoculated with U. parvum (serovar 1; 10<sup>5 </sup>c.f.u.) or control media at ~120 days' gestational age (dGA). Neonates were delivered by elective hysterotom ...[more]

PMID: 28422948

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Project description:Little is known about the repertoire of nonhuman primate kidney genes expressed throughout development. The present work establishes an understanding of the primate renal transcriptome at different stages of fetal development and defines the framework of gene expression in the context of renal maturation, which provides a basis for identifying deviations in transcriptome expression resulting from suboptimal conditions during renal development. The baboon kidney transcriptome was characterized at 60 days gestation (DG), 90DG, 125DG, 160DG and adulthood (6-12 years) using human genome arrays to identify differential gene expression in the context of biological pathways and hierarchical clusters. Whole genome expression profiling showed 11,331 genes that were expressed during kidney development, 4,698 of which were differentially expressed among the developmental time points. Pathway analysis indicated activation of annotated pathways previously reported to be important to kidney development and pathways not reported as relevant to kidney development. QRT-PCR for genes central to these pathways validated expression profiles and revealed differences between males and females at specific times in gestation. Hierarchical clustering indicated that two clusters best fit the data, one containing genes that increased in expression from 60DG to adult and one that decreased. Cluster analysis also revealed gene splice variants with discordant expression profiles during development. For example, SMAD4, which is central to Wnt signaling, TGF-β signaling and cell cycle, showed up-regulation of the full-length splice variant during development and down-regulation of a shorter variant that is missing DNA binding and protein heterotrimerization domains suggesting decreased inhibition of cell proliferation, which may impact renal cell number and maturation. This study provides the first detailed genetic analysis of the developing primate kidney, and our findings of discordant expression of gene splice variants suggest that gene arrays likely provide a simplified view and demonstrate the need to study the fetal renal proteome.

Project description:Background: SSRIs (Selective Serotonin Reuptake Inhibitors) are the most useful drugs to treat depression during pregnancy. Intrauterine exposure to SSRIs may increase the risk of growth restriction, preterm birth and neonatal complications. However, advantages in treating depression seem to exceed potential drug side effects in respect un-treated depression. SSRIs undergo extensive hepatic first-pass metabolism with the involvement of several cytochrome P450 (CYPs) enzymes. Genetic polymorphisms may influence the expression and activity of CYPs genes. The first aim of this study was to evaluate neonatal outcomes in depressed mothers exposed to SSRIs during pregnancy. SSRIs pharmacogenetics was also evaluated in a subset of mothers and fetuses. Methods: In this case-control study, cases (n = 42) were Caucasian women with a diagnosis of depression and/or anxiety, treated with SSRIs for the whole pregnancy. Controls (n = 85) were Caucasian women without a psychiatric diagnosis and not exposed to SSRIs during pregnancy. Exclusion criteria for both groups were other psychotropic drugs, anti-epileptics, drug of abuse, alcohol addiction, maternal or fetal infectious diseases, fetal/neonatal chromosomal genetic abnormalities. Maternal and fetal blood samples were obtained at delivery to analyze genotype in 33 cases. Results: The population was homogenous for demographic, anthropometric, socio-economic and obstetric variables except for smoking and mean hemoglobin values before delivery. Obstetric features were comparable. Newborns exposed to SSRIs during fetal life were significantly more likely to be Low Birth Weight (LBW) (birth weight <2,500 g) (p = 0.01), had significantly lower mean Apgar scores at 1' (p = 0.006) and at 5' (p = 0.023) and worse Apgar distribution at 1' (p = 0.017) and at 5' (p = 0.013). Fifty-six percent of newborns presented one or more symptoms consistent with poor neonatal adaptation syndrome (PNAS). Pharmacogenetic analysis at delivery did not show significant differences in the frequencies of obstetric or neonatal complications in relation to polymorphisms. Conclusions: We found that newborns exposed to SSRIs are at increased risk of poor neonatal outcomes in terms of low birth weight, low Apgar scores and, clinically, poor neonatal adaptation syndrome. Preliminary pharmacogenetic analysis showed that the degree of CYPs alterations, that depends on polymorphisms, may influence neonatal outcomes.

Dataset Information

Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection.

Publications

Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection.

Similar Datasets

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