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Perinatal antibiotic prophylaxis is an effective method for preventing group B Streptococcus (GBS) infection in newborns. Antibiotic exposure unbalances women’s vaginal microbiota, which is associated with the establishment of the newborn gut microbiota. However, the influence of perinatal antibiotic exposure on neonatal gut microbiota colonization and health outcomes remains unclear. In this study, we found that perinatal antibiotic exposure induced microbiota dysbiosis in a woman’s vagina and the neonatal gut, and we highlight a significant decrease in the abundance of Lactobacillus spp. The influence of antibiotic use on the microbiota was greater than that from gestational age. Additionally, full-term newborns without antibiotic exposure had no evidence of early-onset sepsis, whereas in full-term or preterm newborns with antibiotic exposure before birth, at least one infant was diagnosed with early-onset sepsis. These results suggest an association between perinatal antibiotic exposure and microbial dysbiosis in maternal vaginal and neonatal gut environments, which may be related to the occurrence of early-onset sepsis. Intrapartum antibiotic prophylaxis reduces the risk of infection to a mother and neonate, but antibiotic-mediated maternal and neonatal microbiota dysbiosis increases other health risks to newborn infants. We studied the impact of perinatal antibiotic prophylaxis on the microbiota in mothers and newborns with full-term or preterm delivery. Ninety-eight pregnant women and their neonates were divided into the following four groups: full term without antibiotic exposure (FT), full term with antibiotic exposure (FTA), preterm without antibiotic exposure (PT), and preterm with antibiotic exposure (PTA). Bacterial composition was analyzed by sequencing the 16S rRNA gene from maternal vaginal swabs (V) and neonatal meconium (F). The results showed that in maternal vaginal and neonatal meconium microbiota, FT and PT groups had a higher load of Lactobacillus spp. than did the FTA and PTA groups. In addition, whether in the mother or newborn, the dissimilarity in microbiota between FT and PT was the lowest compared to that between other groups. Compared to the FT and PT groups, the dissimilarity in microbial structures between the vagina and meconium decreased in the FTA and PTA groups. The health outcome of infants reveals an association between early-onset sepsis and antibiotic-mediated microbiota dysbiosis. In conclusion, perinatal antibiotic exposure is related to the establishment of gut microbiota and health risks in newborns. Promoting the rational usage of antibiotics with pregnant women will improve neonatal health. IMPORTANCE Perinatal antibiotic prophylaxis is an effective method for preventing group B Streptococcus (GBS) infection in newborns. Antibiotic exposure unbalances women’s vaginal microbiota, which is associated with the establishment of the newborn gut microbiota. However, the influence of perinatal antibiotic exposure on neonatal gut microbiota colonization and health outcomes remains unclear. In this study, we found that perinatal antibiotic exposure induced microbiota dysbiosis in a woman’s vagina and the neonatal gut, and we highlight a significant decrease in the abundance of Lactobacillus spp. The influence of antibiotic use on the microbiota was greater than that from gestational age. Additionally, full-term newborns without antibiotic exposure had no evidence of early-onset sepsis, whereas in full-term or preterm newborns with antibiotic exposure before birth, at least one infant was diagnosed with early-onset sepsis. These results suggest an association between perinatal antibiotic exposure and microbial dysbiosis in maternal vaginal and neonatal gut environments, which may be related to the occurrence of early-onset sepsis.

Fetal Alcohol Spectrum Disorders (FASDs) are comprised of developmental, behavioral, and cognitive abnormalities caused by prenatal alcohol exposure, affecting an estimated 2%–5% of children and costing $4 billion annually in the United States. While some behavioral therapies help, the neurobiological mechanisms that underpin FASDs need further elucidation for development of effective pharmacotherapeutics. The role of the tau protein in the hippocampus is likely to be involved. Tau catalyzes microtubule polymerization in developing neurons. However, this function can become disrupted by hyperphosphorylation. Many of the cognitive deficits observed in neurodegenerative tauopathies overlap to some degree with what is observed in juvenile developmental disabilities, such as FASDs (e.g., selective memory, executive dysfunction). Thus, tau protein phosphorylation may be one important mechanism of dysfunction in FASDs. The purpose of this study is to provide an empirical basis for a tauopathic characterization of FASDs. To do so, hippocampal slices were extracted from rats at postnatal day 10 (PND10); hippocampal slices were then exposed to 5 days of 50-mM ethanol between 6 days in vitro (DIV) and 11DIV. Immunoblots were taken for Total and p-Tau (Threonine231) at 12DIV and 24DIV. Immunohistochemical fluorescent images were taken for p-Tau (Threonine231) at 12DIV and 24DIV. Separate p-Tau measures were taken for the cornu ammonis 1 (CA1), CA3, and dentate gyrus (DG). Total Tau protein expression remained unchanged between 12DIV and 24DIV regardless of ethanol condition. In the control group, longer DIV was associated with decreased p-Tau. However, in the ethanol-exposed group, p-Tau was sustained across DIV. This is the first study to show that ethanol exposure sustains tau Threonine231 phosphorylation in the perinatal hippocampus regardless of Total Tau expression. These findings could lead to innovative pharmacotherapeutic targets for the treatment of cognitive deficits seen in FASDs. •Total Tau protein expression is unaffected by ethanol in cultured rat hippocampus.•Tau phosphorylation decrements across days in vitro in cultured rat hippocampus.•Ethanol exposure prolongs tau phosphorylation in cultured rat hippocampus.•Tau phosphorylation is sustained in cultured rat hippocampal CA1 and DG.•Tau phosphorylation is unaffected by ethanol in cultured rat hippocampal CA3.

Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior.

Background Bisphenol S (BPS) is a common bisphenol A (BPA) substitute, since BPA is virtually banned worldwide. However, BPS and BPA have both endocrine disrupting properties. Their effects appear mostly in adulthood following perinatal exposures. The objective of the present study was to investigate the impact of perinatal and chronic exposure to BPS at the low dose of 1.5 μg/kg body weight/day on the transcriptome and methylome of the liver in 23 weeks-old C57BL6/J male mice. Results This multi-omic study highlights a major impact of BPS on gene expression (374 significant deregulated genes) and Gene Set Enrichment Analysis show an enrichment focused on several biological pathways related to metabolic liver regulation. BPS exposure also induces a hypomethylation in 58.5% of the differentially methylated regions (DMR). Systematic connections were not found between gene expression and methylation profile excepted for 18 genes, including 4 genes involved in lipid metabolism pathways (Fasn, Hmgcr, Elovl6, Lpin1), which were downregulated and featured differentially methylated CpGs in their exons or introns. Conclusions This descriptive study shows an impact of BPS on biological pathways mainly related to an integrative disruption of metabolism (energy metabolism, detoxification, protein and steroid metabolism) and, like most high-throughput studies, contributes to the identification of potential exposure biomarkers. Graphical abstract

Recent years have been transformational in regard to the perception of the health risks and benefits of cannabis with increased acceptance of use. This has unintended neurodevelopmental implications given the increased use of cannabis and the potent levels of Δ9-tetrahydrocannabinol today being consumed by pregnant women, young mothers and teens. In this Review, we provide an overview of the neurobiological effects of cannabinoid exposure during prenatal/perinatal and adolescent periods, in which the endogenous cannabinoid system plays a fundamental role in neurodevelopmental processes. We highlight impaired synaptic plasticity as characteristic of developmental exposure and the important contribution of epigenetic reprogramming that maintains the long-term impact into adulthood and across generations. Such epigenetic influence by its very nature being highly responsive to the environment also provides the potential to diminish neural perturbations associated with developmental cannabis exposure.Sociopolitical changes regarding cannabis and its potential harm for vulnerable populations raise concern as more pregnant women and teens use cannabis. Hurd and colleagues discuss neurobiological effects of cannabis exposure during development and highlight an epigenetic link for synaptic reprogramming.

Metformin is increasingly offered as an acceptable and economic alternative to insulin for treatment of gestational diabetes mellitus (GDM) in many countries. However, the impact of maternal metformin treatment on the trajectory of fetal, infant, and childhood growth is unknown. PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and the Cochrane database were systematically searched (from database inception to 26 February 2019). Outcomes of GDM-affected pregnancies randomised to treatment with metformin versus insulin were included (randomised controlled trials and prospective randomised controlled studies) from cohorts including European, American, Asian, Australian, and African women. Studies including pregnant women with pre-existing diabetes or non-diabetic women were excluded, as were trials comparing metformin treatment with oral glucose-lowering agents other than insulin. Two reviewers independently assessed articles for eligibility and risk of bias, and conflicts were resolved by a third reviewer. Outcome measures were parameters of fetal, infant, and childhood growth, including weight, height, BMI, and body composition. In total, 28 studies (n = 3,976 participants) met eligibility criteria and were included in the meta-analysis. No studies reported fetal growth parameters; 19 studies (n = 3,723 neonates) reported measures of neonatal growth. Neonates born to metformin-treated mothers had lower birth weights (mean difference -107.7 g, 95% CI -182.3 to -32.7, I2 = 83%, p = 0.005) and lower ponderal indices (mean difference -0.13 kg/m3, 95% CI -0.26 to 0.00, I2 = 0%, p = 0.04) than neonates of insulin-treated mothers. The odds of macrosomia (odds ratio [OR] 0.59, 95% CI 0.46 to 0.77, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99, p = 0.04) were lower following maternal treatment with metformin compared to insulin. There was no difference in neonatal height or incidence of small for gestational age between groups. Two studies (n = 411 infants) reported measures of infant growth (18-24 months of age). In contrast to the neonatal phase, metformin-exposed infants were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830, I2 = 4%, p = 0.03). Three studies (n = 520 children) reported mid-childhood growth parameters (5-9 years). In mid-childhood, BMI was significantly higher (mean difference 0.78 kg/m2, 95% CI 0.23 to 1.33, I2 = 7%, p = 0.005) following metformin exposure than following insulin exposure, although the difference in absolute weights between the groups was not significantly different (p = 0.09). Limited evidence (1 study with data treated as 2 cohorts) suggested that adiposity indices (abdominal [p = 0.02] and visceral [p = 0.03] fat volumes) may be higher in children born to metformin-treated compared to insulin-treated mothers. Study limitations include heterogeneity in metformin dosing, heterogeneity in diagnostic criteria for GDM, and the scarcity of reporting of childhood outcomes. Following intrauterine exposure to metformin for treatment of maternal GDM, neonates are significantly smaller than neonates whose mothers were treated with insulin during pregnancy. Despite lower average birth weight, metformin-exposed children appear to experience accelerated postnatal growth, resulting in heavier infants and higher BMI by mid-childhood compared to children whose mothers were treated with insulin. Such patterns of low birth weight and postnatal catch-up growth have been reported to be associated with adverse long-term cardio-metabolic outcomes. This suggests a need for further studies examining longitudinal perinatal and childhood outcomes following intrauterine metformin exposure. This review protocol was registered with PROSPERO under registration number CRD42018117503.

ObjectiveActive inflammatory bowel disease (IBD) during pregnancy may require the use of corticosteroids. The aim of this study was to investigate the impact of in utero corticosteroid exposure on adverse pregnancy outcomes, congenital malformations, infections and neurocognitive development among offspring of mothers with IBD.DesignUsing the prospective Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes registry, data were collected at each trimester, delivery; and in the 12 months post partum. Bivariate statistics and multivariate logistic regression models compared pregnancy outcomes by corticosteroid exposure.ResultsA total of 1490 mothers with IBD were enrolled, with 1431 live births recorded. Corticosteroid use was associated with increased risk of preterm birth, small for gestational age, low birth weight (LBW), intrauterine growth restriction and neonatal intensive care unit (NICU) admission. On adjusted multivariate models, corticosteroid use was associated with preterm birth (OR 1.79, 95% CI 1.18 to 2.73), LBW (OR 1.76, 95% CI 1.07 to 2.88) and NICU admission (OR 1.54, 95% CI 1.03 to 2.30). Late corticosteroid use (second and/or third trimester) was associated with serious infections at 9 and 12 months (4% vs 2% and 5% vs 2%, respectively, p=0.03 and p=0.001). There were five newborns with in utero corticosteroid exposure born with orofacial clefts versus one without corticosteroid exposure. Developmental milestones were similar across corticosteroid exposure groups.ConclusionIn this prospective pregnancy registry, offspring of women exposed to corticosteroids during pregnancy were more likely to have adverse pregnancy outcomes. This emphasises the importance of controlling disease activity before and during pregnancy with steroid-sparing therapy.

Bisphenol-A (BPA) has been reported to be associated to female infertility. Indeed, BPA has been found to be more frequently detected in infertile women thus leading to hypothesize a possible effect of BPA on natural conception and spontaneous fecundity. In addition, in procedures of medically assisted reproduction BPA exposure has been found to be negatively associated with peak serum estradiol levels during gonadotropin stimulation, number of retrieved oocytes, number of normally fertilized oocytes and implantation. BPA deleterious effects are more critical during perinatal exposure, causing dysregulation of hypothalamic-pituitary-ovarian axis in pups and adults, with a precocious maturation of the axis through a damage of GnRH pulsatility, gonadotropin signaling and sex steroid hormone production. Further, BPA exposure during early lifestage may have a transgenerational effect predisposing the subsequent generations to the risk of developing BPA related disease. Experimental studies suggested that prenatal, perinatal and postnatal exposure to BPA can impair several steps of ovarian development, induce ovarian morphology rearrangement and impair ovarian function, particularly folliculogenesis, as well as can impair uterus morphology and function, in female adult animal and offspring. Finally, studies carried out in animal models have been reported the occurrence of endometriosis-like lesions after BPA exposure. Moreover, BPA exposure has been described to encourage the genesis of PCOS-like abnormalities through the impairment of the secretion of sex hormones affecting ovarian morphology and functions, particularly folliculogenesis. The current manuscript summarizes the evidence regarding the association between BPA exposure and female infertility, reviewing both clinical and preclinical studies.

258 million people reside outside their country of birth; however, to date no global systematic reviews or meta-analyses of mortality data for these international migrants have been done. We aimed to review and synthesise available mortality data on international migrants. In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, and Google Scholar databases for observational studies, systematic reviews, and randomised controlled trials published between Jan 1, 2001, and March 31, 2017, without language restrictions. We included studies reporting mortality outcomes for international migrants of any age residing outside their country of birth. Studies that recruited participants exclusively from intensive care or high dependency hospital units, with an existing health condition or status, or a particular health exposure were excluded. We also excluded studies limited to maternal or perinatal outcomes. We screened studies using systematic review software and extracted data from published reports. The main outcomes were all-cause and International Classification of Diseases, tenth revision (ICD-10) cause-specific standardised mortality ratios (SMRs) and absolute mortality rates. We calculated summary estimates using random-effects models. This study is registered with PROSPERO, number CRD42017073608. Of the 12 480 articles identified by our search, 96 studies were eligible for inclusion. The studies were geographically diverse and included data from all global regions and for 92 countries. 5464 mortality estimates for more than 15·2 million migrants were included, of which 5327 (97%) were from high-income countries, 115 (2%) were from middle-income countries, and 22 (<1%) were from low-income countries. Few studies included mortality estimates for refugees (110 estimates), asylum seekers (144 estimates), or labour migrants (six estimates). The summary estimate of all-cause SMR for international migrants was lower than one when compared with the general population in destination countries (0·70 [95% CI 0·65–0·76]; I2=99·8%). All-cause SMR was lower in both male migrants (0·72 [0·63–0·81]; I2=99·8%) and female migrants (0·75 [0·67–0·84]; I2=99·8%) compared with the general population. A mortality advantage was evident for refugees (SMR 0·50 [0·46–0·54]; I2=89·8%), but not for asylum seekers (1·05 [0·89–1·24]; I2=54·4%), although limited data was available on these groups. SMRs for all causes of death were lower in migrants compared with the general populations in the destination country across all 13 ICD-10 categories analysed, with the exception of infectious diseases and external causes. Heterogeneity was high across the majority of analyses. Point estimates of all-cause age-standardised mortality in migrants ranged from 420 to 874 per 100 000 population. Our study showed that international migrants have a mortality advantage compared with general populations, and that this advantage persisted across the majority of ICD-10 disease categories. The mortality advantage identified will be representative of international migrants in high-income countries who are studying, working, or have joined family members in these countries. However, our results might not reflect the health outcomes of more marginalised groups in low-income and middle-income countries because little data were available for these groups, highlighting an important gap in existing research. Our results present an opportunity to reframe the public discourse on international migration and health in high-income countries. Wellcome Trust, National Institute for Health Research, Medical Research Council, Alliance for Health Policy and Systems Research, Department for International Development, Fogarty International Center, Grand Challenges Canada, International Development Research Centre Canada, Inter-American Institute for Global Change Research, National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Mental Health, Swiss National Science Foundation, World Diabetes Foundation, UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, and European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Group Research Funding for the ESCMID Study Group for Infections in Travellers and Migrants.