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(Abstracted from JAMA2023;330(22):2182–2190)Preexisting type 2 diabetes in pregnant people increases the risk for adverse pregnancy outcomes, intrapartum complications, and neonatal hypoglycemia at birth. To achieve normal maternal glucose levels and optimize pregnancy outcomes, management includes maternal blood glucose monitoring, dietary management, and insulin therapy.

AbstractPrenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6–51 and HR = 7.0, 95% CI 1.5–33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88–1.5) or diabetes (HR = 1.1, 95% CI 0.9–1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84–20) or general population (SIR: 1.9, 95% CI 1.0–3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

The COVID-19 pandemic has sparked an urgent need to uncover the underlying biology of this devastating disease. Though RNA viruses mutate more rapidly than DNA viruses, there are a relatively small number of single nucleotide polymorphisms (SNPs) that differentiate the main SARS-CoV-2 lineages that have spread throughout the world. In this study, we investigated 129 RNA-seq data sets and 6928 consensus genomes to contrast the intra-host and inter-host diversity of SARS-CoV-2. Our analyses yielded three major observations. First, the mutational profile of SARS-CoV-2 highlights intra-host single nucleotide variant (iSNV) and SNP similarity, albeit with differences in C > U changes. Second, iSNV and SNP patterns in SARS-CoV-2 are more similar to MERS-CoV than SARS-CoV-1. Third, a significant fraction of insertions and deletions contribute to the genetic diversity of SARS-CoV-2. Altogether, our findings provide insight into SARS-CoV-2 genomic diversity, inform the design of detection tests, and highlight the potential of iSNVs for tracking the transmission of SARS-CoV-2.

Atmospheric pollution represents a complex mixture of air chemicals that continually interact and transform, making it difficult to accurately evaluate associated toxicity responses representative of real-world exposure. This study leveraged data from a previously published article and reevaluated lung cell transcriptional response induced by outdoor atmospheric pollution mixtures using field-based exposure conditions in the industrialized Houston Ship Channel. The tested hypothesis was that individual and co-occurring chemicals in the atmosphere relate to altered expression of critical genes involved in inflammation and cancer-related processes in lung cells. Human lung cells were exposed at an air–liquid interface to ambient air mixtures for 4 h, with experiments replicated across 5 days. Real-time monitoring of primary and secondary gas-phase pollutants, as well as other atmospheric conditions, was simultaneously conducted. Transcriptional analysis of exposed cells identified critical genes showing differential expression associated with both individual and chemical mixtures. The individual pollutant identified with the largest amount of associated transcriptional response was benzene. Tumor necrosis factor (TNF) and interferon regulatory factor 1 (IRFN1) were identified as key upstream transcription factor regulators of the cellular response to benzene. This study is among the first to measure lung cell transcriptional responses in relation to real-world, gas-phase air mixtures.

The human body is cohabitated with trillions of commensal bacteria that are essential for our health. However, certain bacteria can also cause diseases in the human host. Before the microbiome can be attributed to disease risk and pathogenesis, normal acquisition and development of the microbiome must be understood. Here, we explore the evidence surrounding in utero microbial exposures and the significant of this exposure in the proper development of the fetal and neonatal microbiome. We further explore the development of the fetal and neonatal microbiome and its relationship to preterm birth, feeding practices, and mode of delivery, and maternal diet.

The microbiome is thought to play a role in the maintenance of a healthy pregnancy and thus may either contribute to or protect from preterm birth. Study of the human microbiome has been aided by metagenomic sequencing approaches, providing greater insight into the commensal bacteria that coexist in and on our bodies. The vaginal microbiome has been the most widely studied, though there have been recent efforts to explore the gut, cervical-vaginal, placental and oral microbiomes in the further search of etiologies of preterm birth. To date, a specific microbiome community or microorganism has yet to be reliably associated with preterm birth. This is partly due to the fact that the ‘normal’ constituents' microbiome can vary widely between healthy individuals. Before our knowledge of the microbiome can be utilized and applied in clinical practice, a greater understanding of the ‘healthy’ microbiome must be achieved. In particular, we must first appreciate how our microbes influence our biology to promote a healthy pregnancy or alternately render preterm birth.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.

The human microbiome acquires its vastness and diversity over a relatively short time period during development. Much is unknown, however, about the precise prenatal versus postnatal timing or its sources and determinants. Given early evidence of a role for influences during pregnancy and early neonatal and infant life on the microbiome and subsequent metabolic health, research investigating the development and shaping of the microbiome in the fetus and neonate is an important arena for study. This article reviews the relevant available literature and future questions on what shapes the microbiome during early development and mechanisms for doing so.

Human microbial communities are characterized by their taxonomic, metagenomic and metabolic diversity, which varies by distinct body sites and influences human physiology. However, when and how microbial communities within each body niche acquire unique taxonomical and functional signatures in early life remains underexplored. We thus sought to determine the taxonomic composition and potential metabolic function of the neonatal and early infant microbiota across multiple body sites and assess the effect of the mode of delivery and its potential confounders or modifiers. A cohort of pregnant women in their early third trimester (n = 81) were prospectively enrolled for longitudinal sampling through 6 weeks after delivery, and a second matched cross-sectional cohort (n = 81) was additionally recruited for sampling once at the time of delivery. Samples across multiple body sites, including stool, oral gingiva, nares, skin and vagina were collected for each maternal–infant dyad. Whole-genome shotgun sequencing and sequencing analysis of the gene encoding the 16S rRNA were performed to interrogate the composition and function of the neonatal and maternal microbiota. We found that the neonatal microbiota and its associated functional pathways were relatively homogeneous across all body sites at delivery, with the notable exception of the neonatal meconium. However, by 6 weeks after delivery, the infant microbiota structure and function had substantially expanded and diversified, with the body site serving as the primary determinant of the composition of the bacterial community and its functional capacity. Although minor variations in the neonatal (immediately at birth) microbiota community structure were associated with the cesarean mode of delivery in some body sites (oral gingiva, nares and skin; R2= 0.038), this was not true for neonatal stool (meconium; Mann–Whitney P > 0.05), and there was no observable difference in community function regardless of delivery mode. For infants at 6 weeks of age, the microbiota structure and function had expanded and diversified with demonstrable body site specificity (P < 0.001, R2= 0.189) but without discernable differences in community structure or function between infants delivered vaginally or by cesarean surgery (P = 0.057, R2= 0.007). We conclude that within the first 6 weeks of life, the infant microbiota undergoes substantial reorganization, which is primarily driven by body site and not by mode of delivery.

Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to increasing prevalence of these diseases, yet mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, and functional levels in bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring and in hematopoietic stem and progenitor cells (HSPCs) from fetal and juvenile bone marrow and fetal liver. mWSD exposure is also associated with increased oleic acid in fetal and juvenile bone marrow and fetal liver. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling of HSPCs and BMDMs from mWSD-exposed juveniles supports a model in which HSPCs transmit pro-inflammatory memory to myeloid cells beginning in utero. These findings show that maternal diet alters long-term immune cell developmental programming in HSPCs with proposed consequences for chronic diseases featuring altered immune/inflammatory activation across the lifespan.

ABSTRACTEvidence supporting the Developmental Origins of Health and Disease Hypothesis indicates that maternal nutrition in pregnancy has a significant impact on offspring disease risk later in life, likely by modulating developmental processes in utero. Gut microbiota have recently been explored as a potential mediating factor, as dietary components strongly influence microbiota abundance, function and its impact on host physiology. A growing body of evidence has additionally indicated that the intrauterine environment is not sterile as once presumed, indicating that maternal-fetal transmission of microbiota may occur during pregnancy. In this article, we will review the body of literature that supports this emerging hypothesis, as well as highlight the work in relevant animal models demonstrating associations with maternal gestational nutrition and the offspring gut microbiome that may influence offspring physiology and susceptibility to disease.

The placenta is the principal regulator of the in uteroenvironment, and disruptions to this environment can result in adverse offspring health outcomes. To better characterize the impact of in uteroperturbations, we assessed the influence of known environmental pollutants on the expression of microRNA (miRNA) in placental samples collected from the National Children's Study (NCS) Vanguard birth cohort. This study analyzed the expression of 654 miRNAs in 110 term placentas. Environmental pollutants measured in these placentas included dichlorodiphenyldichloroethylene (DDE), bisphenol A (BPA), polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), arsenic (As), mercury (Hg), lead (Pb), and cadmium (Cd). A moderated t-test was used to identify a panel of differentially expressed miRNAs, which were further analyzed using generalized linear models. We observed 112 miRNAs consistently expressed in >70% of the samples. Consistent with the literature, miRNAs located within the imprinted placenta-specific C19MC cluster, specifically mir-517a, mir-517c, mir-522, and mir-23a, are among the top expressed miRNA in our study. We observed a positive association between PBDE 209 and miR-188–5p and an inverse association between PBDE 99 and let-7c. Both PCBs and Cd were positively associated with miR-1537 expression level. In addition, multiple let-7 family members were downregulated with increasing levels of Hg and Pb. We did not observe DDE or BPA levels to be associated with placental miRNA expression. This is the first birth cohort study linking environmental pollutants and placental expression of miRNAs. Our results suggest that placental miRNA profiles may signal in uteroexposures to environmental chemicals.

Background:Expression of circadian gene, Npas2, is altered in fetal life with maternal high-fat (HF) diet exposure by virtue of alterations in the fetal histone code. We postulated that these disruptions would persist postnatally.Methods:Pregnant macaques were fed a control (CTR) or HF diet and delivered at term. When offspring were weaned, they were placed on either CTR or HF diet for a period of 5 mo to yield four exposure models (in utero diet/postweaning diet: CTR/CTR n = 5; CTR/HF n = 4; HF/CTR n = 4; and HF/HF n = 5). Liver specimens were obtained at necropsy at 1 y of age.Results:Hepatic trimethylation of lysine 4 of histone H3 is decreased (CTR/HF 0.87-fold, P = 0.038; HF/CTR 0.84-fold, P = 0.038), whereas hepatic methyltransferase activity increased by virtue of diet exposure (HF/HF 1.3-fold, P = 0.019). Using chromatin immunoprecipitation to determine Npas2 promoter occupancy, we found alterations of both repressive and permissive histone modifications specifically with postweaning HF diet exposure.Conclusion:We found that altered Npas2 expression corresponds with a change in the histone code within the Npas2 promoter.

Human microbial communities are characterized by their metagenomic and metabolic diversity, which varies by distinct body sites and influences human physiology. We are only beginning to characterize the complex set of interactions which alters both community membership and function in early development. With respect to the potential source of microbiota at birth, it has been generally assumed that the majority of seeding microbes originate from the maternal lower genital tract, with microbiota ascending into the otherwise sterile intrauterine. However, we and subsequently others have recently demonstrated that (1) the vaginal and gut microbiome communities are distinctly structured in pregnancy, and (2) the intrauterine environment and the fetus is in fact not sterile, but rather harbors a low-abundance microbiome which varies by several measured exposures, and (3) the maternal diet during both gestation and lactation, and notably a high fat diet, has a particularly strong impact on the developing and early in life microbial community structure. We have taken two dynamic approaches to answering these questions in our studies. First, we use large and robust longitudinal cohorts of maternal-infant dyads collected across gestation and into infancy to gain deeper insight into both source and sink of the early developmental microbiome and its role on determining length of gestation. Second, we utilize our well established primate models of maternal high fat dietary exposure, both in the absence and presence of maternal obesity, to determine the impact of maternal diet on both the microbiome and the resultant offspring metabolic phenotype.

Lactobacilluswas described as a keystone bacterial taxon in the human vagina >100 years ago. Using metagenomics, we and others have characterized lactobacilli and other vaginal taxa across health and disease states, including pregnancy. While shifts in community membership have been resolved at the genus/species level, strain dynamics remain poorly characterized.

•Sphingolipid signaling pathways are altered in provoked vestibulodynia (PVD).•Dysregulated sphingolipid metabolites are linked to increased symptom severity.•Dysregulated metabolites are associated with brain functional connectivity.•Alterations in sphingolipid pathways may be an important molecular marker in PVD.•Alterations in sphingolipid metabolism could provide new targets for treatment.

Animal models of human congenital infection are needed to understand when, how and why Zika virus (ZIKV) is transmitted to the fetus. The recent development of mouse models of ZIKV placental transmission, which results in high rates of pregnancy loss, alongside fetal brain and ocular malformations, have started to unravel the mysteries of placental infection and transmission.

Three studies investigate the bacteria in the guts of malnourished children and find that, when this microbiota is transferred into mice, supplements of certain microbes or sugars from human breast milk can restore normal growth.

Obstet Gynecol Surv 2016;71(4):199–200Spina bifida and the spectrum of open neural tube defects (ONTDs) are of significant public health concern as more than 1500 affected fetuses are born each year in the United States.

Placental samples contain very small volumes of blood, and blood-borne bacteria are not likely to be detected in microbiome analysis.