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Kathleen M Antony,1,2 Judy Levison,1 Melissa A Suter,1 Susan Raine,1 Grace Chiudzu,3 Henry Phiri,3 Joseph Sclafani,1,3,4 Michael Belfort,1 Peter Kazembe,4 Kjersti M Aagaard1 1Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA; 2Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin-Madison, Madison, WI, USA; 3Department of Obstetrics and Gynecology, Kamuzu Central Hospital, Lilongwe, Malawi; 4Baylor College of Medicine Children’s Clinical Center of Excellence, Kamuzu Central Hospital, Lilongwe, Malawi Background: In 2012, we performed a needs assessment and gap analysis to qualitatively assess providers’ and patients’ knowledge and perceptions regarding preterm birth (PTB). During the study, we identified knowledge gaps surrounding methods to reduce the risk of occurrence of PTB and management options if preterm labor/birth occur. We targeted health messages toward these gaps. The objective of the present study was to assess the impact of our community health worker-based patient education program 3 years after it was implemented.Methods: Fifteen focus groups including 70 participants were included in the study. The groups comprised either patients/patient couples or health providers. A minimum of two facilitators led each group using 22 a priori designed and standardized lead-in prompts for participants with four additional prompts for providers only. A single researcher recorded responses, and transcript notes were reviewed by the facilitators and interpreters immediately following each group discussion to ensure accuracy.Results: The understanding of term vs preterm gestation was generally accurate. Every participant knew of women who had experienced PTB, and the general perception was that two to three women out of every ten had this experience. The majority of respondents thought that women should present to their local health clinic if they experience preterm contractions; few were aware of the use of antenatal steroids for promoting fetal lung maturity, but many acknowledged that the neonate may be able to receive life-sustaining treatment if born at a higher level of care facility. The majority of participants were aware that PTB could recur in subsequent pregnancies. All respondents were able to list ways that women could potentially reduce the risk of PTB.Conclusion: After employing targeted health messages, the majority of participants expressed improved understanding of the definition of PTB, methods to prevent risk of PTB, and management options for preterm labor or PTB. Keywords: preterm birth, qualitative research, global women’s health, pregnancy, periodontal disease, prenatal education

Single‐cell technologies capture cellular heterogeneity to focus on previously poorly described subpopulations of cells. Work by our laboratory and many others has metagenomically characterised a low biomass intrauterine microbial community, alongside microbial transcripts, antigens and metabolites, but the functional importance of low biomass microbial communities in placental immuno‐microenvironments is still being elucidated. Given their hypothesised role in modulating inflammation and immune ontogeny to enable tolerance of beneficial microbes while warding off pathogens, there is a need for single‐cell resolution. Herein, we summarise the potential for mechanistic understanding of these and other key fundamental early developmental processes by applying single‐cell approaches. Single‐cell approaches will be vital to understanding how placenta cells differentiate maternal and microbial antigens #BJOG #scRNA‐seq @norsketexsci @barrozophd. [ABSTRACT FROM AUTHOR]

Background: In recent years, pragmatic metformin use in pregnancy has stretched to include prediabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, and (most recently) preeclampsia. However, with its expanded use, concerns of unintended harm have been raised., Objective: This study developed an experimental primate model and applied ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry for direct quantitation of maternal and fetal tissue metformin levels with detailed fetal biometry and histopathology., Study Design: Within 30 days of confirmed conception (defined as early pregnancy), 13 time-bred (timed-mated breeding) Rhesus dams with pregnancies designated for fetal necropsy were initiated on twice-daily human dose-equivalent 10 mg/kg metformin or vehicle control. Pregnant dams were maintained as pairs and fed either a control chow or 36% fat Western-style diet. Metformin or placebo vehicle control was delivered in various treats while the animals were separated via a slide. A cesarean delivery was performed at gestational day 145, and amniotic fluid and blood were collected, and the fetus and placenta were delivered. The fetus was immediately necropsied by trained primate center personnel. All fetal organs were dissected, measured, sectioned, and processed per clinical standards. Fluid and tissue metformin levels were assayed using validated ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry in selected reaction monitoring against standard curves., Results: Among 13 pregnancies at gestational day 145 with fetal necropsy, 1 dam and its fetal tissues had detectable metformin levels despite being allocated to the vehicle control group (>1 μmol metformin/kg maternal weight or fetal or placental tissue), whereas a second fetus allocated to the vehicle control group had severe fetal growth restriction (birthweight of 248.32 g [<1%]) and was suspected of having a fetal congenital condition. After excluding these 2 fetal pregnancies from further analyses, 11 fetuses from dams initiated on either vehicle control (n=4: 3 female and 1 male fetuses) or 10 mg/kg metformin (n=7: 5 female and 2 male fetuses) were available for analyses. Among dams initiated on metformin at gestational day 30 (regardless of maternal diet), significant bioaccumulation within the fetal kidney (0.78-6.06 μmol/kg; mean of 2.48 μmol/kg), liver (0.16-0.73 μmol/kg; mean of 0.38 μmol/kg), fetal gut (0.28-1.22 μmol/kg; mean of 0.70 μmol/kg), amniotic fluid (0.43-3.33 μmol/L; mean of 1.88 μmol/L), placenta (0.16-1.00 μmol/kg; mean of 0.50 μmol/kg), fetal serum (0.00-0.66 μmol/L; mean of 0.23 μmol/L), and fetal urine (4.10-174.10 μmol/L; mean of 38.5 μmol/L) was observed, with fetal levels near biomolar equivalent to maternal levels (maternal serum: 0.18-0.86 μmol/L [mean of 0.46 μmol/L]; maternal urine: 42.60-254.00 μmol/L [mean of 149.30 μmol/L]). Western-style diet feeding neither accelerated nor reduced metformin bioaccumulations in maternal or fetal serum, urine, amniotic fluid, placenta, or fetal tissues. In these 11 animals, fetal bioaccumulation of metformin was associated with less fetal skeletal muscle (57% lower cross-sectional area of gastrocnemius) and decreased liver, heart, and retroperitoneal fat masses (P<.05), collectively driving lower delivery weight (P<.0001) without changing the crown-rump length. Sagittal sections of fetal kidneys demonstrated delayed maturation, with disorganized glomerular generations and increased cortical thickness. This renal dysmorphology was not accompanied by structural or functional changes indicative of renal insufficiency., Conclusion: Our study demonstrates fetal bioaccumulation of metformin with associated fetal growth restriction and renal dysmorphology after maternal initiation of the drug within 30 days of conception in primates. Given these results and the prevalence of metformin use during pregnancy, additional investigation of any potential immediate and enduring effects of prenatal metformin use is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

This review explores genetic contributors to drug interactions, known as drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively). This article is part of a mini-review issue led by the International Society for the Study of Xenobiotics (ISSX) New Investigators Group. Pharmacogenetics (PGx) is the study of the impact of genetic variation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse drug reactions. Genetic variation in pharmacogenes, including drug metabolizing enzymes and drug transporters, is common and can increase the risk of adverse drug events or contribute to reduced efficacy. In this review, we summarize clinically actionable genetic variants, and touch on methodologies such as genotyping patient DNA to identify genetic variation in targeted genes, and deep mutational scanning as a high-throughput in vitro approach to study the impact of genetic variation on protein function and/or expression in vitro . We highlight the utility of physiologically based pharmacokinetic (PBPK) models to integrate genetic and chemical inhibitor and inducer data for more accurate human PK simulations. Additionally, we analyze the limitations of historical ethnic descriptors in pharmacogenomics research. Altogether, the work herein underscores the importance of identifying and understanding complex DGI and DDGIs with the intention to provide better treatment outcomes for patients. We also highlight current barriers to wide-scale implementation of PGx-guided dosing as standard or care in clinical settings.

In this issue of Cell Host & Microbe, Sinha et al. describe their randomized trial assessing whether antibiotics given for maternal benefit prior to Cesarean disrupted the infants' microbiomes. Despite pre-incision antibiotics reaching the neonate, there was no meaningful alteration to the infant microbiome-especially when compared with breastmilk feeding., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To estimate the association between maternal metformin use for the treatment of early gestational or pre-existing type 2 diabetes and preterm preeclampsia., Methods: This is a planned secondary analysis of the MOMPOD study (Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy), a randomized trial comparing the effect of adding metformin with insulin treatment on composite neonatal outcome in singleton pregnancies with early gestational or type 2 diabetes. Participants were randomized at 11-23 weeks of gestation to 1,000 mg metformin twice daily or placebo until delivery. A subset of participants had maternal blood collected at 24-30 weeks of gestation, and serum soluble endoglin, apolipoprotein B, vascular cell adhesion molecule-1, soluble fms-like tyrosine kinase 1, placental growth factor, high-sensitivity C-reactive protein, adiponectin, and vascular endothelial growth factor levels were measured. Our primary outcome was preterm preeclampsia , defined as preeclampsia requiring delivery before 37 weeks of gestation. Secondary outcomes included preterm preeclampsia requiring delivery before 34 weeks of gestation and differences in serum biomarkers. Multivariable regression analysis was used to estimate the associations between metformin use and primary or secondary study outcomes., Results: Of 831 participants, 119 (14.3%) developed preeclampsia requiring delivery before 37 weeks of gestation: 57 of 416 (13.7%) in the placebo group and 62 of 415 (14.9%) in the metformin group. Thirty-seven (4.4%) developed preeclampsia requiring delivery before 34 weeks of gestation: 15 (3.6%) receiving placebo and 22 (5.3%) receiving metformin. Compared with placebo, metformin was not associated with a significant difference in the occurrence of preeclampsia before 37 weeks of gestation (adjusted odds ratio [aOR] 1.04, 95% CI, 0.70-1.56) or before 34 weeks (aOR 1.43, 95% CI, 0.73-2.81). Similarly, there was no association between maternal metformin use and serum biomarker levels., Conclusion: Among parturients with early gestational or pre-existing type 2 diabetes, the addition of metformin to insulin was not associated with lower odds of preterm preeclampsia or with serum biomarkers associated with cardiovascular disease risk., Competing Interests: Financial Disclosure Maya Patel reports money paid to her by National Institute of Diabetes and Digestive and Kidney Diseases. Gayle Olson discloses she is the chair of ACOG District XI, sits on the Board of Directors, and receives support from ACOG. Celeste Durnwald reports that money was paid to her institution from DexCom. Christina Scifres reports money paid to her by Visterra/Otsuka Pharmaceuticals. Amy Valent reports that money was paid to her institution from Dexcom and Mannkind. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Using a non-human primate (NHP) model of maternal Western-style diet (mWSD) feeding during pregnancy and lactation, we previously reported altered offspring beta:alpha cell ratio in vivo and insulin hyper-secretion ex vivo. Mitochondria are known to maintain beta-cell function by producing ATP for insulin secretion. In response to nutrient stress, the mitochondrial network within beta cells undergoes morphological changes to maintain respiration and metabolic adaptability. Given that mitochondrial dynamics have also been associated with cellular fate transitions, we assessed whether mWSD exposure was associated with changes in markers of beta-cell maturity and/or mitochondrial morphology that might explain the offspring islet phenotype., Methods: We evaluated the expression of beta-cell identity/maturity markers (NKX6.1, MAFB, UCN3) via florescence microscopy in islets of Japanese macaque pre-adolescent (1 year old) and peri-adolescent (3-year-old) offspring born to dams fed either a control diet or WSD during pregnancy and lactation and weaned onto WSD. Mitochondrial morphology in NHP offspring beta cells was analyzed in 2D by transmission electron microscopy and in 3D using super resolution microscopy to deconvolve the beta-cell mitochondrial network., Results: There was no difference in the percent of beta cells expressing key maturity markers in NHP offspring from WSD-fed dams at 1 or 3 years of age; however, beta cells of WSD-exposed 3 year old offspring showed increased levels of NKX6.1 per beta cell at 3 years of age. Regardless of maternal diet, the beta-cell mitochondrial network was found to be primarily short and fragmented at both ages in NHP; overall mitochondrial volume increased with age. In utero and lactational exposure to maternal WSD consumption may increase mitochondrial fragmentation., Discussion: Despite mWSD consumption having clear developmental effects on offspring beta:alpha cell ratio and insulin secretory response to glucose, this does not appear to be mediated by changes to beta-cell maturity or the beta-cell mitochondrial network. In general, the more fragmented mitochondrial network in NHP beta cells suggests greater ability for metabolic flexibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Carroll, Miller, Fuhr, Elsakr, Ricciardi, Del Bene, Stephens, Krystofiak, Lindsley, Kirigiti, Takahashi, Dean, Wesolowski, McCurdy, Friedman, Aagaard, Kievit and Gannon.)

Background: Gestational diabetes mellitus affects up to 10% of pregnancies and is classified into subtypes gestational diabetes subtype A1 (GDMA1) (managed by lifestyle modifications) and gestational diabetes subtype A2 (GDMA2) (requiring medication). However, whether these subtypes are distinct clinical entities or more reflective of an extended spectrum of normal pregnancy endocrine physiology remains unclear., Objective: Integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomics harbors the potential to reveal disease gene signatures in subsets of cells and tissue microenvironments. We aimed to combine these high-resolution technologies with rigorous classification of diabetes subtypes in pregnancy. We hypothesized that differences between preexisting type 2 and gestational diabetes subtypes would be associated with altered gene expression profiles in specific placental cell populations., Study Design: In a large case-cohort design, we compared validated cases of GDMA1, GDMA2, and type 2 diabetes mellitus (T2DM) to healthy controls by bulk RNA-seq (n=54). Quantitative analyses with reverse transcription and quantitative PCR of presumptive genes of significant interest were undertaken in an independent and nonoverlapping validation cohort of similarly well-characterized cases and controls (n=122). Additional integrated analyses of term placental single-cell, single-nuclei, and spatial transcriptomics data enabled us to determine the cellular subpopulations and niches that aligned with the GDMA1, GDMA2, and T2DM gene expression signatures at higher resolution and with greater confidence., Results: Dimensional reduction of the bulk RNA-seq data revealed that the most common source of placental gene expression variation was the diabetic disease subtype. Relative to controls, we found 2052 unique and significantly differentially expressed genes (-22 [fold-change]>2 thresholds; q<0.05 Wald Test) among GDMA1 placental specimens, 267 among GDMA2, and 1520 among T2DM. Several candidate marker genes (chorionic somatomammotropin hormone 1 [CSH1], period circadian regulator 1 [PER1], phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [PIK3CB], forkhead box O1 [FOXO1], epidermal growth factor receptor [EGFR], interleukin 2 receptor subunit beta [IL2RB], superoxide dismutase 3 [SOD3], dedicator of cytokinesis 5 [DOCK5], suppressor of glucose, and autophagy associated 1 [SOGA1]) were validated in an independent and nonoverlapping validation cohort (q<0.05 Tukey). Functional enrichment revealed the pathways and genes most impacted for each diabetes subtype, and the degree of proximal similarity to other subclassifications. Surprisingly, GDMA1 and T2DM placental signatures were more alike by virtue of increased expression of chromatin remodeling and epigenetic regulation genes, while albumin was the top marker for GDMA2 with increased expression of placental genes in the wound healing pathway. Assessment of these gene signatures in single-cell, single-nuclei, and spatial transcriptomics data revealed high specificity and variability by placental cell and microarchitecture types. For example, at the cellular and spatial (eg, microarchitectural) levels, distinguishing features were observed in extravillous trophoblasts (GDMA1) and macrophages (GDMA2). Lastly, we utilized these data to train and evaluate 4 machine learning models to estimate our confidence in predicting the control or diabetes status of placental transcriptome specimens with no available clinical metadata., Conclusion: Consistent with the distinct association of perinatal outcome risk, placentae from GDMA1, GDMA2, and T2DM-affected pregnancies harbor unique gene signatures that can be further distinguished by altered placental cellular subtypes and microarchitectural niches., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Postpartum hemorrhage is difficult to predict, is associated with significant maternal morbidity, and is the leading cause of maternal mortality worldwide. The identification of maternal biomarkers that can predict increased postpartum hemorrhage risk would enhance clinical care and may uncover mechanisms that lead to postpartum hemorrhage., Objective: This retrospective case-control study employed agnostic proteomic profiling of maternal plasma samples to identify differentially abundant proteins in controls and postpartum hemorrhage cases., Study Design: Maternal plasma samples were procured from a cohort of >60,000 participants in a single institution's perinatal repository. Postpartum hemorrhage was defined as a decrease in hematocrit of ≥10% or receipt of transfusion within 24 hours after delivery. Postpartum hemorrhage cases (n=30) were matched by maternal age and delivery mode (vaginal or cesarean) with controls (n=56). Mass spectrometry was used to identify differentially abundant proteins using integrated peptide peak areas. Statistically significant differences between groups were defined as P<.05 after controlling for multiple comparisons., Results: By study design, cases and controls did not differ in race, ethnicity, gestational age at delivery, blood type, or predelivery platelet count. Cases had slightly but significantly lower predelivery and postdelivery hematocrit and hemoglobin. Mass spectrometry detected 1140 proteins, including 77 proteins for which relative abundance differed significantly between cases and controls (fold change >1.15, P<.05). Of these differentially abundant plasma proteins, most had likely liver or placental origins. Gene ontology term analysis mapped to protein clusters involved in responses to wound healing, stress response, and host immune defense. Significantly differentially abundant proteins with the highest fold change (prostaglandin D2 synthase, periostin, and several serine protease inhibitors) did not correlate with predelivery hematocrit or hemoglobin but identified postpartum hemorrhage cases with logistic regression modeling revealing good-to-excellent area under the operator receiver characteristic curves (0.802-0.874). Incorporating predelivery hemoglobin with these candidate proteins further improved the identification of postpartum hemorrhage cases., Conclusion: Agnostic analysis of maternal plasma samples identified differentially abundant proteins in controls and postpartum hemorrhage cases. Several of these proteins are known to participate in biologically plausible pathways for postpartum hemorrhage risk and have potential value for predicting postpartum hemorrhage. These findings identify candidate protein biomarkers for future validation and mechanistic studies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: We aimed to evaluate whether there is a significant association between a placental pathology diagnosis basal plate myofibers (BPMF) in an index pregnancy with placenta accreta spectrum (PAS) in the subsequent pregnancy., Study Design: We conducted a retrospective nested cohort study of all cases with a histopathological finding of BPMF between August 2012 and March 2020 at a single tertiary referral center. Data were collected for all subjects (cases and controls) with at least two consecutive pregnancies (the initial index pregnancy and at least one subsequent pregnancy) accompanied by a concomitant record of histopathological study of the placenta at our center. The primary outcome was pathologically confirmed PAS in the subsequent pregnancy. Data are presented as percentage or median, interquartile range accordingly., Results: A total of n  = 1,344 participants were included, of which n  = 119 (index cases) carried a contemporaneous histopathological diagnosis of BPMF during the index pregnancy and n  = 1,225 did not (index controls). Among the index cases, patients with BPMF were older (31.0 [20, 42] vs. 29.0 [15, 43], p  < 0.001), more likely to have undergone in vitro fertilization (IVF) for conception (10.9 vs. 3.8%, p  = 0.001) and were of a more advanced gestational age at delivery (39.0 [25, 41] vs. 38.0 [20, 42], p  = 0.006). In the subsequent pregnancy, the rate of PAS was significantly higher among the BPMF index cases (6.7 vs. 1.1%, p  < 0.001). After adjusting for maternal age and IVF, a histopathological diagnosis of BPMF in an index pregnancy was shown to be a significant risk factor for PAS in the subsequent gestation (hazard ratio: 5.67 [95% confidence interval: 2.28, 14.06], p  < 0.001)., Conclusion: Our findings support that a histopathological diagnosis of BPMF is an independent risk factor for PAS in the subsequent pregnancy., Key Points: · BPMF may indicate morbid adherence of placenta.. · Patients with BPMF were older and more likely to have undergone IVF for conception.. · The BPMF in the current pregnancy is an independent risk factor for PAS in the subsequent pregnancy.., Competing Interests: None declared., (Thieme. All rights reserved.)

The exponential increase in global plastic usage has led to the emergence of nano- and microplastic (NMP) pollution as a pressing environmental issue due to its implications for human and other mammalian health. We have developed methodologies to extract solid materials from human tissue samples by saponification and ultracentrifugation, allowing for highly specific and quantitative analysis of plastics by pyrolysis-gas chromatography and mass spectrometry (Py-GC-MS). As a benchmark, placenta tissue samples were analyzed using fluorescence microscopy and automated particle count, which demonstrated the presence of >1-micron particles and fibers, but not nano-sized plastic particles. Analyses of the samples (n = 10) using attenuated total reflectance-Fourier transform infrared spectroscopy indicated presence of rayon, polystyrene, polyethylene, and unclassified plastic particles. By contrast, among 62 placenta samples, Py-GC-MS revealed that microplastics were present in all participants' placentae, with concentrations ranging widely from 6.5 to 685 µg NMPs per gram of placental tissue, averaging 126.8 ± 147.5 µg/g (mean±SD). Polyethylene was the most prevalent polymer, accounting for 54% of total NMPs and consistently found in nearly all samples (mean 68.8 ± 93.2 µg/g placenta). Polyvinyl chloride and nylon each represented approximately 10% of the NMPs by weight, with the remaining 26% of the composition represented by 9 other polymers. Together, these data demonstrate advancements in the unbiased quantitative resolution of Py-GC-MS applied to the identification and quantification of NMP species at the maternal-fetal interface. This method, paired with clinical metadata, will be pivotal to evaluating potential impacts of NMPs on adverse pregnancy outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The Maternal and Infant Environmental Health Riskscape (MIEHR) Center was established to address the interplay among chemical and non-chemical stressors in the biological, physical, social, and built environments that disproportionately impact perinatal health among Black pregnant people in a large and diverse urban area with documented disparities in the U.S., Methods: The MIEHR cohort is recruiting non-Hispanic Black and non-Hispanic white pregnant people who deliver their infants at major obstetric hospitals in Houston, Texas. At enrollment, all participants are asked to provide urine samples for chemical [metals, cotinine, and polycyclic aromatic hydrocarbons (PAHs)] analyses and blood samples. A subset of the cohort is asked to provide oral and vaginal swabs, and fecal samples. Questionnaire and electronic health record data gather information about residential address history during pregnancy, pregnancy history and prenatal care, sociodemographic and lifestyle factors, experiences of discrimination and stress, and sources of social support. Using information on where a participant lived during their pregnancy, features of their neighborhood environment are characterized. We provide summaries of key individual- and neighborhood-level features of the entire cohort, as well as for Black and white participants separately., Results: Between April 2021 and February 2023, 1,244 pregnant people were recruited. Nearly all participants provided urine samples and slightly less than half provided blood samples. PAH exposure patterns as assessed on 47% of participants thus far showed varying levels depending on metabolite as compared to previous studies. Additionally, analyses suggest differences between Black and white pregnant people in experiences of discrimination, stress, and levels of social support, as well as in neighborhood characteristics., Discussion: Our findings to date highlight racial differences in experiences of discrimination, stress, and levels of support, as well as neighborhood characteristics. Recruitment of the cohort is ongoing and additional neighborhood metrics are being constructed. Biospecimens will be analyzed for metals and PAH metabolites (urine samples), miRNAs (plasma samples) and the microbiome (oral swabs). Once enrollment ends, formal assessments are planned to elucidate individual- and neighborhood-level features in the environmental riskscape that contribute to Black-White disparities in perinatal health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CH declared a past co-authorship with the author KK to the handling editor. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Symanski, Whitworth, Mendez-Figueroa, Aagaard, Moussa, Alvarez, Chardon Fabian, Kannan, Walker, Coarfa, Suter and Salihu.)

Obesity in children remains a major public health problem, with the current prevalence in youth ages 2-19 years estimated to be 19.7%. Despite progress in identifying risk factors, current models do not accurately predict development of obesity in early childhood. There is also substantial individual variability in response to a given intervention that is not well understood. On April 29-30, 2021, the National Institutes of Health convened a virtual workshop on "Understanding Risk and Causal Mechanisms for Developing Obesity in Infants and Young Children." The workshop brought together scientists from diverse disciplines to discuss (1) what is known regarding epidemiology and underlying biological and behavioral mechanisms for rapid weight gain and development of obesity and (2) what new approaches can improve risk prediction and gain novel insights into causes of obesity in early life. Participants identified gaps and opportunities for future research to advance understanding of risk and underlying mechanisms for development of obesity in early life. It was emphasized that future studies will require multi-disciplinary efforts across basic, behavioral, and clinical sciences. An exposome framework is needed to elucidate how behavioral, biological, and environmental risk factors interact. Use of novel statistical methods may provide greater insights into causal mechanisms., (© 2024 World Obesity Federation.)

Background: Zika virus congenital infection evades double-stranded RNA detection and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. Understanding how viruses can persist and replicate in the placenta without causing overt cellular or tissue damage is fundamental to deciphering mechanisms of maternal-fetal vertical transmission., Objective: Placenta-specific microRNAs are believed to be a tenet of viral resistance at the maternal-fetal interface. We aimed to test the hypothesis that the Zika virus functionally disrupts placental microRNAs, enabling viral persistence and fetal pathogenesis., Study Design: To test this hypothesis, we used orthogonal approaches in human and murine experimental models. In primary human trophoblast cultures (n=5 donor placentae), we performed Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation to identify any significant alterations in the functional loading of microRNAs and their targets onto the RNA-induced silencing complex. Trophoblasts from same-donors were split and infected with a contemporary first-passage Zika virus strain HN16 (multiplicity of infection=1 plaque forming unit per cell) or mock infected. To functionally cross-validate microRNA-messenger RNA interactions, we compared our Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation results with an independent analysis of published bulk RNA-sequencing data from human placental disk specimens (n=3 subjects; Zika virus positive in first, second, or third trimester, CD45 - cells sorted by flow cytometry) and compared it with uninfected controls (n=2 subjects). To investigate the importance of these microRNA and RNA interference networks in Zika virus pathogenesis, we used a gnotobiotic mouse model uniquely susceptible to the Zika virus. We evaluated if small-molecule enhancement of microRNA and RNA interference pathways with enoxacin influenced Zika virus pathogenesis (n=20 dams total yielding 187 fetal specimens). Lastly, placentae (n=14 total) from this mouse model were analyzed with Visium spatial transcriptomics (9743 spatial transcriptomes) to identify potential Zika virus-associated alterations in immune microenvironments., Results: We found that Zika virus infection of primary human trophoblast cells led to an unexpected disruption of placental microRNA regulation networks. When compared with uninfected controls, Zika virus-infected placentae had significantly altered SLC12A8, SDK1, and VLDLR RNA-induced silencing complex loading and transcript levels (-22 (fold-change)>2; adjusted P value <.05; Wald-test with false discovery rate correction q<0.05). In silico microRNA target analyses revealed that 26 of 119 transcripts (22%) in the transforming growth factor-β signaling pathway were targeted by microRNAs that were found to be dysregulated following Zika virus infection in trophoblasts. In gnotobiotic mice, relative to mock controls, Zika virus-associated fetal pathogenesis included fetal growth restriction (P=.036) and viral persistence in placental tissue (P=.011). Moreover, spatial transcriptomics of murine placentae revealed that Zika virus-specific placental niches were defined by significant up-regulation of complement cascade components and coordinated changes in transforming growth factor-β gene expression. Finally, treatment of Zika virus-infected mice with enoxacin abolished placental Zika virus persistence, rescued the associated fetal growth restriction, and the Zika virus-associated transcriptional changes in placental immune microenvironments were no longer observed., Conclusion: These results collectively suggest that (1) Zika virus infection and persistence is associated with functionally perturbed microRNA and RNA interference pathways specifically related to immune regulation in placental microenvironments and (2) enhancement of placental microRNA and RNA interference pathways in mice rescued Zika virus-associated pathogenesis, specifically persistence of viral transcripts in placental microenvironments and fetal growth restriction., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Given limited evidence of previous studies, we evaluated the role of environmental justice (EJ) burden (i.e., a neighborhood characterized by both increased environmental burden and socioeconomic deprivation) in Black-White disparities in spontaneous preterm birth (sPTB) in Harris County, Texas and compared results that evaluated neighborhood-level socioeconomic deprivation alone., Methods: We conducted a retrospective analysis using PeriBank, a database and biospecimen repository of gravidae giving birth at two hospitals in the Texas Medical Center. We included 3,703 non-Hispanic Black and 5,475 non-Hispanic white gravidae who were U.S.-born, delivered from August 2011-December 2020, and resided in Harris County, TX. We used data from the U.S. EPA EJScreen to characterize the EJ burden of participant's zip code of residence from fine particulate matter (PM 2.5 ), ozone, and proximity to National Priorities List (NPL) sites and calculated zip-code level Area Deprivation Index (ADI). We assessed the contribution of neighborhood-level variables to the Black-White disparity in sPTB by evaluating attenuation of the odds ratio (OR) representing the effect of race in multivariable logistic regression models, controlling for individual-level characteristics. We also conducted race-stratified analyses between each neighborhood variable and sPTB. Exposure indices were treated as continuous variables; in stratified models, ORs and 95% Confidence Intervals (CIs) are presented per 10-unit increase in the neighborhood variable., Results: Accounting for individual-level variables, Black gravidae had 79% higher odds of sPTB than white gravidae (OR = 1.79, 95%CI = 1.32, 2.44); the disparity was moderately attenuated when accounting for EJ burden or ADI (ORs ranged from 1.58 to 1.69). Though we observed no association between any of the EJ burden indices and sPTB among white gravidae, we found increased risks among Black gravidae, with ORs of similar magnitude for each EJ variable. For example, Black gravidae experienced 17% increased odds of sPTB associated with a 10-unit increase in the EJ burden index for PM 2.5 (OR = 1.17, 95%CI = 0.97, 1.40). No racial differences were observed in the association of ADI with sPTB., Discussion: Though we observed limited evidence of the contribution of living in EJ neighborhoods to the Black-White disparity in sPTB, our study suggests living in an EJ neighborhood may differentially impact Black and white gravidae., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Whitworth, Moussa, Salihu, Chardon Fabian, Suter, Aagaard and symanski.)

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes., Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome., Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022., Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery., Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy., Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group., Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation., Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

Maternal consumption of a Western-style diet (mWD) during pregnancy alters fatty acid metabolism and reduces insulin sensitivity in fetal skeletal muscle. The long-term impact of these fetal adaptations and the pathways underlying disordered lipid metabolism are incompletely understood. Therefore, we tested whether a mWD chronically fed to lean, insulin-sensitive adult Japanese macaques throughout pregnancy and lactation would impact skeletal muscle oxidative capacity and lipid metabolism in adolescent offspring fed a postweaning (pw) Western-style diet (WD) or control diet (CD). Although body weight was not different, retroperitoneal fat mass and subscapular skinfold thickness were significantly higher in pwWD offspring consistent with elevated fasting insulin and glucose. Maximal complex I (CI)-dependent respiration in muscle was lower in mWD offspring in the presence of fatty acids, suggesting that mWD impacts muscle integration of lipid with nonlipid oxidation. Abundance of all five oxidative phosphorylation complexes and VDAC, but not ETF/ETFDH, were reduced with mWD, partially explaining the lower respiratory capacity with lipids. Muscle triglycerides increased with pwWD; however, the fold increase in lipid saturation, 1,2-diacylglycerides, and C18 ceramide compared between pwCD and pwWD was greatest in mWD offspring. Reductions in CI abundance and VDAC correlated with reduced markers of oxidative stress, suggesting that these reductions may be an early-life adaptation to mWD to mitigate excess reactive oxygen species. Altogether, mWD, independent of maternal obesity or insulin resistance, results in sustained metabolic reprogramming in offspring muscle despite a healthy diet intervention., Article Highlights: In lean, active adolescent offspring, a postweaning Western-style diet (pwWD) leads to shifts in body fat distribution that are associated with poorer insulin sensitivity. Fatty acid-linked oxidative metabolism was reduced in skeletal muscles from offspring exposed to maternal Western-style diet (mWD) even when weaned to a healthy control diet for years. Reduced oxidative phosphorylation complex I-V and VDAC1 abundance partially explain decreased skeletal muscle respiration in mWD offspring. Prior exposure to mWD results in greater fold increase with pwWD in saturated lipids and bioactive lipid molecules (i.e. ceramide and sphingomyelin) associated with insulin resistance., (© 2023 by the American Diabetes Association.)

Introduction: There is an increasing incidence of pregnancies with twin gestations. One outcome more likely to occur with multiple gestations is gestational diabetes mellitus. Studies have suggested that in singleton pregnancies, fetal sex may affect insulin resistance. However, the effects of fetal sex in twins and the development of gestational diabetes mellitus are unknown. We hypothesized that rates of gestational diabetes mellitus and degree of insulin resistance might vary in twin gestations based on the fetal sex pairing: male-male, male-female or female-female. We aimed to employ a large population-based database to ascertain any correlations between fetal sex and gestational diabetes mellitus in multifetal gestations., Material and Methods: A two-hospital, single academic institution database comprised of over 39 000 participants with pregnancy data from August 2011 to January 2022 was employed. All twin deliveries of live-born neonates >24 weeks' gestational age from gravidae without preexisting diabetes or twin-twin transfusion syndrome were included. Entries were then grouped based on the fetal sex of the pairing. The presence or absence of gestational diabetes and type of gestational diabetes - diet-controlled (gestational diabetes mellitus classification A1) vs medication-controlled (gestational diabetes mellitus classification A2) - were identified. Statistical analysis was performed using a generalized linear mixed method, and a P-value ≤0.05 was considered statistically significant., Results: We identified 1924 twin deliveries that met the inclusion criteria in our database (male-male =652; male-female = 638; female-female = 634). We found no association between fetal sex pairing and the development of gestational diabetes mellitus. There was a significant association between the fetal sex pairing and the type of gestational diabetes mellitus developed, with 32.0% of male-male twins, 33.3% of male-female twins and 58.3% of the female-female twin deliveries associated with medication-controlled gestational diabetes classification A2: male-female vs female-female (P = 0.05) and male-male vs female-female (P = 0.046)., Conclusions: While gestational diabetes mellitus is of multifactorial origin, we found a significant association between the fetal sex pairing and the treatment needed for gravidae with twins who develop gestational diabetes mellitus. A higher proportion of female-female twins was associated with gestational diabetes classification A2 compared with male-female or male-male deliveries. Further research on the physiology driving this association is warranted., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Although the earth's climate has been continuously changing over billions of years, human influence has accelerated that rate of change. While high latitudes suffer the greatest increase in incremental temperature, moderate latitudes are highly vulnerable due to their temperate/tropical rain storms and hurricanes that bring about extreme flooding events. We and others have shown that there is a link between the occurrence and severity of these climate events and risk of adverse perinatal outcomes. In this review, we will discuss the data and consider interacting near and intermediate sequelae of worsening natural disasters-including food scarcity, disrupted or compromised built environments and infrastructure, and loss of communities with human migration. While certainly tackling these and other proximal mediators of adverse perinatal outcomes will benefit maternal and child health, a failure to meaningfully address the root causes of climate change and resultant environmental chemical exposures will be of little long-term benefit., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Little is known about how community characteristics influence placenta accreta spectrum (PAS) outcomes. Our objective was to evaluate whether adverse maternal outcomes among pregnant people (gravidae) with PAS delivering at a single referral center differ by community-level measures of social deprivation., Study Design: We conducted a retrospective cohort study of singleton gravidae with histopathology confirmed PAS delivering from January 2011 to June 2021 at a referral center. Data abstraction collected relevant patient information, including resident zip code, which was linked to Social Deprivation Index (SDI) score (a measure of area-level social deprivation). SDI scores were divided into quartiles for analysis. Primary outcome was a composite of maternal adverse outcomes. Bivariate analyses and multivariable logistic regression were performed., Results: Among our cohort ( n  = 264), those in the lowest (least deprived) SDI quartile were older, had lower body mass index, and were more likely to identify as non-Hispanic white. Composite maternal adverse outcome occurred in 81 (30.7%), and did not differ significantly by SDI quartile. Intraoperative transfusion of ≥4 red blood cell units occurred more often among those living in deprived areas (31.2% in the highest [most deprived] vs. 22.7% in the lowest [least deprived] SDI quartile, p  = 0.04). No other outcomes differed by SDI quartile. In multivariable logistic regression, a quartile increase in SDI was associated with 32% increased odds of transfusion of ≥4 red blood cell units (adjusted odds ratio: 1.32, 95% confidence interval: 1.01-1.75)., Conclusion: Within a cohort of gravidae with PAS delivered at a single referral center, we found that those living in more socially deprived communities were more likely to receive transfusion of ≥4 red blood cell units, but other maternal adverse outcomes did not differ. Our findings highlight the importance of considering how characteristics of the surrounding community can impact PAS outcomes and may assist with risk stratification and resource deployment., Key Points: · Little is known about how community characteristics influence PAS outcomes.. · In a referral center, transfusion was more common in gravidae living in socially deprived areas.. · Future research should consider how community characteristics can impact PAS outcomes.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Functional placental niches are presumed to spatially separate maternal-fetal antigens and restrict the vertical transmission of pathogens. We hypothesized a high-resolution map of placental transcription could provide direct evidence for niche microenvironments with unique functions and transcription profiles., Methods: We utilized Visium Spatial Transcriptomics paired with H&E staining to generate 17,927 spatial transcriptomes. By integrating these spatial transcriptomes with 273,944 placental single-cell and single-nuclei transcriptomes, we generated an atlas composed of at least 22 subpopulations in the maternal decidua, fetal chorionic villi, and chorioamniotic membranes., Findings: Comparisons of placentae from uninfected healthy controls (n = 4) with COVID-19 asymptomatic (n = 4) and symptomatic (n = 5) infected participants demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection in syncytiotrophoblasts occurred in both the presence and the absence of maternal clinical disease. With spatial transcriptomics, we found that the limit of detection for SARS-CoV-2 was 1/7,000 cells, and placental niches without detectable viral transcripts were unperturbed. In contrast, niches with high SARS-CoV-2 transcript levels were associated with significant upregulation in pro-inflammatory cytokines and interferon-stimulated genes, altered metallopeptidase signaling (TIMP1), with coordinated shifts in macrophage polarization, histiocytic intervillositis, and perivillous fibrin deposition. Fetal sex differences in gene expression responses to SARS-CoV-2 were limited, with confirmed mapping limited to the maternal decidua in males., Conclusions: High-resolution placental transcriptomics with spatial resolution revealed dynamic responses to SARS-CoV-2 in coordinate microenvironments in the absence and presence of clinically evident disease., Funding: This work was supported by the NIH (R01HD091731 and T32-HD098069), NSF (2208903), the Burroughs Welcome Fund and the March of Dimes Preterm Birth Research Initiatives, and a Career Development Award from the American Society of Gene and Cell Therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Metformin is used by women during pregnancy to manage diabetes and crosses the placenta, yet its effects on the fetus are unclear. We show that the liver is a site of metformin action in fetal sheep and macaques, given relatively abundant OCT1 transporter expression and hepatic uptake following metformin infusion into fetal sheep. To determine the effects of metformin action, we performed studies in primary hepatocytes from fetal sheep, fetal macaques, and juvenile macaques. Metformin increases AMP-activated protein kinase (AMPK) signaling, decreases mammalian target of rapamycin (mTOR) signaling, and decreases glucose production in fetal and juvenile hepatocytes. Metformin also decreases oxygen consumption in fetal hepatocytes. Unique to fetal hepatocytes, metformin activates stress pathways (e.g., increased PGC1A gene expression, NRF-2 protein abundance, and phosphorylation of eIF2α and CREB proteins) alongside perturbations in hepatokine expression (e.g., increased growth/differentiation factor 15 [GDF15] and fibroblast growth factor 21 [FGF21] expression and decreased insulin-like growth factor 2 [IGF2] expression). Similarly, in liver tissue from sheep fetuses infused with metformin in vivo, AMPK phosphorylation, NRF-2 protein, and PGC1A expression are increased. These results demonstrate disruption of signaling and metabolism, induction of stress, and alterations in hepatokine expression in association with metformin exposure in fetal hepatocytes., Article Highlights: The major metformin uptake transporter OCT1 is expressed in the fetal liver, and fetal hepatic uptake of metformin is observed in vivo. Metformin activates AMPK, reduces glucose production, and decreases oxygen consumption in fetal hepatocytes, demonstrating similar effects as in juvenile hepatocytes. Unique to fetal hepatocytes, metformin activates metabolic stress pathways and alters the expression of secreted growth factors and hepatokines. Disruption of signaling and metabolism with increased stress pathways and reduced anabolic pathways by metformin in the fetal liver may underlie reduced growth in fetuses exposed to metformin., (© 2023 by the American Diabetes Association.)

Objective: As the awareness of the accompanying morbidity of placenta accreta spectrum (PAS) has increased over recent decades. We sought to analyze the precision and reliability of the currently available content regarding PAS on YouTube., Study Design: A YouTube search was performed on June 17, 2019 by using the search terms "placenta accreta," "PAS," and "invasive placentation." Search results were sorted by relevance, and up to 200 videos per search term were systematically evaluated by four independent reviewers. A quality assessment checklist relating to aspects of PAS was developed with a Likert's scale from 0 to 12 points to quantify video content. Videos were classified as poor educational quality (grade 0 to ≤4), moderate quality (grade >4-8), and high quality (grade >8-12)., Results: Of the 318 videos identified, 99 videos met inclusion criteria. The majority of videos (61.6%) were produced by a professional source, that is, appearing to be from a hospital, university, or educational service. Of the remaining videos, 16.2% were classified as personal, that is, posted from personal YouTube accounts and depicting a personal or family member experience, and 22.2% were classified as other. The majority of the "other" category consisted of news segments and short clips from talk shows. Overall, 60.6% of videos were of poor educational quality, 32.3% were of moderate quality, and 7.1% were deemed high quality. All seven of the high-quality videos were produced by a professional source and intended for an audience of medical professionals. There were neither high-quality videos intended for the general public nor the likely affected and relevant patient population., Conclusion: This study suggests that the currently available videos on YouTube regarding PAS are poor educational sources for patients seeking information, and demonstrates a need for high-quality content videos produced by medical professionals specifically focused on meeting the needs of patient population., Key Points: · Awareness of the accompanying morbidity of placenta accreta spectrum has increased over recent decades.. · YouTube videos are poor educational sources for patients seeking information regarding PAS.. · YouTube videos and all social media warrant improvements regarding patient's information.., Competing Interests: None declared., (Thieme. All rights reserved.)

Maternal overnutrition is associated with increased susceptibility to type 2 diabetes in the offspring. Rodent models have shown that maternal overnutrition influences islet function in offspring. To determine whether maternal Western-style diet (WSD) alters prejuvenile islet function in a model that approximates that of human offspring, we utilized a well-characterized Japanese macaque model. We compared islet function from offspring exposed to WSD throughout pregnancy and lactation and weaned to WSD (WSD/WSD) compared with islets from offspring exposed only to postweaning WSD (CD/WSD) at 1 yr of age. WSD/WSD offspring islets showed increased basal insulin secretion and an exaggerated increase in glucose-stimulated insulin secretion, as assessed by dynamic ex vivo perifusion assays, relative to CD/WSD-exposed offspring. We probed potential mechanisms underlying insulin hypersecretion using transmission electron microscopy to evaluate β-cell ultrastructure, qRT-PCR to quantify candidate gene expression, and Seahorse assay to assess mitochondrial function. Insulin granule density, mitochondrial density, and mitochondrial DNA ratio were similar between groups. However, islets from WSD/WSD male and female offspring had increased expression of transcripts known to facilitate stimulus-secretion coupling and changes in the expression of cell stress genes. Seahorse assay revealed increased spare respiratory capacity in islets from WSD/WSD male offspring. Overall, these results show that maternal WSD feeding confers changes to genes governing insulin secretory coupling and results in insulin hypersecretion as early as the postweaning period. The results suggest a maternal diet leads to early adaptation and developmental programming in offspring islet genes that may underlie future β-cell dysfunction. NEW & NOTEWORTHY Programed adaptations in islets in response to maternal WSD exposure may alter β-cell response to metabolic stress in offspring. We show that islets from maternal WSD-exposed offspring hypersecrete insulin, possibly due to increased components of stimulus-secretion coupling. These findings suggest that islet hyperfunction is programed by maternal diet, and changes can be detected as early as the postweaning period in nonhuman primate offspring.

Background: Polycystic ovarian syndrome is characterized by elevated androgens and is a well-known risk factor for the occurrence of gestational diabetes mellitus. Androgens (particularly dehydroepiandrosterone-sulfate) are crucial for the development and characteristics of the male reproductive tract during fetal life, and fetal dehydroepiandrosterone-sulfate enters the placenta where it is metabolized and functions as an estrogen substrate. Given this unique sex-specific relationship with androgens and the association of serum dehydroepiandrosterone-sulfate concentration with insulin resistance, we hypothesized that metabolic comorbidities in pregnancy might differ by fetal sex in gravidae with polycystic ovarian syndrome, notably in those with infertility., Objective: This study aimed to evaluate the data in a large population-based database to explore if fetal sex was significantly associated with gestational diabetes mellitus in gravidae with infertility and polycystic ovarian syndrome after controlling for confounders., Study Design: This study was designed to evaluate the risk for the occurrence and rates of gestational diabetes mellitus among gravidae with infertility and a history of polycystic ovarian syndrome. We used a 2-hospital, single academic institution database comprising more than 30,000 subjects enrolled from September 2011 to June 2021 to identify all gravidae with diagnoses of infertility and polycystic ovarian syndrome at the time of delivery and to compare them with gravidae who lacked these comorbidities. Data on covariates, including but not limited to maternal age, body mass index, fetal sex, race, ethnicity, presence or absence of hypertensive disease, and presence or absence of gestational diabetes were identified. Unadjusted and adjusted odds rations were calculated., Results: We found a statistically significant association between fetal female sex and the development of gestational diabetes mellitus in gravidae with polycystic ovarian syndrome (odds ratio for female vs male, 2.13; 95% confidence interval, 1.06-4.32; P=.03). After adjusting for potential confounders identified in our univariate analyses, there continued to be a statistically significant association between female fetuses and the development of gestational diabetes mellitus (adjusted odds ratio for female vs male, 2.10; 95% confidence interval, 1.04-4.41; P=.04). In contrast, there was no significant association between fetal sex and the development of gestational diabetes mellitus in our similar analysis of gravidae without infertility and polycystic ovarian syndrome (P=.99)., Conclusion: Although the origin of gestational diabetes mellitus is multifactorial, we found that female fetal sex is associated with gestational diabetes mellitus in gravidae with infertility and polycystic ovarian syndrome but not in their comparative controls. Further research on the molecular mechanisms driving the association between female fetuses and the development of gestational diabetes mellitus in the context of maternal polycystic ovarian syndrome is warranted., (Copyright © 2023. Published by Elsevier Inc.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Obesity in pregnancy bears unique maternal and fetal risks. Obesity has also been associated with chronic inflammation, including elevated serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher serum lipopolysaccharide (LPS) levels have been implicated in driving this inflammation, a phenomenon called metabolic endotoxemia (ME). GLP-2, a proglucagon-derived peptide, is believed to be integral in maintaining the integrity of the intestine in the face of LPS-mediated endotoxemia. We hypothesized that obesity and/or excess weight gain in pregnancy would be associated with an increase in maternal and neonatal markers of ME, as well as GLP-2., Study Design: Paired maternal and neonatal (cord blood) serum samples ( n  = 159) were obtained from our pregnancy biobank repository. Serum levels of LPS, endotoxin core antibody-immunoglobulin M (EndoCAb-IgM), and GLP-2 were measured by ELISA. IL-6 and TNF-α were measured using a Milliplex assay. Results were stratified by maternal body mass index (BMI), maternal diabetes, and gestational weight gain (GWG)., Results: Maternal IL-6 is significantly decreased in the obese, diabetic cohort compared with the nonobese, nondiabetic cohorts (95.28 vs. 99.48 pg/mL, p  = 0.047), whereas GLP-2 is significantly increased (1.92 vs. 2.89 ng/mL, p  = 0.026). Neonatal TNF-α is significantly decreased in the obese cohort compared with the nonobese cohort (12.43 vs. 13.93 pg/mL, p  = 0.044). Maternal GLP-2 is significantly increased in women with excess GWG compared with those with normal GWG (2.27 vs. 1.48 ng/mL, p  = 0.014). We further found that neonatal IL-6 and TNF-α are negatively correlated with maternal BMI (-0.186, p  = 0.036 and -0.179, p  = 0.044, respectively) and that maternal and neonatal IL-6 showed a positive correlation (0.348, p  < 0.001)., Conclusion: Although we observed altered levels of markers of inflammation (IL-6 and TNF-α) with maternal obesity and diabetes, no changes in LPS or endoCAb-IgM were observed. We hypothesize that the increased GLP-2 levels in maternal serum in association with excess GWG may protect against ME in pregnancy., Key Points: · Maternal serum levels of GLP-2, a proglucagon-derived peptide, are increased in obese, diabetic gravidae.. · Maternal serum GLP-2 levels are also increased in association with excess gestational weight gain compared with normal gestational weight gain.. · GLP-2 may be increased in association with obesity and weight gain to protect against metabolic endotoxemia in pregnancy.., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Periodontitis during pregnancy is associated with an increased risk of preterm birth (<37 weeks of gestation) or low birthweight (<2500 g) offspring. Beyond periodontal disease, the risk of preterm birth varies both by previous history of preterm birth and in association with social determinants prevalent among vulnerable and marginalized populations. This study hypothesized that the timing of periodontal treatment during pregnancy and/or social vulnerability measures modified the response to dental scaling and root planing for the treatment of periodontitis and prevention of preterm birth., Objective: This study aimed to determine the association of timing of dental scaling and root planing for gravidae with a diagnosed periodontal disease on the rates of preterm birth or low birthweight offspring among subgroups or strata of gravidae as part of the Maternal Oral Therapy to Reduce Obstetric Risk randomized controlled trial. All participants in the study had clinically diagnosed periodontal disease and differed by the timing of the periodontal treatment (dental scaling and root planing at <24 weeks [per protocol] or after delivery) or by baseline characteristics. Although all participants met the well-accepted clinical criteria for periodontitis, not all participants acknowledged a priori that they had periodontal disease., Study Design: This was a per-protocol analysis of data from 1455 participants of the Maternal Oral Therapy to Reduce Obstetric Risk trial evaluating dental scaling and root planing on the risk of preterm birth or low birthweight offspring. Adjusted multiple logistic regression to control for confounders was used to estimate associations comparing the timing of periodontal treatment in pregnancy to receiving treatment after pregnancy (referent control) on rates of preterm birth or low birthweight among subgroups of gravidae with known periodontal disease. Study analyses were stratified, and the associations with the following characteristics-body mass index, self-described race and ethnicity, household income, maternal education, recency of immigration, and self-acknowledgment of poor oral health, were explored., Results: Dental scaling and root planing during the second or third trimester of pregnancy were associated with an increased adjusted odds ratio of preterm birth among those at the lower body mass index strata (18.5 to <25.0 kg/m 2 ) (adjusted odds ratio, 2.21; 95% confidence interval, 1.07-4.98), but not among individuals who were overweight (body mass index of 25.0 to <30.0 kg/m 2 ; adjusted odds ratio, 0.68; 95% confidence interval, 0.29-1.59) or obese (body mass index of ≥30 kg/m 2 ; adjusted odds ratio, 1.26; 95% confidence interval, 0.65-2.49). There was no significant difference in pregnancy outcomes related to the other evaluated variables: self-described race and ethnicity, household income, maternal education, immigration status, or self-acknowledgment of poor oral health., Conclusion: In this per-protocol analysis of the Maternal Oral Therapy to Reduce Obstetric Risk trial, dental scaling and root planing had no preventive benefit against adverse obstetrical outcomes and were associated with increased odds of preterm birth among individuals at lower body mass index strata. There was no significant difference in the occurrence of preterm birth or low birthweight after dental scaling and root planing periodontitis treatment concerning other analyzed social determinants of preterm birth., (© 2023 The Authors.)

Pediatric NAFLD has distinct and variable pathology, yet causation remains unclear. We have shown that maternal Western-style diet (mWSD) compared with maternal chow diet (CD) consumption in nonhuman primates produces hepatic injury and steatosis in fetal offspring. Here, we define the role of mWSD and postweaning Western-style diet (pwWSD) exposures on molecular mechanisms linked to NAFLD development in a cohort of 3-year-old juvenile nonhuman primates offspring exposed to maternal CD or mWSD followed by CD or Western-style diet after weaning. We used histologic, transcriptomic, and metabolomic analyses to identify hepatic pathways regulating NAFLD. Offspring exposed to mWSD showed increased hepatic periportal collagen deposition but unchanged hepatic triglyceride levels and body weight. mWSD was associated with a downregulation of gene expression pathways underlying HNF4α activity and protein, and downregulation of antioxidant signaling, mitochondrial biogenesis, and PPAR signaling pathways. In offspring exposed to both mWSD and pwWSD, liver RNA profiles showed upregulation of pathways promoting fibrosis and endoplasmic reticulum stress and increased BiP protein expression with pwWSD. pwWSD increased acylcarnitines and decreased anti-inflammatory fatty acids, which was more pronounced when coupled with mWSD exposure. Further, mWSD shifted liver metabolites towards decreased purine catabolism in favor of synthesis, suggesting a mitochondrial DNA repair response. Our findings demonstrate that 3-year-old offspring exposed to mWSD but weaned to a CD have periportal collagen deposition, with transcriptional and metabolic pathways underlying hepatic oxidative stress, compromised mitochondrial lipid sensing, and decreased antioxidant response. Exposure to pwWSD worsens these phenotypes, triggers endoplasmic reticulum stress, and increases fibrosis. Overall, mWSD exposure is associated with altered expression of candidate genes and metabolites related to NAFLD that persist in juvenile offspring preceding clinical presentation of NAFLD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Computational analysis of host-associated microbiomes has opened the door to numerous discoveries relevant to human health and disease. However, contaminant sequences in metagenomic samples can potentially impact the interpretation of findings reported in microbiome studies, especially in low-biomass environments. Contamination from DNA extraction kits or sampling lab environments leaves taxonomic "bread crumbs" across multiple distinct sample types. Here we describe Squeegee, a de novo contamination detection tool that is based upon this principle, allowing the detection of microbial contaminants when negative controls are unavailable. On the low-biomass samples, we compare Squeegee predictions to experimental negative control data and show that Squeegee accurately recovers putative contaminants. We analyze samples of varying biomass from the Human Microbiome Project and identify likely, previously unreported kit contamination. Collectively, our results highlight that Squeegee can identify microbial contaminants with high precision and thus represents a computational approach for contaminant detection when negative controls are unavailable., (© 2022. The Author(s).)

We aimed to perform a meta-analysis of the literature concerning histopathologic findings in the placentas of women with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection during pregnancy. Searches for articles in English included PubMed, Web of Science, Google Scholar, and reference lists (up to April 2021). Studies presenting data on placental histopathology according to the Amsterdam Consensus Group criteria in SARS-CoV-2 positive and negative pregnancies were identified. Lesions were categorized into: maternal and fetal vascular malperfusion (MVM and FVM, respectively), acute placental inflammation with maternal and fetal inflammatory response (MIR and FIR, respectively), chronic inflammatory lesions (CILs), and increased perivillous fibrin deposition (PVFD). A total of 15 studies reporting on 19,025 placentas, n  = 699 of which were derived from women who were identified as being infected with SARS-CoV-2 and 18,326 as SARS-CoV-2-negative controls, were eligible for analysis. No significant difference in incidence of MVM (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 0.73-1.90), FVM (OR: 1.23, 95% CI: 0.63-2.42), MIR (OR: 0.66, 95% CI: 0.29-1.52) or FIR (OR: 0.85, 95% CI: 0.44-1.63), and CILs (OR: 0.97, 95% CI: 0.55-1.72) was found between placentae from gravida identified as being SARS-CoV-2 infected. However, placenta from gravida identified as being infected with SARS-CoV-2 were associated with significantly increased occurrence of PVFD (OR: 2.77, 95% CI: 1.06-7.27). After subgroup analyses based on clinical severity of COVID-19 infection, no significant difference was observed in terms of reported placental pathology between symptomatic or asymptomatic SARS-CoV-2 gravidae placenta. Current evidence based on the available literature suggests that the only pathologic finding in the placentae of women who are pregnant identified as having been infected with SARS-CoV-2 was an increased prevalence of PVFD. KEY POINTS: · No association between SARS-CoV-2 and maternal or fetal placental malperfusion.. · No association between SARS-CoV-2 and maternal or fetal inflammatory response.. · SARS-CoV-2 is associated with increased perivillous fibrin deposition in placenta.., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose of the Study: Viral respiratory diseases, like those caused by novel strains of influenza and Coronaviridae, have historically disproportionately affected pregnant women and conferred increased risk of adverse perinatal outcomes. Initial reports published from Wuhan, China identified only limited symptoms in pregnant women and no cases of mortality, but more recent reports from other regions of the world have reported contrasting information. The purpose of the study was to evaluate initially published cases of SARS-CoV-2 infection in pregnant women in China and compare them to subsequently published studies from the remainder of the world. Materials and Methods: This review curates 199 maternal published cases of SARS-CoV-2 infection and COVID-19 initially reported in the literature from China and contrasts them to more recent literature reporting clinical findings and outcomes of 729 selected cases from the rest of the world, including the United States. Results: Overall, initial case reports and series from China reported no cases of maternal mortality, which contrasts with subsequent reports from other regions of the world demonstrating significant morbidity and mortality can and does occur in pregnant women infected with SARS-CoV-2. Conclusion: While initial reports suggest limited risks of infection in pregnancy with SARS-CoV-2, subsequent findings have demonstrated pregnant women are at risk for severe morbidity and mortality. Case studies and series that are imperative in the early stages of a pandemic to provide data on a novel pathogen cannot be used to provide generalizable information predicting group risks.

Importance: Primary studies proposed that aberrant maternal antiviral immunity and/or giving birth in quarantine, such as during the ongoing COVID-19 pandemic, may be associated with the risk of neurodevelopmental impairment (NDI) in offspring., Objectives: To evaluate the associations of birth and being raised during the COVID-19 pandemic with risk of NDI among infants and to assess the association of gestational exposure to SARS-CoV-2 with risk of NDI., Data Sources: PubMed, Web of Science, Scopus, Embase, and preprint servers were systematically searched from inception to March 25, 2022., Study Selection: Studies evaluating the neurodevelopment of infants born during the SARS-CoV-2 pandemic were included in this systematic review and meta-analysis. Studies using Ages and Stages Questionnaires, Third Edition (ASQ-3), were used for quantitative meta-analysis., Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, a random-effects model meta-analysis was used to pool the proportion and odds ratios (ORs) of overall NDI, as well as each developmental domain on ASQ-3 with the corresponding 95% CI., Main Outcomes and Measures: The primary outcome was the risk of overall NDI among infants screened during the pandemic vs prepandemic. The secondary outcome was the comparison of NDI by ASQ-3 domain among infants born to women with known gestational exposure to SARS-CoV-2 vs no exposure., Results: A total of 8 studies were included, including 21 419 infants (11 438 screened in pandemic and 9981 in prepandemic period). NDI was present in 330 of 8992 infants (7%; 95% CI, 4%-10%) screened during the COVID-19 pandemic from January 2020 to January 2021. Among the pandemic cohort, the prevalence of NDI among infants with gestational exposure to SARS-CoV-2 was 77 of 691 (12%; 95% CI, 6%-18%). Compared with the prepandemic cohort (2015-2019), the pandemic cohort was more likely to have communication impairment (OR, 1.70; 95% CI, 1.37-2.11; P < .001), without significant differences in other ASQ-3 domains (eg, gross motor, fine motor, personal-social, and problem-solving). In contrast, maternal SARS-CoV-2 infection was not associated with significant differences in any neurodevelopment domain in offspring, except for increasing the odds of fine motor impairment (OR, 3.46; 95% CI, 1.43-8.38; P < .001)., Conclusions and Relevance: In this systematic review and meta-analysis examining the association between COVID-19 pandemic and the risk of NDI, findings suggest that overall neurodevelopment in the first year of life was not changed by either being born or raised during the SARS-CoV-2 pandemic or by gestational exposure to SARS-CoV-2. Interestingly, the first year of life during the COVID-19 pandemic, regardless of maternal infection, was significantly associated with the risk of communication delay among the offspring.

Background: Herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), and human herpesvirus 6 (HHV-6) cause severe infections in immunocompromised hosts. Interventions to optimize virus-specific adaptive immunity may have advantages over antivirals in the prophylaxis and treatment of these infections., Objectives: We sought to review adaptive immune responses and methods for assessing and replenishing cellular and humoral immunity to HSV, VZV, and HHV-6 in solid organ transplant and hematopoietic cell transplant recipients., Sources: We searched PubMed for relevant studies on immune responses to HSV, VZV, and HHV-6 as well as studies describing methods for evaluating and restoring cell-mediated immunity to other double-stranded DNA viruses in transplant recipients. Recent studies, randomized controlled trials, and investigations highlighting key concepts in clinical virology were prioritized for inclusion., Content: We describe the mechanisms of adaptive immunity to HSV, VZV, and HHV-6 and limitations of antivirals as prophylaxis and treatment for these infections in solid organ transplant and hematopoietic cell transplant recipients. We review methods for measuring and restoring cellular immunity to double-stranded DNA viruses; their potential applications to management of HSV, VZV, and HHV-6 in immunocompromised hosts; and barriers to clinical use. Vaccination and virus-specific T cell therapies are discussed in detail., Implications: The growing repertoire of diagnostic and therapeutic techniques focused on virus-specific adaptive immunity provides a novel approach to management of viral infections in transplant recipients. Investigations to optimize such interventions specifically in HSV, VZV, and HHV-6 are needed., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

As rates of Cesarean delivery and common non-communicable disorders (NCDs), such as obesity, metabolic disease, and atopy/asthma, have concomitantly increased in recent decades, investigators have attempted to discern a causal link. One line of research has led to a hypothesis that Cesarean birth disrupts the presumed normal process of colonization of the neonatal microbiome with vaginal microbes, yielding NCDs later in life. However, a direct link between a disrupted microbiota transfer at time of delivery and acute and/or chronic illness in infants born via Cesarean has not been causally established. Microbiota seeding from maternal vaginal or stool sources has been preliminarily evaluated as an intervention designed to compensate for the lack of (or limited) exposure to such sources among Cesarean-delivered neonates. However, to date, clinical trials have yet to show a clear health benefit with neonatal 'vaginal seeding' practices. Until the long-term effects of these microbiome alterations can be fully determined, it is paramount to conduct parallel meaningful and mechanistic-minded interrogations of the impact of clinically modifiable maternal, nutritional, or environmental exposure on the functional microbiome over the duration of pregnancy and lactation to determine their role in the mitigation of childhood and adult NCDs., Competing Interests: Declaration of interests No interests to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Shift work has been associated with adverse pregnancy outcomes. The objective of this study was to evaluate the association between sleep disturbances and adverse pregnancy outcomes., Methods and Findings: This was a secondary analysis of a prospective study of participants enrolled in a prospective observational study wherein gravidae were screened for sleep apnea (2010-2012). A screening questionnaire with standard sleep apnea questionnaires as well as novel items about shift work and nocturnal sleep duration was administered at a prenatal care visit. Short sleep duration was defined as less than 7 hours. Prolonged sleep duration was defined as greater than 9 hours. In a cohort of 1125 pregnant people, 9.4% reported shift work at the time of screening. Gravidae who reported shift work were more likely than gravidae who reported no shift work to develop preeclampsia (28.3% versus 13.0%, P<0.001), preeclamspsia with severe features (16.0% versus 8.5%, P = 0.010), gestational diabetes (28.3% versus 19.9%, P = 0.041), and a composite of adverse obstetric outcomes (61.3% versus 47.8%, P = 0.008). After adjusting for potentially confounding variables, shift work was associated with an increased risk for preeclampsia with (adjusted relative risk (aRR) 1.70, 95% CI 1.03-2.79, p = 0.036) and without (aRR 2.03, 95% CI 1.43-2.90, p<0.001) severe features, and gestational diabetes mellitus class A1 (aRR 1.47, 95% CI 1.05-2.05, p = 0.023) and class A2 (aRR 1.67, 95% CI 1.13-2.44, p = 0.009). Sleep duration was associated with gestational diabetes (31.3% among those with short sleep duration, 25.2% among those with normal sleep duration and 14.0% among those with prolonged sleep duration, P<0.001) and gestational diabetes class A2 (29.5%, 17.9%, and 10.1%, respectively, P<0.001). Gravidae with prolonged sleep duration experienced less composite adverse pregnancy outcomes at 42.6% compared to 57.4% for those with short sleep duration or 52.5% for those with normal sleep duration, P = 0.002., Conclusions: Shift work and sleep duration are both associated with adverse pregnancy outcomes. Further research on the impact of sleep disturbance on pregnancy outcomes is warranted., Competing Interests: The authors have declared that no competing interests exist.

Widespread public health campaigns have reduces the prevalence of tobacco and nicotine exposures during pregnancy in the United States. However, tobacco and nicotine exposures during pregnancy persist as a common modifiable perinatal risk exposure. Furthermore, declines in tobacco use have been accompanied by parallel rises in both the prevalence and incidence of marijuana use in pregnancy. This is worrisome, as the macromolecules which comprise tobacco and marijuana smoke affect placental function. In this chapter we summarize the decades of evidence contributing to our understanding of the placental molecular pathophysiology accompanying these chemical exposures, thereby rendering risk of adverse perinatal outcomes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Anemia during pregnancy is associated with increased risks of preterm birth, preeclampsia, cesarean delivery, and maternal morbidity. The most prevalent modifiable cause of pregnancy-associated anemia is iron deficiency. However, it is still unclear whether iron therapy can reduce the risks of adverse outcomes in women with anemia., Objective: This study aimed to determine whether response to iron therapy among women with anemia is associated with a change in odds of adverse maternal and neonatal outcomes., Study Design: This was a population-based cohort study (2011-2019) using an institutional database composed of obstetrical patients from 2 delivery hospitals. Patients with adequate prenatal care were classified as being anemic or nonanemic (reference). Patients with anemia were further stratified by success or failure of treatment with oral iron therapy using the American College of Obstetricians and Gynecologists criteria for anemia at the time of admission for delivery: successfully treated (Hgb≥11 g/dL) or unsuccessfully treated ("refractory;" Hgb<11 g/dL). All categories of women with anemia categories were compared with the reference group of women without anemia using chi-square and logistic regression analyses. The primary outcomes were preterm birth and preeclampsia., Results: Among the 20,690 women observed, 7416 (35.8%) were anemic. Among women with anemia, 1319 (17.8%) were refractory to iron therapy, 2695 (36.3%) had a successful response to therapy, and 3402 (45.9%) were untreated. Successfully treated patients with anemia had a significant reduction in the odds of preterm birth (5.1% vs 8.3%; adjusted odds ratio, 0.59; 95% confidence interval, 0.47-0.72) and preeclampsia (5.9% vs 8.3%; adjusted odds ratio, 0.75; 95% confidence interval, 0.61-0.91). Refractory and untreated patients had significantly increased odds of preterm birth (adjusted odds ratio, 1.44 [95% confidence interval, 1.16-1.76] and 1.45 [95% confidence interval, 1.26-1.67], respectively) and preeclampsia (adjusted odds ratio, 1.54 [95% confidence interval, 1.24-1.89] and 1.44 [95% confidence interval, 1.25-1.67], respectively). All groups of women with anemia had increased odds of postpartum hemorrhage and decreased odds of delivering a small for gestational age neonate. There was no difference in composite neonatal morbidity., Conclusion: Successful treatment of anemia with oral iron therapy was associated with a reduction in the odds of preterm birth and preeclampsia. Women with refractory anemia had similar outcomes to those who were untreated, emphasizing the importance of monitoring response to iron therapy during pregnancy., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

At the dawn of the twentieth century, the medical care of mothers and children was largely relegated to family members and informally trained birth attendants. As the industrial era progressed, early and key public health observations among women and children linked the persistence of adverse health outcomes to poverty and poor nutrition. In the time hence, numerous studies connecting genetics ("nature") to public health and epidemiologic data on the role of the environment ("nurture") have yielded insights into the importance of early life exposures in relation to the occurrence of common diseases, such as diabetes, allergic and atopic disease, cardiovascular disease, and obesity. As a result of these parallel efforts in science, medicine, and public health, the developing brain, immune system, and metabolic physiology are now recognized as being particularly vulnerable to poor nutrition and stressful environments from the start of pregnancy to 3 years of age. In particular, compelling evidence arising from a diverse array of studies across mammalian lineages suggest that modifications to our metagenome and/or microbiome occur following certain environmental exposures during pregnancy and lactation, which in turn render risk of childhood and adult diseases. In this review, we will consider the evidence suggesting that development of the offspring microbiome may be vulnerable to maternal exposures, including an analysis of the data regarding the presence or absence of a low-biomass intrauterine microbiome., (© 2021. The Author(s).)

Maternal obesity affects nearly one-third of pregnancies and is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in adolescent offspring, yet the mechanisms behind NAFLD remain poorly understood. Here, we demonstrate that nonhuman primate fetuses exposed to maternal Western-style diet (WSD) displayed increased fibrillar collagen deposition in the liver periportal region, with increased ACTA2 and TIMP1 staining, indicating localized hepatic stellate cell (HSC) and myofibroblast activation. This collagen deposition pattern persisted in 1-year-old offspring, despite weaning to a control diet (CD). Maternal WSD exposure increased the frequency of DCs and reduced memory CD4+ T cells in fetal liver without affecting systemic or hepatic inflammatory cytokines. Switching obese dams from WSD to CD before conception or supplementation of the WSD with resveratrol decreased fetal hepatic collagen deposition and reduced markers of portal triad fibrosis, oxidative stress, and fetal hypoxemia. These results demonstrate that HSCs and myofibroblasts are sensitive to maternal WSD-associated oxidative stress in the fetal liver, which is accompanied by increased periportal collagen deposition, indicative of early fibrogenesis beginning in utero. Alleviating maternal WSD-driven oxidative stress in the fetal liver holds promise for halting steatosis and fibrosis and preventing developmental programming of NAFLD.

With the recent advances in gene editing with systems such as CRISPR-Cas9, precise genome editing in utero is on the horizon. Sickle cell disease is an excellent candidate for in utero fetal gene therapy, because the disease is monogenic, causes irreversible harm, and has life-limiting morbidity. Gene therapy has recently been proven to be effective in an adolescent patient. Several hurdles still impede the progress for fetal gene therapy in humans, including an incomplete understanding of the fetal immune system, unclear maternal immune responses to in utero gene therapy, risks of off-target effects from gene editing, gestational age constraints, and ethical questions surrounding fetal genetic intervention. However, none of these barriers appears insurmountable, and the journey to in utero gene therapy for sickle cell disease and other conditions should be well underway., (Copyright © 2021. Published by Elsevier Inc.)

The COVID-19 global pandemic has broad implications for obstetrical care and perinatal outcomes. As we approach the 2-year mark into an unprecedented international pandemic, this review presents the progress and opportunities for research related to COVID-19 and pregnancy. Research is the basis for evidence-based clinical guidelines, and we aim to provide the structure and guidance for framing COVID-19-related obstetrical research. This structure will pertain not only to this pandemic but future ones as well., (Copyright © 2021. Published by Elsevier Inc.)

Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention. PERSPECTIVE: This manuscript presents the results of a robust, unbiased molecular assessment of plasma and vaginal fluid samples in women with provoked vestibulodynia compared to healthy controls. The findings suggest that alterations in sphingolipid signaling pathways are associated with symptoms and brain biomarkers and may be an important molecular marker that could provide new targets for therapeutic intervention., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The influence of prenatal diethylstilbestrol (DES) exposure on cancer incidence among middle-aged men has not been well-characterized. We investigated whether exposure to DES before birth impacts overall cancer risk, and risk of site-specific cancers., Methods: Men (mean age in 2016 = 62.0 years) who were or were not prenatally DES exposed were identified between 1953 and 1994 and followed for cancer primarily via questionnaire approximately every 5 years between 1994 and 2016. The overall and site-specific cancer rates of the two groups were compared using Poisson regression and proportional hazards modeling with adjustment for age., Results: DES exposure was not associated with either overall cancer [hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.77-1.15] or total prostate cancer rates (HR, 0.95; 95% CI, 0.68-1.33), but was inversely associated with urinary tract cancer incidence (HR, 0.48; 95% CI, 0.23-1.00)., Conclusions: There was no increase in either overall or prostate cancer rates among men prenatally DES exposed relative to those unexposed. An unexpected risk reduction was observed for urinary system cancers among the exposed relative to those unexposed. These findings suggest that prenatal DES exposure is unlikely to be an important contributor to cancer development in middle-aged men., Impact: The results of this study could lend reassurance to middle-aged men who were prenatally DES exposed that their exposure does not adversely influence their overall cancer risk., (©2021 American Association for Cancer Research.)