RNA profiles reveal signatures of future health and disease in pregnancy.

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

Study Design and Protocol of the Multisite Pregnancy 24/7 Cohort Study.

Hypertensive disorders of pregnancy and other adverse pregnancy outcomes (APOs) are associated with an increased risk of future maternal cardiovascular disease. Physical activity during pregnancy reduces the risk of these APOs, yet few meet physical activity guidelines during pregnancy. Little is known about the role of sedentary behavior or sleep in APOs, a critical gap in knowledge given these behaviors comprise the majority of a 24-hour day. To address this knowledge gap, the Pregnancy 24/7 cohort study (2020-2025) uses 2 devices for 24-hour activity assessment in each trimester of pregnancy to examine associations of sedentary behavior, sleep, and the 24-hour activity cycle (composition of sedentary behavior, physical activity, and sleep) with hypertensive disorders and other APOs. Participants (n = 500) are recruited from the University of Iowa, University of Pittsburgh, and West Virginia University in early pregnancy and followed through delivery. The activPAL3 micro and Actiwatch Spectrum Plus are worn in each trimester for 7 days of 24-hour wear to assess the 24-hour activity cycle. APOs are abstracted from medical charts. This study will provide critical data to fuel future research examining how modifying the 24-hour activity cycle in pregnancy can improve maternal health.

A Statewide Mobile Simulation Program For Improving Obstetric Skills in Rural Hospitals.

BACKGROUND: Closure of rural obstetric (OB) units has led to maternal care deserts, causing mothers to travel long distances for maternity care. Emergency departments (EDs) in hospitals where OB units have closed require regular training for personnel to maintain OB skills, as do rural Level-1 OB units with low volumes of maternity cases. We used a federal grant to develop an OB mobile simulation program to bring simulation-based training to rural providers. Our goal was to improve OB skills and standardize care through the framework of the Alliance for Innovation in Maternal Health (AIM) Patient Safety Bundles. METHODS: We conducted needs assessments and built a mobile simulation unit. We defined 2 groups of learners: those in Level-1 OB units and those in EDs without OB units. For Level-1 OB units, we created a train-the-trainer curriculum, to create a statewide cohort of simulation experts to implement simulations in their facilities between our visits. We gifted each Level-1 unit an OB task trainer, implemented virtual train-the-trainer simulation and task trainer workshops, and conducted post-workshop assessments. We then traveled to each Level-1 unit and helped the cohort implement in situ simulations for their staff using facility-specific resources. We conducted assessments for the cohort and the hospital staff after the simulations. For EDs, we delivered virtual didactics to improve basic OB knowledge, then traveled to ED units, implemented in situ simulations, and conducted post-simulation assessments. We chose a postpartum hemorrhage (PPH) scenario for our first round of simulations. RESULTS: After train-the-trainer simulation workshops, 98% of participants surveyed agreed that workshop goals and objectives were achieved. After the task trainer workshop, 95% surveyed agreed that their knowledge of using the simulator had improved. After implementing in situ simulations in Level-1 OB units, 98.8% of the train-the-trainer cohort found that their ability to implement simulations had improved. The hospital staff participating in the simulations identified a 30% increase in ability to manage PPH. For the ED staff, postdidactic evaluations identified that 95.4% of participants reported moderate improvement in basic OB knowledge and after participation in the simulations >95% reported better skills as an ED team member when caring for pregnant patients. CONCLUSIONS: These results demonstrate improved skills of hospital staff in simulated PPH in Level-1 OB units and simulated OB emergencies in EDs that no longer have OB units. Further studies are warranted to assess improvement in maternal outcomes.

Maternal and fetal mitochondrial gene dysregulation in hypertensive disorders of pregnancy.

Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.NEW & NOTEWORTHY This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.

Differences in H3K4me3 and chromatin accessibility contribute to altered T-cell receptor signaling in neonatal naïve CD4 T cells.

Neonatal CD4+ T cells have reduced or delayed T-cell receptor (TCR) signaling responses compared with adult cells, but the mechanisms underlying this are poorly understood. This study tested the hypothesis that human neonatal naïve CD4+ TCR signaling and activation deficits are related to differences in H3K4me3 patterning and chromatin accessibility. Following initiation of TCR signaling using anti-CD3/anti-CD28 beads, adult naïve CD4+ T cells demonstrated increased CD69, phospho-CD3ε and interleukin (IL)-2, tumor necrosis factor-α (TNF-α), interferon-γ and IL-17A compared with neonatal cells. By contrast, following TCR-independent activation using phorbol myristate acetate (PMA)/ionomycin, neonatal cells demonstrated increased expression of CD69, IL-2 and TNF-α and equivalent phospho-ERK compared with adult cells. H3K4me3 chromatin immunoprecipitation-sequencing (ChIP-seq) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were performed on separate cohorts of naïve CD4+ T cells from term neonates and adults, and RNA-seq data from neonatal and adult naïve CD4+ T cells were obtained from the Blueprint Consortium. Adult cells demonstrated overall increased chromatin accessibility and a higher proportion of H3K4me3 sites associated with open chromatin and active gene transcription compared with neonatal cells. Adult cells demonstrated increased mRNA expression of the TCR-associated genes FYN, ITK, CD4, LCK and LAT, which was associated with increased H3K4me3 at the FYN and ITK gene loci and increased chromatin accessibility at the CD4, LCK and LAT loci. These findings indicate that neonatal TCR-dependent defects in activation are epigenetically regulated and provide a potentially targetable mechanism to enhance neonatal CD4+ T-cell responses.

Association between plasma leptin and cesarean section after induction of labor: a case control study.

BACKGROUND: Obesity in pregnancy is common, with more than 50% of pregnant women being overweight or obese. Obesity has been identified as an independent predictor of dysfunctional labor and is associated with increased risk of failed induction of labor resulting in cesarean section. Leptin, an adipokine, is secreted from adipose tissue under the control of the obesity gene. Concentrations of leptin increase with increasing percent body fat due to elevated leptin production from the adipose tissue of obese individuals. Interestingly, the placenta is also a major source of leptin production during pregnancy. Leptin has regulatory effects on neuronal tissue, vascular smooth muscle, and nonvascular smooth muscle systems. It has also been demonstrated that leptin has an inhibitory effect on myometrial contractility with both intensity and frequency of contractions decreased. These findings suggest that leptin may play an important role in dysfunctional labor and be associated with the outcome of induction of labor at term. Our aim is to determine whether maternal plasma leptin concentration is indicative of the outcome of induction of labor at term. We hypothesize that elevated maternal plasma leptin levels are associated with a failed term induction of labor resulting in a cesarean delivery. METHODS: In this case-control study, leptin was measured in 3rd trimester plasma samples. To analyze labor outcomes, 174 women were selected based on having undergone an induction of labor (IOL), (115 women with successful IOL and 59 women with a failed IOL). Plasma samples and clinical information were obtained from the UI Maternal Fetal Tissue Bank (IRB# 200910784). Maternal plasma leptin and total protein concentrations were measured using commercially available assays. Bivariate analyses and logistic regression models were constructed using regression identified clinically significant confounding variables. All variables were tested at significance level of 0.05. RESULTS: Women with failed IOL had higher maternal plasma leptin values (0.5 vs 0.3 pg, P = 0.01). These women were more likely to have obesity (mean BMI 32 vs 27 kg/m2, P = 0.0002) as well as require multiple induction methods (93% vs 73%, p = 0.008). Logistic regression showed Bishop score (OR 1.5, p < 0.001), BMI (OR 0.92, P < 0.001), preeclampsia (OR 0.12, P = 0.010), use of multiple methods of induction (OR 0.22, P = 0.008) and leptin (OR 0.42, P = 0.017) were significantly associated with IOL outcome. Specifically, after controlling for BMI, Bishop Score, and preeclampsia, leptin was still predictive of a failed IOL with an odds ratio of 0.47 (P = 0.046). Finally, using leptin as a predictor for fetal outcomes, leptin was also associated with of fetal intolerance of labor, with an odds ratio of 2.3 (P = 0.027). This association remained but failed to meet statistical significance when controlling for successful (IOL) (OR 1.5, P = 0.50). CONCLUSIONS: Maternal plasma leptin may be a useful tool for determining which women are likely to have a failed induction of labor and for counseling women about undertaking an induction of labor versus proceeding with cesarean delivery.

Need for Improved Collection and Harmonization of Rural Maternal Healthcare Data.

Representation in data sets is critical to improving healthcare for the largest possible number of people. Unfortunately, pregnancy is a very understudied period of time. Further, the gap in available data is wide between pregnancies in urban areas versus rural areas. There are many limitations in the current data that is available. Herein, we review these limitations and strengths of available data sources. In addition, we propose a new mechanism to enhance the granularity, depth, and speed with which data is made available regarding rural pregnancy.

The Serotonin-Immune Axis in Preeclampsia.

PURPOSE OF REVIEW: To review the literature and detail the potential immune mechanisms by which hyperserotonemia may drive pro-inflammation in preeclampsia and to provide insights into potential avenues for therapeutic discovery. RECENT FINDINGS: Preeclampsia is a severe hypertensive complication of pregnancy associated with significant maternal and fetal risk. Though it lacks any effective treatment aside from delivery of the fetus and placenta, recent work suggests that targeting serotonin systems may be one effective therapeutic avenue. Serotonin dysregulation underlies multiple domains of physiologic dysfunction in preeclampsia, including vascular hyporeactivity and excess platelet aggregation. Broadly, serotonin is increased across maternal and placental domains, driven by decreased catabolism and increased availability of tryptophan precursor. Pro-inflammation, another hallmark of the disease, may drive hyperserotonemia in preeclampsia. Interactions between immunologic dysfunction and hyperserotonemia in preeclampsia depend on multiple mechanisms, which we discuss in the present review. These include altered immune cell, kynurenine pathway metabolism, and aberrant cytokine production mechanisms, which we detail. Future work may leverage animal and in vitro models to reveal serotonin targets in the context of preeclampsia's immune biology, and ultimately to mitigate vascular and platelet dysfunction in the disease. Hyperserotonemia in preeclampsia drives pro-inflammation via metabolic, immune cell, and cytokine-based mechanisms. These immune mechanisms may be targeted to treat vascular and platelet endophenotypes in preeclampsia.

Prevalence and Distribution of Electronic Cigarette Use Before and During Pregnancy Among Women in 38 States of the United States.

INTRODUCTION: To examine the prevalence and the changing pattern of e-cigarette use from preconception to pregnancy. AIMS AND METHODS: This is a cross-sectional study using data from the multi-site Pregnancy Risk Assessment Monitoring System in the United States, 2016-2017. All participating mothers with information on e-cigarette use before and during pregnancy were included. Self-reported information about e-cigarette use were assessed using questionnaires. Weighted prevalences of e-cigarette use before and during pregnancy were calculated. Multivariable logistic regressions were used to examine the association between various demographic characteristics and e-cigarette use before or during pregnancy. RESULTS: This study included 69 508 pregnant women from 38 states in the United States. The weighted prevalence of e-cigarette use before pregnancy and during the last 3 months of pregnancy was 3.6% (95% confidence interval [CI] 3.4%-3.9%) and 1.1% (0.9%-1.2%), respectively. The prevalence varied across states, ranging from 1.3% to 8.3% for e-cigarette use before pregnancy and from 0.1% to 3.4% for e-cigarette use during the last 3 months of pregnancy. Among women who used e-cigarettes before pregnancy, 24.4% (21.7%-27.1%) continued to use e-cigarettes during pregnancy. Among women who used e-cigarettes during pregnancy, 62.3% (56.5%-68.0%) were dual users. In multivariable analyses, cigarette smoking was most strongly associated with e-cigarette use. The adjusted odds ratio comparing smokers with nonsmokers before pregnancy was 11.10 (95% CI 9.34-13.20) for e-cigarette use before pregnancy and 6.72 (95% CI 4.38-10.31) for e-cigarette use during pregnancy. CONCLUSIONS: Using data from 38 states in the United States, we showed geographical variations in the prevalence of e-cigarette use before and during pregnancy. Among women who used e-cigarettes before pregnancy, a quarter of them continued to use e-cigarettes during pregnancy. Conventional cigarette use is a strong risk factor for e-cigarette use before and during pregnancy. The prevalence of e-cigarette use needs to be monitored continuously. IMPLICATIONS: This study provides important information to understand the status and changing patterns of e-cigarette use in pregnant women in the United States. Among pregnant women in 38 states in the United States, 3.6% of them used e-cigarettes during the 3 months before pregnancy and 1.1% used them during the last 3 months of pregnancy. The prevalence varied across states. A quarter of women who used e-cigarettes before pregnancy continued to use e-cigarettes during pregnancy. Cigarette smoking is the strongest predictor of e-cigarette use. Future research about health effects of e-cigarette use during pregnancy is in urgent need.

Origins of neonatal leptin deficiency in preterm infants.

BACKGROUND: Cord blood leptin increases with advancing gestation. Preterm delivery leads to premature separation from the maternal and placental leptin source predisposing infants to postnatal leptin deficiency, but this has not been fully described. METHOD: Blood leptin levels were measured for infants born before 33 weeks gestation daily for the first 2 days, then weekly until 36 weeks postmenstrual age (PMA). Cord blood was obtained to provide gestational age (GA)-specific standards. RESULTS: Cord blood leptin levels were positively associated with GA at birth, maternal body mass index (BMI) and pregnancy weight gain (all P < 0.05). Following birth, infant leptin levels decreased rapidly (74% decrease within 48 h). The extent of this decline correlated with GA (P < 0.05). Postnatal leptin began to increase by 33-36 weeks PMA, but remained below cord blood leptin levels (P < 0.01). At 36 weeks PMA, leptin levels were influenced by infant's weight and sex (P < 0.01), with females having higher leptin levels (1213 pg/ml vs. 984, P < 0.05). CONCLUSION: Cord blood leptin is influenced by maternal weight gain and BMI, suggesting an important role for trans-placental leptin delivery. Preterm delivery leads to sustained leptin deficiency through 36 weeks PMA, with the most premature male infants facing the longest and harshest deficiency.

The Preconception Period analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. OBJECTIVES: The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. POPULATION: A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. DESIGN: The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. METHODS: Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. PRELIMINARY RESULTS: Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. CONCLUSIONS: The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.

Levels of tin and organotin compounds in human urine samples from Iowa, United States.

Exposure to tin in the general US population is near ubiquitous, as determined using urinary tin levels measured by inductively coupled plasma mass spectrometry (ICP-MS). Urinary tin levels are associated with chronic health outcomes, such as diabetes; however, it is unclear if these associations are due to the presence of inorganic and organic forms of tin in urine. To address this knowledge gap, levels of total tin and several organotin compounds (OTCs) were measured in convenience urine samples from pregnant women and adults from Iowa, United States. Total tin and OTC levels in urine samples were quantified using ICP-MS and gas chromatography with pulsed flame photometric detection (GC-PFPD), respectively. ICP-MS detected tin in almost all urine samples from both study populations. Low levels of dibutyltin were detected in two out of fifty human urine samples. Importantly, storage of urine samples in plastic containers, but not HNO3-pretreated glass vials drastically reduced the recoveries of OTCs, in particular, tributyltin. Although their detection frequency is low, exposures to OTC should be considered when studying associations between human exposures to tin compounds and adverse health outcomes; however, urinary OTC levels measured in banked urine samples may not be suitable as biomarkers of OTC exposure.

Elevated vasopressin in pregnant mice induces T-helper subset alterations consistent with human preeclampsia.

The pathogenesis of preeclampsia (PreE), a hypertensive disorder of pregnancy, involves imbalanced T helper (TH) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated copeptin (an inert biomarker of arginine vasopressin (AVP)), secretion precedes the development of symptoms in PreE in humans, and infusion of AVP proximal to and throughout gestation is sufficient to initiate cardiovascular and renal phenotypes of PreE in wild-type C57BL/6J mice. We hypothesize that AVP infusion in wild-type mice is sufficient to induce the immune changes observed in human PreE. AVP infusion throughout gestation in mice resulted in increased pro-inflammatory interferon γ (IFNg) (TH1) in the maternal plasma. The TH17-associated cytokine interleukin (IL)-17 was elevated in the maternal plasma, amniotic fluid, and placenta following AVP infusion. Conversely, the TH2-associated anti-inflammatory cytokine IL-4 was decreased in the maternal and fetal kidneys from AVP-infused dams, while IL-10 was decreased in the maternal kidney and all fetal tissues. Collectively, these results demonstrate the sufficiency of AVP to induce the immune changes typical of PreE. We investigated if T cells can respond directly to AVP by evaluating the expression of AVP receptors (AVPRs) on mouse and human CD4+ T cells. Mouse and human T cells expressed AVPR1a, AVPR1b, and AVPR2. The expression of AVPR1a was decreased in CD4+ T cells obtained from PreE-affected women. In total, our data are consistent with a potential initiating role for AVP in the immune dysfunction typical of PreE and identifies putative signaling mechanism(s) for future investigation.

Differential Regulation of Human and Mouse Myometrial Contractile Activity by FSH as a Function of FSH Receptor Density.

Previous studies from our laboratory revealed that the follicle-stimulating hormone receptor (FSHR) is expressed at low levels in nonpregnant human myometrium and that it is up-regulated in pregnant term nonlaboring myometrium; however, the physiological relevance of these findings was unknown. Herein, we examined signaling pathways stimulated by FSH in immortalized uterine myocytes expressing recombinant FSHR at different densities and showed that cAMP accumulation is stimulated in all cases but that inositol phosphate accumulation is stimulated only at high FSHR densities. Because an increase in cAMP quiets myometrial contractile activity but an increase in 1,4,5-triphosphoinositol stimulates contractile activity, we hypothesized that FSHR density dictates whether FSH quiets or stimulates myometrial contractility. Indeed, in human and mouse nonpregnant myometrium, which express low levels of FSHR, application of FSH resulted in a quieting of contractile activity. In contrast, in pregnant term nonlaboring myometrium, which expresses higher levels of FSHR, application of FSH resulted in increased contractile activity. Examination of pregnant mouse myometrium from different stages of gestation revealed that FSHR levels remained low throughout most of pregnancy. Accordingly, through mid-gestation, the application of FSH resulted in a quieting of contractile activity. At Pregnancy Day (PD) 16.5, FSHR was up-regulated, although not yet sufficiently to mediate stimulation of contractility in response to FSH. This outcome was not observed until PD 19.5, when FSHR was further up-regulated. Our studies describe a novel FSHR signaling pathway that regulates myometrial contractility, and suggest that myometrial FSHR levels dictate the quieting vs. stimulation of uterine contractility in response to FSH.

Mast Cells Release Chemokine CCL2 in Response to Parkinsonian Toxin 1-Methyl-4-Phenyl-Pyridinium (MPP(+)).

Microglial activation and release of inflammatory cytokines and chemokines are crucial events in neuroinflammation. Microglial cells interact and respond to other inflammatory cells such as T cells and mast cells as well as inflammatory mediators secreted from these cells. Recent studies have shown that neuroinflammation causes and accelerates neurodegenerative disease such as Parkinson's disease (PD) pathogenesis. 1-methyl-4-phenyl-pyridinium ion (MPP(+)), the active metabolite of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine activates glial cells and mediate neurodegeneration through release of inflammatory mediators. We have shown that glia maturation factor (GMF) activates glia and induces neuroinflammation and neurodegeneration and that MPP(+) activates mast cells and release proinflammatory cytokines and chemokines. The chemokine (C-C motif) ligand 2 (CCL2) levels have been shown to be elevated and play a role in PD pathogenesis. In the present study, we analyzed if MPP(+) activates mouse and human mast cells to release chemokine CCL2. Mouse bone marrow-derived mast cells (BMMCs) and human umbilical cord blood-derived cultured mast cells (hCBMCs) were incubated with MPP(+) (10 µM) for 24 h and CCL2 levels were measured in the supernatant media by ELISA. MPP(+)-significantly induced CCL2 release from BMMCs and hCBMCs. Additionally, GMF overexpression in BMMCs obtained from wild-type mice released significantly more CCL2, while BMMCs obtained from GMF-deficient mice showed less CCL2 release. Further, we show that MPP(+)-induced CCL2 release was greater in BMMCs-astrocyte co-culture conditions. Uncoupling protein 4 (UCP4) which is implicated in neurodegenerative diseases including PD was detected in BMMCs by immunocytochemistry. Our results suggest that mast cells may play role in PD pathogenesis.

Vasopressin: the missing link for preeclampsia?

Preeclampsia is a devastating cardiovascular disorder of late pregnancy, affecting 5-7% of all pregnancies and claiming the lives of 76,000 mothers and 500,000 children each year. Various lines of evidence support a "tissue rejection" type reaction toward the placenta as the primary initiating event in the development of preeclampsia, followed by a complex interplay among immune, vascular, renal, and angiogenic mechanisms that have been implicated in the pathogenesis of preeclampsia beginning around the end of the first trimester. Critically, it remains unclear what mechanism links the initiating event and these pathogenic mechanisms. We and others have now demonstrated an early and sustained increase in maternal plasma concentrations of copeptin, a protein by-product of arginine vasopressin (AVP) synthesis and release, during preeclampsia. Furthermore, chronic infusion of AVP during pregnancy is sufficient to phenocopy essentially all maternal and fetal symptoms of preeclampsia in mice. As various groups have demonstrated interactions between AVP and immune, renal, and vascular systems in the nonpregnant state, elevations of this hormone are therefore positioned both in time (early pregnancy) and function to contribute to preeclampsia. We therefore posit that AVP represents a missing mechanistic link between initiating events and established midpregnancy dysfunctions that cause preeclampsia.

FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice.

Expression and function of the follicle-stimulating hormone receptor (FSHR) in females were long thought to be limited to the ovary. Here, however, we identify extragonadal FSHR in both the human female reproductive tract and the placenta, and test its physiological relevance in mice. We show that in nonpregnant women FSHR is present on: endothelial cells of blood vessels in the endometrium, myometrium, and cervix; endometrial glands of the proliferative and secretory endometrium; cervical glands and the cervical stroma; and (at low levels) stromal cells and muscle fibers of the myometrium. In pregnant women, placental FSHR was detected as early as 8-10 wk of gestation and continued through term. It was expressed on: endothelial cells in fetal portions of the placenta and the umbilical cord; epithelial cells of the amnion; decidualized cells surrounding the maternal arteries in the maternal decidua; and the stromal cells and muscle fibers of the myometrium, with particularly strong expression at term. These findings suggest that FSHR expression is upregulated during decidualization and upregulated in myometrium as a function of pregnancy. The presence of FSHR in the placental vasculature suggests a role in placental angiogenesis. Analysis of genetically modified mice in which Fshr is lacking in fetal portions of the placenta revealed adverse effects on fetoplacental development. Our data further demonstrate FSHB and CGA mRNAs in placenta and uterus, consistent with potential local sources of FSH. Collectively, our data suggest heretofore unappreciated roles of extragonadal FSHR in female reproductive physiology.

Skin-to-Skin Contact and Breastfeeding After Planned Cesarean Birth Before and During the COVID-19 Pandemic.

Background: Benefits of early skin-to-skin contact (SSC) between mother and newborn are widely documented, including improved breastfeeding outcomes. While promoting immediate SSC is standard practice for vaginal birth, it happens less often after cesarean birth. It is not known how changes in hospital practices and staffing shortages during the COVID-19 pandemic have influenced the practice of SSC in the operating room (OR). This study aims to identify the relationship between SSC after cesarean birth and breastfeeding and compare SSC before and during the COVID-19 pandemic at a single institution. Materials and Methods: This was a retrospective cohort study of 244 subjects who had scheduled cesarean births during 2019 and 2020. The primary outcome was newborn feeding at hospital discharge. Secondary outcomes were time to initiate breastfeeding, newborn feeding at 4-8-weeks postpartum, and location of SSC initiation in 2019 versus 2020. Results: SSC within 3 days of birth was significantly associated with feeding type on discharge and/or 4-8 weeks postpartum. More subjects intending to exclusively breastfeed met this intention at discharge with SSC in the OR. Newborns who had SSC in the OR had significantly earlier initiation of breastfeeding. There was an increase in SSC in the OR between 2019 (27%) and 2020 (39%). Conclusion: SSC in the OR was associated with improved short-term breastfeeding outcomes in our study. If immediate SSC is not possible, SSC within 3 days of birth may have breastfeeding benefits. The increase in SSC in the OR during the COVID-19 pandemic indicates that SSC practices can be implemented, despite challenging circumstances.

Emergency department use in the postpartum period: a retrospective cohort study.

Background: Visits to the emergency room (ED) by women in the postpartum period may reflect gaps in postpartum care and disparities in access to obstetric and primary care services. This study aimed to characterize the patients who visited the ED in the first year after delivery, their reasons for coming to the ED, and the care they received. Methods: The electronic health record was reviewed for all patients who delivered at University of Iowa Health Care between 2009 and 2023 and visited the ED within 365 days after delivery. Data drawn directly from the EHR included patient demographics and medical history, pregnancy and delivery information, and newborn characteristics. The charts were then reviewed manually for information regarding ED visits including time from delivery, chief complaint, diagnosis, and disposition. Results: 555 pregnancies had ED visits within one year of delivery, with a total 814 ED visits across the study sample. 46.7% of ED visits occurred in the first 30 days following delivery, and 35% of ED visits for obstetric complaints occurred in the first 2 weeks after delivery. Black patients visited the ED more often (mean=1.84 visits, SD=1.30) than white (mean=1.34, SD=0.92, p<0.001) or Hispanic patients (mean=1.35, SD=0.67, p = 0.004). The most common categories of chief complaint were obstetric (34.6%) and gastrointestinal (18.8%), while the most common categories of diagnosis were obstetric (31.8%) and immune/infectious (28.1%). Conclusions: Visits to the ED are common in the year following delivery. Almost half of these visits occur in the first 30 days after birth. The plurality of postpartum ED visits are due to obstetric complaints, especially in the first few weeks. Black women are more likely to use the ED during this period, potentially due to disparities in healthcare access. These findings suggest that some of these ED visits may be preventable, and that there is room for improvement in post-delivery follow-up, communication between patients and the obstetrics team, and access to outpatient obstetric care.

A role for adverse childhood experiences and depression in preeclampsia.

Introduction: Adverse childhood experiences (ACEs) are a measure of childhood adversity and are associated with life-long morbidity. The impacts of ACEs on peripartum health including preeclampsia, a common and dangerous hypertensive disorder of pregnancy, remain unclear, however. Therefore, we aimed to determine ACE association with peripartum psychiatric health and prevalence of preeclampsia using a case-control design. Methods: Clinical data were aggregated and validated using a large, intergenerational knowledgebase developed at our institution. Depression symptoms were measured by standard clinical screeners: the Patient Health Questionnaire-9 (PHQ-9) and the Edinburgh Postnatal Depression Scale (EPDS). ACEs were assessed via survey. Scores were compared between participants with (N = 32) and without (N = 46) prior preeclampsia. Results: Participants with ACE scores ≥4 had significantly greater odds of preeclampsia than those with scores ≤ 3 (adjusted odds ratio = 6.71, 95% confidence interval:1.13-40.00; p = 0.037). Subsequent speculative analyses revealed that increased odds of preeclampsia may be driven by increased childhood abuse and neglect dimensions of the ACE score. PHQ-9 scores (3.73 vs. 1.86, p = 0.03), EPDS scores (6.38 vs. 3.71, p = 0.01), and the incidence of depression (37.5% vs. 23.9%, p = 0.05) were significantly higher in participants with a history of preeclampsia versus controls. Conclusions: Childhood sets the stage for life-long health. Our findings suggest that ACEs may be a risk factor for preeclampsia and depression, uniting the developmental origins of psychiatric and obstetric risk.