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Background: To determine the impact of the COVID-19 pandemic on prenatal and postpartum depressive symptoms in rural versus urban populations., Methods: A retrospective cohort study was conducted among 24,227 cisgender women who gave birth from 2010 to 2021 at an academic medical center located in a rural midwestern state. Exclusion criteria were <18 years old, incarcerated, or without a documented zip code. The Patient Health Questionnaire-9 (PHQ-9) was administered during pregnancy and the Edinburgh Postnatal Depression Scale (EPDS) during postpartum. A sub-cohort also completed a COVID-related questionnaire. Rurality was defined as living in a county with <50,000 people. The COVID-19 era was defined as 1/1/2020 to 9/25/2021. Chi-square and Fisher exact tests were used as appropriate. Significance was set at α < 0.05., Results: Rural participants were more likely (p ≤ 0.001) to exhibit clinical depression symptoms before the pandemic in both the prenatal (8.63 % of rural participants vs. 6.49 % of urban participants) and postpartum periods (11.19 % rural vs. 9.28 % urban). During the pandemic, urban participants had increased postpartum depression. Rural participants endorsed more financial and labor concerns, whereas urban participants expressed support system concerns., Limitations: Study data were gathered from participants who gave birth at a single, midwestern hospital. Results may not be widely generalizable given the homogeneity of participants., Conclusions: Rural women experienced higher rates of prenatal and postpartum depressive symptoms compared to their urban counterparts. The COVID-19 pandemic was a significant stressor, revealing specific mental health vulnerabilities among birthing people., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Donna Santillan reports financial support was provided by National Institutes of Health. Stephen K. Hunter reports financial support was provided by Health Resources and Services Administration. Stephen K. Hunter reports financial support was provided by Iowa Department of Health and Human Services. Mark K. Santillan reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction : Preeclampsia, a hypertensive disorder of pregnancy, results in increased lifetime cardiovascular disease (CVD) risk. Total aortic stiffness, a robust risk factor for CVD, is composed of load-dependent (blood pressure load on arterial wall) and structural (intrinsic changes in arterial wall) mechanisms. Total aortic stiffness is also associated with reduced cardiovagal baroreflex sensitivity (BRS). We sought to determine 1) whether elevated total aortic stiffness among women with a history of preeclampsia (hxPE) is attributed to load-dependent or structural stiffness, and 2) whether either mechanism is associated with lower BRS. Methods : Total aortic stiffness (carotid-femoral pulse wave velocity) and spontaneous cardiovagal BRS (sequence technique) were measured among women 1-5 years postpartum (n=115; age 34 ±4yrs; hxPE n=51; controls n=64). Structural aortic stiffness was calculated from participant-specific exponential models, standardizing aortic stiffness to a 'reference' blood pressure. Load-dependent stiffness was calculated as total minus structural stiffness. Results : Total (+0.8 m/sec, 95% CI (-0.99, -0.23), p=0.002) and load-dependent (+0.4 m/sec, 95% CI (-0.56, -0.22), P<0.001), but not structural (95% CI (-0.52, 0.08), p=0.16), aortic stiffness were higher among women with hxPE compared with controls. Women with a hxPE had lower BRS (p=0.042) that was negatively associated with total (B =-3.24 ms/mmHg, 95% CI (-6.35, -0.13), p=0.042) and load-dependent (B =-5.91ms/mmHg, 95% CI (-11.31, -0.51), p=0.033) aortic stiffness. Conclusion : Load-dependent, not structural, aortic stiffness mechanisms contribute to higher total aortic stiffness among women with hxPE and was associated with lower cardiovagal BRS. Postpartum BP monitoring is critical to reduce increased CVD risk in preeclampsia.

The maternal cardiovascular system undergoes functional and structural adaptations during pregnancy and postpartum to support increased metabolic demands of offspring and placental growth, labor, and delivery, as well as recovery from childbirth. Thus, pregnancy imposes physiological stress upon the maternal cardiovascular system, and in the absence of an appropriate response it imparts potential risks for cardiovascular complications and adverse outcomes. The proportion of pregnancy-related maternal deaths from cardiovascular events has been steadily increasing, contributing to high rates of maternal mortality. Despite advances in cardiovascular physiology research, there is still no comprehensive understanding of maternal cardiovascular adaptations in healthy pregnancies. Furthermore, current approaches for the prognosis of cardiovascular complications during pregnancy are limited. Machine learning (ML) offers new and effective tools for investigating mechanisms involved in pregnancy-related cardiovascular complications as well as the development of potential therapies. The main goal of this review is to summarize existing research that uses ML to understand mechanisms of cardiovascular physiology during pregnancy and develop prediction models for clinical application in pregnant patients. We also provide an overview of ML platforms that can be used to comprehensively understand cardiovascular adaptations to pregnancy and discuss the interpretability of ML outcomes, the consequences of model bias, and the importance of ethical consideration in ML use.

Gestational diabetes mellitus (GDM) is a pregnancy disorder associated with short- and long-term adverse outcomes in both mothers and infants. The current clinical test of blood glucose levels late in the second trimester is inadequate for early detection of GDM. Here we show the utility of Raman spectroscopy (RS) for rapid and highly sensitive maternal metabolome screening for GDM in the first trimester. Key metabolites, including phospholipids, carbohydrates, and major amino acids, were identified with RS and validated with mass spectrometry, enabling insights into associated metabolic pathway enrichment. Using classical machine learning (ML) approaches, we showed the performance of the RS metabolic model (cross-validation AUC 0.97) surpassed that achieved with patients' clinical data alone (cross-validation AUC 0.59) or prior studies with single biomarkers. Further, we analyzed novel proteins and identified fetuin-A as a promising candidate for early GDM prediction. A correlation analysis showed a moderate to strong correlation between multiple metabolites and proteins, suggesting a combined protein-metabolic analysis integrated with ML would enable a powerful screening platform for first trimester diagnosis. Our study underscores RS metabolic profiling as a cost-effective tool that can be integrated into the current clinical workflow for accurate risk stratification of GDM and to improve both maternal and neonatal outcomes., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Objectives: Preeclampsia and depression in pregnancy are among the most prevalent obstetric disorders with no known cures. While depression and preeclampsia each increase risk for the other, shared mechansisms are unclear. One possibility is low levels of Indoleamine 2,3 dioxygenase (IDO), which links immune dysregulation and oxidative arterial damage resulting in poor vascular function in both preeclampsia and depression. We hypothesized low circulating IDO activity levels in pregnancy would correspond to poor vascular function and depression symptoms., Study Design: In this nested case-control study, clinical, demographic, and biologic data from a cohort of pregnant women recruited to longitudinal studies measuring noninvasive vascular function and circulating factors were analyzed., Main Outcome Measure: IDO activity across all three trimesters of pregnancy was measured using a colorimetric assay. Carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness, was also assessed throughout gestation by non-invasive applanation tonometry. Depression symptoms were assessed in pregnancy via the validated patient health questionnaire 9 (PHQ9)., Results: Participants with low second and third trimester IDO activity had significantly decreased cfPWV. This association remained statistically significant when controlled for confounders such as BMI and chronic hypertension in the third but not second trimester. While PHQ9 scores were not associated with cfPWV differences, IDO activity was lower in moderate and severely depressed relative to non-depressed pregnant individuals., Conclusion: These results implicate IDO in arterial stiffness and depression symptoms, suggesting that decreased IDO may be a central target for improved psycho-obstetric health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: None., (© The Author(s) 2024.)

Preeclampsia is a life-threatening pregnancy disorder. Current clinical assays cannot predict the onset of preeclampsia until the late 2nd trimester, which often leads to poor maternal and neonatal outcomes. Here we show that Raman spectroscopy combined with machine learning in pregnant patient plasma enables rapid, highly sensitive maternal metabolome screening that predicts preeclampsia as early as the 1st trimester with >82% accuracy. We identified 12, 15 and 17 statistically significant metabolites in the 1st, 2nd and 3rd trimesters, respectively. Metabolic pathway analysis shows multiple pathways corresponding to amino acids, fatty acids, retinol, and sugars are enriched in the preeclamptic cohort relative to a healthy pregnancy. Leveraging Pearson's correlation analysis, we show for the first time with Raman Spectroscopy that metabolites are associated with several clinical factors, including patients' body mass index, gestational age at delivery, history of preeclampsia, and severity of preeclampsia. We also show that protein quantification alone of proinflammatory cytokines and clinically relevant angiogenic markers are inadequate in identifying at-risk patients. Our findings demonstrate that Raman spectroscopy is a powerful tool that may complement current clinical assays in early diagnosis and in the prognosis of the severity of preeclampsia to ultimately enable comprehensive prenatal care for all patients., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.)

Preterm birth (PTB) is the leading cause of infant deaths globally. Current clinical measures often fail to identify women who may deliver preterm. Therefore, accurate screening tools are imperative for early prediction of PTB. Here, we show that Raman spectroscopy is a promising tool for studying biological interfaces, and we examine differences in the maternal metabolome of the first trimester plasma of PTB patients and those that delivered at term (healthy). We identified fifteen statistically significant metabolites that are predictive of the onset of PTB. Mass spectrometry metabolomics validates the Raman findings identifying key metabolic pathways that are enriched in PTB. We also show that patient clinical information alone and protein quantification of standard inflammatory cytokines both fail to identify PTB patients. We show for the first time that synergistic integration of Raman and clinical data guided with machine learning results in an unprecedented 85.1% accuracy of risk stratification of PTB in the first trimester that is currently not possible clinically. Correlations between metabolites and clinical features highlight the body mass index and maternal age as contributors of metabolic rewiring. Our findings show that Raman spectral screening may complement current prenatal care for early prediction of PTB, and our approach can be translated to other patient-specific biological interfaces.

Preterm delivery can be precipitated by preeclampsia or infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (clinical chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22-32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. Independent of gestational age, MCP-1 was significantly increased ( p < 0.001) in association with maternal preeclampsia, but MCP-1 was decreased ( p < 0.01), and CRP was increased ( p < 0.01) in the presence of chorioamnionitis with funisitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection, with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age, including over a 2-fold increase in MCP-1 among newborns of mothers with preeclampsia. Further, in those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants delivered for maternal indications.

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.

Arginine vasopressin (AVP) signaling is altered in preeclampsia and physiologic stress. AVP is implicated in fluid homeostasis and cardiovascular (CV) function, which is disrupted in some progeny from preeclamptic pregnancies. However, whether altered fetal AVP signaling occurs in preeclampsia is unknown. Here, we measured CV-related transcripts (e.g., AVP receptors) in cord blood via quantitative PCR. Chronic hypertension decreased AVPR1b, AVPR2, OXTR, LNPEP, and CUL5. AVPR1a, AVPR1b, and AVPR2 were decreased while OXTR was increased in preeclamptic cord blood. In sum, we found prenatal exposure to hypertension in pregnancy alters fetal AVP signaling and may thereby prime offspring CV disease risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Depression and preeclampsia share risk factors and are bi-directionally associated with increased risk for each other. Despite epidemiological evidence linking selective serotonin reuptake inhibitors (SSRIs) in pregnancy to preeclampsia, serotonin (5-HT) and vasopressin (AVP) secretion mechanisms suggest that SSRIs may attenuate preeclampsia risk. However, there is a need to clarify the relationship between SSRIs and preeclampsia in humans to determine therapeutic potential. This retrospective cohort study included clinical data from 9558 SSRI-untreated and 9046 SSRI-treated pregnancies. In a subcohort of 233 pregnancies, early pregnancy (< 20 weeks) maternal plasma copeptin, an inert and stable AVP prosegment secreted 1:1 with AVP, was measured by enzyme-linked immunosorbent assay. Diagnoses and depression symptoms (Patient Health Questionnaire-9 [PHQ-9]) were identified via medical records review. Descriptive, univariate, and multivariate regression analyses were conducted (α = 0.05). SSRI use was associated with decreased preeclampsia after controlling for clinical confounders (depression severity, chronic hypertension, diabetes, body mass index, age) (OR = 0.9 [0.7-1.0], p = 0.05). Moderate-to-severe depression symptoms were associated with significantly higher copeptin secretion than mild-to-no depression symptoms (240 ± 29 vs. 142 ± 10 ng/mL, p < 0.001). SSRIs significantly attenuated first trimester plasma copeptin (78 ± 22 users vs. 240 ± 29 ng/ml non-users, p < 0.001). In preeclampsia, SSRI treatment was associated with significantly lower copeptin levels (657 ± 164 vs. 175 ± 134 ng/mL, p = 0.04). Interaction between SSRI treatment and preeclampsia was also significant (p = 0.04). SSRIs may modulate preeclampsia risk and mechanisms, although further studies are needed to investigate the relationships between 5-HT and AVP in depression and preeclampsia., (© 2022. The Author(s).)

Background: We have previously shown coxsackievirus B (CVB) to be a potent inducer of congenital heart disease (CHD) in mice. The clinical relevance of these findings in humans and the roles of other viruses in the pathogenesis of CHD remain unknown., Methods: We obtained plasma samples, collected at all trimesters, from 89 subjects (104 pregnancies), 73 healthy controls (88 pregnancies), and 16 with CHD-affected birth (16 pregnancies), from the Perinatal Family Tissue Bank (PFTB). We performed CVB IgG/IgM serological assays on plasma. We also used ViroCap sequencing and PCR to test for viral nucleic acid in plasma, circulating leukocytes from the buffy coat, and in the media of a co-culture system., Results: CVB IgG/IgM results indicated that prior exposure was 7.8 times more common in the CHD group (95% CI, 1.14-54.24, adj. p -value = 0.036). However, the CVB viral genome was not detected in plasma, buffy coat, or co-culture supernatant by molecular assays, although other viruses were detected., Conclusion: Detection of viral nucleic acid in plasma was infrequent and specifically no CVB genome was detected. However, serology demonstrated that prior CVB exposure is higher in CHD-affected pregnancies. Further studies are warranted to understand the magnitude of the contribution of the maternal blood virome to the pathogenesis of CHD.

Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality., (© 2023. The Author(s).)

Early stopping is an extremely common tool to minimize overfitting, which would otherwise be a cause of poor generalization of the model to novel data. However, early stopping is a heuristic that, while effective, primarily relies on ad hoc parameters and metrics. Optimizing when to stop remains a challenge. In this paper, we suggest that for some biomedical applications, a natural dichotomy of invasive/non-invasive measurements, or more generally proximal vs distal measurements of a biological system can be exploited to provide objective advice on early stopping. We discuss the conditions where invasive measurements of a biological process should provide better predictions than non-invasive measurements, or at best offer parity. Hence, if data from an invasive measurement are available locally, or from the literature, that information can be leveraged to know with high certainty whether a model of non-invasive data is overfitted. We present paired invasive/non-invasive cardiac and coronary artery measurements from two mouse strains, one of which spontaneously develops type 2 diabetes, posed as a classification problem. Examination of the various stopping rules shows that generalization is reduced with more training epochs and commonly applied stopping rules give widely different generalization error estimates. The use of an empirically derived training ceiling is demonstrated to be helpful as added information to leverage early stopping in order to reduce overfitting., Competing Interests: Conflict of InterestThe authors declare that there is no conflict of interest., (© The Author(s) 2023.)

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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Serotonin modulates vascular, immune, and neurophysiology and is dysregulated in preeclampsia. Despite biological plausibility that selective serotonin reuptake inhibitors (SSRIs) prevent preeclampsia pathophysiology, observational studies have indicated increased risk and providers may be hesitant. The objective of this meta-analysis and quality assessment was to evaluate the evidence linking SSRI use in pregnancy to preeclampsia/gestational hypertension. PubMed was searched through June 5, 2020 manually and using combinations of terms: "preeclampsia", "serotonin", and "SSRI". This review followed MOOSE guidelines. Inclusion criteria were: 1) Observational cohort or population study, 2) exposure defined as SSRI use during pregnancy, 3) cases defined as preeclampsia or gestational hypertension, and 4) human participants. Studies were selected that addressed the hypothesis that gestational SSRI use modulates preeclampsia and/or gestational hypertension risk. Review Manager Web was used to synthesize study findings. Articles were read and scored (Newcastle-Ottawa Quality Assessment Scale) for quality by two independent reviewers. Publication bias was assessed using a funnel plot and the Egger test. Of 179 screened studies, nine were included. The pooled risk ratio (random effects model) was 1.43 (95 % CI: 1.15-1.78, P < 0.001; range 0.96-4.86). Two studies were rated as moderate quality (both with total score of 6); others were high quality. Heterogeneity was high (I2 = 88 %) and funnel asymmetry was significant (p < 0.00001). Despite evidence for increased preeclampsia risk with SSRIs, shared risk factors and other variables are poorly controlled. Depression treatment should not be withheld due to perceived gestational hypertension risk. Mechanistic evidence for serotonin modulation in preeclampsia demonstrates a need for future research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: Examine a mechanism of PLAC1 regulation and its potential role in preeclampsia (PE)., Materials and Methods: Placental tissue samples and detailed clinical information were obtained through the University of Iowa Maternal Fetal Tissue Bank (IRB# 200910784) from gestational and maternal age-matched control ( n  = 17) and PE affected pregnancies ( n  = 12). PLAC1 and PLAC1 promoter-specific expression was measured using quantitative polymerase chain reaction (qPCR) and differences were assessed via the standard ΔΔCt method. In addition, the role of hypoxia in PLAC1 transcription was investigated through the exposure of HTR8/SVneo human trophoblast cells to the hypoxia mimic dimethyloxaloylglycine (DMOG)., Results: PLAC1 expression is seen to be 8.9-fold lower in human placentas affected by preeclampsia in comparison with controls ( p  < .05). Further, this decrease is paralleled by a significantly lower expression of the P2 or proximal PLAC1 promoter ( p  < .05). Expression of mediator complex subunit 1 (MED1), a known hypoxia-sensitive transcription coactivator and PLAC1 effector, is significantly correlated with PLAC 1 expression ( r 2 = 0.607, p  < .001). These data suggest that PLAC1 expression is significantly down-regulated in preeclampsia at least in part via a MED1 hypoxia-mediated mechanism., Conclusions: We confirm that PLAC1 transcription is suppressed in the placentae of women affected by preeclampsia. We further demonstrate that this suppression is driven through the P2 or proximal PLAC1 promoter. This demonstration led to the identification of the MED1-TRAP cofactor complex as the hypoxia-sensitive driver.

Human pegivirus (HPgV) is best known for persistent, presumably non-pathogenic, infection and a propensity to co-infect with human immunodeficiency virus or hepatitis C virus. However, unique attributes, such as the increased risk of malignancy or immune modulation, have been recently recognized for HPgV. We have identified a unique case of a woman with high levels HPgV infection in two pregnancies, which occurred 4 years apart and without evidence of human immunodeficiency virus or hepatitis C virus infection. The second pregnancy was complicated by congenital heart disease. A high level of HPgV infection was detected in the maternal blood from different trimesters by RT-PCR and identified as HPgV type 1 genotype 2 in both pregnancies. In the second pregnancy, the decidua and intervillous tissue of the placenta were positive for HPgV by PCR but not the chorion or cord blood (from both pregnancies), suggesting no vertical transmission despite high levels of viremia. The HPgV genome sequence was remarkably conserved over the 4 years. Using VirScan, sera antibodies for HPgV were detected in the first trimester of both pregnancies. We observed the same anti-HPgV antibodies against the non-structural NS5 protein in both pregnancies, suggesting a similar non-E2 protein humoral immune response over time. To the best of our knowledge, this is the first report of persistent HPgV infection involving placental tissues with no clear indication of vertical transmission. Our results reveal a more elaborate viral-host interaction than previously reported, expand our knowledge about tropism, and opens avenues for exploring the replication sites of this virus.

Introduction: Pregnancy is a time of increased healthcare screening, and past adherence to evolving guidelines informs best practices. Although studies of Group B Streptococcus guideline adherence have focused primarily on treatment of Group B Streptococcus carriers, this study broadly evaluated long-term adherence to both Group B Streptococcus screening and treatment guidelines. Adherence was evaluated across provider types (obstetrics and gynecology, certified nurse midwives, and family medicine)., Methods: We conducted a retrospective cohort study. Demographic and clinical information were extracted from all prenatal care and delivery patients at a single institution in a single year. Vancomycin prescriptions in pregnancy were tracked for 10 years to determine long-term adherence. Adherence was defined as no deviation from 2010 Group B Streptococcus screening and treatment guidelines., Results: Adherence occurred in 89% (1,610/1,810) of patients. Reasons for deviations from guidelines could not always be determined. There was no significant difference in maternal age, race, prenatal provider type, provider type at delivery, gestational age at delivery, delivery mode, or whether antibiotic sensitivities were performed between compliant and noncompliant groups. Significant differences in adherence were found between obstetric clinics (high-risk obstetrics clinic, maternal‒fetal medicine fellows clinic, continuity of care clinic, and faculty private clinic) ( p <0.0001) and between the faculty family medicine clinic and resident family medicine clinic ( p =0.001). Vancomycin prescription practice did not change significantly over the10-year period., Conclusions: High rates of adherence to Group B Streptococcus screening and treatment guidelines in pregnancy have positive implications for reducing antibiotic resistance. Given evolving guidelines, there is a need to periodically evaluate adherence and to re-educate providers about standard practices and best documentation practices., (© 2022 The Author(s).)

Women with a history of preeclampsia (hxPE) are at a four-fold higher risk for chronic hypertension after pregnancy compared with healthy pregnancy, but 'masked' hypertension cases are missed by clinical assessment alone. Twenty-four hour ambulatory blood pressure monitoring (ABPM) is the reference-standard for confirmation of hypertension diagnoses or detection of masked hypertension outside of clinical settings, whereas home blood pressure monitoring (HBPM) may represent a well-tolerated and practical alternative to ABPM in the postpartum period. The objectives of this study were to 1) assess concordance between ABPM and HBPM postpartum in women with a hxPE compared with healthy pregnancy controls and 2) evaluate HBPM in the detection of masked postpartum hypertension. Young women with a hxPE (N = 26) and controls (N = 36) underwent in-office, 24-h ABPM and 7-day HBPM 1-4 years postpartum. Chronic hypertension was more prevalent among women with a hxPE by all three blood pressure measures, but the prevalence of masked postpartum hypertension did not differ (36% vs 37%, P = 0.97). HBPM showed excellent agreement with ABPM (systolic: r = 0.78, intraclass coefficient [ICC] = 0.83; diastolic: r = 0.82, ICC = 0.88) and moderate concordance in classification of hypertension (κ = 0.54, P < 0.001). HBPM identified 21% of masked postpartum hypertension cases without false-positive cases, and HBPM measures among those with normotensive in-office readings could detect ABPM-defined masked hypertension (area under the curve [AUC] = 0.88 ± 0.06, P < 0.0001). The findings of the present study indicate that HBPM may be a useful screening modality prior or complementary to ABPM in the detection and management of postpartum hypertension., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

To advance the application of clinical data to address maternal health we developed and implemented a Maternal Child Knowledgebase (MCK). The MCK integrates data from every pregnancy that received care at the University of Iowa Hospitals & Clinics (UIHC) and links information from the pregnancy episode to the delivery episode and between the mother and child. This knowledgebase contains integrated information regarding diagnoses, medications, mother and child vitals, hospital admissions, depression screenings, laboratory value results, and procedure information. It also collates information from the electronic health record (EPIC), the Social Security Death Index, and the Medication Administration Record into one knowledgebase. To enhance usability, we designed a custom viewer with several pre-designed queries and reports that eliminates the need for users to be proficient in SQL coding. The recent implementation of the MCK has supported multiple projects and reduced the number of Obstetrics-related data queries to the Biomedical Informatics group., (©2022 AMIA - All rights reserved.)

Blood pressure is the key vital sign to detecting hypertensive disorders in pregnancy. The importance of taking blood pressure properly was recently underscored by the publication of updated ACC/AHA guidelines for measuring blood pressure in patients. However, the recommended position of seating with arms and back supported is not always feasible to achieve clinically, especially for inpatient women who are pregnant. Therefore, it is clinically important to understand the effects of alternative patient positioning on blood pressure measurements. We conducted a review of studies which considered patient position on the effect of blood pressure in pregnancy. This review demonstrates that clinically significant differences may occur based on patient positioning. Despite the small number of primary studies that include pregnant women, notable reductions in blood pressure measurements have been observed in the left lateral recumbent position, a common position during labor or during monitoring, in comparison to measurements taken in the supported seated position. Ultimately, these differences could affect the clinical management of patients and care should be taken to document and consider the position in which the reading was taken., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Diabetes during pregnancy is associated with elevated maternal insulin, leptin and IL-6. Within the placenta, IL-6 can further stimulate leptin production. Despite structural similarities and shared roles in inflammation, leptin and IL-6 have contrasting effects on neurodevelopment, and the relative importance of maternal diabetes or chorioamnionitis on fetal hormone exposure has not been defined. We hypothesized that there would be a positive correlation between IL-6 and leptin with progressively increased levels in pregnancies complicated by maternal diabetes and chorioamnionitis. To test this hypothesis, cord blood samples were obtained from 104 term infants, including 47 exposed to maternal diabetes. Leptin, insulin, and IL-6 were quantified by multiplex assay. Factors independently associated with hormone levels were identified by univariate and multivariate linear regression. Unlike IL-6, leptin and insulin were significantly increased by maternal diabetes. Maternal BMI and birth weight were independent predictors of leptin and insulin with birth weight the strongest predictor of leptin. Clinically diagnosed chorioamnionitis and neonatal sepsis were associated with increased IL-6 but not leptin. Among appropriate for gestational age infants without sepsis, IL-6 and leptin were strongly correlated (R=0.6, P<0.001). In summary, maternal diabetes and birth weight are associated with leptin while chorioamnionitis is associated with IL-6. The constraint of the positive association between leptin and IL-6 to infants without sepsis suggests that the term infant and placenta may have a limited capacity to increase cord blood levels of the neuroprotective hormone leptin in the presence of increased cord blood levels of the potential neurotoxin IL-6., 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 © 2022 Vasilakos, Steinbrekera, Santillan, Santillan, Brandt, Dagle and Roghair.)

Background Circulating cell-free mitochondrial DNA (ccf-mtDNA) is a damage-associated molecular pattern that reflects cell stress responses and tissue damage, but little is known about ccf-mtDNA in preeclampsia. The main objectives of this study were to determine (1) absolute concentrations of ccf-mtDNA in plasma and mitochondrial DNA content in peripheral blood mononuclear cells and (2) forms of ccf-mtDNA transport in blood from women with preeclampsia and healthy controls. In addition, we sought to establish the association between aberrance in circulating DNA-related metrics, including ccf-mtDNA and DNA clearance mechanisms, and the clinical diagnosis of preeclampsia using bootstrapped penalized logistic regression. Methods and Results Absolute concentrations of ccf-mtDNA were reduced in plasma from women with preeclampsia compared with healthy controls ( P ≤0.02), while mtDNA copy number in peripheral blood mononuclear cells did not differ between groups ( P >0.05). While the pattern of reduced ccf-mtDNA in patients with preeclampsia remained, DNA isolation from plasma using membrane lysis buffer resulted in 1000-fold higher ccf-mtDNA concentrations in the preeclampsia group ( P =0.0014) and 430-fold higher ccf-mtDNA concentrations in the control group ( P <0.0001). Plasma from women with preeclampsia did not induce greater Toll-like receptor-9-induced nuclear factor kappa-light-chain enhancer of activated B cells-dependent responses in human embryonic kidney 293 cells overexpressing the human TLR-9 gene ( P >0.05). Penalized regression analysis showed that women with preeclampsia were more likely to have lower concentrations of ccf-mtDNA as well as higher concentrations of nuclear DNA and DNase I compared with their matched controls. Conclusions Women with preeclampsia have aberrant circulating DNA dynamics, including reduced ccf-mtDNA concentrations and DNA clearance mechanisms, compared with gestational age-matched healthy pregnant women.

Introduction: To improve maternal health outcomes, increased diversity is needed among pregnant people in research studies and community surveillance. To expand the pool, we sought to develop a network encompassing academic and community obstetrics clinics. Typical challenges in developing a network include site identification, contracting, onboarding sites, staff engagement, participant recruitment, funding, and institutional review board approvals. While not insurmountable, these challenges became magnified as we built a research network during a global pandemic. Our objective is to describe the framework utilized to resolve pandemic-related issues., Methods: We developed a framework for site-specific adaptation of the generalized study protocol. Twice monthly video meetings were held between the lead academic sites to identify local challenges and to generate ideas for solutions. We identified site and participant recruitment challenges and then implemented solutions tailored to the local workflow. These solutions included the use of an electronic consent and videoconferences with local clinic leadership and staff. The processes for network development and maintenance changed to address issues related to the COVID-19 pandemic. However, aspects of the sample processing/storage and data collection elements were held constant between sites., Results: Adapting our consenting approach enabled maintaining study enrollment during the pandemic. The pandemic amplified issues related to contracting, onboarding, and IRB approval. Maintaining continuity in sample management and clinical data collection allowed for pooling of information between sites., Conclusions: Adaptability is key to maintaining network sites. Rapidly changing guidelines for beginning and continuing research during the pandemic required frequent intra- and inter-institutional communication to navigate., Competing Interests: The authors have no conflicts of interest to report., (© The Author(s) 2022.)

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/m 2 , 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., (© 2022. The Author(s).)

Preeclampsia (PreE) is a placental disorder characterized by hypertension (HTN), proteinuria, and oxidative stress. Individuals with PreE and their children are at an increased risk of serious short- and long-term complications, such as cardiovascular disease, end-organ failure, HTN, neurodevelopmental disorders, and more. Currently, delivery is the only cure for PreE, which remains a leading cause of morbidity and mortality among pregnant individuals and neonates. There is evidence that an imbalance favoring a pro-inflammatory CD4+ T cell milieu is associated with the inadequate spiral artery remodeling and subsequent oxidative stress that prime PreE's clinical symptoms. Immunomodulatory therapies targeting CD4+ T cell mechanisms have been investigated for other immune-mediated inflammatory diseases, and the application of these prevention tactics to PreE is promising, as we review here. These immunomodulatory therapies may, among other things, decrease tumor necrosis factor alpha (TNF-α), cytolytic natural killer cells, reduce pro-inflammatory cytokine production [e.g. interleukin (IL)-17 and IL-6], stimulate regulatory T cells (Tregs), inhibit type 1 and 17 T helper cells, prevent inappropriate dendritic cell maturation, and induce anti-inflammatory cytokine action [e.g. IL-10, Interferon gamma (IFN-γ)]. We review therapies including neutralizing monoclonal antibodies against TNF-α, IL-17, IL-6, and CD28; statins; 17-hydroxyprogesterone caproate, a synthetic hormone; adoptive exogenous Treg therapy; and endothelin-1 pathway inhibitors. Rebalancing the maternal inflammatory milieu may allow for proper spiral artery invasion, placentation, and maternal tolerance of foreign fetal/paternal antigens, thereby combatting early PreE pathogenesis., 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 © 2022 Murray, Gumusoglu, Santillan and Santillan.)

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden 1 . 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 method 2 . 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., (© 2022. The Author(s).)

Background: Women with a history of preeclampsia (hxPE) exhibit sustained arterial stiffness and elevated blood pressure postpartum. Aortic stiffness and 24-hour blood pressure variability (BPV) are associated with age-related cognitive decline. Although hxPE is related to altered cognitive function, the association between aortic stiffness and BPV with cognitive performance in young women with hxPE has not been investigated. The objectives of this study were to (i) test whether cognitive performance is lower in young women with hxPE and (ii) determine whether aortic stiffness and BPV are associated with cognitive performance independent of 24-hour average blood pressure., Methods: Women with hxPE (N = 23) and healthy pregnancy controls (N = 38) were enrolled 1-3 years postpartum. Cognitive performance was assessed in domains of memory, processing speed, and executive function. Twenty-four-hour ambulatory blood pressure monitoring and carotid-femoral pulse wave velocity (cfPWV) were used to measure BPV and aortic stiffness, respectively., Results: Women with hxPE had slower processing speed (-0.56 ± 0.17 vs. 0.34 ± 0.11 Z-score, P < 0.001) and lower executive function (-0.43 ± 0.14 vs. 0.31 ± 0.10 Z-score, P = 0.004) compared with controls independent of education, whereas memory did not differ. BPV and cfPWV (adjusted for blood pressure) did not differ between women with hxPE and controls. Greater diastolic BPV was associated with lower executive function independent of 24-hour average blood pressure and education in women with hxPE (r = -0.48, P = 0.03) but not controls (r = 0.15, P = 0.38)., Conclusions: Select cognitive functions are reduced postpartum in young women with a recent hxPE and linked with elevated 24-hour diastolic BPV., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Maternal infection has been implicated in the pathogenesis of preterm birth through intrauterine inflammatory response. Chlamydia, gonorrhea, and syphilis are among the most common sexually transmitted infections worldwide, but studies on their association with preterm birth are sparse., Objective: To examine the association between maternal chlamydia, gonorrhea, and syphilis infections in pregnancy and the risk of preterm birth in a large population-based study in the US., Design, Setting, and Participants: This population-based retrospective cohort study examined nationwide birth certificate data from the US National Vital Statistics System between 2016 and 2019. All mothers who had a singleton live birth and available data on chlamydia, gonorrhea, or syphilis infection before or during pregnancy and gestational age at birth were included in analysis., Exposures: Sexually transmitted infection (chlamydia, gonorrhea, or syphilis) occurring before or during pregnancy., Main Outcomes and Measures: Preterm birth, defined as gestational age less than 37 weeks., Results: This study included 14 373 023 mothers (mean [SD] age 29 [5.8] years; Hispanic, 3 435 333 [23.9%]; non-Hispanic Asian, 912 425 [6.3%]; non-Hispanic Black, 2 058 006 [14.3%]; and non-Hispanic White, 7 386 568 [51.4%]). Among the mothers, 267 260 (1.9%) had chlamydia, 43 147 (0.3%) had gonorrhea, and 16 321 (0.1%) had syphilis. Among the newborns, 1 146 800 (8.0%) were preterm births. The rate of preterm birth was 9.9%, 12.2%, and 13.3% among women with chlamydia, gonorrhea, and syphilis infection, respectively. After adjustment for sociodemographic and medical and/or health factors, the adjusted odds ratio of preterm birth was 1.03 (95% CI, 1.02-1.04) for chlamydia, 1.11 (95% CI, 1.08-1.15) for gonorrhea, 1.17 (95% CI, 1.11-1.22) for syphilis, and 1.06 (95% CI, 1.05-1.07) for any of these sexually transmitted infections comparing mothers with these conditions and those without., Conclusions and Relevance: Maternal sexually transmitted infections (gonorrhea, syphilis, or chlamydia) were associated with an increased risk of preterm birth. Pregnant women with sexually transmitted infections before or during pregnancy might benefit from targeted prevention for preterm birth.

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In 2015, the American Heart Association awarded 4-year funding for a Strategically Focused Research Network focused on hypertension composed of 4 Centers: Cincinnati Children's Hospital, Medical College of Wisconsin, University of Alabama at Birmingham, and University of Iowa. Each center proposed 3 integrated (basic, clinical, and population science) projects around a single area of focus relevant to hypertension. Along with scientific progress, the American Heart Association put a significant emphasis on training of next-generation hypertension researchers by sponsoring 3 postdoctoral fellows per center over 4 years. With the center projects being spread across the continuum of basic, clinical, and population sciences, postdoctoral fellows were expected to garner experience in various types of research methodologies. The American Heart Association also provided a number of leadership development opportunities for fellows and investigators in these centers. In addition, collaboration was highly encouraged among the centers (both within and outside the network) with the American Heart Association providing multiple opportunities for meeting and expanding associations. The area of focus for the Cincinnati Children's Hospital Center was hypertension and target organ damage in children utilizing ambulatory blood pressure measurements. The Medical College of Wisconsin Center focused on epigenetic modifications and their role in pathogenesis of hypertension using human and animal studies. The University of Alabama at Birmingham Center's areas of research were diurnal blood pressure patterns and clock genes. The University of Iowa Center evaluated copeptin as a possible early biomarker for preeclampsia and vascular endothelial function during pregnancy. In this review, challenges faced and successes achieved by the investigators of each of the centers are presented.

Preeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate-putamen volume, increased caudate-putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate-putamen volume, while females had increased caudate-putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

A study that describes the development of an electronic informed consent, using the REDCap platform, and the results of a pilot study to assess participants' understanding and acceptance of that electronic informed consent for use in a research study.

Objective: To examine the association of maternal prepregnancy diabetes, gestational diabetes mellitus (GDM), and 12 subtypes of congenital anomalies of the newborn., Research Design and Methods: We included 29,211,974 live births with maternal age ranging from 18 to 49 years old documented in the National Vital Statistics System in the U.S. from 2011 to 2018. Information on prepregnancy diabetes, GDM, and congenital anomalies was retrieved from birth certificates. Log-binomial regression was used to estimate risk ratios (RRs) and 95% CIs for congenital anomalies overall and by subtypes., Results: Of the 29,211,974 live births, there were 90,061 infants who had congenital anomalies identified at birth. The adjusted RRs of congenital anomalies at birth were 2.44 (95% CI 2.33-2.55) for prepregnancy diabetes and 1.28 (95% CI 1.24-1.31) for GDM. The associations were generally consistent across subgroups by maternal age, race/ethnicity, prepregnancy obesity status, and infant sex. For specific subtypes of congenital anomalies, maternal prepregnancy diabetes or GDM was associated with an increased risk of most subtypes. For example, the adjusted RRs of cyanotic congenital heart disease were 4.61 (95% CI 4.28-4.96) for prepregnancy diabetes and 1.50 (95% CI 1.43-1.58) for GDM; the adjusted RRs of hypospadias were 1.88 (95% CI 1.67-2.12) for prepregnancy diabetes and 1.29 (95% CI 1.21-1.36) for GDM., Conclusions: Prepregnancy diabetes and, to a lesser extent, GDM were associated with several subtypes of congenital anomalies of the newborn. These findings suggest potential benefits of preconception counseling in women with preexisting diabetes or at risk for GDM for the prevention of congenital anomalies., (© 2020 by the American Diabetes Association.)

Women with preeclampsia, a hypertensive disorder of pregnancy, exhibit greater beat-to-beat blood pressure variability (BPV) in the third trimester after clinical onset of the disorder. However, it remains unknown whether elevated BPV precedes the development of preeclampsia. A prospective study cohort of 139 women (age 30.2±4.0 years) were enrolled in early pregnancy (<14 weeks gestation). BPV was quantified by time domain analyses of 10-minute continuous beat-to-beat blood pressure recordings via finger photoplethysmography in the first, second, and third trimesters. Aortic stiffness (carotid-femoral pulse wave velocity) and spontaneous cardiovagal baroreflex sensitivity were also measured each trimester. Eighteen women (13%) developed preeclampsia. Systolic BPV was higher in all trimesters among women who developed versus did not develop preeclampsia (first: 4.8±1.3 versus 3.7±1.2, P =0.001; second: 5.1±1.8 versus 3.8±1.1, P =0.02; third: 5.2±0.8 versus 4.0±1.1 mm Hg, P =0.002). Elevated first trimester systolic BPV was associated with preeclampsia (odds ratio, 1.94 [95% CI, 1.27-2.99]), even after adjusting for risk factors (age, body mass index, systolic blood pressure, history of preeclampsia, and diabetes mellitus) and was a significant predictor of preeclampsia (area under the receiver operator characteristic curve=0.75±0.07; P =0.002). Carotid-femoral pulse wave velocity was elevated in the first trimester among women who developed preeclampsia (5.9±0.8 versus 5.2±0.8 m/s; P =0.002) and was associated with BPV after adjustment for mean blood pressure ( r =0.26; P =0.005). First trimester baroreflex sensitivity did not differ between groups ( P =0.23) and was not related to BPV ( P =0.36). Elevated systolic BPV is independently associated with the development of preeclampsia as early as the first trimester, possibly mediated in part by higher aortic stiffness.

Background: Asian Americans are among the fastest growing subpopulations in the United States. However, evidence about maternal prepregnancy body mass index (BMI) and preterm birth among Asian Americans is lacking., Methods: This population-based study used nationwide birth certificate data from the US National Vital Statistics System 2014 to 2018. All Asian American mothers who had a singleton live birth were included. According to Asian-specific cutoffs, maternal prepregnancy BMI was classified into underweight (BMI < 18.5 kg/m 2 ), normal weight (BMI 18.5-22.9 kg/m 2 ), overweight (BMI 23.0-27.4 kg/m 2 ), class I obesity (BMI 27.5-32.4 kg/m 2 ), class II obesity (BMI 32.5-37.4 kg/m 2 ), and class III obesity (BMI ≥37.5 kg/m 2 ). Preterm birth was defined as gestational age less than 37 weeks. Multivariable logistic regression models were used to estimate the odds ratio (OR) of preterm birth., Results: We included 1 081 341 Asian American mother-infant pairs. The rate of preterm birth was 6.51% (n = 70 434). The rate of maternal prepregnancy overweight and obesity was 46.80% (n = 506 042). Compared with mothers with normal weight, the adjusted OR of preterm delivery was 1.04 (95% CI, 1.01-1.07) for underweight mothers, 1.18 (95% CI, 1.16-1.20) for overweight mothers, 1.41 (95% CI, 1.37-1.44) for mothers with class I obesity, 1.69 (95% CI, 1.63-1.76) for mothers with class II obesity, and 1.78 (95% CI, 1.66-1.90) for mothers with class III obesity. Similar patterns of associations were observed in Asian American mothers across different country origins., Conclusions: Among Asian American mothers, maternal prepregnancy overweight or obesity, defined by Asian-specific, lower BMI cutoffs, was significantly associated with an increased risk of preterm birth. The risk of preterm birth increased with increasing obesity severity. These findings highlight the importance of using Asian-specific BMI cutoffs in assessing risk of preterm birth among Asian American mothers., (© 2020 Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Objective: To identify microRNAs (miRNAs) differentially expressed in plasma exosomes collected in women diagnosed with preeclampsia compared with women with uncomplicated pregnancies. Materials and methods: Exosomes were purified from plasma samples obtained at each trimester from four women subsequently diagnosed with preeclampsia and from five matched healthy controls. RNA was purified from the exosomes, and expression of 368 miRNAs was profiled using A-Set TaqMan low density array (TLDA). Results: One-third of the 368 miRNAs profiled are not expressed in exosomes. Further, those that are not expressed tend to be evolutionarily younger and have a significantly different mature sequence signature than do miRNAs that are expressed in exosomes. Among miRNAs that are expressed in exosomes, a total of eight ( miR-134, miR-196b, miR-302c, miR-346, miR-376c, miR-486-3p , miR-590-5p , and miR-618 ) were found to display statistically significant differential expression between women who developed preeclampsia as compared with those who did not. Moreover, half of these miRNAs ( miR-134, miR-376c , miR-486-3p , and miR-590-5p ) displayed statistically significant differential expression in the first trimester. Conclusions: Not all miRNAs are expressed in exosomes. Those that tend to be evolutionarily older and have a significantly different mature sequence signature than those that are not. A few exosome-expressed miRNAs do display expression patterns in women subsequently diagnosed with preeclampsia that are significantly different than in women having an uncomplicated and, among these, several appear in the first trimester. These miRNAs are potential early markers of preeclampsia risk.

Chronic rheumatic diseases often occur in women of reproductive age, and the effect rheumatic disease has on pregnancy varies depending on the condition. Medical management of rheumatic diseases during pregnancy may prevent joint or organ damage and minimize the adverse effects of the disease itself on pregnancy outcomes. Each patient requires individual assessment to control disease activity while minimizing or avoiding medications with potential maternal or fetal toxicity. An open discussion with shared decision making between patients, obstetricians, rheumatologists, and pharmacists is imperative to create an individualized treatment plan that meets patients' goals. This article will review the current literature for use of disease modifying antirheumatic drugs and biologics during pregnancy and lactation, providing health care professionals with the most up-to-date information available.

Preeclampsia is a dangerous hypertensive disorder of pregnancy with known links to negative child health outcomes. Here, we review epidemiological and basic neuroscience work from the past several decades linking prenatal preeclampsia to altered neurodevelopment. This work demonstrates increased rates of neuropsychiatric disorders [e.g., increased autism spectrum disorder, attention deficit hyperactivity disorder (ADHD)] in children of preeclamptic pregnancies, as well as increased rates of cognitive impairments [e.g., decreased intelligence quotient (IQ), academic performance] and neurological disease (e.g., stroke and epilepsy). We also review findings from multiple animal models of preeclampsia. Manipulation of key clinical preeclampsia processes in these models (e.g., placental hypoxia, immune dysfunction, angiogenesis, oxidative stress) causes various disruptions in offspring, including ones in white matter/glia, glucocorticoid receptors, neuroimmune outcomes, cerebrovascular structure, and cognition/behavior. This animal work implicates potentially high-yield targets that may be leveraged in the future for clinical application., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cascade-specific termination of G protein signaling is catalyzed by the RGS (regulator of G protein signaling) family members, including RGS2 . Angiotensin, vasopressin, and endothelin are implicated in preeclampsia, and RGS2 is known to inhibit G protein cascades activated by these hormones. Mutations in RGS2 are associated with human hypertension and increased risk of developing preeclampsia and its sequelae. RGS family members are known to influence maternal vascular function, but the role of RGS2 within the placenta has not been explored. Here, we hypothesized that reduced expression of RGS2 within the placenta represents a risk factor for the development of preeclampsia. Although cAMP/CREB signaling was enriched in placentas from human pregnancies affected by preeclampsia compared with clinically matched controls and RGS2 is known to be a CREB-responsive gene, RGS2 mRNA was reduced in placentas from pregnancies affected by preeclampsia. Experimentally reducing Rgs2 expression within the feto-placental unit was sufficient to induce preeclampsia-like phenotypes in pregnant wild-type C57BL/6J mice. Stimulation of RGS2 transcription within immortalized human HTR8/SVneo trophoblasts by cAMP/CREB signaling was discovered to be dependent on the activity of histone deacetylase activity, and more specifically, HDAC9 (histone deacetylase-9), and HDAC9 expression was reduced in placentas from human pregnancies affected by preeclampsia. We conclude that reduced expression of RGS2 within the placenta may mechanistically contribute to preeclampsia. More generally, this work identifies RGS2 as an HDAC9 -dependent CREB-responsive gene, which may contribute to reduced RGS2 expression in placenta during preeclampsia.

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., (© 2019 John Wiley & Sons Ltd.)

Background: The relation between maternal pre-pregnancy obesity and preterm birth is controversial and inconclusive. We aimed to clarify the association between pre-pregnancy obesity and preterm birth by maternal age and race or ethnicity in a large, multiracial, multiethnic, and diverse population in the USA., Methods: We did a population-based cohort study using nationwide birth certificate data from the US National Vital Statistics System for 2016 and 2017. We included all mothers who had a live singleton birth and who did not have pre-existing hypertension or diabetes. Pre-pregnancy obesity was defined as a pre-pregnancy BMI of at least 30 kg/m 2 . Preterm birth was defined as gestational age of less than 37 weeks. We used logistic regression models adjusted for maternal age, race or ethnicity, parity, education levels, smoking during pregnancy, previous history of preterm birth, marital status, infant sex, and timing of initiation of prenatal care to estimate the odds ratio (OR) of preterm birth., Findings: We included 7 141 630 singleton livebirths in our analysis, 527 637 (7·4%) of which were preterm births. 127 611 (7·5%) Hispanic mothers, 244 578 (6·6%) non-Hispanic white mothers, and 102 509 (10·4%) non-Hispanic black mothers had preterm births. In the overall population, maternal pre-pregnancy obesity was significantly associated with an increased risk of preterm birth compared with maternal pre-pregnancy healthy weight (ie, BMI of 18·5-24·9 kg/m 2 ; adjusted OR 1·18 [95% CI 1·18-1·19]). In non-Hispanic white women, maternal obesity was inversely associated with preterm birth among those younger than 20 years (adjusted OR 0·92 [95% CI 0·88-0·97]), but positively associated with preterm birth among those aged 20 years or older (1·04 [1·01-1·06], 1·20 [1·18-1·23], 1·34 [1·31-1·37], 1·40 [1·36-1·43], and 1·39 [1·31-1·46] among those aged 20-24 years, 25-29 years, 30-34 years, 35-39 years, and ≥40 years, respectively). In Hispanic women, maternal obesity was not associated with preterm birth among those younger than 20 years (0·98 [0·93-1·04]), but positively associated with preterm birth among those aged 20 years or older (1·06 [1·03-1·09], 1·21 [1·17-1·24], 1·32 [1·28-1·36], 1·38 [1·33-1·43], and 1·30 [1·22-1·40] among those aged 20-24 years, 25-29 years, 30-34 years, 35-39 years, and ≥40 years, respectively). In non-Hispanic black women, maternal obesity was inversely associated with preterm birth among those younger than 30 years (0·76 [0·71-0·81] in those <20 years, 0·83 [0·80-0·86] in those aged 20-24 years, and 0·98 [0·95-1·01] among those aged 25-29 years), but positively associated with preterm birth among those aged 30 years or older (1·15 [1·11-1·19], 1·26 [1·20-1·32], and 1·29 [1·18-1·42] among those aged 30-34 years, 35-39 years, and ≥40 years, respectively)., Interpretation: Maternal pre-pregnancy obesity is significantly associated with the risk of preterm birth in the general population, but the risk differs according to maternal age and race or ethnicity. Future investigation is warranted to understand the underlying mechanisms., Funding: US National Institutes of Health., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Preeclampsia is a hypertensive disorder of pregnancy associated with vascular dysfunction and cardiovascular risk to offspring. We hypothesize that endothelial PPARγ (peroxisome proliferator-activated receptor-γ) provides cardiovascular protection in offspring from pregnancies complicated by hypertension. C57BL/6J dams were bred with E-V290M sires, which express a dominant-negative allele of PPARγ selectively in the endothelium. Arginine vasopressin was infused throughout gestation. Vasopressin elevated maternal blood pressure at gestational day 14 to 15 and urinary protein at day 17 consistent. Systolic blood pressure and vasodilation responses to acetylcholine were similar in vasopressin-exposed offspring compared to offspring from control pregnancies. We treated offspring with a subpressor dose of angiotensin II to test if hypertension during pregnancy predisposes offspring to hypertension. Male and female angiotensin II-treated E-V290M offspring from vasopressin-exposed but not control pregnancy exhibited significant impairment in acetylcholine-induced relaxation in carotid artery. Endothelial dysfunction in angiotensin II-treated E-V290M vasopressin-exposed offspring was attenuated by tempol, an effect which was more prominent in male offspring. Nrf2 (nuclear factor-E2-related factor) protein levels were significantly elevated in aorta from male E-V290M offspring, but not female offspring compared to controls. Blockade of ROCK (Rho-kinase) signaling and incubation with a ROCK2-specific inhibitor improved endothelial function in both male and female E-V290M offspring from vasopressin-exposed pregnancy. Our data suggest that interference with endothelial PPARγ in offspring from vasopressin-exposed pregnancies increases the risk for endothelial dysfunction on exposure to a cardiovascular stressor in adulthood. This implies that endothelial PPARγ provides protection to cardiovascular stressors in offspring of a pregnancy complicated by hypertension and perhaps in preeclampsia.