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.

Predicting the onset of preeclampsia by longitudinal monitoring of metabolic changes throughout pregnancy with Raman spectroscopy.

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.

Low indoleamine 2, 3 dioxygenase (IDO) activity is associated with psycho-obstetric risk.

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.

Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

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.

Inflammatory Biomarker Profiles in Very Preterm Infants within the Context of Preeclampsia, Chorioamnionitis, and Clinically Diagnosed Postnatal Infection.

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.

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.

Virome Analysis and Association of Positive Coxsackievirus B Serology during Pregnancy with Congenital Heart Disease.

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.

Invasive or More Direct Measurements Can Provide an Objective Early-Stopping Ceiling for Training Deep Neural Networks on Non-invasive or Less-Direct Biomedical Data.

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.

Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum.

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.

Selective Serotonin Reuptake Inhibitor Use in Pregnancy and Protective Mechanisms in Preeclampsia.

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.

A Case of Persistent Human Pegivirus Infection in Two Separate Pregnancies of a Woman.

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.

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.

Selective serotonin reuptake inhibitors and preeclampsia: A quality assessment and meta-analysis.

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.

Implementation of a Maternal Child Knowledgebase.

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.

Barriers and solutions to developing and maintaining research networks during a pandemic: An example from the iELEVATE perinatal network.

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.

Postpartum ambulatory and home blood pressure monitoring in women with history of preeclampsia: Diagnostic agreement and detection of masked hypertension.

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.

Umbilical Cord Blood Leptin and IL-6 in the Presence of Maternal Diabetes or Chorioamnionitis.

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.

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.

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.