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BackgroundWhile preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study’s purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls).ResultsIn the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases,n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significancepvalue threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases,n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated withTRAF3IP2-AS1/TRAF3IP2genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample.ConclusionsThe discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1–2 and significant DMRs that were not examined in the replication phase.

Remote delivery of care improves outcomes following hypertensive disorders of pregnancy, but little is known about the implementation of a multidisciplinary clinic in the virtual space. In this study, we developed a multidisciplinary postpartum hypertension clinic with a telehealth component run jointly with Maternal-Fetal Medicine and Cardiology.Women were referred from Cardiology and Obstetrics providers or through our postpartum remote blood pressure (BP) program and were offered the option of an in-person or telemedicine visit. For virtual visits, BP was recorded by home measurement. We compared clinical and demographic characteristics by visit type (virtual vs. in-person).Of 175 patients scheduled (2019-2021), 140 attended visits (80% show rate) a mean of 11 weeks postpartum, with 92 (65.7%) seen virtually and 48 (34.2%) seen in-person. Clinical and demographic factors, including self-reported race and insurance type, did not differ between women seen virtually versus in-person. Overall, 97 (69.3%) of women were still on antihypertensive agents at the time of their visit with 33 (34.0%) on more than one antihypertensive agent, which did not differ by visit type. Women who were seen virtually lived a farther distance from the clinic (median 11.6 [interquartile range; IQR 7.7, 30.8] vs. median 7.9 [IQR 5.8, 21.1] miles;Implementation of a multidisciplinary postpartum hypertension clinic in the virtual space is feasible, targets women at high risk for persistently elevated postpartum BP, and maintains equal attendance compared with in-person visits. Virtual visits deliver care equitably across different racial and socioeconomic groups and may improve access to care in rural areas.

Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. Chronological age and race are associated with preeclampsia, but the role of these factors is not entirely understood. We hypothesized that DNA methylation age, a measure of biological age, would be higher in individuals with preeclampsia than in individuals with normotensive pregnancy and that DNA methylation age would differ by race across pregnancy. This was a longitudinal, exploratory study of 56 pregnant individuals (n = 28 preeclampsia cases and n = 28 normotensive controls). Genome-wide DNA methylation data were generated from trimester-specific peripheral blood samples. DNA methylation age was estimated using the "Improved Precision" clock, and ∆age, the difference between DNA methylation age and chronological age, was computed. DNA methylation age was compared with chronological age using Pearson correlations. The relationships between ∆age and preeclampsia status, self-reported race, and covariates were tested using multiple linear regression and performed both with and without consideration of cell-type heterogeneity. We observed strong correlation between chronological age and DNA methylation age across pregnancy, with significantly stronger correlation observed in White participants than in Black participants. We observed no association between ∆age and preeclampsia status. However, ∆age was higher in participants with higher pre-pregnancy body mass index in trimester 1 and lower in Black participants than in White participants in trimesters 2 and 3. Observations were largely consistent when controlling for cell-type heterogeneity. Our findings in a small sample support the need for additional studies to investigate the relationship between race and biological age, which could provide further insight into racial disparities across pregnancy. However, this study does not support an association between ∆age and preeclampsia status.

Background: Though moderate- to vigorous-intensity physical activity is recommended, limited research exists on sedentary behavior (SED) during pregnancy. Methods: The authors conducted a prospective cohort study to describe objectively measured patterns of SED and activity during each trimester of pregnancy. Women wore thigh- (activPAL3) and waist-mounted (ActiGraph GT3X) activity monitors. SED and activity were compared across trimesters using likelihood ratio tests and described using group-based trajectories. Exploratory analyses associated SED and activity trajectories with adverse pregnancy outcomes and excessive gestational weight gain. Results: Pregnant women (n = 105; mean [SD] age = 31 [5] y; prepregnancy body mass index = 26.2 [6.6] kg/m2) had mean SED of 9.7, 9.5, and 9.5 hours per day (P = .062) across trimesters, respectively. Some activities differed across trimesters: standing (increased, P = .01), stepping (highest in second trimester, P = .04), steps per day (highest in second trimester, P = .008), and moderate- to vigorous-intensity physical activity (decreased, P P > .05). In exploratory analyses, higher SED and lower standing, stepping, and steps per day trajectories were associated with increased odds of adverse pregnancy outcomes (P Conclusions: Pregnant women exhibited stable SED of nearly 10 hours per day across pregnancy. Future research evaluating SED across pregnancy and adverse pregnancy outcome risk is warranted.

Background Shorter gestation or smaller birth size are indicators of a suboptimal fetal environment and negatively impact short- and long-term offspring health. Understanding how modifiable maternal behaviours, such as moderate-to-vigorous intensity physical activity (MVPA) or sedentary behaviour (SED), improve fetal outcomes could inform strategies to improve health across the lifespan. Objectives The objective of this study was to examine the association of MVPA and SED across pregnancy trimesters on gestational age at delivery and newborn anthropometrics. Methods The MoM Health Study measured SED (thigh-mounted activPAL3 micro) and MVPA (waist-worn Actigraph GTX3) in each trimester of pregnancy. Birth outcomes (gestational age at delivery, birthweight, birth length, and head circumference) were abstracted from medical records and used to calculate ponderal index (grams*100/cm3 ) and size-for-gestational age percentiles. Associations of group-based trajectories and trimester-specific SED and MVPA with birth outcomes were analysed using regression models. Results Low, medium, and high trajectory groups were generated SED and MVPA in 103 and 99 pregnant women, respectively. High vs low SED trajectory was associated with earlier gestational age at delivery (β -1.03 weeks, 95% CI -2.01, -0.06), larger head circumference (β 0.83 cm, 95% CI 0.24, 1.63), longer birth length (β 1.37 cm, 95% CI 0.09, 2.64), and lower ponderal index (β -0.24 g*100/cm3 , 95% CI -0.42, -0.06), after adjustment for demographics, pre-pregnancy BMI, and (for newborn anthropometric outcomes) gestational age. The association of high SED with lower ponderal index was the most robust across progressively adjusted models (β -0.25 g*100/cm3 , 95% CI -0.44, -0.07). SED trajectory was not associated with birthweight or size-for-gestational age. High vs low MVPA trajectory was only associated with smaller head circumference (β -0.86 cm, 95% CI -1.70, -0.02). Conclusions Higher SED during pregnancy may result in shorter gestation and inhibited fetal growth. Further research evaluating the effect of reducing SED during pregnancy on birth outcomes is warranted.

Objective: To test the feasibility of a randomized trial of home blood pressure monitoring paired with a remote lifestyle intervention vs. home blood pressure monitoring alone vs. control in individuals with a hypertensive disorder of pregnancy in the first year postpartum. Design: Single-blinded randomized clinical trial Setting: Two tertiary hospitals and a community organization Population: Overweight and obese individuals with a hypertensive disorder of pregnancy and without pre-pregnancy hypertension or diabetes. Methods: We assessed the feasibility of recruitment and retention of 150 participants to study completion at one-year postpartum with randomization 1:1:1 into each arm. Secondary aims were to test effects of the interventions on weight, blood pressure and self-efficacy. Results: Over 23 months, we enrolled 148 of 400 eligible, screened individuals (37%); 28% Black or Other race, and mean pre-pregnancy BMI of 33.4±6.7 kg/m2. In total, 129 (87%) participants completed the one-year postpartum study visit. Overall, 22% of participants developed stage 2 hypertension [≥140/90 mmHg or on anti-hypertensive medications] by one-year postpartum. Individuals in the lifestyle intervention arm had a greater, non-significant decrease in mean arterial pressure (MAP) compared to individuals in the HBPM alone and control arm [mean change in MAP (95%CI) -3.7(-6.5, -0.9), -0.5(-1.5, 2.6), -1.0(-4.1, 2.2) mmHg], respectively. There were no differences in weight or self-efficacy by study arms. Conclusion: In this pilot, randomized trial, we demonstrate feasibility of HBPM paired with a lifestyle intervention in the first year postpartum. We detected high rates of ongoing hypertension emphasizing the need for effective interventions in this population.

Background: Women with hypertensive disorders of pregnancy are at increased risk of cardiovascular disease in later life. We sought to determine the association between lactation and markers of maternal cardiovascular health among postpartum women with and without hypertensive disorders of pregnancy via measures of inflammation (high-sensitivity C-reactive protein [hsCRP]) and renal function (cystatin C). Materials and Methods: This prospective cohort study enrolled primarily overweight and obese women during early pregnancy. At a postpartum study visit occurring 6-24 months after delivery, we collected data on lactation duration and measured hsCRP and cystatin C. We assessed associations between lactation duration and levels of hsCRP and cystatin C among normotensive women and women with preeclampsia or gestational hypertension using analysis of variance and chi-squared tests. Linear regression models adjusted for age, race, education, prepregnancy body mass index, current smoking, and time since delivery. Results: Of 425 women, 37 (9%) had preeclampsia and 48 (11%) had gestational hypertension during enrollment pregnancy. The postpartum visit occurred at a mean of 8.6 ± 4.4 months after delivery. Women with a history of preeclampsia had significantly higher levels of cystatin C (mean 0.86 versus 0.78 mg/L; p = 0.03) compared with normotensive women, but nonsignificant elevation in hsCRP (mean 8.39 versus 6.04 mg/L; p = 0.08). Women with gestational hypertension had no differences in mean hsCRP or cystatin C compared with normotensive women. Among the 237 women with any lactation, 78 (18%) lactated for at least 6 months. Lactation duration both in the overall sample and among women with gestational hypertension or preeclampsia was not associated with levels of hsCRP or cystatin C. Conclusions: Preeclampsia history was associated with elevated postpartum levels of cystatin C; however, duration of lactation was not associated with postpartum hsCRP or cystatin C, regardless of history of gestational hypertension or preeclampsia. Further research is needed on mechanisms through which lactation may affect maternal risk of cardiovascular disease.

Visual Abstract, Highlights • The impact of breastfeeding on prolactin, cellular immune activation, and myocardial recovery was analyzed in 100 women with peripartum cardiomyopathy • Cardiac function was assessed by echocardiography at presentation and at serial intervals over the first year postpartum • The levels of circulating prolactin were assessed by ELISA, and cellular immunophenotyping by flow cytometry, and compared between breastfeeding and nonbreastfeeding women • Prolactin levels were higher in breastfeeding women and correlated with significant increases in CD8+ T cells • Despite significantly higher prolactin levels and increased CD8+ cells, myocardial recovery was similar in breastfeeding and nonbreastfeeding women, Summary The etiology of peripartum cardiomyopathy remains unknown. One hypothesis is that an increase in the 16-kDa form of prolactin is pathogenic and suggests that breastfeeding may worsen peripartum cardiomyopathy by increasing prolactin, while bromocriptine, which blocks prolactin release, may be therapeutic. An autoimmune etiology has also been proposed. The authors investigated the impact of breastfeeding on cellular immunity and myocardial recovery for women with peripartum cardiomyopathy in the IPAC (Investigations in Pregnancy Associated Cardiomyopathy) study. Women who breastfed had elevated prolactin, and prolactin levels correlated with elevations in CD8+ T cells. However, despite elevated prolactin and cytotoxic T cell subsets, myocardial recovery was not impaired in breastfeeding women.

Objective: Examine white blood cell (WBC) proportions across preeclamptic (n = 28 cases) and normotensive (n = 28 controls) pregnancy in individuals with overweight/obesity. Methods: WBC proportions were inferred from genome-wide DNA methylation data and compared by case/control status and self-identified race. Results: In Trimester 1, ean B cell proportions were suggestively lower in cases in the overall sample and significantly lower in White participants but not in Black participants. More significant WBC proportion changes were observed across normotensive than preeclamptic pregnancy. Conclusions: These findings in a small sample demonstrate need for additional studies investigating the relationship between self-identified race and WBCs in pregnancy.

BackgroundPreeclampsia is a leading cause of maternal and neonatal morbidity and mortality. Chronological age and race are associated with increased risk of preeclampsia; however, the pathophysiology of preeclampsia and how these risk factors impact its development, are not entirely understood. This gap precludes clinical interventions to prevent preeclampsia occurrence or to address stark racial disparities in maternal and neonatal outcomes. Of note, cellular aging rates can differ between individuals and chronological age is often a poor surrogate of biological age. DNA methylation age provides a marker of biological aging, and those with a DNA methylation age greater than their chronological age have ‘age acceleration’. Examining age acceleration in the context of preeclampsia status, and race, could strengthen our understanding of preeclampsia pathophysiology, inform future interventions to improve maternal/neonatal outcomes, and provide insight to racial disparities across pregnancy.ObjectivesThe purpose of this exploratory study was to examine associations between age acceleration, preeclampsia status, and race across pregnancy.Study designThis was a longitudinal, observational, case-control study of 56 pregnant individuals who developed preeclampsia (n=28) or were normotensive controls (n=28). Peripheral blood samples were collected at trimester-specific time points and genome-wide DNA methylation data were generated using the Infinium MethylationEPIC Beadchip. DNA methylation age was estimated using the Elastic Net ‘Improved Precision’ clock and age acceleration was computed as Δage, the difference between DNA methylation age and chronological age. DNA methylation age was compared with chronological age using scatterplots and Pearson correlations, while considering preeclampsia status and race. The relationships between preeclampsia status, race, and Δage were formally tested using multiple linear regression, while adjusting for pre-pregnancy body mass index, chronological age, and (chronological age)2. Regressions were performed both with and without consideration of cell-type heterogeneity.ResultsWe observed strong correlations between chronological age and DNA methylation age in all trimesters, ranging from R=0.91-0.95 in cases and R=0.86-0.90 in controls. We observed significantly stronger correlations between chronological age and DNA methylation age in White versus Black participants ranging from R=0.89-0.98 in White participants and R=0.77-0.83 in Black participants. We observed no association between Δage and preeclampsia status within trimesters. However, even while controlling for covariates, Δage was higher in trimester 1 in participants with higher pre-pregnancy BMI (β=0.12, 95% CI=0.02 to 0.22, p=0.02) and lower in Black participants relative to White participants in trimesters 2 (β=−2.68, 95% CI=−4.43 to −0.94, p=0.003) and 3 (β=−2.10, 95% CI=−4.03 to −0.17, p=0.03). When controlling for cell-type heterogeneity, the observations with BMI in trimester 1 and race in trimester 2 persisted.ConclusionsWe report no association between Δage and preeclampsia status, although there were associations with pre-pregnancy BMI and race. In particular, our findings in a small sample demonstrate the need for additional studies to not only investigate the complex pathophysiology of preeclampsia, but also the relationship between race and biological aging, which could provide further insight into racial disparities in pregnancy and birth. Future efforts to confirm these findings in larger samples, including exploration and applications of other epigenetic clocks, is needed.

ObjectiveWe utilized epigenome-wide DNA methylation data to estimate/compare white blood cell (WBC) proportions in plasma across preeclamptic (case) and uncomplicated, normotensive (control) pregnancy.MethodsWe previously collected methylation data using Infinium® MethylationEPIC Beadchips during the three trimesters in 28 cases and 28 controls (21 Black, 7 White participants/group). We employed Houseman’s regression calibration method to estimate and compare neutrophil, monocyte, B cell, NK cell, CD4+ T and CD8+ T cell proportions across pregnancy and between cases and controls.ResultsWe observed changes in WBC proportions across pregnancy within cases and controls that varied by cell type and race. Neutrophils represented the largest WBC mean proportion in all three trimesters for cases (Mean±SD: 67.2±9.6% – 74.4±12%) and controls (64.2±11% – 74.0±7.9%). Mean B cell proportions were significantly lower in cases than controls in Trimester 1 (5.25±0.02% versus 6.30±0.02%, p=0.02). The remaining mean cell proportions did not significantly differ in the overall sample. Stratified analyses revealed race-specific differences. In White participants (n=14): (1) neutrophil proportions were significantly higher in cases in Trimester 1 (p=0.04), but significantly lower in Trimester 2 (p=0.02), (2) B cell proportions were significantly lower in cases in Trimester 1 (p=0.001). No significant differences were detected among Black participants (n=42).ConclusionsAlthough chronic inflammation characterizes preeclampsia, few studies have investigated WBCs across pregnancy. We report differences between cases and controls across pregnancy. Our findings in a small sample demonstrate the need for additional studies investigating the relationship between race and WBCs in pregnancy, which could provide insight into preeclampsia pathophysiology.

Objectives Hypertension and obesity are common cardiometabolic risk factors in reproductive age women. The association of hypertensive disorders of pregnancy with later-life cardiovascular disease is well-established, however, it is unknown how obesity and hypertensive disorders of pregnancy converge to accelerate development of hypertension in the postpartum period. The aim of this study was to characterize rates of sustained hypertension at one year postpartum using the new American Heart Association/American College of Cardiology Guidelines among overweight and obese women with a normotensive pregnancy or hypertensive disorder of pregnancy. Study design 315 early pregnant women were enrolled prospectively and followed up to 12 months after delivery (mean 7.0 ± 1.8 months). At a postpartum research visit, we measured blood pressure and collected blood samples to measure cystatin C and high sensitivity C-reactive protein. Results A total of 254 women had a normotensive pregnancy, 39 had gestational hypertension (12.4%) and 22 had preeclampsia (7.0%). 91 women had hypertension at the postpartum study visit (28.9%). After adjustment for maternal age, BMI, lactation and time postpartum, preeclampsia was associated with an aOR 2.35 (95%CI 1.63–3.41) of development of sustained hypertension and an aOR 3.23 (95%CI 1.56–6.68) of hypertension with abnormal biomarkers compared to women with normotensive pregnancies. Conclusions We demonstrate a high prevalence of hypertension and abnormal biomarkers associated with hypertensive disorders of pregnancy among overweight and obese women. Our findings support the need for structured follow up and risk reduction in overweight and obese women with hypertensive disorders of pregnancy as early as the first year postpartum.

BACKGROUND: New-onset postpartum preeclampsia has a higher risk of maternal morbidity and mortality when compared to preeclampsia with antepartum onset, underscoring the need for earlier identification of elevated blood pressure among this population. Given the decrease in healthcare engagement that is typical of the postpartum period, new-onset postpartum hypertension often goes unrecognized. Currently, there are no recommendations for universal postpartum blood pressure surveillance in women without hypertensive disorders of pregnancy. With the shift to telemedicine related to the COVID 19 pandemic, our institution’s approach was to distribute blood pressure cuffs to women receiving any portion of their prenatal care virtually, thus also providing access to an opportunity for blood pressure measurement during the postpartum period for all women. OBJECTIVE: To explore the feasibility of a patient-driven universal postpartum home blood pressure monitoring program in women without a diagnosis of a hypertensive disorder of pregnancy. STUDY DESIGN: A prospective observational study of all postpartum women who were discharged from our institution from July 2020 through June 2021 not previously identified to have hypertension. A clinical algorithm was developed and followed. All women received discharge educational materials and were called at a 1-week interval by a nurse to review blood pressure and preeclampsia symptoms. Maternal demographics and delivery outcomes were recorded. RESULTS: Of the 10,092 deliveries during the study period, 5,959 (59%) were successfully contacted. 352 were excluded as they did not deliver at the primary hospital, 1,052 (18%) had a prior hypertensive disorder of pregnancy diagnosis, 1,522 (26%) did not have a blood pressure cuff, and 1,841 (31%) planned to take their blood pressure at a later time. Precautions and blood pressure parameters were given to this last group. Of the remaining 1,192, 222 (19%) had an initial elevated blood pressure. Of these, 98 had a second elevated blood pressure on recheck, 17 were referred to the emergency room for evaluation with 8 being diagnosed with severe preeclampsia, and the remainder were recommended to follow with their obstetric provider and enrolled in our institution’s remote blood pressure management program. Of 1,192 women, 8.2% of women potentially had a new diagnosis of a hypertensive disorder of pregnancy with 0.7% having severe hypertension. Compared to women without elevated blood pressures, those with elevated blood pressures were more likely to be of non-Hispanic black race and were also more likely to have a higher early pregnancy body mass index. CONCLUSIONS: Our study indicates a patient-driven postpartum blood pressure monitoring program is feasible and may be incorporated using existing resources. Additionally, our findings suggest the incidence of new-onset postpartum hypertensive disorders of pregnancy may be higher than previously assessed in retrospective cohorts. Thus, there may be a role for closer surveillance of all women with patient-driven home blood pressure monitoring, particularly those with risk factors or in the setting of limited resources.

Introduction Women with adverse pregnancy outcomes (APOs) have excess risk of later life cardiovascular disease (CVD) perhaps related to an underlying high-risk vascular phenotype. We sought to determine if placental evidence of maternal malperfusion in uncomplicated pregnancies is associated with an increased risk of APOs in subsequent pregnancies. Methods 536 women with more than one delivery and an initial uncomplicated pregnancy with placental pathology examination between 2008 and 2012 were included. APOs (small for gestational age, preterm delivery, or preeclampsia) were identified for each delivery. Multivariable log-binomial regression was used to estimate the risk of an APO in a subsequent pregnancy associated with MVM lesions in index pregnancy with adjustment for covariates. Results Placental pathology from the initial pregnancy was compared between women with no APO in any pregnancy (-APO/-APO; n = 403) and women with an initial uncomplicated pregnancy and a subsequent adverse outcome (-APO/+APO; n = 133). Women with MVM lesions had an increased risk of an APO in a subsequent pregnancy relative to women with no MVM lesions after adjusting for covariates (aOR = 1.61; 95%CI = 1.06–2.46). Decidual vasculopathy was found in 13/133 (9.8%) of -APO/+APO women compared with 16/403 (4.0%) of -APO/-APO women, with an adjusted odds ratio of 2.51 (95% CI = 1.31–4.80). Discussion MVM lesions found in placentas in uncomplicated pregnancies are associated with an increased risk of an adverse outcome in a subsequent pregnancy. Placental evidence of vascular malperfusion could offer a novel approach to risk stratification for subsequent pregnancy complications and perhaps future CVD.

To identify clinical risk factors associated with development of delayed-onset postpartum preeclampsia, and to characterize management and subsequent risk of cardiovascular disease.This is a case-control study of women admitted to the hospital with delayed-onset postpartum preeclampsia (defined as a new diagnosis of preeclampsia presenting between 48 hours and 6 weeks postpartum) compared with women with full-term, uncomplicated pregnancies without a hypertensive diagnosis or diabetes. Included women delivered between January 2014 and June 2018 at a single tertiary care center. Women with an antenatal diagnosis of preeclampsia or chronic hypertension were excluded. Univariate analysis was used to identify risk factors associated with delayed-onset postpartum preeclampsia and to compare rates of hypertension and antihypertensive medication use, with follow-up beyond 3 months postpartum among a subset of women in the control group who were matched 2:1 with women in the case group. Multivariable logistic regression was performed and included covariates identified in a backward stepwise approach.Compared with women in the control group (n=26,936), women with delayed-onset postpartum preeclampsia (n=121) were significantly more likely to be of non-Hispanic black race (31.4% vs 18.0%), obese (39.7% vs 20.1%), and deliver by cesarean (40.5% vs 25.8%), all P.01. For women diagnosed with delayed-onset postpartum preeclampsia, the median postpartum day of presentation was 7.0 (interquartile range 5.0-9.0), with 93.4% presenting secondary to symptoms, which was most commonly a headache. A majority (73.6%) underwent imaging studies, and 49.6% received intravenous antihypertensive agents. A total of 86 (71.0%) women with delayed-onset postpartum preeclampsia and 169 (72.8%) women in the control group had longer term information available, with a median follow-up time of 1.5 years (interquartile range 0.8-2.8). Delayed-onset postpartum preeclampsia was associated with higher blood pressures at 3 months postpartum or later (median systolic 130 mm Hg vs 112 mm Hg and median diastolic 80 mm Hg vs 70 mm Hg, P.001).Delayed-onset postpartum preeclampsia is associated with variable management strategies. There is substantial overlap between the clinical risk factors for delayed-onset postpartum preeclampsia and antepartum preeclampsia. Our findings suggest that delayed-onset postpartum preeclampsia is also associated with an increased risk of progression to chronic hypertension.

Preeclampsia (PE) is a pregnancy-specific, multisystemic disorder that occurs in roughly 5% of pregnancies in the United States.1,2 The rates of PE in the United States have been steadily rising over the past 30 years with PE being a leading cause of maternal and fetal/neonatal morbidity and mortality.3 Women with PE, as well as their offspring, are at greater risk for chronic diseases, including cardiovascular disease (CVD) later in life.4,5 Despite being the leading cause of maternal death and a major contributor to maternal and perinatal morbidity, drug treatment to prevent PE is at best minimally effective, and current management therapies have significant limitations. In fact, at present, delivery is considered the only effective intervention for treating PE6 and even then PE may continue in the postpartum period or present de novo.7 The lack of progress in identifying new therapeutic targets for the treatment of PE is due in part to a paucity of animal models that address the heterogeneity of human PE as well as lack of understanding of basic disease mechanisms. There are no models of spontaneously developing PE in animals. Developing novel animal models to mimic human PE, identifying biomarkers to predict PE, conducting basic studies to better understand disease mechanisms, and ultimately, developing novel therapeutic strategies are clearly needed. The National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), held a workshop to examine the topic of Predicting, Preventing and Treating Preeclampsia on May 21–22, 2018, in Bethesda, MD. Speakers were chosen for expertise in general areas identified as important and cutting edge by the organizers. Specific topics discussed during the workshop were: i) pathophysiology of PE; ii) immunological origins of PE; iii) how to define subsets of PE; iv) biomarkers; v) nutritional factors; vi) genetics and epigenetics; vii) animal models; viii) collaboration, harmonization, sharing large data and samples sets in the study of PE; ix) periconceptional contributors to pathophysiology; x) clinical risk factors for PE; xi) novel therapies for the prevention and treatment of PE; xii) long-term cardiovascular consequences of PE and xiii) patient perspectives. Based on these discussions, recommendations for future research were developed in the following general areas: 1) Pathophysiology of PE; 2) Impact of PE on long-term health outcomes; 3) Biomarkers and diagnostic tools; 4) Translational research and novel treatment strategies. The purpose of this report is to summarize the scientific research recommendations arising from deliberations of the invited speakers and meeting attendees. These research recommendations are summarized in Table 1 (which is keyed to the manuscript text) and are presented in no particular order of priority. The goal of the recommendations is to provide guidance regarding future research on PE and its short- and long-term consequences. Table1: Summary of recommendations from the NIH workshop on “Predicting, Preventing and Treating Preeclampsia”

We evaluated the association between plasma soluble endoglin (sENG) and maternal vascular malperfusion (MVM) lesions of the placenta in women with preeclampsia. We measured sENG (sCD105) by ELISA in N=70 women diagnosed with preeclampsia (median [IQR] GA at sampling=36.4 [6.0] weeks) and available placental pathology. Placental pathology reports were reviewed for evidence of MVM based on the presence of ≥ 1 of the following: villous infarct, decidual vasculopathy, accelerated villous maturation, intervillous fibrin deposition, and/or low placental weight (

Background We have previously shown that protein biomarkers associated with circulating microparticles proteins (CMPs) obtained at the end of the first trimester may detect physiologic changes in maternal–fetal interaction such that the risk of spontaneous preterm delivery ≤35 weeks can be stratified. Objectives We present here a study extension and validation of the CMP protein multiplex concept using a larger sample set from a multicenter population that allows for model derivation in a training set and characterization in a separate testing set. Materials and Methods Ethylenediaminetetraacetic acid (EDTA) plasma was obtained from 3 established biobanks (Seattle, Boston, and Pittsburgh). Samples were from patients at a median of 10–12 weeks’ gestation, and the CMPs were isolated via size-exclusion chromatography followed by protein identification via targeted protein analysis using liquid chromatography–multiple reaction monitoring-mass (LC-MRM) spectrometry. A total of 87 women delivered at ≤35 weeks, and 174 women who delivered at term were matched by maternal age (±2 years) and gestational age at sample draw (±2 weeks). From our prior work, the CMP protein multiplex comprising F13A, FBLN1, IC1, ITIH2, and LCAT was selected for validation. Results For delivery at ≤35 weeks, the receiver operating characteristic (ROC) curve for a panel of CMP proteins (F13A, FBLN1, IC1, ITIH2, and LCAT) revealed an associated area under the ROC curve (AUC) of 0.74 (95% CI, 0.63–0.81). A separate panel of markers (IC1, LCAT, TRFE, and ITIH4), which stratified risk among mothers with a parity of 0, showed an AUC of 0.77 (95% CI, 0.61–0.90). Conclusion We have identified a set of CMP proteins that provide, at 10–12 weeks gestation, a clinically useful AUC in an independent test population. Furthermore, we determined that parity is pertinent to the diagnostic testing performance of the biomarkers for risk stratification.

Impaired uterine invasion by extravillous trophoblast in early gestation is implicated in the genesis of preeclampsia, a potentially lethal malady of human pregnancy. However, reasons for extravillous trophoblast dysfunction remain unclear because of virtual inaccessibility of early placental and uterine tissues from women who develop preeclampsia, and the absence of animal models in which the disease spontaneously occurs. Consequently, the possibility that deficient or defective maturation of the endometrium (decidualization) may compromise extravillous trophoblast invasion in preeclampsia remains unexplored. Using a bioinformatics approach, we tested this hypothesis identifying 396 differentially expressed genes (DEG) in chorionic villous samples from women at ≈11.5 gestational weeks who developed severe preeclampsia symptoms 6 months later compared with chorionic villous samples from normal pregnancies. A large number, 154 or 40%, overlapped with DEG associated with various stages of normal endometrial maturation before and after implantation as identified by other microarray data sets (P=4.7×10−14). One-hundred and sixteen of the 154 DEG or 75% overlapped with DEG associated with normal decidualization in the absence of extravillous trophoblast, ie, late-secretory endometrium (LSE) and endometrium from tubal ectopic pregnancy (EP; P=4.2×10−9). Finally, 112 of these 154 DEG or 73% changed in the opposite direction in microarray data sets related to normal endometrial maturation (P=0.01), including 16 DEG upregulated in decidual (relative to peripheral blood) natural killer cells that were downregulated in chorionic villous samples from women who developed preeclampsia (P

Objective:We compared blood-based DNA methylation levels of endoglin ( ENG) and transforming growth factor beta receptor 2 ( TGFβR2) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies.Methods:We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of ENG (CpG Island 114642) and TGFβR2 (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [( ENG subset: n = 20 (9 cases, 11 controls); TGFβR2 subset: n = 28 (15 cases, 13 controls)].Results:The majority of the preeclampsia cases delivered at ⩾34 weeks’ gestation (83%). Average methylation levels for ENG ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; P = .102) and TGFβR2 (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; P = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the ENG analytic subset revealed a trend between levels of ENG methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; P = .062).Conclusion:Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that ENG and TGFβR2 DNA methylation plays in preeclampsia pathophysiology.

Early-onset preeclampsia (EPE) is a severe form of preeclampsia that involves life-threatening neurological complications. However, the underlying mechanism by which EPE affects the maternal brain is not known. We hypothesized that plasma from women with EPE increases blood-brain barrier (BBB) permeability vs. plasma from women with late-onset preeclampsia (LPE) or normal pregnancy (NP) and investigated its underlying mechanism by perfusing cerebral veins from nonpregnant rats (n=6–7/group) with human plasma from women with EPE, LPE, or NP and measuring permeability. We show that plasma from women with EPE significantly increased BBB permeability vs. plasma from women with LPE or NP (P

Preeclampsia is a heterogeneous syndrome affecting 3% to 5% of all pregnancies. An imbalance of the antiangiogenic and proangiogenic factors, soluble receptor fms-like tyrosine kinase 1 and placental growth factor (PGF), is thought to contribute to the pathophysiology of preeclampsia. Maternal plasma PGF and soluble receptor fms-like tyrosine kinase 1 were quantified by specific immunoassays in cross-sectional samples from 130 preeclamptic subjects and 342 normotensive controls at delivery and longitudinally in samples from 50 women who developed preeclampsia and 250 normotensive controls. Among women who developed preeclampsia, 46% (n=23) evidenced a pattern of consistently low maternal PGF across pregnancy below the lower 95% CI of controls from 15 weeks' gestation to term. In contrast, the remaining 54% (n=27) of women who developed preeclampsia had maternal PGF concentrations similar to or above (n=7) those of normotensive controls. Subjects with low PGF across pregnancy who developed preeclampsia evidenced significantly higher blood pressure in early pregnancy ( P P P

Preeclampsia is a common and potentially lethal pregnancy disorder with lifelong increased risk of cardiovascular disease in survivors. Our prior global gene expression microarray analysis led to a novel set of 36 candidates in first trimester placentas of women who subsequently developed preeclampsia. In this report, we present preliminary studies demonstrating biomarkers of genotype and methylation variations in a subset of these candidate genes in maternal leukocyte and fetoplacental DNA of 28 case and 27 control dyads. We tested 84 single nucleotide polymorphisms (SNPs) using MassArray iPLEX and 50 CpG sites using EpiTYPER assays. Promising prediction modeling was identified with 25 SNPs selected using Fisher's exact tests (p < 0.05) and 20 CpG sites selected on fold change. Genotype Distribution Analysis identified SNP variations that differed between nine paired cases versus paired controls. The findings validate the examined candidate genes and support feasibility of methods for further biomarker development. The integrative approach that was implemented begins to translate the 36 candidates toward clinical utility as a screening modality for preeclampsia. Clin Trans Sci 2012; Volume 5: 333–339

Background. The goal of this study was to further validate eight candidate genes identified in a microarray analysis of first trimester placentas in preeclampsia. Material and method. Surplus chorionic villus sampling (CVS) specimens of 4 women subsequently diagnosed with preeclampsia (PE) and 8 control women (C) without preeclampsia analyzed previously by microarray and 24 independent additional control samples (AS) were submitted for confirmatory studies by quantitative real-time polymerase chain reaction (qRT-PCR). Results. Downregulation was significant in FSTL3 in PE as compared to C and AS (p = .04). PAEP was downregulated, but the difference was only significant between C and AS (p = .002) rather than between PE and either of the control groups. Expression levels for CFH, EPAS1, IGFBP1, MMP12, and SEMA3C were not statistically different among groups, but trends were consistent with microarray results; there was no anti-correlation. S100A8 was not measurable in all samples, probably because different probes and primers were needed. Conclusions. This study corroborates reduced FSTL3 expression in the first trimester of preeclampsia. Nonsignificant trends in the other genes may require follow-up in studies powered for medium or medium/large effect sizes. qRT-PCR verification of the prior microarray of CVS may support the placental origins of preeclampsia hypothesis. Replication is needed for the candidate genes as potential biomarkers of susceptibility, early detection, and/or individualized care of maternal—infant preeclampsia.

OBJECTIVE To examine whether clean catch urine specimens correlate with catheterized specimens for determination of protein/creatinine ratios in pregnant women being evaluated for preeclampsia. METHODS Sixty pregnant women who were at least at 20 weeks of gestation were enrolled. Patients with ruptured membranes, vaginal bleeding, or urinary tract infections were excluded. Midstream clean catch urine specimens were collected. Catheterized specimens were then collected and used for clinical management. The specimens were analyzed for protein, creatinine, urinalysis, and culture. Based on sample size calculations, 60 participants were needed to detect a correlation of 0.90 with 80% power and alpha=0.05. RESULTS Mean gestational age at enrollment was 35.9 weeks (range 23.1-41.7 weeks). Median (range) clean catch and catheterized protein/creatinine ratios were 0.204 (0.089-3.465) and 0.181 (0.067-3.335), respectively, with a correlation coefficient of 0.897 (P

BACKGROUND Cigarette smoking during pregnancy is paradoxically associated with a reduced risk of developing preeclampsia. Both smoking and preeclampsia are associated with alterations in circulating angiogenic factors. The objective of this study was to investigate the relationship between cigarette smoking and the angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in pregnant women with and without preeclampsia. METHODS Plasma sFlt-1, PlGF, and cotinine were measured using enzyme-linked immunosorbent assay in 125 women with uncomplicated pregnancies (controls) and 58 women with preeclampsia. RESULTS In uncomplicated pregnancies, maternal sFlt-1 concentrations were lower in smokers compared to nonsmokers (779.6 (487.5-1,140.8) vs. 1,116.5 (793.6-1,905.2) pg/ml, P < 0.005). Preeclamptic women who smoked also demonstrated a trend toward lower concentrations of sFlt-1 compared to nonsmokers (3,423.0 (2,183.4-5,689.0) vs. 5,504.9 (3,418.0-6,361.3) pg/ml, P = 0.07). Maternal PlGF concentrations were higher in smokers with uncomplicated pregnancies (398.4 (165.2-621.7) vs. 191.4 (104.6-446.8) pg/ml); however, this was not a statistically significant difference (P = 0.07). PlGF concentrations were not different in preeclamptic smokers compared to nonsmokers. The sFlt/PlGF ratio was significantly lower in smokers with uncomplicated pregnancies, but not in smokers with preeclampsia compared to nonsmokers. CONCLUSIONS Cigarette smoking is associated with lower maternal sFlt-1 concentrations during pregnancy and preeclampsia. On the basis of these data, cigarette smoke exposure may decrease the risk of preeclampsia in part by moderating the anti-angiogenic phenotype observed in the syndrome.

Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion are believed to underlie the pregnancy pathologies preeclampsia (PE) and intrauterine growth restriction (IUGR). The main objective of this study was to investigate hypoxia-inducible transcription factor-alpha (HIF-alpha) and downstream genes (VEGF receptor-1) Flt-1 and soluble fms-like tyrosine kinase 1 (sFlt-1) proteins in IUGR placentas. Placentas from normal pregnant (NP; n = 18), PE (n = 18), and IUGR (n = 10) patients were investigated. Normotensive patients with IUGR delivered babies ator= 37 wk of gestation with birth weights of10% and asymmetrical growth. HIF-1 alpha, -2 alpha, Flt-1, and sFlt-1 protein, and mRNA were assessed by Western and Northern blot analyses, respectively. The results are expressed as ratios of the densitometric values for each pair of pathologic and normal placentas, a ratio of 1.0 indicating no difference. Comparable to our earlier studies, the PE/NP ratios for HIF-1 alpha, -2 alpha, and Flt proteins were significantly increased by 50-100% (all P0.01 vs. 1.0). Unexpectedly, the IUGR/NP ratios for HIF-1 alpha and -2 alpha proteins were 1.03 +/- 0.07 and 0.96 +/- 0.16, respectively, and for Flt and sFlt were 1.14 +/- 0.15 and 0.95 +/- 0.12, respectively (all P = not significant vs. 1.0). Northern blot analysis revealed comparable levels of HIF-alpha mRNA in abnormal and normal placentas. In contrast to PE, HIF-alpha proteins and regulated genes are not increased in placentas from normotensive pregnant women delivering small, asymmetrically grown babiesor= 37 wk of gestation. The absence of an increase in HIF-alpha protein is not due to insufficient HIF-alpha mRNA for protein synthesis. Thus, the placentas from women with PE and late IUGR are fundamentally different at the molecular level.

This chapter reviews presentation and management of chronic hypertension (primary and secondary) during pregnancy. Most gravidas have “essential” or primary hypertension and a>20% risk of superimposed preeclampsia but generally experience successful gestation. Essential hypertension, which in young women is often stage 1 (BP 140–150/90–99), may remain unrecognized because of the early physiological decrease in blood pressure, and then incorrectly labeled gestational hypertension or preeclampsia when frankly abnormal values appear after midgestation. Pheochromocytoma may be lethal and initially present during gestation. Contrarily, the hypokalemia and hypertension of aldosteronism are sometimes ameliorated by pregnancy because of the high circulating levels of progesterone which block the mineralocorticoid receptor, similar to spironolactone. Renal artery stenosis and Cushing syndrome are both associated with substantial morbidity, particularly if first diagnosed during pregnancy. Pregnancy changes in circulating levels of all components of the renin−angiotensin−aldosterone system and corticosteroids make diagnoses difficult, underscoring the need to develop test ranges for pregnancy. The status of antihypertensive drugs in pregnancy is reviewed.

The metabolic syndrome, also known as syndrome X or the insulin resistance syndrome, represents a clustering of metabolic factors and physical conditions associated with increased risk of development of type 2 diabetes and cardiovascular disease. This chapter first overviews some of the ways in which the metabolic syndrome is thought to promote cardiovascular disease. It then uses this as a platform to present evidence that the components of the metabolic syndrome, particularly chronic insulin resistance and dyslipidemia, interact with placental factors to generate maternal inflammation, endothelial cell dysfunction and the preeclampsia syndrome. The chapter then summarizes evidence suggesting that the same underlying metabolic syndrome-related factors that contribute to preeclampsia also increase a woman’s risk of developing cardiovascular disease in later life. Perhaps diverging from conventional thinking, the review then extends this hypothesis by suggesting that the metabolic syndrome actually contributes to poor placental development, with maternal and placental processes then cooperating in a vicious circle of inflammation and endothelial dysfunction. The intended “take-home” message is that obesity and other factors related to the metabolic syndrome construct should be a focus for research and clinical strategies for prevention of preeclampsia and related pregnancy complications, and their cardiovascular sequelae.

The purpose of this study was to examine circulating maternal follistatin-like 3 (FSTL-3) by gestational age and obesity in pregnancy and preeclampsia. FSTL-3 was quantified in maternal plasma collected in each trimester from prepregnancy body mass index-determined groups: 15 lean and 24 obese controls and 20 obese women who developed preeclampsia. Repeated measures mixed models and logistic regression were conducted (P ≤ .05). FSTL-3 was not related to maternal adiposity. FSTL-3 changed across pregnancy in lean controls and obese preeclampsia but not in obese controls. FSTL-3 was higher in preeclampsia in the second trimester compared to lean controls and in the third trimester compared to both control groups. Elevated FSTL-3 at mid-gestation was associated with an increased odds of preeclampsia (odds ratio 3.15; 95% confidence interval 1.19-8.36; P = .02). Elevated FSTL-3 concentrations were attributable to preeclampsia and were associated with increased likelihood of later developing preeclampsia, suggesting further study as a biomarker prior to clinically evident disease.