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Background Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results Among 4471 primiparous women, we related first‐trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80 mm Hg or antihypertensive use) 2 to 7 years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6 mm Hg], glucose [5.0 versus 4.8 mmol/L], insulin [77.6 versus 60.1 pmol/L], triglycerides [1.4 versus 1.3 mmol/L], and high‐sensitivity C‐reactive protein [5.6 versus 4.0 nmol/L], and lower high‐density lipoprotein cholesterol [1.8 versus 1.9 mmol/L]; P P Conclusions Individual and combined first‐trimester atherogenic characteristics are associated with APO/GDM occurrence and hypertension 2 to 7 years later. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02231398.

Background Preeclampsia is a prominent risk factor for long‐term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A. During pregnancy, elevated activin A levels are associated with impaired cardiac global longitudinal strain at 1 year, but whether these changes persist beyond 1 year is not known. We hypothesized that activin A levels would remain increased more than 1 year after a preeclamptic pregnancy and correlate with impaired cardiac function. Methods and Results To test our hypothesis, we performed echocardiograms and measured activin A levels in women approximately 10 years after an uncomplicated pregnancy (n=25) or a pregnancy complicated by preeclampsia (n=21). Compared with women with a previously normal pregnancy, women with preeclampsia had worse global longitudinal strain (−18.3% versus −21.3%, P =0.001), left ventricular posterior wall thickness (0.91 mm versus 0.80 mm, P =0.003), and interventricular septal thickness (0.96 mm versus 0.81 mm, P =0.0002). Women with preeclampsia also had higher levels of activin A (0.52 versus 0.37 ng/mL, P =0.02) and activin/follistatin‐like 3 ratio (0.03 versus 0.02, P =0.04). In a multivariable model, the relationship between activin A levels and worsening global longitudinal strain persisted after adjusting for age at enrollment, mean arterial pressure, race, and body mass index ( P =0.003). Conclusions Our findings suggest that both activin A levels and global longitudinal strain are elevated 10 years after a pregnancy complicated by preeclampsia. Future studies are needed to better understand the relationship between preeclampsia, activin A, and long‐term cardiac function.

Background Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results Among 4471 primiparous women, we related first-trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80mmHg or antihypertensive use) 2 to 7years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6mmHg], glucose [5.0 versus 4.8mmol/L], insulin [77.6 versus 60.1pmol/L], triglycerides [1.4 versus 1.3mmol/L], and high-sensitivity C-reactive protein [5.6 versus 4.0nmol/L], and lower high-density lipoprotein cholesterol [1.8 versus 1.9mmol/L]; P

Background Pregnancy complications such as preterm birth and fetal growth restriction are associated with altered prenatal and postnatal cardiac development. We studied whether there were changes related specifically to pregnancy hypertension. Methods and Results Left and right ventricular volumes, mass, and function were assessed at birth and 3 months of age by echocardiography in 134 term‐born infants. Fifty‐four had been born to mothers who had normotensive pregnancy and 80 had a diagnosis of preeclampsia or pregnancy‐induced hypertension. Differences between groups were interpreted, taking into account severity of pregnancy disorder, sex, body size, and blood pressure. Left and right ventricular mass indexed to body surface area (LVMI and RVMI) were similar in both groups at birth (LVMI 20.9±3.7 versus 20.6±4.0 g/m2, P=0.64, RVMI 17.5±3.7 versus 18.1±4.7 g/m2, P=0.57). However, right ventricular end diastolic volume index was significantly smaller in those born to hypertensive pregnancy (16.8±5.3 versus 12.7±4.7 mL/m2, P=0.001), persisting at 3 months of age (16.4±3.2 versus 14.4±4.8 mL/m2, P=0.04). By 3 months of age these infants also had significantly greater LVMI and RVMI (LVMI 24.9±4.6 versus 26.8±4.9 g/m2, P=0.04; RVMI 17.1±4.2 versus 21.1±3.9 g/m2, P

Background Assessing and optimizing cardiovascular health ( CVH ) early in life, such as in pregnancy, could lead to a longer lifetime spent in better CVH and reduce the risk of cardiovascular disease. This might especially benefit women with a hypertensive disorder of pregnancy ( HDP ) who are more likely to develop atherosclerosis and cardiovascular disease. We hypothesized that CVH in pregnancy is related to later life CVH and carotid intima‐media thickness ( CIMT ), and that these associations differ between women with a normotensive pregnancy and women with an HDP . Methods and Results This study was conducted within the prospective population‐based Generation R Study. CVH in pregnancy was based on 5 metrics (blood pressure, total‐cholesterol, glucose, smoking, and body mass index). Postpartum CVH additionally included physical activity and diet scores, according to the American Heart Association classification. Postpartum CVH and CIMT were measured 10 years after pregnancy. Results were analyzed for women with a normotensive pregnancy and those with an HDP . Women with a normotensive pregnancy (n=1786) and women with an HDP (n=138) were evaluated from early pregnancy until 10 years postpartum. Better CVH in early pregnancy was associated with a smaller CIMT and better postpartum CVH in all women, especially in those with an HDP ( CIMT : −9.82 μm [95% CI : −17.98, −1.67]). Conclusions Already in pregnancy, better CVH is associated with a smaller CIMT and better CVH 10 years postpartum, especially in women with an HDP . As pregnancy is an incentive for women to improve lifestyle, assessing CVH in pregnancy might help improve postpartum CVH and reduce cardiovascular disease risk.

Background The endothelial glycocalyx is a vasoprotective barrier between the blood and endothelium. We hypothesized that glycocalyx degradation is present in preeclampsia, a pregnancy‐specific hypertensive disorder characterized by endothelial dysfunction and activation. Methods and Results We examined the sublingual glycocalyx noninvasively using sidestream dark field imaging in the third trimester among women with normotensive pregnancies (n=73), early (n=14) or late (n=29) onset preeclampsia, or gestational diabetes mellitus (n=21). We calculated the width of the glycocalyx that was permeable to red blood cells (called the perfused boundary region , a measure of glycocalyx degradation) and the percentage of vessels that were filled with red blood cells ≥50% of the time (a measure of microvascular perfusion). In addition, we measured circulating levels of glycocalyx components, including heparan sulfate proteoglycans, hyaluronic acid, and SDC1 (syndecan 1), in a subset of participants by ELISA . Repeated‐measures ANOVA was performed to adjust for vessel diameter and caffeine intake. Women with early onset preeclampsia showed higher glycocalyx degradation, indicated by a larger perfused boundary region (mean: 2.14 [95% CI, 2.05–2.20]), than the remaining groups (mean: normotensive: 1.99 [95% CI, 1.95–2.02], P =0.002; late‐onset preeclampsia: 2.01 [95% CI, 1.96–2.07], P =0.024; gestational diabetes mellitus: 1.97 [95% CI, 1.91–2.04], P =0.004). The percentage of vessels that were filled with red blood cells was significantly lower in early onset preeclampsia. These structural glycocalyx changes were accompanied by elevated plasma concentrations of the glycocalyx components, heparan sulfate proteoglycans and hyaluronic acid, in early onset preeclampsia compared with normotensive pregnancy. Conclusions Glycocalyx degradation and reduced microvascular perfusion are associated with endothelial dysfunction and activation and vascular injury in early onset preeclampsia.

Hypertensive disorders of pregnancy (HDP) complicate 5% to 10% of pregnancies and are increasing with the rising prevalence of cardiometabolic diseases in younger women.1 Normal pregnancy is marked by an initial drop in mean arterial pressure, with an eventual rise in blood pressure (BP) to prepregnancy levels.2 The development of HDP involves a number of factors that result in volume and hemodynamic alterations that fail to adapt to the changes accompanying pregnancy. There are well established associations between HDP and the development of maternal cardiovascular disease (CVD) later in life. Although the associations between preeclampsia and future CVD have long been known, newer evidence suggests that there are also long‐term CVD risks associated with gestational hypertension (GH), although the etiology of GH is thought to be distinct from that of preeclampsia. Whether preeclampsia and GH result as manifestations of already preexisting CVD risk or whether they contribute to the pathogenesis of later CVD development is unclear. A history of HDP has the unique potential to identify women at higher risk of future CVD, for whom targeted risk‐reduction interventions may be particularly helpful. In this review, we discuss the evidence for the long‐ and short‐term risks of maternal CVD associated with HDP, with a focus on preeclampsia and GH. We also outline current recommendations for screening and prevention of CVD in women with a history of HDP and highlight important areas in which additional research is needed.

Background Magnesium sulfate (Mg SO 4 ) has been used as a common therapy for preeclampsia and eclampsia for many years. Mg SO 4 decreases peripheral vascular resistance so as to reduce maternal blood pressure. Whether placental blood vessels react to Mg SO 4 in the same patterns as that in maternal vessels is largely unknown. Methods and Results This study compared placental vessels ( PV ) versus nonplacental vessels (non‐ PV ) in human and animal models. Mg SO 4 ‐caused vascular dilation was significantly weaker in PV than that in non‐ PV . Prostaglandin I 2 synthetase affected Mg SO 4 ‐mediated vasodilatation in PV , not in umbilical vessels, while cyclooxygenase did not influence Mg SO 4 ‐induced relaxation in both PV and non‐ PV . Mg 2+ ‐caused vasodilatation was mainly through calcium channels. In PV , calcium channel activities were significantly weaker in PV than that in non‐ PV . Relative mRNA expression of CACNA 1D , CACNB 2 , and CACNB 3 was significantly higher in PV than those in umbilical vessels, despite the fact that the expression of CACNA 1F was less in PV . The contractile phenotype of smooth muscle cell marker ( CALD 1) was less and the synthetic phenotype ( MYH 10) was more in PV than that in UV . Conclusions These results demonstrated that PV were characterized by much weaker responses to Mg SO 4 compared with nonplacental vessels. The difference was related to weaker calcium channel activity and minor contractile phenotype smooth muscle cells in PV , providing important information for further understanding treatments with Mg SO 4 in preeclampsia.

Background Hypertensive disorders complicating pregnancy are a major cause of maternal death. Our objective was to evaluate maternal clinical, hemodynamic, and placental prognostic indicators in a consolidated manner to identify women who develop hypertension in pregnancy. Methods and Results Twenty‐six normotensive pregnant women from a specialized Placenta Clinic at increased risk of developing de novo hypertension and 20 normotensive healthy pregnant controls were recruited at 22 to 26 weeks' gestation. Fourteen maternal clinical, hemodynamic, and placental characteristics were assessed in the second trimester and aggregated. Principal component analysis of this combined data set determined that 3 dimensions accounted for 56% of the cohort variability. The first dimension accounted for 31% of the cohort variability, with significant contributions from total peripheral resistance, endoglin, and cardiac output. The second dimension was predominantly influenced by body mass index and mean arterial pressure, while uric acid and myeloperoxidase mainly contributed to the third dimension. Unsupervised clustering identified 3 groups within this combined data set. Total peripheral resistance was the most significant distinguishing parameter between these groups ( P P Conclusions Consolidated assessment of prognostic indicators in the second trimester of pregnancy may be useful to characterize and distinguish pathways by which women may develop hypertension in pregnancy. This approach could contribute to the development of pathway‐specific preventative and antihypertensive treatment strategies.

Hypertensive disorders in pregnancy are the most common medical complications of pregnancy, affecting 5% to 10% of pregnancies. It has been long believed that all the problems of gestational hypertension get solved within 6 weeks postpartum. However, gestational hypertension, and preeclampsia in

Background Exposure to preeclampsia or gestational hypertension is associated with higher offspring systolic blood pressure ( SBP ), but less is known about associations with other cardiometabolic risk markers. Methods and Results We studied 1097 children from the Project Viva cohort born 1999‐2002. Exposures were preeclampsia or gestational hypertension and mean maternal SBP in each trimester from prenatal records. Outcomes were research measures in midchildhood (mean 8.0 years) of SBP , overall adiposity, and a global cardiometabolic risk score comprising measures of SBP , waist circumference, glycemia, and lipids. We conducted linear regression analyses adjusted for maternal characteristics and offspring sex and age. In adjusted models, maternal preeclampsia or gestational hypertension (n=98, 9.1%) versus normal blood pressure was associated with slightly higher offspring SBP z‐score (0.15 units; 95% confidence interval [CI] −0.03, 0.32) but otherwise predicted better cardiometabolic health markers including metabolic risk z‐score (−0.23 units; −95% CI 0.44, −0.03) and several of its components as well as lower body mass index z‐score (−0.27 units; 95% CI −0.48, −0.06) and lower fat mass index (−0.91 kg/m 2 ; 95% CI −1.35, −0.47). Similarly, higher mean third‐trimester maternal SBP was associated with higher offspring SBP z‐score (0.09 units per 10 mm Hg; 95% CI 0.02, 0.16) and lower overall and central adiposity but not with biomarkers of metabolic risk. Results for second‐trimester SBP were generally similar. First‐trimester blood pressure was associated with higher offspring blood pressure but not with other outcomes. Conclusions Higher maternal late‐pregnancy SBP and hypertensive disorders of pregnancy were associated with higher offspring SBP but otherwise better cardiometabolic health.

Background Fetal exposure to preeclampsia is associated with higher blood pressure and later risk of stroke. We aimed to investigate the associations of maternal preeclampsia, gestational hypertension, and maternal blood pressure change in pregnancy with offspring cardiac structure and function in adolescence. Methods and Results Using data from a prospective birth cohort study, we included offspring who underwent echocardiography (mean age, 17.7 years; SD , 0.3; N=1592). We examined whether hypertensive disorders of pregnancy were associated with offspring cardiac structure and systolic/diastolic function using linear regression. Using multilevel linear spline models (measurement occasions within women), we also investigated whether rate of maternal systolic/diastolic blood pressure change during pregnancy (weeks 8–18, 18–30, 30–36, and 36 or more) were associated with offspring outcomes. Main models were typically adjusted for maternal age, offspring age and sex, prepregnancy body mass index, parity, glycosuria/diabetes mellitus, education, and maternal smoking. Exposure to maternal preeclampsia (0.025; 95% CI, 0.008–0.043) and gestational hypertension (0.010; 0.002–0.017) were associated with greater relative wall thickness. Furthermore, preeclampsia was also associated with a smaller left ventricular end‐diastolic volume (−9.0 mL; −15 to −3.1). No associations were found between hypertensive disorders of pregnancy and offspring cardiac function. Positive rate of maternal systolic blood pressure change during weeks 8 to 18 was associated with greater offspring left ventricular end‐diastolic volume, left ventricular mass indexed to height 2.7 , and E/A. Conclusions Adolescent offspring exposed to maternal preeclampsia had greater relative wall thickness and reduced left ventricular end‐diastolic volume, which could be early signs of concentric remodeling and affect future cardiac function as well as risk of cardiovascular disease.