Low-dose aspirin, maternal cardiometabolic health, and offspring respiratory health 9 to 14 years after delivery: Findings from the EAGeR Follow-up Study.

BACKGROUND: Accumulating evidence shows that peri-conceptional and in-utero exposures have lifetime health impacts for mothers and their offspring. OBJECTIVES: We conducted a Follow-Up Study of the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial with two objectives. First, we determined if women who enrolled at the Utah site (N = 1001) of the EAGeR trial (2007-2011, N = 1228) could successfully be contacted and agree to complete an online questionnaire on their reproductive, cardio-metabolic, and offspring respiratory health 9-14 years after original enrollment. Second, we evaluated if maternal exposure to low-dose aspirin (LDA) during pregnancy was associated with maternal cardio-metabolic health and offspring respiratory health. METHODS: The original EAGeR study population included women, 18-40 years of age, who had 1-2 prior pregnancy losses, and who were trying to become pregnant. At follow-up (2020-2021), participants from the Utah cohort completed a 13-item online questionnaire on reproductive and cardio-metabolic health, and those who had a live birth during EAGeR additionally completed a 7-item questionnaire on the index child's respiratory health. Primary maternal outcomes included hypertension and hypercholesterolemia; primary offspring outcomes included wheezing and asthma. RESULTS: Sixty-eight percent (n = 678) of participants enrolled in the follow-up study, with 10% and 15% reporting maternal hypertension and hypercholesterolemia, respectively; and 18% and 10% reporting offspring wheezing and asthma. We found no association between maternal LDA exposure and hypertension (risk difference [RD] -0.001, 95% confidence interval [CI] -0.05, 0.04) or hypercholesterolemia (RD -0.01, 95% CI -0.06, 0.05) at 9-14 years follow-up. Maternal LDA exposure was not associated with offspring wheezing (RD -0.002, 95% CI -0.08, 0.08) or asthma (RD 0.13, 95% CI 0.11, 0.37) at follow-up. Findings remained robust after considering potential confounding and selection bias. CONCLUSIONS: We observed no association between LDA exposure during pregnancy and maternal cardiometabolic or offspring respiratory health.

Sensory integration and segmental control of posture during pregnancy.

BACKGROUND: Approximately 25% of pregnant people fall, yet the underlying mechanisms of this increased fall-risk remain unclear. Prior studies examining pregnancy and balance have utilized center of pressure analyses and reported mixed results. The purpose of this study was to examine sensory and segmental contributions to postural control throughout pregnancy using accelerometer-based measures of sway. METHODS: Thirty pregnant people (first trimester: n = 10, second trimester: n = 10, third trimester: n = 10) and 10 healthy, nonpregnant control people stood quietly for one minute in four conditions: eyes open on a firm surface, eyes closed on a firm surface, eyes open on a foam pad, and eyes closed on foam. Postural sway was quantified using the root mean square accelerations in the anterior-posterior and medial-lateral directions from an inertial sensor at the lumbar region. Sensory sway ratios, segmental coherence and co-phase, were calculated to assess sensory contributions and segmental control, respectively. FINDINGS: Pregnant people did not display greater sway compared to healthy, nonpregnant controls. There were no group differences in vestibular, visual, or somatosensory sway ratios, and no significant differences in balance control strategies between pregnant and nonpregnant participants across sensory conditions. INTERPRETATION: The small effects observed here contrast prior studies and suggest larger, definitive studies are needed to assess the effect of pregnancy on postural control. This study serves as a preliminary exploration of pregnant sensory and segmental postural control and highlights the need for future to hone the role of balance in fall risk during pregnancy.

Cardiovascular morbidity and mortality following hypertensive disorders of pregnancy.

OBJECTIVES: To determine whether hypertensive disorders of pregnancy (HDP) are associated with maternal coronary artery disease (CAD) and other cardiovascular (CV) diseases within 10-20 years following delivery. STUDY DESIGN: Retrospective cohort including all women who delivered ≥ 1 pregnancy ≥ 20 weeks' gestation within a single health system from 1998 to 2008. We excluded those with CV risk factors preceding first delivery or with no follow-up after delivery. The exposure of interest was any HDP, determined by ICD coding. MAIN OUTCOME MEASURES: The primary outcome was a composite of ICD codes for CAD, peripheral vascular disease, and CV events (myocardial infarction, stroke, and death). Multivariable Cox proportional hazards estimated the association between exposure and outcomes. A nested cohort of women who underwent cardiac catheterization had a primary outcome of angiographic CAD, and multivariable logistic regression estimated the association between HDP and CAD. RESULTS: Of 33,959 women included, 2,385 women had HDP. HDP was associated with the composite outcome (adjusted HR 1.50, 95 % CI 1.11, 2.03). There was a significant difference in event-free survival between groups (p = 0.003) with a median follow-up of 17.3 years. 592 women (1.7 %) underwent cardiac catheterization: 20 of 90 women with HDP had CAD (22.2 %) on angiography vs 49 of 502 without HDP (9.8 %, p < 0.001). HDP was associated with angiographic CAD (adjusted OR 2.08, 95 % CI 1.05, 4.11). CONCLUSIONS: Women with HDP had twice the incidence of CAD on angiography compared to parous women without HDP. Obstetric history may inform the decision to perform cardiac catheterization in relatively young women.

Thermoregulation-Focused Implementation of Delayed Cord Clamping among <34 Weeks' Gestational Age Neonates.

OBJECTIVE: Delayed cord clamping (DCC) is recommended for all neonates; however, adapting such practice can be slow or unsustainable, especially among preterm neonates. During DCC neonates are exposed to a cool environment, raising concerns for neonatal hypothermia. Moderate hypothermia may induce morbidities that counteract the potential benefits of DCC. A quality improvement project on a thermoregulation-focused DCC protocol was implemented for neonates less than 34 weeks' gestational age (GA). The aim was to increase the compliance rate of DCC while maintaining normothermia. STUDY DESIGN: The DCC protocol was implemented on October 1, 2020 in a large Level III neonatal intensive care unit. The thermoregulation measures included increasing delivery room temperature and using heat conservation supplies (sterile polyethylene suit, warm towels, and thermal pads). Baseline characteristics, the compliance rate of DCC, and admission temperatures were compared 4 months' preimplementation and 26 months' postimplementation RESULTS: The rate of DCC increased from 20% (11/54) in preimplementation to 57% (240/425) in postimplementation (p < 0.001). The balancing measure of admission normothermia remained unchanged. In a postimplementation subgroup analysis, the DCC cohort had less tendency to experience admission moderate hypothermia (<36°C; 9.2 vs. 14.1%, p = 0.11). The DCC cohort had more favorable secondary outcomes including higher admission hematocrit, less blood transfusions, less intraventricular hemorrhage, and lower mortality. Improving the process measure of accurate documentation could help to identify implementation barriers. CONCLUSION: Performing DCC in preterm neonates was feasible and beneficial without increasing admission hypothermia. KEY POINTS: · Thermoregulation-focused DCC protocol was implemented to increase DCC while maintaining normothermia.. · DCC rate increased from 20 to 57% while admission normothermia rate remained the same.. · DCC practice on preterm neonates is safe and feasible while maintaining normothermia..

Body Mass Index, Adverse Pregnancy Outcomes, and Cardiovascular Disease Risk.

BACKGROUND: Obesity is a well-established risk factor for both adverse pregnancy outcomes (APOs) and cardiovascular disease (CVD). However, it is not known whether APOs are mediators or markers of the obesity-CVD relationship. This study examined the association between body mass index, APOs, and postpartum CVD risk factors. METHODS: The sample included adults from the nuMoM2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be) Heart Health Study who were enrolled in their first trimester (6 weeks-13 weeks 6 days gestation) from 8 United States sites. Participants had a follow-up visit at 3.7 years postpartum. APOs, which included hypertensive disorders of pregnancy, preterm birth, small-for-gestational-age birth, and gestational diabetes, were centrally adjudicated. Mediation analyses estimated the association between early pregnancy body mass index and postpartum CVD risk factors (hypertension, hyperlipidemia, and diabetes) and the proportion mediated by each APO adjusted for demographics and baseline health behaviors, psychosocial stressors, and CVD risk factor levels. RESULTS: Among 4216 participants enrolled, mean±SD maternal age was 27±6 years. Early pregnancy prevalence of overweight was 25%, and obesity was 22%. Hypertensive disorders of pregnancy occurred in 15%, preterm birth in 8%, small-for-gestational-age birth in 11%, and gestational diabetes in 4%. Early pregnancy obesity, compared with normal body mass index, was associated with significantly higher incidence of postpartum hypertension (adjusted odds ratio, 1.14 [95% CI, 1.10-1.18]), hyperlipidemia (1.11 [95% CI, 1.08-1.14]), and diabetes (1.03 [95% CI, 1.01-1.04]) even after adjustment for baseline CVD risk factor levels. APOs were associated with higher incidence of postpartum hypertension (1.97 [95% CI, 1.61-2.40]) and hyperlipidemia (1.31 [95% CI, 1.03-1.67]). Hypertensive disorders of pregnancy mediated a small proportion of the association between obesity and incident hypertension (13% [11%-15%]) and did not mediate associations with incident hyperlipidemia or diabetes. There was no significant mediation by preterm birth or small-for-gestational-age birth. CONCLUSIONS: There was heterogeneity across APO subtypes in their association with postpartum CVD risk factors and mediation of the association between early pregnancy obesity and postpartum CVD risk factors. However, only a small or nonsignificant proportion of the association between obesity and CVD risk factors was mediated by any of the APOs, suggesting APOs are a marker of prepregnancy CVD risk and not a predominant cause of postpartum CVD risk.

Hypertensive disorders of pregnancy and subsequent risk of Alzheimer's disease and other dementias.

Introduction: Women with hypertensive disorders of pregnancy (HDP) have an increased risk of cardiovascular disease. Whether HDP is also associated with later-life dementia has not been fully explored. Methods: Using the Utah Population Database, we performed an 80-year retrospective cohort study of 59,668 parous women. Results: Women with, versus without, HDP, had a 1.37 higher risk of all-cause dementia (95% confidence interval [CI]: 1.26, 1.50) after adjustment for maternal age at index birth, birth year, and parity. HDP was associated with a 1.64 higher risk of vascular dementia (95% CI: 1.19, 2.26) and 1.49 higher risk of other dementia (95% CI: 1.34, 1.65) but not Alzheimer's disease dementia (adjusted hazard ratio = 1.04; 95% CI: 0.87, 1.24). Gestational hypertension and preeclampsia/eclampsia showed similar increased dementia risk. Nine mid-life cardiometabolic and mental health conditions explained 61% of HDP's effect on subsequent dementia risk. Discussion: Improved HDP and mid-life care could reduce the risk of dementia.

Long-term maternal mortality risk following spontaneous preterm birth: A retrospective cohort study.

OBJECTIVE: To determine whether women with spontaneous preterm birth (PTB) have increased risks for long-term mortality. DESIGN: Retrospective cohort. SETTING: Births in Utah between 1939 and 1977. POPULATION: We included women with a singleton live birth ≥20 weeks who survived at least 1 year following delivery. We excluded those who had never lived in Utah, had improbable birthweight/gestational age combinations, underwent induction (except for preterm membrane rupture) or had another diagnosis likely to cause PTB. METHODS: Exposed women had ≥1 spontaneous PTB between 20+0 weeks and 37+0 weeks. Women with >1 spontaneous PTB were included only once. Unexposed women had all deliveries at or beyond 38+0 weeks. Exposed women were matched to unexposed women by birth year, infant sex, maternal age group and infant birth order. Included women were followed up to 39 years after index delivery. MAIN OUTCOME MEASURES: Overall and cause-specific mortality risks were compared using Cox regression. RESULTS: We included 29 048 exposed and 57 992 matched unexposed women. There were 3551 deaths among exposed (12.2%) and 6013 deaths among unexposed women (10.4%). Spontaneous PTB was associated with all-cause mortality (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.21-1.31), death from neoplasms (aHR 1.10, 95% CI 1.02-1.18), circulatory disease (aHR 1.35, 95% CI 1.25-1.46), respiratory disease (aHR 1.73, 95% CI 1.46-2.06), digestive disease (aHR 1.33, 95% CI 1.12-1.58), genito-urinary disease (aHR 1.60, 95% CI 1.15-2.23) and external causes (aHR 1.39, 95% CI 1.22-1.58). CONCLUSIONS: Spontaneous PTB is associated with modestly increased risks for all-cause and some cause-specific mortality.

Hypertensive disorders of pregnancy pre- and postaspirin guideline publication in individuals with pregestational diabetes mellitus.

BACKGROUND: The US Preventive Services Taskforce published guidelines in 2014 recommending that low-dose aspirin be initiated between 12 and 28 weeks of gestation among high-risk patients for preeclampsia prophylaxis. Moreover, low-dose aspirin is recommended by some clinicians for the prevention of preterm birth. OBJECTIVE: This study aimed to evaluate whether there is an association between the US Preventive Services Taskforce aspirin guideline hypertensive disorders of pregnancy and the rates of hypertensive disorders of pregnancy and preterm birth in individuals with pregestational diabetes mellitus. STUDY DESIGN: This was a repeated cross-sectional analysis of individuals with pregestational diabetes mellitus and at least 1 singleton delivery at >20 weeks of gestation with records available in the National Vital Statistics System between 2010 and 2018. The primary outcome was hypertensive disorders of pregnancy, and the secondary outcome was preterm birth. Demographics and clinical characteristics among individuals in the pre-US Preventive Services Taskforce guideline cohort (2010-2013) were compared with that of individuals in the post-US Preventive Services Taskforce guideline cohort (2015-2018). Multivariable regression estimated the odds ratios and 95% confidence intervals for the association between guideline publication and the selected endpoints. Effect modification was assessed for access to prenatal care using the Kotelchuck Index (<80% vs ≥80%). Furthermore, a sensitivity analysis limited to nulliparas was performed. RESULTS: Overall, 224,065 individuals were included. Individuals in the post-US Preventive Services Taskforce guideline cohort were more likely to be older, be obese, and have a history of preterm birth. In unadjusted and adjusted modeling, delivery in the post-US Preventive Services Taskforce guideline cohort was associated with hypertensive disorders of pregnancy (adjusted odds ratio, 1.25; 95% confidence interval, 1.22-1.28) and preterm birth (adjusted odds ratio, 1.10; 95% confidence interval, 1.08-1.12). The adjusted odds ratios for hypertensive disorders of pregnancy and preterm birth were more pronounced among those with less than adequate access to care. The findings were similar in the sensitivity analysis of only nulliparas. CONCLUSION: Delivery after US Preventive Services Taskforce aspirin guideline publication was associated with higher rates of hypertensive disorders of pregnancy and preterm birth in a population of individuals with diabetes mellitus. It is unknown whether patient or practitioner factors, or other changes in obstetrical care, contributed to these findings.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. CONCLUSIONS: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Serum Cotinine and Adverse Cardiovascular Outcomes: A Cross-sectional Secondary Analysis of the nuMoM2b Heart Health Study.

OBJECTIVE: We aimed to (1) compare serum cotinine with self-report for ascertaining smoking status among reproductive-aged women; (2) estimate the relative odds of adverse cardiovascular (CV) outcomes among women by smoking status; (3) assess whether the association between adverse pregnancy outcomes (APOs) and CV outcomes varies by smoking status. STUDY DESIGN: We conducted a cross-sectional study of the nuMoM2b Heart Health Study. Women attended a study visit 2 to 7 years after their first pregnancy. The exposure was smoking status, determined by self-report and by serum cotinine. Outcomes included incident chronic hypertension (HTN), metabolic syndrome (MetS), and dyslipidemia. Multivariable logistic regression estimated odds ratios (ORs) for each outcome by smoking status. RESULTS: Of 4,392 women with serum cotinine measured, 3,610 were categorized as nonsmokers, 62 as secondhand smoke exposure, and 720 as smokers. Of 3,144 women who denied tobacco smoke exposure, serum cotinine was consistent with secondhand smoke exposure in 48 (1.5%) and current smoking in 131 (4.2%) After adjustment for APOs, smoking defined by serum cotinine was associated with MetS (adjusted OR [aOR] = 1.52, 95% confidence interval [CI]: 1.21, 1.91) and dyslipidemia (aOR = 1.28, 95% CI: 1.01, 1.62). When stratified by nicotine exposure, nonsmokers with an APO in their index pregnancy had higher odds of stage 1 (aOR = 1.64, 95% CI: 1.32, 2.03) and stage 2 HTN (aOR = 2.92, 95% CI: 2.17, 3.93), MetS (aOR = 1.76, 95% CI: 1.42, 2.18), and dyslipidemia (aOR = 1.55, 95% CI: 1.25, 1.91) relative to women with no APO. Results were similar when smoking exposure was defined by self-report. CONCLUSION: Whether determined by serum cotinine or self-report, smoking is associated with subsequent CV outcomes in reproductive-aged women. APOs are also independently associated with CV outcomes in women. KEY POINTS: · Cotinine was detected in 5.7% of reported nonsmokers.. · Smoking and APOs were independently associated with CV health.. · Smoking was associated with MetS and dyslipidemia..

Association Between Hypertensive Disorders of Pregnancy and Dementia: a Systematic Review and Meta-Analysis.

BACKGROUND: Prior meta-analyses report a 2- to 4-fold increased risk of later cardiovascular disease among women with a history of hypertensive disorders of pregnancy (HDP). Given HDP's vascular underpinnings, it is hypothesized to also be a risk factor for later dementia. We aim to summarize the evidence for the impact of HDP on dementia and consider unique associations between HDP and dementia subtypes. METHODS: Observational studies on the relationship between HDP and dementia were identified from online electronic databases to July 1, 2021 (PROSPERO identifier: CRD42020185630). We included observational studies published in English. Exposure among women was any HDP and HDP subtypes: gestational hypertension, preeclampsia/eclampsia, or other/unspecified HDP. Outcome was any dementia and dementia subtypes: Alzheimer's disease, vascular dementia, or other/unspecified dementias. RESULTS: For our primary analyses, we included 5 cohort studies with a total of 183 874 women with and 2 309 705 women without HDP. Pooled analysis found a 38% higher risk of all-cause dementia among women with, versus without, any type of HDP (adjusted hazard ratio, 1.38 [95% CI, 1.18-1.61]; P<0.01). When examining association by HDP and dementia subtypes, we found that women with, versus without, any type of HDP had over a 3-fold higher risk of vascular dementia (adjusted hazard ratio, 3.14 [95% CI, 2.32-4.24]; P<0.01). CONCLUSIONS: Our findings indicate that maternal history of HDP is an important risk factor for later development of vascular and all-cause dementia. Further research among more racially/ethnically diverse populations quantifying HDP's effect on all-cause dementia, and specifically vascular dementia, is warranted.

Trends in Hypertensive Disorders of Pregnancy in the United States From 1989 to 2020.

Hypertensive disorders of pregnancy affect up to 8% of pregnancies, but updated national trends are lacking. We performed a repeated cross-sectional analysis of individuals with singleton pregnancies who delivered at greater than 20 weeks of gestation, with data in the U.S. National Vital Statistics System from 1989 to 2020. Temporal trends in hypertensive disorders of pregnancy, chronic hypertension, and eclampsia were characterized using joinpoint regression. Overall, 122,329,914 deliveries were included. Hypertensive disorders of pregnancy increased from 2.79% in 1989 to 8.22% in 2020, representing an average annual percentage change (AAPC) of 3.6% (95% CI 3.0-4.1%). Chronic hypertension increased (AAPC 4.1%, 95% CI 3.3-4.9%), whereas eclampsia decreased (AAPC -2.5%, 95% CI -4.0% to -1.0%). Hypertensive disorders of pregnancy are associated with significant morbidity and mortality; the rising incidence is concerning.

Association between aspirin use during pregnancy and cardiovascular risk factors 2-7 years after delivery: The nuMoM2b Heart Health Study.

OBJECTIVES: To evaluate the association between aspirin use during first pregnancy and later maternal cardiovascular risk. STUDY DESIGN: In this secondary analysis of a prospective cohort, we included participants who carried their first pregnancy to 20 + weeks, had data regarding aspirin use, and attended a study visit 2-7 years following delivery. The exposure was aspirin use during the first pregnancy. We calculated aspirin use propensity scores from logistic regression models including baseline variables associated with aspirin use in pregnancy and cardiovascular risk. Outcomes of interest were incident cardiovascular-related diagnoses 2-7 years following delivery. Robust Poisson regression calculated the risk of outcomes by aspirin exposure, adjusting for the aspirin use propensity score. MAIN OUTCOME MEASURES: The primary outcome was a composite of incident cardiovascular diagnoses at the time of the study visit: cardiovascular events, chronic hypertension, metabolic syndrome, prediabetes or type 2 diabetes, dyslipidemia, and chronic kidney disease. RESULTS: Of 4,480 women included, 84 (1.9%) reported taking aspirin during their first pregnancy. 52.6% of participants in the aspirin-exposed group and 43.0% in the unexposed group had the primary outcome. After adjusting for the aspirin use propensity scores, aspirin use during the first pregnancy was not associated with any of the outcomes. CONCLUSION: We did not detect an association between aspirin use during the first pregnancy and cardiovascular-related diagnoses 2-7 years later. Our study was only powered to detect a large difference in relative risk, so we cannot rule out a smaller difference that may be clinically meaningful.

Association of Preeclampsia With Incident Stroke in Later Life Among Women in the Framingham Heart Study.

Importance: Contemporary research suggests an association between preeclampsia and later-life stroke among women. To our knowledge, no research to date has accounted for the time-varying nature of shared risk factors for preeclampsia and later-life stroke incidence. Objective: To assess the relative risk of incident stroke in later life among women with and without a history of preeclampsia after accounting for time-varying covariates. Design, Setting, and Participants: This population-based cohort study was a secondary analysis of data from the Framingham Heart Study, which was conducted from 1948 to 2016. Women were included in the analysis if they were stroke free at enrollment and had a minimum of 3 study visits and 1 pregnancy before menopause, hysterectomy, or age 45 years. Data on vascular risk factors, history of preeclampsia, and stroke incidence were collected biannually. Participants were followed up until incident stroke or censorship from the study. Marginal structural models were used to evaluate the relative risk of incident stroke among participants with and without a history of preeclampsia after accounting for time-varying covariates. Data were analyzed from May 2019 to December 2020. Exposures: Presence or absence of preeclampsia among women with 1 or more pregnancies. Main Outcomes and Measures: Incident stroke in later life. Results: A total of 1435 women (mean [SD] age, 44.4 [7.7] years at the beginning of the study; 100% White) with 41 422 person-years of follow-up were included in the analytic sample. Of those, 169 women had a history of preeclampsia, and 231 women experienced strokes during follow-up. At baseline, women with preeclampsia were more likely to be younger, to be receiving cholesterol-lowering medications, to have lower cholesterol and higher diastolic blood pressure, and to currently smoke. The association between preeclampsia and stroke in the marginal structural model was only evident when adjustment was made for all vascular risk factors over the life course, which indicated that women with a history of preeclampsia had a higher risk of stroke in later life compared with women without a history of preeclampsia (relative risk, 3.79; 95% CI, 1.24-11.60). Conclusions and Relevance: The findings of this cohort study suggest that preeclampsia may be a risk factor for later-life stroke among women after adjustment for time-varying vascular and demographic factors. Future research is warranted to fully explore the mediation of this association by midlife vascular risk factors.

Platelet activation and placenta-mediated adverse pregnancy outcomes: an ancillary study to the Effects of Aspirin in Gestation and Reproduction trial.

BACKGROUND: Platelet activation may play a role in the pathophysiology of placenta-mediated obstetrical complications, as evidenced by the efficacy of aspirin in preventing preeclampsia, but published data regarding the relationship between biomarkers for platelet activation and adverse obstetrical outcomes are sparse. In particular, it is unknown whether prepregnancy biomarkers of platelet activation are associated with adverse pregnancy outcomes. OBJECTIVE: This study aimed to determine the following: (1) whether maternal plasma concentrations of platelet factor 4 are associated with risk of placenta-mediated adverse obstetrical outcomes, and (2) whether these associations are modified by low-dose aspirin. STUDY DESIGN: This ancillary study included measurement of platelet factor 4 among 1185 of 1228 women of reproductive age enrolled in the Effects of Aspirin in Gestation and Reproduction trial with available plasma samples, with relevant outcomes assessed among 584 women with pregnancies lasting at least 20 weeks' gestation. We measured platelet factor 4 in plasma samples obtained at the prepregnancy study visit (before randomization to low-dose aspirin or placebo), 12 weeks' gestation, and 28 weeks' gestation. The primary outcome was a composite of hypertensive disorders of pregnancy, placental abruption, and small-for-gestational-age infant. We estimated the relative risks (RRs) and 95% confidence intervals (CIs) for the association between platelet factor 4 and the composite and individual outcomes at each time point using log-binomial regression that was weighted to account for potential selection bias and adjusted for age, body mass index, education, income, and smoking. To evaluate the potential effect modification of aspirin, we stratified the analyses by aspirin treatment assignment. RESULTS: During follow-up, 95 women experienced the composite adverse obstetrical outcome, with 57 cases of hypertensive disorders of pregnancy, 35 of small for gestational age, and 6 of placental abruption. Overall, prepregnancy platelet factor 4 was positively associated with the composite outcome (third tertile vs first tertile; relative risk, 2.36; 95% confidence interval, 1.38-4.03) and with hypertensive disorders of pregnancy (third tertile vs first tertile; relative risk, 2.14; 95% confidence interval, 1.08-4.23). In analyses stratified by treatment group, associations were stronger in the placebo group (third tertile vs first tertile; relative risk, 3.36; 95% confidence interval, 1.42-7.93) than in the aspirin group (third tertile vs first tertile; relative risk, 1.78; 95% confidence interval, 0.90-3.50). CONCLUSION: High concentrations of platelet factor 4 before pregnancy are associated with increased risk of placenta-mediated adverse pregnancy outcomes, particularly for hypertensive disorders of pregnancy. Aspirin may mitigate the increased risk of these outcomes among women with higher plasma concentrations of preconception platelet factor 4, but low-dose aspirin nonresponders may require higher doses of aspirin or alternate therapies to achieve obstetrical risk reduction.

Effect of blood contamination on amniotic fluid detection in vitro using immunoassays.

Objective: To determine the accuracy of Actim PROM®, Amnisure®, and ROM Plus® tests for detecting amniotic fluid proteins in the setting of blood contamination.Methods: IGFBP-1 and AFP are proteins present in high concentrations in amniotic fluid, and are detected by three commercially-available immunoassays used for diagnosing ruptured membranes: Actim PROM®, Amnisure®, and ROM Plus®. We used whole blood samples and diluted these with amniotic fluid (containing known concentrations of amniotic fluid proteins) to whole blood levels of 50, 20, 10, 5, and 1%. Actim PROM®, Amnisure®, and ROM Plus® tests were performed on each sample in duplicate according to package insert instructions. Results were interpreted independently at 5, 10, 15, and 20 min by two obstetricians who were blinded to the concentrations of blood and amniotic fluid proteins in each sample. Results of each test were determined to be true positive, false negative, false positive, or true negative based on physician interpretation and whether amniotic fluid had been spiked into the samples in detectable concentrations. Overall accuracy, intraobserver concordance, and interobserver concordance, sensitivity, specificity, and predictive values for each test were calculated. Fisher exact test was used to compare test characteristics, with a p-value of <.05 considered significant.Results: Out of 120 tests performed, there were no false positive results for any test. Overall, ROM Plus® had better accuracy (97.9%) than Amnisure® (80.7%) or Actim® PROM (78.3%). Intra- and interobserver concordance were similar for all three tests (98-100%). ROM Plus® had significantly higher sensitivity than Amnisure® and Actim® PROM (p < .0001). There was no significant difference in sensitivity between Amnisure® and Actim® PROM (p = .51).Conclusion: ROM Plus® maintains strong test characteristics for the detection of amniotic fluid proteins in the setting of blood contamination, and performs significantly better than Amnisure® and Actim® PROM tests in the presence of blood.

Risks of cause-specific mortality in offspring of pregnancies complicated by hypertensive disease of pregnancy.

BACKGROUND: Fetal environment has a substantial influence on an individual's health throughout their life course. Animal models of hypertensive disease of pregnancy have demonstrated adverse health outcomes among offspring exposed to hypertensive disease of pregnancy in utero. Although there are numerous descriptions of the neonatal, infant, and pediatric outcomes of human offspring affected by hypertensive disease of pregnancy, there are few data in US populations on later life outcomes, including mortality. OBJECTIVE: To assess risk for early mortality among offspring of pregnancies complicated by hypertensive disease of pregnancy. STUDY DESIGN: This is a retrospective cohort study of offspring born to women with singleton or twin pregnancies between 1947 and 1967 with birth certificate information in the Utah Population Database. We identified offspring from delivery diagnoses of gestational hypertension, preeclampsia, or eclampsia. Offspring from these pregnancies (exposed) were matched to offspring of pregnancies without hypertensive disease of pregnancy (unexposed) by maternal age at delivery, birth year, sex, and multiple gestation. We also identified unexposed siblings of exposed offspring for a separate sibling analysis. Mortality follow-up of all offspring continued through 2016, at which time they would have been 49-69 years old. Adjusted hazard ratios for cause-specific mortality comparing exposed with unexposed offspring were estimated using Cox proportional hazard models. RESULTS: We compared mortality risks for 4050 exposed offspring and 6989 matched unexposed offspring from the general population and 7496 unexposed siblings. Mortality risks due to metabolic, respiratory, digestive, nervous, and external causes of death did not differ between exposed and unexposed groups. Mortality risks from cardiovascular disease were greater in exposed offspring compared with unexposed offspring (adjusted hazard ratio, 1.57; 95% confidence interval, 1.16-2.12). In sex-specific models among the general population, cardiovascular disease mortality was significantly associated with exposure among male patients (adjusted hazard ratio, 1.92; 95% confidence interval, 1.27-2.88) but not among female patients (adjusted hazard ratio, 0.97; 95% confidence interval, 0.81-1.94). An interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality was significant (P=.047), suggesting that the effect of hypertensive disease of pregnancy on cardiovascular disease mortality increased with higher birth order. Among siblings, the association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality was not significant (adjusted hazard ratio, 1.39; 95% confidence interval, 0.99-1.95), and this was also true for sex-specific analyses of males (adjusted hazard ratio, 1.26; 95% confidence interval, 0.81-1.94) and females (adjusted hazard ratio, 1.71; 95% confidence interval, 0.96-3.04). As in the general population, there was a significant interaction between hypertensive disease of pregnancy exposure and birth order on cardiovascular disease mortality (P=.011). CONCLUSION: In a US population, overall mortality risks are greater for offspring of pregnancies complicated by hypertensive disease of pregnancy compared with unexposed offspring. Among siblings, there was not a significant association between hypertensive disease of pregnancy exposure and cardiovascular disease mortality.

Prospective evaluation of the efficacy of immunoassays in the diagnosis of rupture of the membranes.

Objective: To assess efficacy of immunoassays to diagnose spontaneous rupture of membranes (SROM).Study design: We performed a prospective, observational analysis comparing two immunoassays designed to diagnose SROM (rupture of membranes (ROM) Plus® and Amnisure®) to standard clinical assessment for SROM and 48 h follow-up. Subjects had a singleton pregnancy ≥15 weeks' and suspected SROM. Sterile speculum exam (SSE) for nitrazine, ferning and pooling was performed. Immunoassays were run by independent providers blinded to results of SSE. The primary outcome was a final diagnosis of SROM at 48 h after initial evaluation.Results: Three hundred twenty-four subjects were enrolled (121 (37.3%) with SROM and 203 (62.7%) without SROM). Both ROM Plus® and Amnisure® had sensitivities and specificities >91% for the primary outcome. McNemar's test revealed no significant difference between immunoassay test sensitivities and specificities.Conclusion: Both the ROM Plus® and Amnisure® immunoassays may be used to accurately diagnose SROM. Performance of the two immunoassays was statistically equivalent.

Association of Adverse Pregnancy Outcomes With Hypertension 2 to 7 Years Postpartum.

Background Identifying pregnancy-associated risk factors before the development of major cardiovascular disease events could provide opportunities for prevention. The objective of this study was to determine the association between outcomes in first pregnancies and subsequent cardiovascular health. Methods and Results The Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be Heart Health Study is a prospective observational cohort that followed 4484 women 2 to 7 years (mean 3.2 years) after their first pregnancy. Adverse pregnancy outcomes (defined as hypertensive disorders of pregnancy, small-for-gestational-age birth, preterm birth, and stillbirth) were identified prospectively in 1017 of the women (22.7%) during this pregnancy. The primary outcome was incident hypertension (HTN). Women without adverse pregnancy outcomes served as controls. Risk ratios (RR) and 95% CIs were adjusted for age, smoking, body mass index, insurance type, and race/ethnicity at enrollment during pregnancy. The overall incidence of HTN was 5.4% (95% CI 4.7% to 6.1%). Women with adverse pregnancy outcomes had higher adjusted risk of HTN at follow-up compared with controls (RR 2.4, 95% CI 1.8-3.1). The association held for individual adverse pregnancy outcomes: any hypertensive disorders of pregnancy (RR 2.7, 95% CI 2.0-3.6), preeclampsia (RR 2.8, 95% CI 2.0-4.0), and preterm birth (RR 2.7, 95% CI 1.9-3.8). Women who had an indicated preterm birth and hypertensive disorders of pregnancy had the highest risk of HTN (RR 4.3, 95% CI 2.7-6.7). Conclusions Several pregnancy complications in the first pregnancy are associated with development of HTN 2 to 7 years later. Preventive care for women should include a detailed pregnancy history to aid in counseling about HTN risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT02231398.