Importance:It is unclear whether a higher dose (150-160 mg) or a lower dose (75 mg) of aspirin should be used to prevent preeclampsia. Objectives:To compare the risk of preeclampsia and bleeding complications between women using 150 to 160 mg of aspirin and those using 75 mg of aspirin for preeclampsia prevention. Design, Setting, and Participants:This nationwide cohort study included 13 828 women giving birth at 22 weeks' gestation or later in Sweden between January 2017 and December 2020 who used low dose aspirin (75-160 mg) during pregnancy. Data were analyzed from October to November 2023. Exposure:The use of 150 to 160 mg or 75 mg of aspirin in pregnancy. Main Outcome and Measures:The main outcome was a preeclampsia diagnosis recorded in the maternal birth record at the time of hospital discharge. The main safety outcome was postpartum hemorrhage, defined as bleeding more than 1000 mL after delivery. Relative risks (RRs) and 95% CIs were estimated using a doubly robust inverse probability-weighted regression adjustment model controlling for background characteristics. Results:In the total cohort of 13 828 women, the mean (SD) age was 33.0 (5.5) years and 3003 women (21.7%) were nulliparous. Of the women, 4687 (33.9%) were prescribed 150 to 160 mg of aspirin, and 9141 (66.1%) were prescribed 75 mg of aspirin. A total of 10 635 women (76.9%) had at least 2 dispensed prescriptions of low-dose aspirin. Among women using 150 to 160 mg of aspirin, 443 (9.5%) developed preeclampsia compared with 812 (8.9%) of those using 75 mg of aspirin (adjusted RR [aRR], 1.07; 95% CI, 0.93-1.24). Additionally, the risk of postpartum hemorrhage between the groups was similar, with 326 women (6.9%) using 150 to 160 mg of aspirin experiencing a postpartum hemorrhage compared with 581 (6.4%) in the 75-mg group (aRR, 1.08; 95% CI, 0.90-1.30). Conclusions and Relevance:In this cohort study of 13 828 women, no difference was found in preeclampsia incidence or bleeding complications between those using 150 to 160 mg of aspirin vs 75 mg of aspirin during pregnancy for preeclampsia prevention. These findings suggest that either dose may be a reasonable choice when using aspirin to prevent preeclampsia. However, large randomized trials investigating aspirin dose in pregnancy are still needed.

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.

BACKGROUND:Although in vitro fertilization has been associated with an increased risk for hypertensive disorders of pregnancy, the association of risk with in vitro fertilization treatment parameters is unclear. OBJECTIVE:To evaluate risk for hypertensive disorders of pregnancy by maternal fertility status and in vitro fertilization treatment parameters. MATERIALS AND METHODS:Women in 8 states who underwent in vitro fertilization resulting in a live birth during 2004-2013 were linked to their infant's birth certificates. A 10:1 sample of births from non-in vitro fertilization deliveries were selected for comparison. Those with an indication of infertility treatment on the birth certificate were categorized as subfertile and omitted from the study population; all others were categorized as fertile. The in vitro fertilization pregnancies were additionally categorized by oocyte source (autologous versus donor) and embryo state (fresh versus thawed). Both the fertile and in vitro fertilization births were limited to singletons only, and the in vitro fertilization pregnancies were limited to those using partner sperm. Hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia) were identified from the birth certificate, modeled using logistic regression, and reported as adjusted odds ratios and 95% confidence intervals. For analyses of in vitro fertilization pregnancies from autologous oocytes-fresh embryos, the reference group was fertile women (subgroup analysis 1). For analyses within the in vitro fertilization group, the reference group was autologous oocytes-fresh embryos (subgroup analysis 2). RESULTS:The study population included 1,465,893 pregnancies (1,382,311 births to fertile women and 83,582 births to in vitro fertilization-treated women). Compared to fertile women, in vitro fertilization-treated women with autologous-fresh cycles were not at increased risk for hypertensive disorders of pregnancy (adjusted odds ratio, 1.04; 95% confidence interval, 0.99, 1.08). Among in vitro fertilization births (subgroup analysis 2), the risk for hypertensive disorders of pregnancy was increased for the autologous-thawed (adjusted odds ratio, 1.30; 95% confidence interval, 1.20, 1.40); donor-fresh (adjusted oddds ratio, 1.92; 95% confidence interval, 1.71, 2.15); and donor-thawed (adjusted odds ratio, 1.70; 95% confidence interval, 1.47, 1.96) groups. Excluding women with pregestational diabetes or chronic hypertension as well as adjusting for body mass index and infertility diagnoses did not substantially change the results. When stratified by <34 weeks (early-onset hypertensive disorders of pregnancy) versus ≥34 weeks (late-onset hypertensive disorders of pregnancy), only the donor-fresh group had an increased risk of early-onset hypertensive disorders of pregnancy, but the risks for all other oocyte source-embryo state groups compared to autologous-fresh were increased for late-onset hypertensive disorders of pregnancy. CONCLUSION:The risk for hypertensive disorders of pregnancy is increased for in vitro fertilization-treated women in pregnancies conceived via frozen embryo transfer (with both autologous or donor oocyte) and fresh donor oocyte embryo transfer. No increase in risk was seen with autologous oocyte-fresh embryo transfers in vitro fertilization cycles. Excluding women with pregestational diabetes or chronic hypertension as well as adjusting for body mass index and infertility diagnoses did not substantially change the results.

BACKGROUND:The daily use of low-dose aspirin may be a safe, widely available, and inexpensive intervention for reducing the risk of preterm birth. Data on the potential side effects of low-dose aspirin use during pregnancy in low- and middle-income countries are needed. OBJECTIVE:This study aimed to assess differences in unexpected emergency medical visits and potential maternal side effects from a randomized, double-blind, multicountry, placebo-controlled trial of low-dose aspirin use (81 mg daily, from 6 to 36 weeks' gestation). STUDY DESIGN:This study was a secondary analysis of data from the Aspirin Supplementation for Pregnancy Indicated Risk Reduction In Nulliparas trial, a trial of the Global Network for Women's and Children's Health conducted in India (2 sites), Pakistan, Guatemala, Democratic Republic of the Congo, Kenya, and Zambia. The outcomes for this analysis were unexpected emergency medical visits and the occurrence of the following potential side effects-overall and separately-nausea, vomiting, rash or hives, diarrhea, gastritis, vaginal bleeding, allergic reaction, and any other potential side effects. Analyses were performed overall and by geographic region. RESULTS:Between the aspirin (n=5943) and placebo (n=5936) study groups, there was no statistically significant difference in the risk of unexpected emergency medical visits or the risk of any potential side effect (overall). Of the 8 potential side effects assessed, only 1 (rash or hives) presented a different risk by treatment group (4.2% in the aspirin group vs 3.5% in the placebo group; relative risk, 1.20; 95% confidence interval, 1.01-1.43; =.042). CONCLUSION:The daily use of low-dose aspirin seems to be a safe intervention for reducing the risk of preterm birth and well tolerated by nulliparous pregnant women between 6 and 36 weeks' gestation in low- and middle-income countries.

Preeclampsia is a major cause of maternal and perinatal morbidity and mortality. Early-onset disease requiring preterm delivery is associated with a higher risk of complications in both mothers and babies. Evidence suggests that the administration of low-dose aspirin initiated before 16 weeks' gestation significantly reduces the rate of preterm preeclampsia. Therefore, it is important to identify pregnant women at risk of developing preeclampsia during the first trimester of pregnancy, thus allowing timely therapeutic intervention. Several professional organizations such as the American College of Obstetricians and Gynecologists (ACOG) and National Institute for Health and Care Excellence (NICE) have proposed screening for preeclampsia based on maternal risk factors. The approach recommended by ACOG and NICE essentially treats each risk factor as a separate screening test with additive detection rate and screen-positive rate. Evidence has shown that preeclampsia screening based on the NICE and ACOG approach has suboptimal performance, as the NICE recommendation only achieves detection rates of 41% and 34%, with a 10% false-positive rate, for preterm and term preeclampsia, respectively. Screening based on the 2013 ACOG recommendation can only achieve detection rates of 5% and 2% for preterm and term preeclampsia, respectively, with a 0.2% false-positive rate. Various first trimester prediction models have been developed. Most of them have not undergone or failed external validation. However, it is worthy of note that the Fetal Medicine Foundation (FMF) first trimester prediction model (namely the triple test), which consists of a combination of maternal factors and measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, has undergone successful internal and external validation. The FMF triple test has detection rates of 90% and 75% for the prediction of early and preterm preeclampsia, respectively, with a 10% false-positive rate. Such performance of screening is superior to that of the traditional method by maternal risk factors alone. The use of the FMF prediction model, followed by the administration of low-dose aspirin, has been shown to reduce the rate of preterm preeclampsia by 62%. The number needed to screen to prevent 1 case of preterm preeclampsia by the FMF triple test is 250. The key to maintaining optimal screening performance is to establish standardized protocols for biomarker measurements and regular biomarker quality assessment, as inaccurate measurement can affect screening performance. Tools frequently used to assess quality control include the cumulative sum and target plot. Cumulative sum is a sensitive method to detect small shifts over time, and point of shift can be easily identified. Target plot is a tool to evaluate deviation from the expected multiple of median and the expected median of standard deviation. Target plot is easy to interpret and visualize. However, it is insensitive to detecting small deviations. Adherence to well-defined protocols for the measurements of mean arterial pressure, uterine artery pulsatility index, and placental growth factor is required. This article summarizes the existing literature on the different methods, recommendations by professional organizations, quality assessment of different components of risk assessment, and clinical implementation of the first trimester screening for preeclampsia.

Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is an important cause of maternal and perinatal morbidity and mortality, particularly when of early onset. Although a significant amount of research has been dedicated in identifying preventive measures for preeclampsia, the incidence of the condition has been relatively unchanged in the last decades. This could be attributed to the fact that the underlying pathophysiology of preeclampsia is not entirely understood. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and thrombotic events with placental infarcts. Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation. Such an effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The first possible link between the use of aspirin and the prevention of preeclampsia was suggested by a case report published in 1978, followed by the first randomized controlled trial published in 1985. Since then, numerous randomized trials have been published, reporting the safety of the use of aspirin in pregnancy and the inconsistent effects of aspirin on the rates of preeclampsia. These inconsistencies, however, can be largely explained by a high degree of heterogeneity regarding the selection of trial participants, baseline risk of the included women, dosage of aspirin, gestational age of prophylaxis initiation, and preeclampsia definition. An individual patient data meta-analysis has indicated a modest 10% reduction in preeclampsia rates with the use of aspirin, but later meta-analyses of aggregate data have revealed a dose-response effect of aspirin on preeclampsia rates, which is maximized when the medication is initiated before 16 weeks of gestational age. Recently, the Aspirin for Evidence-Based Preeclampsia Prevention trial has revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks of gestational age, and given at night to a high-risk population, identified by a combined first trimester screening test, reduces the incidence of preterm preeclampsia by 62%. A secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention trial data also indicated a reduction in the length of stay in the neonatal intensive care unit by 68% compared with placebo, mainly because of a reduction in births before 32 weeks of gestational age with preeclampsia. The beneficial effect of aspirin has been found to be similar in subgroups according to different maternal characteristics, except for the presence of chronic hypertension, where no beneficial effect is evident. In addition, the effect size of aspirin has been found to be more pronounced in women with good compliance to treatment. In general, randomized trials are underpowered to investigate the treatment effect of aspirin on the rates of other placental-associated adverse outcomes such as fetal growth restriction and stillbirth. This article summarizes the evidence around aspirin for the prevention of preeclampsia and its complications.

BACKGROUND:Data from the A Randomized Trial of Induction Versus Expectant Management study suggested that low-risk pregnant patients randomized to expectant management at term had a higher risk for developing hypertensive disorders of pregnancy than pregnant patients randomized to elective induction at 39 weeks. In addition, hypertensive disorders of pregnancy were reported to decrease with advancing gestational age when comparing outcomes by gestational age at delivery. OBJECTIVE:This study aimed to verify these contrasting findings by evaluating the relationship between hypertensive disorders of pregnancy at term and gestational age at delivery. STUDY DESIGN:This was a secondary analysis of a multicenter, prospective cohort study of nulliparous pregnant patients with singleton gestations (from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be). Pregnant patients who delivered ≥37+0 weeks' gestation were included. Patients were excluded if they did not provide consent for data release in subsequent studies or if they had missing outcome data. The primary outcome was hypertensive disorders of pregnancy, defined as gestational hypertension or preeclampsia with or without severe features according to the American College of Obstetricians and Gynecologists guidelines. Descriptive statistics were used to evaluate hypertensive disorders of pregnancy in the following 2 ways: analysis (1), incidence of hypertensive disorders of pregnancy by gestational age week among all ongoing pregnancies and analysis (2), the incidence of hypertensive disorders of pregnancy by gestational age week among deliveries at that gestational age week. It was assumed that hypertensive disorders of pregnancy were not expectantly managed at term. RESULTS:Of the 8011 pregnant patients included in this analysis, 1003 (12.5%) had hypertensive disorders of pregnancy: 162 (24.5%) delivered at 37+0 to 37+6 weeks' gestation, 232 (18%) delivered at 38+0 to 38+6 weeks, 310 (12.1%) delivered at 39+0 to 39+6 weeks, 207 (8.7%) delivered at 40+0 to 40+6 weeks, and 92 (8.1%) delivered at ≥41+0 weeks. In analysis 1, the incidence of hypertensive disorders of pregnancy increased with advancing gestational age among all ongoing pregnancies with a hypertensive disorder of pregnancy (2.0% at 37 weeks and 8.1% at 41 weeks). In analysis 2, the incidence of hypertensive disorders of pregnancy decreased with advancing gestational age among deliveries at that gestational age week alone (24.5% at 37 weeks and 8.1% at 41 weeks). CONCLUSION:Our results confirm the findings from the A Randomized Trial of Induction Versus Expectant Management study showing that the risk for hypertensive disorders of pregnancy increases with advancing gestational age, but hypertensive disorders of pregnancy is more common among deliveries at earlier gestational ages. These key differences illustrate how important the study design and analytical approach are to accurately interpret results and apply findings clinically.

OBJECTIVE:To study the extent to which BMI after pregnancy adds to the elevated risk of postpregnancy type 2 diabetes in women with a history of hypertensive disorders of pregnancy (HDP) (preeclampsia or gestational hypertension). RESEARCH DESIGN AND METHODS:We used data from the Nurses' Health Study II, a prospective cohort study. In women aged 45-54 years without prior gestational diabetes mellitus, we investigated the interaction between BMI and HDP history on the risk of type 2 diabetes. For clinical and public health relevance, we focused on additive interaction. The main outcome measure was the relative excess risk due to interaction calculated from multivariable Cox proportional hazards models using normal weight as the reference group. RESULTS:In total, 6,563 (11.7%) of 56,159 participants had a history of HDP and 1,341 women developed type 2 diabetes during 436,333 person-years. BMI was a strong risk factor for type 2 diabetes regardless of HDP history. However, there was evidence of an additive interaction between BMI and HDP for the risk of type 2 diabetes ( = 0.004). The attributable proportion of risk due to the interaction ranged from 0.12 (95% CI -0.22, 0.46) in women who were overweight to 0.36 (95% CI 0.13, 0.59) in women with obesity class I. CONCLUSIONS:Maintaining a healthy weight may be of even greater importance in women with a history of HDP, compared with other women with a history of only normotensive pregnancies, to reduce midlife risk of type 2 diabetes.

Kisspeptin and its receptor are central to reproductive health acting as key regulators of the reproductive endocrine axis in humans. Kisspeptin is most widely recognised as a regulator of gonadotrophin releasing hormone (GnRH) neuronal function. However, recent evidence has demonstrated that kisspeptin and its receptor also play a fundamental role during pregnancy in the regulation of placentation. Kisspeptin is abundantly expressed in syncytiotrophoblasts, and its receptor in both cyto- and syncytio-trophoblasts. Circulating levels of kisspeptin rise dramatically during healthy pregnancy, which have been proposed as having potential as a biomarker of placental function. Indeed, alterations in kisspeptin levels are associated with an increased risk of adverse maternal and foetal complications. This review summarises data evaluating kisspeptin's role as a putative biomarker of pregnancy complications including miscarriage, ectopic pregnancy (EP), preterm birth (PTB), foetal growth restriction (FGR), hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), gestational diabetes mellitus (GDM), and gestational trophoblastic disease (GTD).

IMPORTANCE:Hypertensive disorders of pregnancy are associated with future cardiovascular disease, perhaps because of subclinical cardiac dysfunction before pregnancy leading to impaired adaptation to pregnancy. Natriuretic peptides are promising biomarkers for detecting subclinical cardiac dysfunction outside of pregnancy. OBJECTIVE:To investigate whether higher concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) in early pregnancy would be associated with hypertensive disorders of pregnancy and hypertension 2 to 7 years post partum. DESIGN, SETTING, AND PARTICIPANTS:This cohort study used data from the The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study, a prospective multicenter observational study. A total of 4103 nulliparous women with complete data and no prepregnancy hypertension or diabetes who were treated at 8 clinical sites were included. Women were followed up with for 2 to 7 years after pregnancy. Data were collected from October 2010 to October 2017, and data were analyzed from August 2020 to November 2021. EXPOSURES:NT-proBNP concentration, measured using an electrochemiluminescence immunoassay from a first-trimester blood sample. MAIN OUTCOMES AND MEASURES:Hypertensive disorders of pregnancy and incident hypertension (systolic blood pressure of 130 mm Hg or diastolic blood pressure of 80 mm Hg or use of antihypertensive agents) at follow-up visit. RESULTS:A total of 4103 women met inclusion criteria; the mean (SD) age was 27.0 (5.6) years. Among these women, 909 (22.2%) had an adverse pregnancy outcome, and 817 (19.9%) had hypertension at the follow-up visit. Higher NT-proBNP concentrations were associated with a lower risk of hypertensive disorders of pregnancy (adjusted odds ratio per doubling, 0.81; 95% CI, 0.73-0.91), which persisted after adjustment for age, self-reported race and ethnicity, early-pregnancy body mass index, smoking, and aspirin use. Similarly, higher NT-proBNP concentration in early pregnancy was also associated with a lower risk of incident hypertension 2 to 7 years after delivery (adjusted odds ratio per doubling, 0.84; 95% CI, 0.77-0.93), an association that persisted after controlling for confounders, including hypertensive disorders of pregnancy. CONCLUSIONS AND RELEVANCE:In this cohort study, higher NT-proBNP concentrations in early pregnancy were associated with a lower risk of hypertensive disorders of pregnancy and hypertension 2 to 7 years post partum. These findings suggest that normal early-pregnancy cardiovascular physiology, as assessed by NT-proBNP concentration, may provide biologic insights into both pregnancy outcome and cardiovascular disease risk.

Objective:Adverse pregnancy outcomes have been related to obesity and thinness; however, the changing trends of the specific outcome with pre-pregnancy BMI remain unknown. The aim of this study was to investigate the change in risk trends of specific adverse outcomes for different pre-pregnancy BMI and analyze the recommended BMI range for pre-pregnancy counseling. Methods:Data were extracted from the medical records of 39 public hospitals across 14 provinces in China from 2011 to 2012. The eligibility criteria were singleton birth with delivery week ≥28 weeks. Join-point analysis was adopted to explore changing trends with pre-pregnancy BMI and calculate slopes and join points of different pregnancy complications. Results:A total of 65,188 women were eligible for analysis. There were three categories of trend style. Continuously increasing trends were linear for intrahepatic cholestasis of pregnancy, postpartum hemorrhage, and low 1-min Apgar score, and non-linear for cesarean delivery with one join point of BMI 23, hypertension disorder in pregnancy with two join points of BMI 20 and 28, gestational diabetes mellitus with one join point of BMI 22, and macrosomia with one join point of BMI 19. The trend was continuously and linearly decreasing for anemia. The bidirectional trends were downward and upward for premature rupture of the membrane with join BMI 22, preterm premature rupture of the membrane with join BMI 22, placenta abruption with join BMI 23, preterm birth with join BMI 19, and low birth weight with join BMI 19. Conclusions:The changes in the trends of specific outcomes differed with pre-pregnancy BMI. Our results suggested that a pre-pregnancy BMI ranging between 19 and 23 may help reduce the risk of poor maternal and neonatal outcomes.

Importance:Low birth weight and preterm birth are associated with adverse consequences including increased risk of infant mortality and chronic health conditions. Black infants are more likely than white infants to be born prematurely, which has been associated with disparities in infant mortality and other chronic conditions. Objective:To evaluate whether Medicaid expansion was associated with changes in rates of low birth weight and preterm birth outcomes, both overall and by race/ethnicity. Design, Setting, and Participants:Using US population-based data from the National Center for Health Statistics Birth Data Files (2011-2016), difference-in-differences (DID) and difference-in-difference-in-differences (DDD) models were estimated using multivariable linear probability regressions to compare birth outcomes among infants in Medicaid expansion states relative to non-Medicaid expansion states and changes in relative disparities among racial/ethnic minorities for singleton live births to women aged 19 years and older. Exposures:State Medicaid expansion status and racial/ethnic category. Main Outcomes and Measures:Preterm birth (<37 weeks' gestation), very preterm birth (<32 weeks' gestation), low birth weight (<2500 g), and very low birth weight (<1500 g). Results:The final sample of 15 631 174 births (white infants: 8 244 924, black infants: 2 201 658, and Hispanic infants: 3 944 665) came from the District of Columbia and 18 states that expanded Medicaid (n = 8 530 751) and 17 states that did not (n = 7 100 423). In the DID analyses, there were no significant changes in preterm birth in expansion relative to nonexpansion states (preexpansion to postexpansion period, 6.80% to 6.67% [difference: -0.12] vs 7.86% to 7.78% [difference: -0.08]; adjusted DID: 0.00 percentage points [95% CI, -0.14 to 0.15], P = .98), very preterm birth (0.87% to 0.83% [difference: -0.04] vs 1.02% to 1.03% [difference: 0.01]; adjusted DID: -0.02 percentage points [95% CI, -0.05 to 0.02], P = .37), low birth weight (5.41% to 5.36% [difference: -0.05] vs 6.06% to 6.18% [difference: 0.11]; adjusted DID: -0.08 percentage points [95% CI, -0.20 to 0.04], P = .20), or very low birth weight (0.76% to 0.72% [difference: -0.03] vs 0.88% to 0.90% [difference: 0.02]; adjusted DID: -0.03 percentage points [95% CI, -0.06 to 0.01], P = .14). Disparities for black infants relative to white infants in Medicaid expansion states compared with nonexpansion states declined for all 4 outcomes, indicated by a negative DDD coefficient for preterm birth (-0.43 percentage points [95% CI, -0.84 to -0.02], P = .05), very preterm birth (-0.14 percentage points [95% CI, -0.26 to -0.02], P = .03), low birth weight (-0.53 percentage points [95% CI, -0.96 to -0.10], P = .02), and very low birth weight (-0.13 percentage points [95% CI, -0.25 to -0.01], P = .04). There were no changes in relative disparities for Hispanic infants. Conclusions and Relevance:Based on data from 2011-2016, state Medicaid expansion was not significantly associated with differences in rates of low birth weight or preterm birth outcomes overall, although there were significant improvements in relative disparities for black infants compared with white infants in states that expanded Medicaid vs those that did not.

Importance:Diabetes in pregnancy is associated with a 2-times to 3-times higher rate of very preterm birth than in women without diabetes. Very preterm infants are at high risk of death and severe morbidity. The association of maternal diabetes with these risks is unclear. Objective:To determine the associations between maternal diabetes and in-hospital mortality, as well as neonatal morbidity in very preterm infants with a birth weight of less than 1500 g. Design, Setting, Participants:This retrospective cohort study was conducted at 7 national networks in high-income countries that are part of the International Neonatal Network for Evaluating Outcomes in Neonates and used prospectively collected data on 76 360 very preterm, singleton infants without malformations born between January 1, 2007, and December 31, 2015, at 24 to 31 weeks' gestation with birth weights of less than 1500 g, 3280 (4.3%) of whom were born to diabetic mothers. Exposures:Any type of diabetes during pregnancy. Main Outcomes and Measures:The primary outcome was in-hospital mortality. The secondary outcomes were severe neonatal morbidities, including intraventricular hemorrhages of grade 3 to 4, cystic periventricular leukomalacia, retinopathy of prematurity needing treatment and bronchopulmonary dysplasia, and other morbidities, including respiratory distress, treated patent ductus arteriosus, and necrotizing enterocolitis. Odds ratios (ORs) with 95% confidence intervals were estimated, adjusted for potential confounders, and stratified by gestational age (GA), sex, and network. Results:The mean (SD) birth weight of offspring born to mothers with diabetes was significantly higher at 1081 (262) g than in offspring born to mothers without diabetes (mean [SD] birth weight, 1027 [270] g). Mothers with diabetes were older and had more hypertensive disorders, antenatal steroid treatments, and deliveries by cesarean delivery than mothers without diabetes. Infants of mothers with diabetes were born at a later GA than infants of mothers without diabetes. In-hospital mortality (6.6% vs 8.3%) and the composite of mortality and severe morbidity (31.6% vs 40.6%) were lower in infants of mothers with diabetes. However, in adjusted analyses, no significant differences in in-hospital mortality (adjusted OR, 1.16 (95% CI, 0.97-1.39) or the composite of mortality and severe morbidity (adjusted OR, 0.99 (95% CI, 0.88-1.10) were observed. With few exceptions, outcomes of infants born to mothers with and without diabetes were similar regardless of infant sex, GA, or country of birth. Conclusions and Relevance:In high-resource settings, maternal diabetes is not associated with an increased risk of in-hospital mortality or severe morbidity in very preterm infants with a birth weight of fewer than 1500 g.

BACKGROUND:Thin endometrial thickness (EMT) has been suggested to be associated with reduced incidence of pregnancy rate after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment, but the effect of thin endometrium on obstetric outcome is less investigated. This study aims to determine whether EMT affects the incidence of obstetric complications in fresh IVF/ICSI-embryo transfer (ET) cycles. METHODS:We conducted a retrospective cohort study collecting a total of 9266 women who had singleton livebirths after fresh IVF/ICSI-ET treatment cycles at the Center for Reproductive Medicine Affiliated to Shandong University between January 2014 and December 2018. The women were divided into three groups according to the EMT: 544 women with an EMT ≤8 mm, 6234 with an EMT > 8-12 mm, and 2488 with an EMT > 12 mm. The primary outcomes were the incidence of obstetric complications including hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), placental abruption, placenta previa, postpartum hemorrhage (PPH) and cesarean section. Multivariable logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for associations between the EMT measured on the day of human chorionic gonadotropin (HCG) trigger and the risk of the outcomes of interest. RESULTS:The HDP incidence rate of pregnant women was highest in EMT ≤ 8 mm group and significantly higher than those in EMT from > 8-12 mm and EMT > 12 mm group, respectively (6.8% versus 3.6 and 3.5%, respectively; P = 0.001). After adjustment for confounding variables by multivariate logistic regression analysis, a thin EMT was still statistically significant associated with an increased risk of HDP. Compared with women with an EMT > 8-12 mm, women with an EMT ≤8 mm had an increased risk of HDP (aOR = 1.853, 95% CI 1.281-2.679, P = 0.001). CONCLUSION:A thin endometrium (≤8 mm) was found to be associated with an increased risk of HDP after adjustment for confounding variables, indicating that the thin endometrium itself is a risk factor for HDP. Obstetricians should remain aware of the possibility of HDP when women with a thin EMT achieve pregnancy through fresh IVF/ICSI-ET treatment cycles.

To evaluate the incidence of pregnancy-induced hypertension (PIH) in women with congenital uterine malformations, we examined the pregnancy complications of 67 women with uterine anomalies demonstrated by hysterosalpingography (HSG). The study group was compared with a control group of 130 women with normal-shaped uterus proven by HSG-matched for age, parity and presenting complaint. A significantly increased (p less than 0.04) rate of PIH was found for women with uterine malformation as well as a 2-fold higher frequency of preeclampsia. The etiology for this association is unknown, however; it is suggested that uterine malformation is a predisposing condition to PIH.

PURPOSE:This systematic review and meta-analysis aimed to compare the short-term reproductive and long-term obstetric outcomes after endometrial preparations by ovarian stimulation protocols and hormone replacement therapy (HRT) in women with polycystic ovary syndrome (PCOS) prior to frozen embryo transfer (FET). METHOD:PubMed, EMBASE, Web of Science and the Cochrane Library were searched to identify relevant studies. Primary outcome was live birth rate, secondary outcomes included the rates of clinical pregnancy, miscarriage, implantation and hCG-postive, cycle cancellation, ectopic pregnancy, preterm birth, preeclampsia, gestational hypertension, gestational diabetes mellitus and abnormal placentation. RESULTS:Nine studies, including 8327 patients with PCOS, were identified. Live birth rate was significantly higher (RR = 1.11, 95% CI = 1.03-1.19) and miscarriage rate (RR = 0.60, 95% CI = 0.46-0.78) was significantly lower in stimulated protocol compared to the rates in HRT. While the rates of ongoing pregnancy, clinical pregnancy, implantation, hCG-positive, cycle cancellation and ectopic pregnancy showed no significant difference between the two protocols. Compared HRT with different stimulation protocols, significantly higher clinical pregnancy rate (RR = 1.54, 95% CI = 1.20-1.98) were found in letrozole group, but not in the other subgroups. For the obstetric outcomes, the preterm birth and preeclampsia rates were significantly lower in the stimulated group compared to that in the HRT group (RR = 0.85, 95% CI = 0.74-0.98; RR = 0.57, 95% CI = 0.40-0.82, respectively), while gestational hypertension, gestational diabetes mellitus and abnormal placentation rates showed no significant difference. CONCLUSIONS:The present data suggest that ovarian stimulation protocol as an endometrial preparation regimen prior to FET might be superior to HRT protocol with a significantly higher rate of live birth, lower risk of miscarriage, preterm birth and preeclampsia. Our study showed stimulated protocol is better than HRT regimen as an endometrial preparation for women with PCOS. However, quality of the evidence is low, more well-designed RCT studies are still needed to confirm the results before clinical recommendation, particularly direct comparisons between letrozole and other stimulated regimens.

RESEARCH QUESTION:What are the obstetric and neonatal risks for women conceiving via frozen-thawed embryo transfer (FET) during a modified natural cycle compared with an artificial cycle method. DESIGN:A follow-up study to the ANTARCTICA randomized controlled trial (RCT) (NTR 1586) conducted in the Netherlands, which showed that modified natural cycle FET (NC-FET) was non-inferior to artificial cycle FET (AC-FET) in terms of live birth rates. The current study collected data on obstetric and neonatal outcomes of 98 women who had a singleton live birth. The main outcome was birthweight; additional outcomes included hypertensive disorder of pregnancy, premature birth, gestational diabetes, obstetric haemorrhage and neonatal outcomes including Apgar scores and admission to the neonatal ward or the neonatal intensive care unit and congenital anomalies. RESULTS:Data from 82 out of 98 women were analysed according to the per protocol principle. There was no significant difference in the birthweights of children born between groups (mean difference -124 g [-363 g to 114 g]; P = 0.30). Women who conceived by modified NC-FET have a decreased risk of hypertensive disorders of pregnancy compared with AC-FET (relative risk 0.27; 95% CI 0.08-0.94; P = 0.031). Other outcomes, such as rates of premature birth, gestational diabetes or obstetric haemorrhage and neonatal outcomes, were not significantly different. CONCLUSIONS:The interpretation is that modified NC-FET is the preferred treatment in women with ovulatory cycles undergoing FET when the increased risk of obstetrical complications and potential neonatal complications in AC-FET are considered.

PURPOSE:To compare the effects of different endometrial preparation protocols for frozen-thawed embryo transfer (FET) cycles and present treatment hierarchy. METHODS:Systematic review with meta-analysis was performed by electronic searching of MEDLINE, the Cochrane Library, Embase, ClinicalTrials.gov and Google Scholar up to Dec 26, 2020. Randomised controlled trials (RCTs) or observational studies comparing 7 treatment options (natural cycle with or without human chorionic gonadotrophin trigger (mNC or tNC), artificial cycle with or without gonadotropin-releasing hormone agonist suppression (AC+GnRH or AC), aromatase inhibitor, clomiphene citrate, gonadotropin or follicle stimulating hormone) in FET cycles were included. Meta-analyses were performed within random effects models. Primary outcome was live birth presented as odds ratio (OR) with 95% confidence intervals (CIs). RESULTS:Twenty-six RCTs and 113 cohort studies were included in the meta-analyses. In a network meta-analysis, AC ranked last in effectiveness, with lower live birth rates when compared with other endometrial preparation protocols. In pairwise meta-analyses of observational studies, AC was associated with significant lower live birth rates compared with tNC (OR 0.81, 0.70 to 0.93) and mNC (OR 0.85, 0.77 to 0.93). Women who achieved pregnancy after AC were at an increased risk of pregnancy-induced hypertension (OR 1.82, 1.37 to 2.38), postpartum haemorrhage (OR 2.08, 1.61 to 2.78) and very preterm birth (OR 2.08, 1.45 to 2.94) compared with those after tNC. CONCLUSION:Natural cycle treatment has a higher chance of live birth and lower risks of PIH, PPH and VPTB than AC for endometrial preparation in women receiving FET cycles.

To assess the effect of obesity on implantation rate, pregnancy rate and course of pregnancy in young women undergoing IVF in whom only high-quality embryos were transferred, a cohort study included women attending the IVF unit in 2006-2007 with favourable parameters to achieve pregnancy (<38years, fewer than three IVF cycles, transfer of two high-quality embryos), grouped by body mass index (BMI). Of 230 women, 160 had a BMI ⩽25kg/m(2) (mean 21.6±2.2) and 73 had BMI >25kg/m(2) (mean 29.5±3.7). The overweight group had a higher consumption of gonadotrophins during stimulation. There were no between-group differences in treatment protocols, duration of gonadotrophin stimulation, maximal oestradiol concentrations, endometrial thickness and number of oocytes retrieved/fertilized, or in rates of pregnancy (51.3%, 52.1%), implantation (34.5%, 37.5%), multiple pregnancy, and abortion. Rate of gestational diabetes or pregnancy-induced hypertension was higher in the overweight group (23.3%, 8.2%; P=0.045). Within the overweight group, those with multiple pregnancies were at highest risk (31.3%, 6.9%; P=0.031). In conclusion, implantation and pregnancy rates are not compromised in overweight women when high-quality embryos are transferred. However, in overweight women, pregnancy complications remain high, mainly in those with multiple pregnancies.

OBJECTIVE:To identify the factors associated with the increased risk of developing preeclampsia in twin pregnancies compared with those in singleton pregnancies. METHODS:We reviewed the obstetric records of all deliveries at > or =22 weeks' gestation managed at the Japanese Red Cross Katsushika Maternity Hospital between 2001 and 2007. RESULTS:The incidence of preeclampsia in the twin pregnancies (7.6%: 45 in 593) was significantly higher than that in the singleton pregnancies (1.7%: 196 in 11,311; P < 0.01). In singleton pregnancies, the developing preeclampsia was associated with maternal age at > or =35 years, primiparity, maternal BMI > or =25 before pregnancy, history of infertility therapies such as IVF and having a history of previous preeclampsia. In twin pregnancies, however, the developing preeclampsia was not associated with these variables. CONCLUSIONS:In Japanese women, the factors reported to be associated with the increased risk of preeclampsia in singleton pregnancies may not alter the increased risk of preeclampsia in twin pregnancies.

OBJECTIVES:Overweight and obese women may be heavy users of in vitro fertilization (IVF) owing to obesity-related oligo-anovulation. The higher doses of gonadotropins required to achieve pregnancy in obese women may contribute to impaired placentation and the development of preeclampsia. This study was designed to assess the combined effect of high maternal body mass index (BMI) and IVF on risk of preeclampsia and to evaluate for an interaction between the two factors. METHODS:This is a hospital-based cohort study of 10,013 singleton pregnancies that delivered from 2001 to 2008 at a tertiary hospital in Montreal, Canada. The combined effect of high BMI and IVF on preeclampsia versus no risk factors was estimated in multivariate logistic regression models fitted with an interaction term between high BMI (> 25 or > 30 kg/m(2) ) and IVF. RESULTS:IVF pregnancies in obese women had a considerably higher risk of preeclampsia than spontaneous nonobese pregnancies (OR 6.7, 95% CI 3.3-13.8; p interaction 0.03). IVF was not independently associated with preeclampsia (OR 0.6, 95% CI 0.3-1.4). Analyses were similar in subgroup analyses and in analyses correcting for bias. CONCLUSIONS:High BMI is strongly associated with preeclampsia, and this risk is compounded in IVF pregnancies.

OBJECTIVE:To determine whether singleton pregnancy achieved after preimplantation genetic testing (PGT) is associated with a higher risk of adverse perinatal outcomes than in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) singleton pregnancy. DESIGN:A retrospective cohort study. SETTING:A university-affiliated fertility center. PATIENT(S):This cohort study included singleton live births resulting from PGT (n = 232) and IVF/ICSI singleton pregnancies (n = 2,829) with single frozen-thawed blastocyst transfer. Multiple baseline covariates were used for propensity score matching, yielding 214 PGT singleton pregnancies matched to 617 IVF/ICSI singleton pregnancies. INTERVENTION(S):Trophectoderm biopsy. MAIN OUTCOME MEASURE(S):The primary outcome was gestational hypertension, and various clinical perinatal secondary outcomes related to maternal and neonatal health were measured. RESULT(S):Compared with IVF/ICSI singleton pregnancy, PGT singleton pregnancy was associated with a significantly higher risk of gestational hypertension (adjusted odds ratio, 2.58; 95% confidence interval, 1.32, 5.05). In the matched sample, the risk of gestational hypertension remained higher with PGT singleton pregnancy (odds ratio, 2.33; 95% confidence interval, 1.04, 5.22) than with IVF/ICSI singleton pregnancy. No statistical differences were noted in any other measured outcomes between the groups. CONCLUSION(S):The perinatal outcomes of PGT and IVF/ICSI singleton pregnancies were similar except for the observed potentially higher risk of gestational hypertension with PGT singleton pregnancy. However, because the data on PGT singleton pregnancies are limited, this conclusion warrants further investigation.

OBJECTIVE:To clarify the association between preconception fertility status and obstetric outcomes in women aged 40 years and older. DESIGN:Retrospective study by reviewing medical records. SETTING:Tertiary perinatal center in a university hospital. PATIENT(S):330 women aged 40 years and older who delivered a singleton from 2006 to 2010, and 450 women aged 30 to 34 years who delivered at the same facility as controls. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Incidence of pregnancy-induced hypertension, gestational diabetes mellitus, preterm birth, low birth weight, and mode of delivery assessed based on the mode of conception; spontaneous conception (SC) and in vitro fertilization/intracytoplasmic sperm injection conception (IVF-ICSI). RESULT(S):The incidence of pregnancy-induced hypertension was statistically significantly higher in IVF-ICSI group than the SC group. This gap was commonly observed in both the women aged 40 years and older and those in the 30 to 34 age group. No statistically significant difference was observed in the frequency of gestational diabetes mellitus, preterm birth, or low birth weight. As a characteristic of nulliparous women of advanced age, the rate of operative delivery, which includes emergency cesarean section and instrumental delivery, was statistically significantly higher in IVF-ICSI group than in the SC group. Detailed investigation into the medical indications for operative delivery revealed that the difference was attributable to the elevated incidence of labor protraction and arrest. CONCLUSION(S):Preconception fertility status can be a predicting factor of the incidence of pregnancy-induced hypertension and labor outcome, especially for women aged 40 years and older.

RESEARCH QUESTION:What are the factors associated with the increased incidence of pre-eclampsia in pregnancies conceived through IVF using autologous oocytes? DESIGN:A nested case-control study from the combined cohort of three multicentre randomized trials comparing fresh to frozen embryo transfer, including women who achieved clinical pregnancy after the first embryo transfer. Multivariable logistic regression was used to assess the effect of baseline characteristics, ovarian response parameters, type of fertilization, type of embryo transfer, and number of gestational sacs on the risk of pre-eclampsia. RESULTS:There were 2965 clinical pregnancies and 90 women were diagnosed with pre-eclampsia. Twin gestations (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.50-3.66), mean arterial pressure (OR 1.04, 95% CI 1.01-1.07), frozen embryo transfer (OR 2.06, 95% CI 1.27-3.35), body mass index (BMI) (OR 1.10, 95% CI 1.02-1.18), progesterone level on the day of human chorionic gonadotrophin trigger (OR 1.53, 95% CI 1.07-2.20), and the total dose of gonadotrophin (OR 0.999, 95% CI 0.999-1.000, P = 0.037) were associated with the risk of pre-eclampsia. When the analysis was confined to women who underwent frozen embryo transfer, twin gestations (OR 2.44, 95% CI 1.43-4.18), BMI (OR 1.13, 95% CI 1.03-1.23) and the total dose of gonadotrophin (OR 0.999, 95% CI 0.999-1.000, P = 0.014) were still related to the risk of pre-eclampsia. The embryo stage at transfer was not included in the final models. CONCLUSIONS:Frozen embryo transfer was an independent risk factor of pre-eclampsia in assisted reproductive technology. The high ovarian response may also increase the risk of pre-eclampsia. The embryo stage at transfer was not related to the risk of pre-eclampsia.

BACKGROUND:The great majority of studies performed so far concerning women diagnosed with polycystic ovary syndrome (PCOS) have focused on diagnosis, menstrual cycle abnormalities, hirsutism and infertility. Although progress has been made in developing methods for achieving a pregnancy and reducing multiple gestations in women with PCOS, little attention has been paid to pregnancy complications and subsequent child outcomes. This review aims to summarize current knowledge regarding the clinical and pathophysiological features of pregnancy and children in women with PCOS. METHODS:A literature search up to April 2015 was performed in PubMed, Medline, the Cochrane Library and Web of Science without language restriction. All articles were initially screened for title and abstract and full texts of eligible articles were subsequently selected. Systematic reviews with meta-analysis were initially included for each specific subject. Recent randomised controlled trials (RCTs), which were not included in the systematic reviews, were also included. In addition to evidence from meta-analyses or RCTs, we used non-randomized prospective, uncontrolled prospective, retrospective and experimental studies. When specific data for patients with PCOS were lacking, results from general population studies were reported. RESULTS:Women with PCOS exhibit a clinically significant increased risk of pregnancy complications compared with controls. Data which were not adjusted for BMI or other confounders demonstrated in PCOS a 3-4-fold increased risk of pregnancy-induced hypertension and pre-eclampsia, a 3-fold increased risk of gestational diabetes and 2-fold higher chance for premature delivery. Features characteristic of PCOS, such as hyperandrogenism, obesity, insulin resistance and metabolic abnormalities, may contribute to the increased risk of obstetric and neonatal complications. Limited available data suggest that offspring of women with PCOS have an increased risk for future metabolic and reproductive dysfunction. Underlying pathophysiological mechanisms of pregnancy complications along with its association with health of offspring remain uncertain. To date, the strategies for prevention and management of pregnancy complications in women with PCOS, and whether long-term health of these women is influenced, and to what extent, by pregnancy and/or pregnancy complications, remain to be elucidated. CONCLUSIONS:Women with PCOS show an increased risk of pregnancy complications. Heterogeneous aetiological factors involved in PCOS and associated co-morbidities may all be involved in compromised pregnancy and child outcomes. In women with PCOS, a possible relationship with genetic, environmental, clinical and biochemical factors involved in this complex condition, as well as with pregnancy complications and long-term health for both mother and child, remains to be established.

OBJECTIVE:To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women. DESIGN:Multicentre randomised trial. We utilised a central telephone randomisation server, with computer generated schedule, balanced variable blocks, and stratification for parity, body mass index (BMI) category, and hospital. SETTING:Three public maternity hospitals across South Australia. PARTICIPANTS:2212 women with a singleton pregnancy, between 10+0 and 20+0 weeks' gestation, and BMI ≥ 25. INTERVENTIONS:1108 women were randomised to a comprehensive dietary and lifestyle intervention delivered by research staff; 1104 were randomised to standard care and received pregnancy care according to local guidelines, which did not include such information. MAIN OUTCOME MEASURES:Incidence of infants born large for gestational age (birth weight ≥ 90th centile for gestation and sex). Prespecified secondary outcomes included birth weight >4000 g, hypertension, pre-eclampsia, and gestational diabetes. Analyses used intention to treat principles. RESULTS:2152 women and 2142 liveborn infants were included in the analyses. The risk of the infant being large for gestational age was not significantly different in the two groups (lifestyle advice 203/1075 (19%) v standard care 224/1067 (21%); adjusted relative risk 0.90, 95% confidence interval 0.77 to 1.07; P=0.24). Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g (lifestyle advice 164/1075 (15%) v standard care 201/1067 (19%); 0.82, 0.68 to 0.99; number needed to treat (NNT) 28, 15 to 263; P=0.04). There were no differences in maternal pregnancy and birth outcomes between the two treatment groups. CONCLUSIONS:For women who were overweight or obese, the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes. TRIAL REGISTRATION:Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

OBJECTIVE:To develop a practical evidence based list of clinical risk factors that can be assessed by a clinician at ≤ 16 weeks' gestation to estimate a woman's risk of pre-eclampsia. DESIGN:Systematic review and meta-analysis of cohort studies. DATA SOURCES:PubMed and Embase databases, 2000-15. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Cohort studies with ≥ 1000 participants that evaluated the risk of pre-eclampsia in relation to a common and generally accepted clinical risk factor assessed at ≤ 16 weeks' gestation. DATA EXTRACTION:Two independent reviewers extracted data from included studies. A pooled event rate and pooled relative risk for pre-eclampsia were calculated for each of 14 risk factors. RESULTS:There were 25,356,688 pregnancies among 92 studies. The pooled relative risk for each risk factor significantly exceeded 1.0, except for prior intrauterine growth restriction. Women with antiphospholipid antibody syndrome had the highest pooled rate of pre-eclampsia (17.3%, 95% confidence interval 6.8% to 31.4%). Those with prior pre-eclampsia had the greatest pooled relative risk (8.4, 7.1 to 9.9). Chronic hypertension ranked second, both in terms of its pooled rate (16.0%, 12.6% to 19.7%) and pooled relative risk (5.1, 4.0 to 6.5) of pre-eclampsia. Pregestational diabetes (pooled rate 11.0%, 8.4% to 13.8%; pooled relative risk 3.7, 3.1 to 4.3), prepregnancy body mass index (BMI) >30 (7.1%, 6.1% to 8.2%; 2.8, 2.6 to 3.1), and use of assisted reproductive technology (6.2%, 4.7% to 7.9%; 1.8, 1.6 to 2.1) were other prominent risk factors. CONCLUSIONS:There are several practical clinical risk factors that, either alone or in combination, might identify women in early pregnancy who are at "high risk" of pre-eclampsia. These data can inform the generation of a clinical prediction model for pre-eclampsia and the use of aspirin prophylaxis in pregnancy.

AIMS:The aim of this study was to examine the prevalence of pre-eclampsia in Southern, Eastern, and Northern Finland, and the relationship between history of pre-eclampsia and maternal coronary artery disease (CAD) risk factors. METHODS AND RESULTS:Women aged 25-64 years, who participated in a cross-sectional population survey and had been pregnant (n=3650), were studied. The proportion of women who had ever had pre-eclampsia was lower in Southern (7.9%) compared with Northern Finland (13.9%) (P=0.001), but did not differ from Eastern Finland (11.1%). In the logistic regression model, the age-adjusted prevalence of pre-eclampsia was 1.92-fold in Northern (95% CI: 1.46-2.53, P<0.001) and 1.47-fold in Eastern Finland (95% CI: 1.11-1.96, P=0.008) compared with Southern Finland. The odds ratios (ORs) were 1.70 (95% CI: 1.21-2.38, P=0.002) and 1.16 (95% CI: 0.82-1.64, P=0.40), respectively, when adjusted for age at first birth, current age, parity, body mass index (BMI), increased blood cholesterol, hypertension, diabetes/impaired glucose tolerance, CAD, and mother's myocardial infarction. History of pre-eclampsia was associated with increased blood cholesterol, higher current BMI and blood pressure, and higher current prevalence of hypertension, diabetes/impaired glucose tolerance. CONCLUSIONS:Pre-eclampsia is most prevalent in the Northern part of Finland and could only be partly explained by higher prevalence of CAD risk factors.

Women live longer than men but experience greater disability and a longer period of illness as they age. Despite clear sex differences in aging, the impact of pregnancy and its complications, such as preeclampsia, on aging is an underexplored area of geroscience. This review summarizes our current knowledge about the complex links between pregnancy and age-related diseases, including evidence from epidemiology, clinical research, and genetics. We discuss the relationship between normal and pathological pregnancy and maternal aging, using preeclampsia as a primary example. We review the results of human genetics studies of preeclampsia, including genome wide association studies (GWAS), and attempted to catalog genes involved in preeclampsia as a gateway to mechanisms underlying an increased risk of later life cardio- and neuro- vascular events. Lastly, we discuss challenges in interpreting the GWAS of preeclampsia and provide a functional genomics framework for future research needed to fully realize the promise of GWAS in identifying targets for geroprotective prevention and therapeutics against preeclampsia.

BACKGROUND:Hypertensive disorders of pregnancy are a leading cause of severe maternal morbidity and mortality and confer 4-fold higher perinatal mortality in Black women. Early pregnancy blood pressure patterns may differentiate risk of hypertensive disorders of pregnancy. METHODS:This study identified distinct blood pressure trajectories from 0 to 20 weeks' gestation to evaluate subsequent pregnancy-related hypertension in a retrospective cohort of 174 925 women with no prior hypertension or history of preeclampsia, prenatal care entry ≤14 weeks, and a stillborn or live singleton birth delivered at Kaiser Permanente Northern California hospitals in 2009 to 2019. We used electronic health records to obtain clinical outcomes, covariables, and longitudinal outpatient blood pressure measurements ≤20 weeks' gestation (mean 4.1 measurements). Latent class trajectory modeling identified 6 blood pressure groups: ultra-low-declining(referent), low-declining, moderate-fast-decline, low-increasing, moderate-stable, and elevated-stable. Multivariable logistic regression evaluated trajectory group-associations with the odds of preeclampsia/eclampsia and gestational hypertension' and effect modification by race-ethnicity and prepregnancy body size. RESULTS:Compared with ultra-low-declining, adjusted odds ratios (95% confidence intervals [CIs]) for low-increasing, moderate-stable, and elevated-stable groups were 3.25 (2.7-3.9), 5.3 (4.5-6.3), and 9.2 (7.7-11.1) for preeclampsia/eclampsia' and 6.4 (4.9-8.3), 13.6 (10.5-17.7), and 30.2 (23.2-39.4) for gestational hypertension. Race/ethnicity, and prepregnancy obesity modified the trajectory-group associations with preeclampsia/eclampsia (interaction <0.01), with highest risks for Black, then Hispanic and Asian women for all blood pressure trajectories, and with increasing obesity class. CONCLUSIONS:Early pregnancy blood pressure patterns revealed racial and ethnic differences in associations with preeclampsia/eclampsia risk within equivalent levels and patterns. These blood pressure patterns may improve individual risk stratification permitting targeted surveillance and early mitigation strategies.

In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14-6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94-25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.

Identifying modifiable factors that contribute to preeclampsia risk associated with assisted reproduction can improve maternal health. Vascular dysfunction predates clinical presentation of preeclampsia. Therefore, we examined if a nonphysiological hormonal milieu, a modifiable state, affects maternal vascular health in early pregnancy. Blood pressure, endothelial function, circulating endothelial progenitor cell numbers, lipid levels, and corpus luteum (CL) hormones were compared in a prospective cohort of women with infertility history based on number of CL: 0 CL (programmed frozen embryo transfer [FET], N=18); 1 CL (spontaneous conception [N=16] and natural cycle FET [N=12]); or >3 CL associated with in vitro fertilization [N=11]. Women with 0 or >3 CL lacked the drop in mean arterial blood pressure compared with those with 1 CL (both P=0.05). Reactive hyperemia index was impaired in women with 0 CL compared with 1 CL ( P=0.04) while baseline pulse wave amplitude was higher with > 3 CL compared with 1 CL ( P=0.01) or 0 CL ( P=0.01). Comparing only FET cycles, a lower reactive hyperemia index and a higher augmentation index is noted in FETs with suppressed CL compared with FETs in a natural cycle (both P=0.03). The number of angiogenic and nonangiogenic circulating endothelial progenitor cell numbers was lower in the absence of a CL in FETs ( P=0.01 and P=0.03). Vascular health in early pregnancy is altered in women with aberrant numbers of CL (0 or >3) and might represent insufficient cardiovascular adaptation contributing to an increased risk of preeclampsia.