Aspirin 162 mg versus 81 mg for Preeclampsia Prophylaxis in High-risk Obese Individuals: A Comparative Effectiveness Open Label Randomized Trial (ASPREO).

BACKGROUND: In the United States, leading medical societies recommend 81 mg of aspirin daily for the prevention of preeclampsia (PE) in women at risk, whereas the NICE guidelines in the UK recommend a dose as high as 150 mg of aspirin. Recent data also suggest that in the obese population, inadequate dosing or aspirin resistance may impact the efficacy of aspirin at the currently recommend doses. OBJECTIVE: We evaluated whether daily administration of 162 mg aspirin would be more effective compared to 81 mg in decreasing the rate of PE with severe features in high-risk obese pregnant individuals. STUDY DESIGN: We performed a randomized trial between May 2019 and November 2022. Individuals at 12 to 20-weeks gestational age (GA) with a BMI ≥ 30 kg/m2 at time to enrollment, and at least one of three high risk factors: history of PE in a prior pregnancy, at least stage I hypertension documented in the index pregnancy, pre-gestational diabetes or gestational diabetes diagnosed prior to 20 weeks GA were randomized to either 162 mg or 81 mg of aspirin daily till delivery, participants were not blinded to treatment allocation. Exclusion criteria were: multifetal gestation, known major fetal anomalies, seizure disorder, baseline proteinuria, on aspirin due to other indications, or contraindication to aspirin. The primary outcome was PE with severe features (PE or superimposed PE with severe features, eclampsia, or HELLP). Secondary outcomes included rates of preterm birth due to PE, small for gestational age (SGA), postpartum hemorrhage, abruption, and medication side effects. A sample size of 220 was needed using a preplanned Bayesian analysis of the primary outcome to estimate the posterior probability of benefit or harm with a neutral informative prior. RESULTS: Of 343 eligible individuals, 220 (64.1%) were randomized. The primary outcome was available for 209/220 (95%). Baseline characteristics were similar between groups, median gestational age at enrollment was 15.9 weeks in the 162 mg aspirin group and 15.6 weeks in the 81 mg aspirin group. Enrollment prior to 16 weeks occurred in 55/110 of those assigned to 162 mg and 58/110 of those assigned to 81 mg of aspirin. The primary outcome occurred in 35% in the 162 mg aspirin group and in 40% in the 81 mg aspirin group (posterior relative risk, 0.88; 95% credible interval, 0.64-1.22). Bayesian analysis indicated a 78% probability of a reduction in the primary outcome with 162 mg aspirin compared to 81 mg aspirin dose. Rates of indicated preterm birth due to preeclampsia (21% vs 21%), SGA (6.5% vs 2.9%), abruption (2.8% vs 3.0%) and postpartum hemorrhage (10% vs 8.8%) were similar between groups. Medication adverse effects were also similar. CONCLUSION: Among high-risk obese individuals, there was 78% probability of benefit that 162 mg aspirin compared to 81 mg will decrease the rate of PE with severe features. With a best estimate of a 12% reduction when using 162 mg of aspirin in comparison to 81 mg of aspirin in this population. This trial supports doing a larger multicenter trial.

Well-Child Visits for Early Detection and Management of Maternal Postpartum Hypertensive Disorders.

Importance: Innovative approaches are needed to address the increasing rate of postpartum morbidity and mortality associated with hypertensive disorders. Objective: To determine whether assessing maternal blood pressure (BP) and associated symptoms at time of well-child visits is associated with increased detection of postpartum preeclampsia and need for hospitalization for medical management. Design, Setting, and Participants: This is a pre-post quality improvement (QI) study. Individuals who attended the well-child visits between preimplementation (December 2017 to December 2018) were compared with individuals who enrolled after the implementation of the QI program (March 2019 to December 2019). Individuals were enrolled at an academic pediatric clinic. Eligible participants included birth mothers who delivered at the hospital and brought their newborn for well-child check at 2 days, 2 weeks, and 2 months. A total of 620 individuals were screened in the preintervention cohort and 680 individuals were screened in the QI program. Data was analyzed from March to July 2022. Exposures: BP evaluation and preeclampsia symptoms screening were performed at the time of the well-child visit. A management algorithm-with criteria for routine or early postpartum visits, or prompt referral to the obstetric emergency department-was followed. Main Outcome and Measures: Readmission due to postpartum preeclampsia. Comparisons across groups were performed using a Fisher exact test for categorical variables, and t tests or Mann-Whitney tests for continuous variables. Results: A total of 595 individuals (mean [SD] age, 27.2 [6.1] years) were eligible for analysis in the preintervention cohort and 565 individuals (mean [SD] age, 27.0 [5.8] years) were eligible in the postintervention cohort. Baseline demographic information including age, race and ethnicity, body mass index, nulliparity, and factors associated with increased risk for preeclampsia were not significantly different in the preintervention cohort and postintervention QI program. The rate of readmission for postpartum preeclampsia differed significantly in the preintervention cohort (13 individuals [2.1%]) and the postintervention cohort (29 individuals [5.6%]) (P = .007). In the postintervention QI cohort, there was a significantly earlier time frame of readmission (median [IQR] 10.0 [10.0-11.0] days post partum for preintervention vs 7.0 [6.0-10.5] days post partum for postintervention; P = .001). In both time periods, a total of 42 patients were readmitted due to postpartum preeclampsia, of which 21 (50%) had de novo postpartum preeclampsia. Conclusions and Relevance: This QI program allowed for increased and earlier readmission due to postpartum preeclampsia. Further studies confirming generalizability and mitigating associated adverse outcomes are needed.

Oral combined hydrochlorothiazide and lisinopril vs nifedipine for postpartum hypertension: a comparative-effectiveness pilot randomized controlled trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors and diuretics may be underutilized for postpartum hypertension because of their teratogenicity during pregnancy. OBJECTIVE: We evaluated whether combined oral hydrochlorothiazide and lisinopril therapy produced superior short-term blood pressure control when compared with nifedipine among postpartum individuals with hypertension requiring pharmacologic treatment. STUDY DESIGN: We performed a pilot randomized controlled trial (October 2021 to June 2022) that included individuals with chronic hypertension or hypertensive disorders of pregnancy with 2 systolic blood pressure measurements ≥150 mm Hg and/or diastolic blood pressure measurements ≥100 mm Hg within 72 hours after delivery. Participants were randomized to receive either combined hydrochlorothiazide and lisinopril therapy or nifedipine therapy after stratifying the participants by diagnosis (chronic hypertension vs hypertensive disorders of pregnancy). The primary outcome was stage 2 hypertension (systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg) determined using a home blood pressure monitor on days 7 to 10 after delivery or at readmission to the hospital for blood pressure control. The secondary outcomes included severe maternal morbidity (any of the following: intensive care unit admission; hemolysis, elevated liver enzymes, low platelet count syndrome; eclampsia; stroke; cardiomyopathy; or maternal death), need for intravenous medications after randomization, hospital length of stay, blood pressure during first clinic visit, medication compliance, and adverse events. A pilot trial with 70 individuals was planned given the limited available data on combined hydrochlorothiazide and lisinopril therapy use in postpartum care. We calculated relative risks and 95% credible intervals in an intention-to-treat analysis. Finally, we conducted a preplanned Bayesian analysis to estimate the probability of benefit or harm with a neutral informative prior. RESULTS: Of 111 eligible individuals, 70 (63%) agreed and were randomized (31 in the hydrochlorothiazide and lisinopril group and 36 in the nifedipine group; 3 withdrew consent after randomization), and the characteristics were similar at baseline between the groups. The primary outcome was unavailable for 9 (12.8%) participants. The primary outcome occurred in 27% of participants in the hydrochlorothiazide and lisinopril group and in 43% of the participants in the nifedipine group (posterior adjusted relative risk, 0.74; 95% credible interval, 0.40-1.31). Bayesian analysis indicated an 85% posterior probability of a reduction in the primary outcome with combined hydrochlorothiazide and lisinopril therapy relative to nifedipine treatment. No differences were noted in the secondary outcomes or adverse medication events. CONCLUSION: The results of the pilot trial suggest a high probability that combined hydrochlorothiazide and lisinopril therapy produces superior short-term BP control when compared with nifedipine. These findings should be confirmed in a larger trial.

Racial and Ethnic Disparities among Pregnancies with Chronic Hypertension and Adverse Outcomes.

OBJECTIVE: We aimed to ascertain whether the risk of adverse pregnancy outcomes in the United States among individuals with chronic hypertension differed by maternal race and ethnicity and to assess the temporal trend. STUDY DESIGN: Population-based retrospective study using the U.S. Vital Statistics datasets evaluated pregnancies with chronic hypertension, singleton live births that delivered at 24 to 41 weeks. The coprimary outcomes were a composite maternal adverse outcome (preeclampsia, primary cesarean delivery, intensive care unit admission, blood transfusion, uterine rupture, or unplanned hysterectomy) and a composite neonatal adverse outcome (preterm birth, small for gestational age, Apgar's score <5 at 5 minutes, assisted ventilation> 6 hours, seizure, or death). Multivariable Poisson regression models were used to estimate adjusted relative risks (aRRs) and 95% confidence intervals (CIs). RESULTS: Between 2014 and 2019, the rate of chronic hypertension in pregnancy increased from 1.6 to 2.2%. After multivariable adjustment, an increased risk for the composite maternal adverse outcome was found in Black (aRR = 1.10, 95% CI = 1.09-1.11), Hispanic (aRR = 1.04, 95% CI = 1.02-1.05), and Asian/Pacific Islander (aRR = 1.07, 95% CI = 1.05-1.10), compared with White individuals. Compared with White individuals, the risk of the composite neonatal adverse outcome was higher in Black (aRR = 1.39, 95% CI = 1.37-1.41), Hispanic (aRR = 1.15, 95% CI = 1.13-1.16), Asian/Pacific Islander (aRR = 1.34, 95% CI = 1.31-1.37), and American Indian (aRR = 1.12, 95% CI = 1.07-1.17). The racial and ethnic disparity remained unchanged during the study period. CONCLUSION: We found a racial and ethnic disparity with maternal and neonatal adverse outcomes in pregnancies with chronic hypertension that remained unchanged throughout the study period. KEY POINTS: · Between 2014 and 2019, the rate of chronic hypertension in pregnancy increased.. · Among people with chronic hypertension, there are racial and ethnic disparities in adverse outcomes.. · Black, Hispanic, and Asian/Pacific Islander have a higher risk of the adverse neonatal outcomes..

Management of hypertension in pregnancy.

Hypertensive diseases of pregnancy remain a leading cause of maternal and neonatal morbidity and mortality. Therefore, we sought to review the management of these conditions in pregnancy. In this review we discuss the most updated definitions, different antihypertensives, delivery recommendations and overall goals of management, including their effects on uteroplacental perfusion. We also highlight different medical situations where one antihypertensive may be preferable over others.

Prevalence and Risk Factors for New-Onset Hypertension in Labor.

OBJECTIVE: Little is known about prevalence, risk factors, rate of treatment, or adverse outcomes associated with intrapartum hypertension. Thus, our objective was to describe these findings. STUDY DESIGN: This was a retrospective study of laboring term gestations with no history of hypertensive disorders. Intrapartum blood pressures were reviewed, and women were subdivided based on blood pressures: normal (<140 mm Hg systolic and <90 mm Hg diastolic), mild hypertension (140-159 or 90-109), and severe hypertension (≥ 160 or ≥ 110). Groups were compared using chi-square test and analysis of variance. RESULTS: A total of 724 women were studied during 4 months: 248 (34%) had mild and 69 (10%) had severe hypertension. Severe hypertensives were more likely to be nulliparous, obese, or have received an epidural or oxytocin. There were no cases of eclampsia, stroke, or pulmonary edema in severe hypertensives (95% confidence interval, 0-5). Despite severely elevated pressures, only 4/69 (6%) patients received intravenous antihypertensive therapy, and 3 (4%) required medications at discharge. CONCLUSION: One in 3 women exhibits mild hypertension and 1 in 10 develop severe hypertension in labor. Only 6% of patients received treatment for severe blood pressures. This study highlights lack of treatment of hypertension in labor and further investigation into causes and outcomes of intrapartum elevations of blood pressures.

Adherence to Consensus Guidelines for the Management of Labor Arrest Disorders in a Single Academic Tertiary Care Medical Center.

OBJECTIVE: To evaluate the degree of adherence to the new the American College of Obstetricians and Gynecologists/Society for Maternal-Fetal Medicine guidelines in labor arrest management. STUDY DESIGN: A retrospective study of term, live, singleton deliveries with intrapartum primary cesarean delivery solely for failed induction of labor or labor arrest. Adherence was defined according to the Safe Prevention of the Primary Cesarean Delivery 2014 criteria. We evaluated adherence and compared maternal and perinatal outcomes, delivery time frame, and billing provider. Multivariable Poisson regression models with robust error variance were used to calculate adjusted relative risk (aRR) and 95% confidence interval (CI). RESULTS: Two-hundred six deliveries met the inclusion criteria; 73% were deemed not adherent to the guidelines. The majority of cases were under the care of nonacademic private practice OB/GYN physicians. The adherence rate was higher in the active phase of labor (45%) than in second stage (17%) and latent phase (14%). There were no differences in perinatal outcomes between the two groups. The adherence to guidelines was higher among academic OB/GYN physicians (aRR, 2.24, 95% CI, 1.49-3.36) and during the weekday-night shift (aRR, 1.81, 95% CI, 1.10-2.98). CONCLUSION: Despite recent guidelines aimed to reduce the primary cesarean delivery rate, most cesarean deliveries performed for labor arrest disorders were not adherent to the guidelines.

Liberal versus Indicated Maternal Oxygen Supplementation in Labor: A Before-and-After Trial.

BACKGROUND: Although supplemental oxygen (SO2) is routinely administered to laboring gravidas, benefits and harms are not well studied. OBJECTIVE: This article compares strategies of liberal versus indicated SO2 therapy during labor on cesarean delivery (CD) rate and neonatal outcomes. STUDY DESIGN: A controlled, before-and-after trial of laboring women with term, singleton pregnancies. During an initial 8-week period, maternal SO2 was administered at the discretion of the provider followed by an 8-week period where SO2 was to be given only for protocol indications. RESULTS: Our study included 844 women. There was no difference in number of women receiving SO2 (53% liberal vs. 50% indicated; p = 0.33). For those receiving SO2, there was no difference in SO2 duration (median, 89 minutes [interquartile range, 42-172] vs. 87 minutes [36-152]; p = 0.42). There were no differences in overall CD rate (20% vs. 17%; p = 0.70), CD for nonreassuring fetal status, or use of intrauterine resuscitative measures. There were more 5-minute APGAR < 7 in the indicated group, but no difference in umbilical artery pH < 7.1 or neonatal intensive care unit (NICU) admission. CONCLUSION: Approximately half of women receive SO2 intrapartum regardless of a strategy of liberal or indicated oxygen use. There were no clinically significant differences in outcomes between strategies.

Preterm Preeclampsia with Severe Features: Composite Maternal and Neonatal Morbidities Associated with Fetal Growth Restriction.

OBJECTIVE: The objective of this study was to compare adverse pregnancy outcomes between fetuses with estimated fetal weight (EFW) < 10 to > 10% in women with preterm preeclampsia (PE) with severe features. MATERIALS AND METHODS: All women with preterm PE with severe features and nonanomalous singletons with EFW were identified at a tertiary center. Women with oligohydramnios or absent/reversed umbilical Doppler velocimetry were excluded. Using multivariable analysis, we compared the composite maternal and neonatal morbidities (CMM and CNM) between those with appropriate for gestational age (AGA) fetal growth, defined as EFW at 10 to 90th versus those with fetal growth restriction (FGR), defined as EFW < 10th percentile for gestational age (GA). RESULTS: In this study, 165 patients were included; 112 had EFW at 10th to 90th percentile, and 53 had FGR. Of the 53 with FGR, 33 (62%) had EFW at 5 to 9% for GA and 20 (38%) had EFW < fifth percentile for GA. The CMM was significantly higher among women with FGR versus AGA (29 vs. 7%; p < 0.001). The CNM was significantly higher with FGR versus AGA (20 vs. 6%; p = 0.01). CONCLUSION: Women with preterm PE with severe features and FGR, when compared with those with AGA, have significantly higher risk of CMM and CNM.

Adverse pregnancy outcomes in deliveries prior to, at and beyond 39 weeks; low- and high-risk women.

BACKGROUND: Hypertensive disorders are associated with maternal and neonatal complications. Though they are more common in women with history of prior preeclampsia, they can occur in uncomplicated pregnancies. OBJECTIVE: To determine the proportion of adverse pregnancy outcomes in deliveries prior to or at ≥39 weeks, in uncomplicated singleton nulliparous women (low-risk), as well as women with history of preeclampsia in a prior gestation (high-risk). STUDY DESIGN: This was a secondary analysis from the multicenter trials of low dose aspirin for preeclampsia prevention in low and high-risk pregnancies. The proportion of adverse pregnancy outcomes including hypertensive disorders in pregnancy, small for gestational age, placental abruption, neonatal intensive critical unit admission, and respiratory distress syndrome were evaluated in the two groups. Adverse pregnancy outcomes were stratified by gestational age at delivery (<39 weeks and ≥39 weeks). Descriptive statistics were performed, and results reported as percentages. RESULTS: Three thousand twenty-one pregnancies were included in the low risk group, and 600 in the high risk one. In the low risk group 362 (12%) had hypertensive disorders, with 58% occurring at ≥39 weeks. In the low risk group, the rate of small for gestational age was of 5.9%, placental abruption 0.4%, neonatal intensive care unit admission 9%, and respiratory distress syndrome 3.5%. Sixty percent of all small for gestational age, 31% of all placenta abruptions, 44% of all neonatal intensive care unit admissions and 33% of respiratory distress syndrome cases, occurred at ≥39 weeks in the low risk group. In contrast in the high risk group, 197 (33%) patients developed a hypertensive disorder, with 35.5% occurring at ≥39 weeks. The overall rate of small for gestational age was 9.2%, abruption 2%, neonatal intensive care unit admission 15.5%, and respiratory distress syndrome 5%. In this group, 24% of all small for gestational age, 8.3% of all placental abruptions, 16% of all neonatal intensive care unit admissions and 3% of respiratory distress syndrome cases, were at ≥39 weeks. CONCLUSIONS: We found that in low-risk women, the majority of hypertensive disorders occur at ≥39 weeks, whereas in women with prior preeclampsia the majority develops at <39 weeks. Moreover, a third of all placental abruption occurred at or beyond 39 weeks in the low risk group. Our findings suggest that in low-risk women, a policy of delivery at 39 weeks may prevent most of the adverse outcome that occurs beyond that gestational age cutoff.

Potential of Metformin to Improve Cardiac Risk in Postpartum Women with Gestational Diabetes.

OBJECTIVE: Pregnancy is associated with an increase in total cholesterol, high density lipoproteins (HDL), and low-density lipoproteins (LDL). Postpartum, HDL and LDL decrease over the first 12 weeks postpartum. Oxidized LDL (ox-LDL) is a marker of oxidative stress-related inflammation, which is associated with obesity and also with development of cardiovascular disease. Cardiovascular protection and weight loss are benefits from metformin, especially in women with diabetes. The objective of this study was to compare changes in lipid profiles and biomarkers for obesity during the initial 6 weeks postpartum between women with gestational diabetes mellitus (GDM) treated with metformin versus placebo. METHODS: This was a planned ancillary study of a randomized controlled trial compares metformin versus placebo in women with GDM for postpartum weight loss. Two 3 mL blood samples were collected within 24 h of delivery and 6 weeks postpartum immediately processed after collection then stored at -20°C until completion of clinical trial prior to analysis. Change in the median plasma concentrations of total cholesterol, HDL, ox-LDL, glucose, insulin, leptin, and unacylated ghrelin were compared between study groups. RESULTS: Of the 77 postpartum women were included, 35 received metformin and 42 received placebo. There was less of a reduction in HDL in the metformin group compared to placebo (-2.3 versus -7.5 mg/dL, p = 0.019). In addition, there was a greater reduction in ox-LDL in those receiving metformin (-12.2 versus -3.8 mg/dL, p = 0.038). No other differences were observed in the selected biomarkers evaluated. CONCLUSION: Biomarker levels of HDL and ox-LDL were positively affected during the initial 6 weeks postpartum in GDM women treated with metformin. Additional studies with a longer duration of metformin treatment in the postpartum period are warranted to evaluate long-term potential benefits.

Treatment options for hypertension in pregnancy and puerperium.

INTRODUCTION: Hypertensive disorders have become increasingly prevalent and complicate an increasing number of pregnancies. Therefore it is essential that the medications used to treat these disorders be well understood. Furthermore the management is complicated by special consideration needed for the physiologic changes of pregnancy as well as the consideration for possible adverse fetal effects. Areas covered: We performed a review of the scientific literature of medications used to treat hypertensive disorders in pregnancy. We reviewed the guidelines used by different societies all over the world. We also discussed the pharmacodynamics, pharmacokinetics and possible adverse effects relating to the antihypertensive medications. Finally, we discussed the long-term maternal implications of these diseases. Expert opinion: Overall, we encourage a step-wise approach to treating hypertensive disorders of pregnancy. While making sure to max out the use of one medications prior to shifting to another. Also, it is imperative not to be aggressive with treatment due to risk of compromising utero-placental blood flow. There is research currently involving biomarkers, nano-medicine and the placenta project with hopes of developing new targeted medications with a good fetal safety profile.

Complications of allogeneic hematopoietic stem cell transplantation.

Infection, graft-versus-host disease (GVHD), and to a lesser extent sinusoidal obstructive syndrome (SOS) represent the major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). During the last decade, progress in prevention and treatment of these complications led to improvement in the outcome of these patients. Despite the fact that nonmyeloablative regimens have been increasingly used in elderly patients and in patients with co-morbidities, the nonrelapse related mortality remains a challenge and long-term follow-up is required. The objective of this manuscript is to provide an updated concise review of the complications of AHSCT and of the available treatment interventions.