Pregnancy Outcomes of Nifedipine Compared With Labetalol for Oral Treatment of Mild Chronic Hypertension.

OBJECTIVE: To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. METHODS: We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding. RESULTS: Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine. CONCLUSION: No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02299414.

Optimal Timing of Delivery for Pregnant Individuals With Mild Chronic Hypertension.

OBJECTIVE: To investigate the optimal gestational age to deliver pregnant people with chronic hypertension to improve perinatal outcomes. METHODS: We conducted a planned secondary analysis of a randomized controlled trial of chronic hypertension treatment to different blood pressure goals. Participants with term, singleton gestations were included. Those with fetal anomalies and those with a diagnosis of preeclampsia before 37 weeks of gestation were excluded. The primary maternal composite outcome included death, serious morbidity (heart failure, stroke, encephalopathy, myocardial infarction, pulmonary edema, intensive care unit admission, intubation, renal failure), preeclampsia with severe features, hemorrhage requiring blood transfusion, or abruption. The primary neonatal outcome included fetal or neonatal death, respiratory support beyond oxygen mask, Apgar score less than 3 at 5 minutes, neonatal seizures, or suspected sepsis. Secondary outcomes included intrapartum cesarean birth, length of stay, neonatal intensive care unit admission, respiratory distress syndrome (RDS), transient tachypnea of the newborn, and hypoglycemia. Those with a planned delivery were compared with those expectantly managed at each gestational week. Adjusted odds ratios (aORs) with 95% CIs are reported. RESULTS: We included 1,417 participants with mild chronic hypertension; 305 (21.5%) with a new diagnosis in pregnancy and 1,112 (78.5%) with known preexisting hypertension. Groups differed by body mass index (BMI) and preexisting diabetes. In adjusted models, there was no association between planned delivery and the primary maternal or neonatal composite outcome in any gestational age week compared with expectant management. Planned delivery at 37 weeks of gestation was associated with RDS (7.9% vs 3.0%, aOR 2.70, 95% CI, 1.40-5.22), and planned delivery at 37 and 38 weeks was associated with neonatal hypoglycemia (19.4% vs 10.7%, aOR 1.97, 95% CI, 1.27-3.08 in week 37; 14.4% vs 7.7%, aOR 1.82, 95% CI, 1.06-3.10 in week 38). CONCLUSION: Planned delivery in the early-term period compared with expectant management was not associated with a reduction in adverse maternal outcomes. However, it was associated with increased odds of some neonatal complications. Delivery timing for individuals with mild chronic hypertension should weigh maternal and neonatal outcomes in each gestational week but may be optimized by delivery at 39 weeks.

Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Neonatal outcomes in term and preterm infants following adjunctive azithromycin antibiotic prophylaxis for non-elective cesarean delivery.

OBJECTIVE: It is currently unknown whether adjunctive azithromycin prophylaxis at the time of non-elective cesarean has differential effects on neonatal outcomes in the context of prematurity. The objective of this study was to compare whether neonatal outcomes differ in term and preterm infants exposed to adjunctive azithromycin prophylaxis before non-elective cesarean delivery. STUDY DESIGN: A planned secondary analysis of a multi-center randomized controlled trial that enrolled women with singleton pregnancies ≥24 weeks gestation undergoing non-elective cesarean delivery (during labor or ≥4 h after membrane rupture). Women received standard antibiotic prophylaxis and were randomized to either adjunctive azithromycin (500 mg) or placebo. The primary composite outcome was neonatal death, suspected or confirmed neonatal sepsis, and serious neonatal morbidities (NEC, PVL, IVH, BPD). Secondary outcomes included NICU admission, neonatal readmission, culture positive infections and prevalence of resistant organisms. Odds ratios (OR) for the effect of azithromycin versus placebo were compared between gestational age strata (preterm [less than 37 weeks] versus term [37 weeks or greater]). Tests of interaction examined homogeneity of treatment effect with gestational age. RESULTS: The analysis includes 2,013 infants, 226 preterm (11.2%) and 1,787 term. Mean gestational ages were 34 and 39.5 weeks, respectively. Within term and preterm strata, maternal and delivery characteristics were similar between the azithromycin and placebo groups. There was no difference in the odds of composite neonatal outcome between those exposed to azithromycin versus placebo in preterm neonates (OR 0.82, 95% CI 0.48-1.41) and in term neonates (OR 1.06, 95% CI 0.77-1.46), with no difference between gestational age strata (p = 0.42). Analysis of secondary outcomes also revealed no differences in treatment effects within or between gestational age strata. CONCLUSION: Exposure to adjunctive azithromycin antibiotic prophylaxis for non-elective cesarean delivery does not increase neonatal morbidity or mortality in term or preterm infants. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT01235546.

Mean Arterial Pressure and Neonatal Outcomes in Pregnancies Complicated by Mild Chronic Hypertension.

OBJECTIVE: To estimate the association between mean arterial pressure during pregnancy and neonatal outcomes in participants with chronic hypertension using data from the CHAP (Chronic Hypertension and Pregnancy) trial. METHODS: A secondary analysis of the CHAP trial, an open-label, multicenter randomized trial of antihypertensive treatment in pregnancy, was conducted. The CHAP trial enrolled participants with mild chronic hypertension (blood pressure [BP] 140-159/90-104 mm Hg) and singleton pregnancies less than 23 weeks of gestation, randomizing them to active treatment (maintained on antihypertensive therapy with a goal BP below 140/90 mm Hg) or standard treatment (control; antihypertensives withheld unless BP reached 160 mm Hg systolic BP or higher or 105 mm Hg diastolic BP or higher). We used logistic regression to measure the strength of association between mean arterial pressure (average and highest across study visits) and to select neonatal outcomes. Unadjusted and adjusted odds ratios (per 1-unit increase in millimeters of mercury) of the primary neonatal composite outcome (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage grade 3 or 4) and individual secondary outcomes (neonatal intensive care unit admission [NICU], low birth weight [LBW] below 2,500 g, and small for gestational age [SGA]) were calculated. RESULTS: A total of 2,284 participants were included: 1,155 active and 1,129 control. Adjusted models controlling for randomization group demonstrated that increasing average mean arterial pressure per millimeter of mercury was associated with an increase in each neonatal outcome examined except NEC, specifically neonatal composite (adjusted odds ratio [aOR] 1.12, 95% CI, 1.09-1.16), NICU admission (aOR 1.07, 95% CI, 1.06-1.08), LBW (aOR 1.12, 95% CI, 1.11-1.14), SGA below the fifth percentile (aOR 1.03, 95% CI, 1.01-1.06), and SGA below the 10th percentile (aOR 1.02, 95% CI, 1.01-1.04). Models using the highest mean arterial pressure as opposed to average mean arterial pressure also demonstrated consistent associations. CONCLUSION: Increasing mean arterial pressure was positively associated with most adverse neonatal outcomes except NEC. Given that the relationship between mean arterial pressure and adverse pregnancy outcomes may not be consistent at all mean arterial pressure levels, future work should attempt to further elucidate whether there is an absolute threshold or relative change in mean arterial pressure at which fetal benefits are optimized along with maternal benefits. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans.

In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC0→24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) µM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) µM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC0 → 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) µM*hour, P < 0.001). NAM renal clearance (CLR ; P = 0.184), MNA CLR (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CLR was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination.

Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.

Importance: Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. Objective: To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. Design, Setting, and Participants: This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Intervention: Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. Main Outcome and Measures: The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Results: Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Conclusions and Relevance: Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Trial Registration: ClinicalTrials.gov Identifier: NCT02932475.

Characteristics and Outcomes of Patients With Pregnancy-Related End-Stage Kidney Disease.

Importance: The incidence of pregnancy-related acute kidney injury is increasing and is associated with significant maternal morbidity including progression to end-stage kidney disease (ESKD). Little is known about characteristics and long-term outcomes of patients who develop pregnancy-related ESKD. Objectives: To examine the characteristics and clinical outcomes of patients with pregnancy-related ESKD and to investigate associations between pre-ESKD nephrology care and outcomes. Design, Setting, and Participants: This was a cohort study of 183 640 reproductive-aged women with incident ESKD between January 1, 2000, and November 20, 2020, from the US Renal Data System and maternal data from births captured in the US Centers for Disease Control and Prevention publicly available natality data. Data were analyzed from December 2022 to June 2023. Exposure: Pregnancy-related primary cause of ESKD, per International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes reported at ESKD onset by the primary nephrologist on Centers for Medicare and Medicaid Services form 2728. Main Outcomes Measures: Multivariable Cox proportional hazards and competing risk models were constructed to examine time to (1) mortality, (2) access to kidney transplant (joining the waiting list or receiving a live donor transplant), and (3) receipt of transplant after joining the waitlist. Results: A total of 341 patients with a pregnancy-related primary cause of ESKD were identified (mean [SD] age 30.2 [7.3]). Compared with the general US birthing population, Black patients were overrepresented among those with pregnancy-related ESKD (109 patients [31.9%] vs 585 268 patients [16.2%]). In adjusted analyses, patients with pregnancy-related ESKD had similar or lower hazards of mortality compared with those with glomerulonephritis or cystic kidney disease (adjusted hazard ratio [aHR], 0.96; 95% CI, 0.76-1.19), diabetes or hypertension (aHR, 0.49; 95% CI, 0.39-0.61), or other or unknown primary causes of ESKD (aHR, 0.60; 95% CI, 0.48-0.75). Despite this, patients with pregnancy-related ESKD had significantly lower access to kidney transplant compared with those with other causes of ESKD, including (1) glomerulonephritis or cystic kidney disease (adjusted subhazard ratio [aSHR], 0.51; 95% CI, 0.43-0.66), (2) diabetes or hypertension (aSHR, 0.81; 95% CI, 0.67-0.98), and (3) other or unkown cause (aSHR, 0.82; 95% CI, 0.67-0.99). Those with pregnancy-related ESKD were less likely to have nephrology care or have a graft or arteriovenous fistula placed before ESKD onset (nephrology care: adjusted relative risk [aRR], 0.47; 95% CI, 0.40-0.56; graft or arteriovenous fistula placed: aRR, 0.31; 95% CI, 0.17-0.57). Conclusion and Relevance: In this study, those with pregnancy-related ESKD had reduced access to transplant and nephrology care, which could exacerbate existing disparities in a disproportionately Black population. Increased access to care could improve quality of life and health outcomes among these young adults with high potential for long-term survival.

Aspirin in Pregnancy.

Preeclampsia is associated with significant perinatal morbidity and mortality. Aspirin has been long purported and extensively studied for prevention of preeclampsia. For this reason, the U.S. Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine recommend its use in pregnancy for preeclampsia prevention in those at high risk. Yet, much controversy exists regarding optimal use in pregnancy with guidelines across global organizations varying. In this narrative review, we summarize the published literature related to the safety, optimal dose, and timing and duration of use of aspirin, as well as other indications for which aspirin has been studied in pregnancy.

Oral health during pregnancy: an analysis of interprofessional guideline awareness and practice behaviors among prenatal and oral health providers.

BACKGROUND: Poor oral health during pregnancy has significant implications across the life course, including increased risk for adverse pregnancy, birth outcomes, and the development of early childhood caries. In efforts to improve perinatal oral health in the United States, a set of national interprofessional guidelines were developed that include recommended practice behaviors for both oral health providers and prenatal providers. The purpose of this study was to examine guideline awareness, familiarity, beliefs, and practice behaviors among both provider types. METHODS: Prenatal providers and oral health providers in Florida were recruited via random and convenience sampling to complete an online survey guided by the Consolidated Framework for Implementation Research (CFIR) and the Cabana Framework. The present analysis focused on the Individuals Involved domain (CFIR), awareness and familiarity with the guidelines (Cabana Framework), confidence, and practice behaviors as recommended by prenatal oral health guidelines (assess, advise, refer, share/coordinate). Data were analyzed using chi-square tests, independent samples t-tests, Pearson correlation coefficients, and one-way analysis of variance (ANOVA) and analyses were conducted in SPSS. RESULTS: Prenatal and oral health providers did not differ significantly in their awareness of the guidelines, but awareness was significantly associated with three of the four practice behaviors for prenatal providers. Familiarity with the guidelines was significantly higher among oral health providers and was associated with all four practice behaviors for both provider types. Five out of ten oral health belief items were significantly associated with practicing the guidelines among prenatal providers, but only two among oral health providers. Confidence in performing the practice behaviors was significantly associated with guideline implementation among both groups. Years in practice was significantly associated with performing practice behaviors for prenatal providers, but not for oral health providers. CONCLUSIONS: Our findings highlight the importance of professional organizations and the role of clinical guidelines on practice behaviors. Although provider education is a key implementation strategy, organizational and policy-level system changes could also be critical in supporting practice behaviors.

Perinatal Outcomes Associated With Management of Stage 1 Hypertension.

OBJECTIVE: To evaluate the association between maternal blood pressure (BP) below 130/80 mm Hg compared with 130-139/80-89 mm Hg and pregnancy outcomes. METHODS: We conducted a planned secondary analysis of CHAP (Chronic Hypertension and Pregnancy), an open label, multicenter, randomized controlled trial. Participants with mean BP below 140/90 mm Hg were grouped as below 130/80 mm Hg compared with 130-139/80-89 mm Hg by averaging postrandomization clinic BP throughout pregnancy. The primary composite outcome was preeclampsia with severe features, indicated preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The secondary outcome was small for gestational age (SGA). RESULTS: Of 2,408 patients in CHAP, 2,096 met study criteria; 1,328 had mean BP 130-139/80-89 mm Hg and 768 had mean BP below 130/80 mm Hg. Participants with mean BP below 130/80 mm Hg were more likely to be older, on antihypertensive medication, in the active treatment arm, and to have lower BP at enrollment. Mean clinic BP below 130/80 mm Hg was associated with lower frequency of the primary outcome (16.0% vs 35.8%, adjusted relative risk 0.45; 95% CI 0.38-0.54) as well as lower risk of severe preeclampsia and indicated birth before 35 weeks of gestation. There was no association with SGA. CONCLUSION: In pregnant patients with mild chronic hypertension, mean BP below 130/80 mm Hg was associated with improved pregnancy outcomes without increased risk of SGA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT02299414.

Breastfeeding initiation and duration among people with mild chronic hypertension: a secondary analysis of the Chronic Hypertension and Pregnancy trial.

BACKGROUND: Increased duration of breastfeeding improves maternal cardiovascular health and may be especially beneficial in high-risk populations, such as those with chronic hypertension. Others have shown that individuals with hypertension are less likely to breastfeed, and there has been limited research aimed at supporting breastfeeding goals in this population. The impact of perinatal blood pressure control on breastfeeding outcomes among people with chronic hypertension is unknown. OBJECTIVE: This study aimed to evaluate whether breastfeeding initiation and short-term duration assessed at the postpartum clinic visit differed according to perinatal blood pressure treatment strategy (targeting blood pressure <140/90 mm Hg vs reserving antihypertensive treatment for blood pressure ≥160/105 mm Hg). STUDY DESIGN: We performed a secondary analysis of the Chronic Hypertension and Pregnancy trial. This was an open-label, multicenter, randomized trial where pregnant participants with mild chronic hypertension were randomized to receive antihypertensive medications with goal blood pressure <140/90 mm Hg (active treatment) or deferred treatment until blood pressure ≥160/105 mm Hg (control). The primary outcome was initiation and duration of breastfeeding, assessed at the postpartum clinic visit. We performed bivariate analyses and log-binomial and cumulative logit regression models, adjusting models for variables that were unbalanced in bivariate analyses. We performed additional analyses to explore the relationship between breastfeeding duration and blood pressure measurements at the postpartum visit. RESULTS: Of the 2408 participants from the Chronic Hypertension and Pregnancy trial, 1444 (60%) attended the postpartum study visit and provided breastfeeding information. Participants in the active treatment group had different body mass index class distribution and earlier gestational age at enrollment, and (by design) were more often discharged on antihypertensives. Breastfeeding outcomes did not differ significantly by treatment group. In the active and control treatment groups, 563 (77.5%) and 561 (78.1%) initiated breastfeeding, and mean durations of breastfeeding were 6.5±2.3 and 6.3±2.1 weeks, respectively. The probability of ever breastfeeding (adjusted relative risk, 0.99; 95% confidence interval, 0.93-1.05), current breastfeeding at postpartum visit (adjusted relative risk, 1.01; 95% confidence interval, 0.94-1.10), and weeks of breastfeeding (adjusted odds ratio, 0.87; 95% confidence interval, 0.68-1.12) did not differ by treatment group. Increased duration (≥2 vs <2 weeks) of breastfeeding was associated with slightly lower blood pressure measurements at the postpartum visit, but these differences were not significant in adjusted models. CONCLUSION: In a secondary analysis of the cohort of Chronic Hypertension and Pregnancy trial participants who attended the postpartum study visit and provided breastfeeding information (60% of original trial participants), breastfeeding outcomes did not differ significantly by treatment group. This suggests that maintaining goal blood pressure <140/90 mm Hg throughout the perinatal period is associated with neither harm nor benefit for short-term breastfeeding goals. Further study is needed to understand long-term breastfeeding outcomes among individuals with chronic hypertension and how to support this population in achieving their breastfeeding goals.

Postpartum readmission for hypertension and pre-eclampsia: development and validation of a predictive model.

OBJECTIVE: To develop a model for predicting postpartum readmission for hypertension and pre-eclampsia at delivery discharge and assess external validation or model transportability across clinical sites. DESIGN: Prediction model using data available in the electronic health record from two clinical sites. SETTING: Two tertiary care health systems from the Southern (2014-2015) and Northeastern USA (2017-2019). POPULATION: A total of 28 201 postpartum individuals: 10 100 in the South and 18 101 in the Northeast. METHODS: An internal-external cross validation (IECV) approach was used to assess external validation or model transportability across the two sites. In IECV, data from each health system were first used to develop and internally validate a prediction model; each model was then externally validated using the other health system. Models were fit using penalised logistic regression, and accuracy was estimated using discrimination (concordance index), calibration curves and decision curves. Internal validation was performed using bootstrapping with bias-corrected performance measures. Decision curve analysis was used to display potential cut points where the model provided net benefit for clinical decision-making. MAIN OUTCOME MEASURES: The outcome was postpartum readmission for either hypertension or pre-eclampsia <6 weeks after delivery. RESULTS: The postpartum readmission rate for hypertension and pre-eclampsia overall was 0.9% (0.3% and 1.2% by site, respectively). The final model included six variables: age, parity, maximum postpartum diastolic blood pressure, birthweight, pre-eclampsia before discharge and delivery mode (and interaction between pre-eclampsia × delivery mode). Discrimination was adequate at both health systems on internal validation (c-statistic South: 0.88; 95% confidence interval [CI] 0.87-0.89; Northeast: 0.74; 95% CI 0.74-0.74). In IECV, discrimination was inconsistent across sites, with improved discrimination for the Northeastern model on the Southern cohort (c-statistic 0.61 and 0.86, respectively), but calibration was not adequate. Next, model updating was performed using the combined dataset to develop a new model. This final model had adequate discrimination (c-statistic: 0.80, 95% CI 0.80-0.80), moderate calibration (intercept -0.153, slope 0.960, Emax 0.042) and provided superior net benefit at clinical decision-making thresholds between 1% and 7% for interventions preventing readmission. An online calculator is provided here. CONCLUSIONS: Postpartum readmission for hypertension and pre-eclampsia may be accurately predicted but further model validation is needed. Model updating using data from multiple sites will be needed before use across clinical settings.

Insulin Elevates ID2 Expression in Trophoblasts and Aggravates Preeclampsia in Obese ASB4-Null Mice.

Obesity is a risk factor for preeclampsia. We investigated how obesity influences preeclampsia in mice lacking ankyrin-repeat-and-SOCS-box-containing-protein 4 (ASB4), which promotes trophoblast differentiation via degrading the inhibitor of DNA-binding protein 2 (ID2). Asb4-/- mice on normal chow (NC) develop mild preeclampsia-like phenotypes during pregnancy, including hypertension, proteinuria, and reduced litter size. Wild-type (WT) and Asb4-/- females were placed on a high-fat diet (HFD) starting at weaning. At the age of 8-9 weeks, they were mated with WT or Asb4-/- males, and preeclamptic phenotypes were assessed. HFD-WT dams had no obvious adverse outcomes of pregnancy. In contrast, HFD-Asb4-/- dams had significantly more severe preeclampsia-like phenotypes compared to NC-Asb4-/- dams. The HFD increased white fat weights and plasma leptin and insulin levels in Asb4-/- females. In the HFD-Asb4-/- placenta, ID2 amounts doubled without changing the transcript levels, indicating that insulin likely increases ID2 at a level of post-transcription. In human first-trimester trophoblast HTR8/SVneo cells, exposure to insulin, but not to leptin, led to a significant increase in ID2. HFD-induced obesity markedly worsens the preeclampsia-like phenotypes in the absence of ASB4. Our data indicate that hyperinsulinemia perturbs the timely removal of ID2 and interferes with proper trophoblast differentiation, contributing to enhanced preeclampsia.

Antepartum periodontitis treatment and risk of offspring screening positive for autism spectrum disorder.

BACKGROUND: To evaluate if treating maternal periodontal disease, a pro-inflammatory condition, during pregnancy (intervention) compared to after pregnancy (control) reduces the likelihood of offspring screening positive for autism spectrum disorder (ASD). METHODS: In a follow-up study to the MOTOR randomized trial, we compared rates of positive screens on the Modified Checklist for Autism in Toddlers (M-CHAT) among n = 306 two-year-old toddlers and correlated findings to maternal and cord blood pro-inflammatory interleukin-6 (IL-6). RESULTS: Toddlers in the intervention group had decreased risk of a positive M-CHAT screen (adjusted RR = 0.53, 95% CI 0.29-0.99). Toddlers screening positive compared to negative had higher mean IL-6 in cord blood (1.58 ± 1.14 vs. 1.09 ± 0.72 p = 0.001) and maternal IL-6 change from baseline (1.30 ± 0.61 vs 0.96 ± 0.62 p = 0.03). CONCLUSIONS: Treating periodontal disease during pregnancy reduced risk of a positive ASD screen. M-CHAT positivity was associated with increased IL-6 in maternal and cord blood. CLINICAL TRIAL: Trial Registration numbers: Clinicaltrials.gov NCT03423836.

Sex-Dependent Differences in Mouse Placental Gene Expression following a Maternal High-Fat Diet.

OBJECTIVE: In utero fetal exposures may have sex-specific placental gene responses. Our objective was to measure sex-based differences in placental gene expression from dams fed high-fat diet (HFD) versus control diet (CD). STUDY DESIGN: We fed timed pregnant Friend virus B-strain dams either a CD (n = 5) or an HFD (n = 5). We euthanized dams on embryonic day 17.5 to collect placentas. We extracted placental RNA and hybridized it to a customized 96-gene Nanostring panel focusing on angiogenic, inflammatory, and growth genes. We compared normalized gene expression between CD and HFD, stratified by fetal sex, using analysis of variance. Pathway analysis was used to further interpret the genomic data. RESULTS: Pups from HFD-fed dams were heavier than those from CD-fed dams (0.97 ± 0.06 vs 0.84 ± 0.08 g, p < 0.001). Male pups were heavier than females in the HFD (0.99 ± 0.05 vs 0.94 ± 0.06 g, p = 0.004) but not CD (0.87 ± 0.08 vs 0.83 ± 0.07 g, p = 0.10) group. No sex-based differences in placental gene expression in CD-fed dams were observed. Among HFD-fed dams, placentas from female pups exhibited upregulation of 15 genes (q = 0.01). Network analyses identified a cluster of genes involved in carbohydrate metabolism, cellular function and maintenance, and endocrine system development and function (p = 1 × 10-23). The observed female-specific increased gene expression following in utero HFD exposure was predicted to be regulated by insulin (p = 5.79 × 10-13). CONCLUSION: In female compared with male pups, in utero exposure to HFD upregulated placental gene expression in 15 genes predicted to be regulated by insulin. Sex-specific differences in placental expression of these genes should be further investigated. KEY POINTS: · Male pups were heavier than female pups at the time of sacrifice when dams were fed an HFD.. · HFD was associated with upregulated gene expression in female placentas.. · Female-specific increased gene was predicted to be regulated by insulin..

Single-center serological surveillance of SARS-CoV-2 in pregnant patients presenting to labor and delivery.

OBJECTIVE: To measure maternal/fetal SARS-CoV-2 antibody levels. METHODS: A prospective observational study of eligible parturients admitted to the hospital for infant delivery was conducted between April and September 2020. SARS-CoV-2 antibody levels were measured in maternal and umbilical cord specimens using an in-house ELISA based on the receptor-binding domain (RBD) of the spike protein. Among SARS-CoV-2 seropositive patients, spike RBD antibody isotypes (IgG, IgM, and IgA) and ACE2 inhibiting antibodies were measured. RESULTS: In total, 402 mothers were enrolled and spike RBD antibodies in 388 pregnancies were measured (336 maternal and 52 cord specimens). Of them, 19 were positive (15 maternal, 4 cord) resulting in a seroprevalence estimate of 4.8% (95% confidence interval 2.9-7.4). Of the 15 positive maternal specimens, all had cord blood tested. Of the 15 paired specimens, 14 (93.3%) were concordant. Four of the 15 pairs were from symptomatic mothers, and all four showed high spike-ACE2 blocking antibody levels, compared to only 3 of 11 (27.3%) from asymptomatic mothers. CONCLUSION: A variable antibody response to SARS-CoV-2 in pregnancy among asymptomatic infections compared to symptomatic infections was found, the significance of which is unknown. Although transfer of transplacental neutralizing antibodies occurred, additional research is needed to determine how long maternal antibodies can protect the infant against SARS-CoV-2 infection.

Addressing the Gender Gap in Academic Success: A History of the University of North Carolina Association of Professional Women in the Medical Sciences.

Despite efforts at many institutions, nationally, women still lag behind their male counterparts in leadership, promotion, and seniority. In this paper, we describe the efforts to improve the environment for women faculty at one large academic medical center through the creation of an Association of Professional Women in Medical Sciences. Over the years, the group has helped influence policies that directly affect women faculty, provided high-yield programming on topics related to women's success, and created interprofessional networking opportunities for women faculty. We describe the challenges and successes of this group to serve as a model and inspiration for other institutions.

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort.

OBJECTIVES: Preterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment. METHODS: The ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p < .05). RESULTS: The model predicted improvements for all outcomes. RP-CM decreased neonatal and maternal hospital stay by 19% (p = .029) and 8.5% (p = .001), respectively; neonatal costs' point estimate by 16% (p = .098); and moderate-to-severe neonatal morbidity/mortality by 29% (p = .025). RP-MM strengthened observed reductions and significance. Point estimates of benefit did not differ by race/ethnicity. CONCLUSIONS: Modeled evaluation of a biomarker-based test-and-treat strategy in a diverse population predicts clinically and economically meaningful improvements in neonatal and maternal outcomes.

Preterm birth, defined as delivery before 37 weeks' gestation, is the leading cause of illness and death in newborns. In the United States, more than 10% of infants are born prematurely, and this rate is substantially higher in lower-income, inner-city and Black populations. Prematurity associates with greatly increased risk of short- and long-term medical complications and can generate significant costs throughout the lives of affected children. Annual U.S. health care costs to manage short- and long-term prematurity complications are estimated to exceed $25 billion.Clinical interventions, including case management (increased patient outreach, education and specialist care), pharmacological treatment and their combination can provide benefit to pregnancies at higher risk for preterm birth. Early and sensitive risk detection, however, remains a challenge.We have developed and validated a proteomic biomarker risk predictor for early identification of pregnancies at increased risk of preterm birth. The ACCORDANT study modeled treatments with real-world patient data from a racially and ethnically diverse U.S. population to compare the benefits of risk predictor testing plus clinical intervention for higher-risk pregnancies versus no testing and standard care. Measured outcomes included neonatal and maternal length of hospital stay, associated costs and neonatal morbidity and mortality. The model projected improved outcomes and reduced costs across all subjects, including ethnic and racial minority populations, when predicted higher-risk pregnancies were treated using case management with or without pharmacological treatment. The biomarker risk predictor shows high potential to be a clinically important component of risk stratification for pregnant women, leading to tangible gains in reducing the impact of preterm birth.