Treatment for Mild Chronic Hypertension during Pregnancy.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

Prenatal Infection by Respiratory Viruses Is Associated with Immunoinflammatory Responses in the Fetus.

Rationale: Respiratory viral infections can be transmitted from pregnant women to their offspring, but frequency, mechanisms, and postnatal outcomes remain unclear. Objectives: The aims of this prospective cohort study were to compare the frequencies of transplacental transmission of respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), analyze the concentrations of inflammatory mediators in maternal and fetal blood, and assess clinical consequences. Methods: We recruited pregnant women who developed upper respiratory infections or tested positive for SARS-CoV-2. Maternal and cord blood samples were collected at delivery. Study questionnaires and electronic medical records were used to document demographic and medical information. Measurements and Main Results: From October 2020 to June 2022, droplet digital PCR was used to test blood mononuclear cells from 103 mother-baby dyads. Twice more newborns in our sample were vertically infected with RSV compared with SARS-CoV-2 (25.2% [26 of 103] vs. 11.9% [12 of 101]; P = 0.019). Multiplex ELISA measured significantly increased concentrations of several inflammatory cytokines and chemokines in maternal and cord blood from newborns, with evidence of viral exposure in utero compared with control dyads. Prenatal infection was associated with significantly lower birth weight and postnatal weight growth. Conclusions: Data suggest a higher frequency of vertical transmission for RSV than SARS-CoV-2. Intrauterine exposure is associated with fetal inflammation driven by soluble inflammatory mediators, with expression profiles dependent on the virus type and affecting the rate of viral transmission. Virus-induced inflammation may have pathological consequences already in the first days of life, as shown by its effects on birth weight and postnatal weight growth.

Blood pressure control in pregnant patients with chronic hypertension and diabetes: should <130/80 be the target?

BACKGROUND: The Chronic Hypertension and Pregnancy Study demonstrated that a target blood pressure of <140/90 mm Hg during pregnancy is associated with improved perinatal outcomes. Outside of pregnancy, pharmacologic therapy for patients with diabetes and hypertension is adjusted to a target blood pressure of <130/80 mm Hg. During pregnancy, patients with both diabetes and chronic hypertension may also benefit from tighter control with a target blood pressure <130/80 mm Hg. OBJECTIVE: We compared perinatal outcomes in patients with hypertension and diabetes who achieved blood pressure <130/80 vs 130 to 139/80 to 89 mm Hg. STUDY DESIGN: This was a secondary analysis of a multcenter randomized controlled trial. Participants were included in this secondary analysis if they had diabetes diagnosed prior to pregnancy or at <20 weeks of gestation and at least 2 recorded blood pressure measurements prior to delivery. Average systolic and diastolic blood pressure were calculated using ambulatory antenatal blood pressures. The primary composite outcome was preeclampsia with severe features, indicated preterm birth <35 weeks, or placental abruption. Secondary outcomes were components of the primary outcome, cesarean delivery, fetal or neonatal death, neonatal intensive care unit admission, and small for gestational age. Comparisons were made between those with an average systolic blood pressure <130 mm Hg and average diastolic blood pressure <80 mm Hg and those with an average systolic blood pressure 130 to 139 mm Hg or diastolic blood pressure 80 to 89 mm Hg using Student's t test and chi-squared tests. Multivariable log-binomial regression models were used to evaluate risk ratios between blood pressure groups for dichotomous outcomes while accounting for baseline covariates. RESULTS: Of 434 participants included, 150 (34.6%) had an average blood pressure less than 130/80 mm Hg. Participants with an average blood pressure less than 130/80 were more likely to be on antihypertensive medications at the start of pregnancy and more likely to have newly diagnosed diabetes mellitus prior to 20 weeks. Participants with an average blood pressure less than 130/80 mm Hg were less likely to have the primary adverse perinatal outcome (19.3% vs 46.5%, adjusted relative risk 0.43, 95% confidence interval 0.30-0.61, P<.01), with decreased risks specifically of preeclampsia with severe features (adjusted relative risk 0.35, 95% confidence interval 0.23-0.54) and indicated preterm birth prior to 35 weeks (adjusted relative risk 0.44, 95% confidence interval 0.24-0.79). The risk of neonatal intensive care unit admission was lower in the lower blood pressure group (adjusted relative risk 0.74, 95% confidence interval 0.59-0.94). No differences were noted in cesarean delivery (adjusted relative risk 1.04, 95% confidence interval 0.90-1.20), fetal or neonatal death (adjusted relative risk 0.59, 95% confidence interval 0.12-2.92). Small for gestational age less than the 10th percentile was lower in the lower blood pressure group (adjusted relative risk 0.37, 95% confidence interval 0.14-0.96). CONCLUSION: In those with chronic hypertension and diabetes prior to 20 weeks, achieving an average goal blood pressure of <130/80 mm Hg may be associated with improved perinatal outcomes.

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.

Value of HbA1c in Obese Women with Gestational Diabetes.

OBJECTIVE: We sought to assess the association of hemoglobin A1c (HbA1c) with adverse perinatal outcomes in obese women with gestational diabetes mellitus (GDM). STUDY DESIGN: This was a secondary analysis of a multicenter randomized controlled trial assessing early (14-20 weeks) versus routine (24-28 weeks) screening for GDM in obese women. Women were included if they were diagnosed with GDM at either time during pregnancy and had a HbA1c result available. The primary exposure was HbA1c at 24 to 28 weeks. The primary outcome was a composite of macrosomia, primary cesarean, pregnancy-induced hypertension, shoulder dystocia, neonatal hypoglycemia, or hyperbilirubinemia. Receiver operating characteristics (ROC) curves were used to assess the association of HbA1c with the composite outcome. The Liu method was used to select an optimal HbA1c cutoff, and the incidence of the outcome compared. RESULTS: Of 125 women with GDM, 93 (74%) had a HbA1c at 24 to 28 weeks and 103 (82.4%) had a HbA1c at 14 to 20 weeks. Baseline characteristics were balanced between groups above and below the cutoff. The area under the ROC curve for HbA1c and its association with the adverse perinatal composite outcome was 0.6 (95% confidence interval [CI]: 0.5-0.7). The frequency of the primary outcome was similar among women with low and high HbA1c at 24 to 28 weeks (adjusted relative risk, 1.12, 95% CI: 0.97-1.29). Compared with women with a decreasing HbA1c during pregnancy, women with a stable or increasing HbA1c did not have a significant increase in the primary adverse perinatal composite outcome. However, the frequency of preterm delivery was higher among women with stable or increasing HbA1c compared with those with a decreasing HbA1c (26.1 vs. 6.7%, p = 0.03). CONCLUSION: A single HbA1c in women with GDM is not associated with a composite perinatal adverse outcome, but a HbA1c that increases or remains stable between 14 to 20 and 24 to 28 weeks is associated with an increase in preterm delivery. KEY POINTS: · A single HbA1c in GDM is not associated with a composite perinatal adverse outcome.. · HbA1c that increases or remains stable may be associated with an increase in preterm delivery.. · HbA1c at 24 to 28 weeks was not significantly associated with the adverse perinatal composite outcome..

Timing of Maternal Discharge after Cesarean Delivery and Risk of Maternal Readmission.

OBJECTIVE: Despite legislation and hospital policies (present in some institutions) mandating a minimum length of stay in an effort to decrease the frequency of hospital readmissions, the effectiveness of this approach remains uncertain.We hypothesized that following cesarean delivery (CD), the rates of maternal readmission or unscheduled health care visits are lower in patients discharged on postoperative day (POD) 3 or ≥4 as compared with those discharged earlier on POD 2. METHODS: This is a secondary analysis of a multicenter randomized trial comparing adjunctive azithromycin for unscheduled CD to prevent infection. Groups were compared based on the duration of hospitalization measured in days from delivery (POD 0) to day of discharge and categorized as POD 2, 3, and ≥4. The primary outcome was the composite of any maternal postpartum readmission, unscheduled clinic, or emergency room (ER) visit, within 6 weeks of delivery. Secondary outcomes included components of the primary outcome and neonatal readmissions. We excluded women with hypertensive disorders of pregnancy and infections diagnosed prior to POD 2. RESULTS: A total of 1,391 patients were included. The rate of the primary outcome of any readmission increased with POD at discharge: 5.9% for POD 2, 9.4% for POD 3, and 10.9% for POD ≥4 group (trend for p = 0.03). The primary outcome increased with later discharge (POD ≥4 when compared with POD 2). Among components of the composite, ER and unscheduled clinic visits, but not maternal readmissions, increased with the timing of discharge for patients discharged on POD ≥4 when compared with POD 2. Using logistic regression, discharge on POD 3 and on POD ≥4 was significantly associated with the composite (adjusted odds ratios [aOR] 2.6, 95% confidence interval [CI] [1.3-5.3]; aOR 2.9, 95% CI [1.3-6.4], respectively) compared with POD 2. CONCLUSION: The risk of maternal readmission composite following uncomplicated but unscheduled CD was not lower in patients discharged home on POD 3 or ≥4 compared with patients discharged earlier (POD 2). KEY POINTS: · Risk of maternal readmission is higher in patients discharged on POD 3 or 4 compared with POD 2.. · No significant differences by the timing of discharge were observed for any neonatal readmissions.. · Timing of discharge should include an individualized approach with the option of discharge by POD 2..

Early gestational diabetes screening in obese women: a randomized controlled trial.

BACKGROUND: Although in 2013 the American College of Obstetricians and Gynecologists recommended early screening for gestational diabetes in obese women, no studies demonstrate an improvement in perinatal outcomes with this strategy. OBJECTIVE: We sought to determine whether early screening for gestational diabetes improves perinatal outcomes in obese women. MATERIALS AND METHODS: Randomized controlled trial comparing early gestational diabetes screening (14-20 weeks) to routine screening (24-28 weeks) in obese women (body mass index ≥30 kg/m2) at 2 tertiary care centers in the United States. Screening was performed using a 50-g, 1-hour glucose challenge test followed by a 100-g, 3-hour glucose tolerance test if the initial screen was ≥135 mg/dL. Gestational diabetes was diagnosed using Carpenter-Coustan criteria. Women not diagnosed at 14 to 20 weeks were rescreened at 24 to 28 weeks. Exclusion criteria were pre-existing diabetes, major medical illness, bariatric surgery, and prior cesarean delivery. The primary outcome was a composite of macrosomia (>4000 g), primary cesarean delivery, hypertensive disease of pregnancy, shoulder dystocia, neonatal hyperbilirubinemia, and neonatal hypoglycemia (assessed within 48 hours of birth). RESULTS: A total of 962 women were randomized, and outcomes were available for 922. Of these 922 women, 459 (49.8%) were assigned to early screen and 463 (50.2%) to routine screen. Baseline characteristics were balanced between groups. In the early screening group, 69 (15.0%; 95% confidence interval, 11.9-18.6%) were diagnosed with gestational diabetes: 29 (6.3%; 95% confidence interval, 4.3-8.9%) at <20 weeks and 40 (8.7%; 95% confidence interval, 6.3-11.7%) at >24 weeks. Of those randomized to routine screening, 56 (12.1%; 95% confidence interval, 9.3-15.4%) had gestational diabetes. Early screening did not reduce the incidence of the primary outcome (56.9% in the early screen versus 50.8% in the routine screen, P = .07; relative risk, 1.12; 95% confidence interval, 0.99-1.26). CONCLUSION: Early screening for gestational diabetes in obese women did not reduce the composite perinatal outcome.

Prospective, randomized, double-blind, placebo-controlled evaluation of the Pharmacokinetics, Safety and Efficacy of Recombinant Antithrombin Versus Placebo in Preterm Preeclampsia.

BACKGROUND: Despite expectant management, preeclampsia remote from term usually results in preterm delivery. Antithrombin, which displays antiinflammatory and anticoagulant properties, may have a therapeutic role in treating preterm preeclampsia, a disorder characterized by endothelial dysfunction, inflammation, and activation of the coagulation system. OBJECTIVE: This randomized, placebo-controlled clinical trial aimed to evaluate whether intravenous recombinant human antithrombin could prolong gestation and therefore improve maternal and fetal outcomes. STUDY DESIGN: We performed a double-blind, placebo-controlled trial at 23 hospitals. Women were eligible if they had a singleton pregnancy, early-onset or superimposed preeclampsia at 23 0/7 to 30 0/7 weeks' gestation, and planned expectant management. In addition to standard therapy, patients were randomized to receive either recombinant human antithrombin 250 mg loading dose followed by a continuous infusion of 2000 mg per 24 hours or an identical saline infusion until delivery. The primary outcome was days gained from randomization until delivery. The secondary outcome was composite neonatal morbidity score. A total of 120 women were randomized. RESULTS: There was no difference in median gestational age at enrollment (27.3 weeks' gestation for the recombinant human antithrombin group [range, 23.1-30.0] and 27.6 weeks' gestation for the placebo group [range, 23.0-30.0]; P=.67). There were no differences in median increase in days gained (5.0 in the recombinant human antithrombin group [range, 0-75] and 6.0 for the placebo group [range, 0-85]; P=.95). There were no differences between groups in composite neonatal morbidity scores or in maternal complications. No safety issues related to recombinant human antithrombin were noted in this study, despite the achievement of supraphysiological antithrombin concentrations. CONCLUSION: The administration of recombinant human antithrombin in preterm preeclampsia neither prolonged pregnancy nor improved neonatal or maternal outcomes.

Effect of Prophylactic Negative Pressure Wound Therapy vs Standard Wound Dressing on Surgical-Site Infection in Obese Women After Cesarean Delivery: A Randomized Clinical Trial.

Importance: Obesity increases the risk of both cesarean delivery and surgical-site infection. Despite widespread use, it is unclear whether prophylactic negative pressure wound therapy reduces surgical-site infection after cesarean delivery in obese women. Objective: To evaluate whether prophylactic negative pressure wound therapy, initiated immediately after cesarean delivery, lowers the risk of surgical-site infections compared with standard wound dressing in obese women. Design, Setting, and Participants: Multicenter randomized trial conducted from February 8, 2017, through November 13, 2019, at 4 academic and 2 community hospitals across the United States. Obese women undergoing planned or unplanned cesarean delivery were eligible. The study was terminated after 1624 of 2850 participants were recruited when a planned interim analysis showed increased adverse events in the negative pressure group and futility for the primary outcome. Final follow-up was December 18, 2019. Interventions: Participants were randomly assigned to either undergo prophylactic negative pressure wound therapy, with application of the negative pressure device immediately after repair of the surgical incision (n = 816), or receive standard wound dressing (n = 808). Main Outcomes and Measures: The primary outcome was superficial or deep surgical-site infection according to the Centers for Disease Control and Prevention definitions. Secondary outcomes included other wound complications, composite of surgical-site infections and other wound complications, and adverse skin reactions. Results: Of the 1624 women randomized (mean age, 30.4 years, mean body mass index, 39.5), 1608 (99%) completed the study: 806 in the negative pressure group (median duration of negative pressure, 4 days) and 802 in the standard dressing group. Superficial or deep surgical-site infection was diagnosed in 29 participants (3.6%) in the negative pressure group and 27 (3.4%) in the standard dressing group (difference, 0.36%; 95% CI, -1.46% to 2.19%, P = .70). Of 30 prespecified secondary end points, 25 showed no significant differences, including other wound complications (2.6% vs 3.1%; difference, -0.53%; 95% CI, -1.93% to 0.88%; P = .46) and composite of surgical-site infections and other wound complications (6.5% vs 6.7%; difference, -0.27%; 95% CI, -2.71% to 2.25%; P = .83). Adverse skin reactions were significantly more frequent in the negative pressure group (7.0% vs 0.6%; difference, 6.95%; 95% CI, 1.86% to 12.03%; P < .001). Conclusions and Relevance: Among obese women undergoing cesarean delivery, prophylactic negative pressure wound therapy, compared with standard wound dressing, did not significantly reduce the risk of surgical-site infection. These findings do not support routine use of prophylactic negative pressure wound therapy in obese women after cesarean delivery. Trial Registration: ClinicalTrials.gov Identifier: NCT03009110.

Adjunctive Azithromycin Prophylaxis for Cesarean Delivery.

BACKGROUND: The addition of azithromycin to standard regimens for antibiotic prophylaxis before cesarean delivery may further reduce the rate of postoperative infection. We evaluated the benefits and safety of azithromycin-based extended-spectrum prophylaxis in women undergoing nonelective cesarean section. METHODS: In this trial conducted at 14 centers in the United States, we studied 2013 women who had a singleton pregnancy with a gestation of 24 weeks or more and who were undergoing cesarean delivery during labor or after membrane rupture. We randomly assigned 1019 to receive 500 mg of intravenous azithromycin and 994 to receive placebo. All the women were also scheduled to receive standard antibiotic prophylaxis. The primary outcome was a composite of endometritis, wound infection, or other infection occurring within 6 weeks. RESULTS: The primary outcome occurred in 62 women (6.1%) who received azithromycin and in 119 (12.0%) who received placebo (relative risk, 0.51; 95% confidence interval [CI], 0.38 to 0.68; P<0.001). There were significant differences between the azithromycin group and the placebo group in rates of endometritis (3.8% vs. 6.1%, P=0.02), wound infection (2.4% vs. 6.6%, P<0.001), and serious maternal adverse events (1.5% vs. 2.9%, P=0.03). There was no significant between-group difference in a secondary neonatal composite outcome that included neonatal death and serious neonatal complications (14.3% vs. 13.6%, P=0.63). CONCLUSIONS: Among women undergoing nonelective cesarean delivery who were all receiving standard antibiotic prophylaxis, extended-spectrum prophylaxis with adjunctive azithromycin was more effective than placebo in reducing the risk of postoperative infection. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; C/SOAP ClinicalTrials.gov number, NCT01235546 .).

Impact of Azithromycin-Based Extended-Spectrum Antibiotic Prophylaxis on Noninfectious Cesarean Wound Complications.

OBJECTIVE: Adding azithromycin to standard antibiotic prophylaxis for unscheduled cesarean delivery has been shown to reduce postcesarean infections. Because wound infection with ureaplasmas may not be overtly purulent, we assessed the hypothesis that azithromycin-based extended-spectrum antibiotic prophylaxis also reduces wound complications that are identified as noninfectious. STUDY DESIGN: This is a secondary analysis of the C/SOAP (Cesarean Section Optimal Antibiotic Prophylaxis) randomized controlled trial, which enrolled women with singleton pregnancies ≥24 weeks who were undergoing nonelective cesarean. Women were randomized to adjunctive azithromycin or identical placebo up to 1 hour preincision. All wound complications occurring within 6 weeks were adjudicated into infection and noninfectious wound complications (seroma, hematoma, local cellulitis, and other noninfectious wound breakdown). The primary outcome for this analysis is the composite of noninfectious wound complications. RESULTS: At a total of 14 sites, 2,013 women were randomized to adjunctive azithromycin (n = 1,019) or placebo (n = 994). Groups were similar at baseline. Although there was a lower rate of noninfectious wound complications in the azithromycin group compared with placebo (2.9 vs. 3.8%), this was not statistically significant (p = 0.22). CONCLUSION: While adding azithromycin to usual antibiotic prophylaxis for nonelective cesarean delivery does reduce the risk of postcesarean infections, it did not significantly reduce the risk of postcesarean noninfectious wound complications.

Incidence and Risk Factors for Hospital Readmission or Unexpected Visits in Women Undergoing Unscheduled Cesarean Delivery.

OBJECTIVE: Hospital readmissions are increasingly tracked and assessed for value-based compensation. Our objective was to determine the incidence and risk factors associated with post-cesarean delivery (CD) readmissions or unexpected visits, defined as unexpected office or emergency room visits. STUDY DESIGN: This is a secondary analysis of a multicenter randomized controlled trial of adjunctive azithromycin prophylaxis for CD performed in laboring patients with viable pregnancies. Patients were followed up to 6 weeks postpartum. Our primary outcome was a composite of hospital readmission or unexpected visit, defined as unscheduled clinic or emergency department visits. Data of hospital readmissions, unexpected visits, and their reasons were collected. Demographics, antepartum, intrapartum, and postpartum risk factors were evaluated in bivariate analyses and multivariable logistic regression modeling. RESULTS: A total of 1,019 women were randomized to azithromycin and 994 to placebo. The prevalence of readmission or unexpected visit was 10.2% (95% confidence interval [CI]: 8.9-11.6), with rates of 3.8% (95% CI: 3.0-4.7%) hospital readmissions, 6.9% (95% CI: 5.8-8.0%) emergency room visits, and 4.2% (95% CI: 3.4-5.2%) unexpected clinic visits. The most common causes were infectious disease and hypertensive disorder. Women with readmissions or unexpected visits were more likely to be obese and diabetic, as well as experience longer length of ruptured membranes, intrauterine pressure catheter placement, and postpartum fevers. On multivariable analysis, diabetes (adjusted odds ratio [aOR]: 1.6, 95% CI: 1.1-2.4), prolonged ruptured membranes (aOR: 1.9, 95% CI: 1.3-2.8), and postpartum fevers (aOR: 4.6, 95% CI: 3.0-7.0) were significantly positively associated with readmission or unscheduled visit, while azithromycin was a protective (aOR: 0.6, 95% CI: 0.5-0.9). CONCLUSION: Women who had postpartum fever were at especially high risk for readmission or unexpected visits. Diabetes, prolonged ruptured membranes, and postpartum fevers were significantly associated with the adverse outcome, and azithromycin was associated with lower rates of readmission and unexpected visits.

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.

Association Between Metformin Use in Early Gestational or Type 2 Diabetes in Pregnancy and Preterm Preeclampsia.

OBJECTIVE: To estimate the association between maternal metformin use for the treatment of early gestational or pre-existing type 2 diabetes and preterm preeclampsia. METHODS: This is a planned secondary analysis of the MOMPOD study (Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy), a randomized trial comparing the effect of adding metformin with insulin treatment on composite neonatal outcome in singleton pregnancies with early gestational or type 2 diabetes. Participants were randomized at 11-23 weeks of gestation to 1,000 mg metformin twice daily or placebo until delivery. A subset of participants had maternal blood collected at 24-30 weeks of gestation, and serum soluble endoglin, apolipoprotein B, vascular cell adhesion molecule-1, soluble fms-like tyrosine kinase 1, placental growth factor, high-sensitivity C-reactive protein, adiponectin, and vascular endothelial growth factor levels were measured. Our primary outcome was preterm preeclampsia , defined as preeclampsia requiring delivery before 37 weeks of gestation. Secondary outcomes included preterm preeclampsia requiring delivery before 34 weeks of gestation and differences in serum biomarkers. Multivariable regression analysis was used to estimate the associations between metformin use and primary or secondary study outcomes. RESULTS: Of 831 participants, 119 (14.3%) developed preeclampsia requiring delivery before 37 weeks of gestation: 57 of 416 (13.7%) in the placebo group and 62 of 415 (14.9%) in the metformin group. Thirty-seven (4.4%) developed preeclampsia requiring delivery before 34 weeks of gestation: 15 (3.6%) receiving placebo and 22 (5.3%) receiving metformin. Compared with placebo, metformin was not associated with a significant difference in the occurrence of preeclampsia before 37 weeks of gestation (adjusted odds ratio [aOR] 1.04, 95% CI, 0.70-1.56) or before 34 weeks (aOR 1.43, 95% CI, 0.73-2.81). Similarly, there was no association between maternal metformin use and serum biomarker levels. CONCLUSION: Among parturients with early gestational or pre-existing type 2 diabetes, the addition of metformin to insulin was not associated with lower odds of preterm preeclampsia or with serum biomarkers associated with cardiovascular disease risk.

Passive antibody transfer from pregnant women to their fetus are maximized after SARS-CoV-2 vaccination irrespective of prior infection.

Background: Pregnancy is associated with a higher risk of adverse symptoms and outcomes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for both mother and neonate. Antibodies can provide protection against SARS-CoV-2 infection and are induced in pregnant women after vaccination or infection. Passive transfer of these antibodies from mother to fetus in utero may provide protection to the neonate against infection. However, it is unclear whether the magnitude or quality and kinetics of maternally derived fetal antibodies differs in the context of maternal infection or vaccination. Objective: We aimed to determine whether antibodies transferred from maternal to fetus differed in quality or quantity between infection- or vaccination-induced humoral immune responses. Methods: We evaluated 93 paired maternal and neonatal umbilical cord blood plasma samples collected between October 2020 and February 2022 from a birth cohort of pregnant women from New Orleans, Louisiana, with histories of SARS-CoV-2 infection and/or vaccination. Plasma was profiled for the levels of spike-specific antibodies and induction of antiviral humoral immune functions, including neutralization and Fc-mediated innate immune effector functions. Responses were compared between 4 groups according to maternal infection and vaccination. Results: We found that SARS-CoV-2 vaccination or infection during pregnancy increased the levels of antiviral antibodies compared to naive subjects. Vaccinated mothers and cord samples had the highest anti-spike antibody levels and antiviral function independent of the time of vaccination during pregnancy. Conclusions: These results show that the most effective passive transfer of functional antibodies against SARS-CoV-2 in utero is achieved through vaccination, highlighting the importance of vaccination in pregnant women.

Antihypertensive therapy and unplanned maternal postpartum health care utilization in patients with mild chronic hypertension.

OBJECTIVE: To test whether treatment of mild chronic hypertension (CHTN) in pregnancy is associated with lower rates of unplanned maternal healthcare utilization postpartum. METHODS: This was a secondary analysis of the CHTN and pregnancy (CHAP) study, a prospective, open-label, pragmatic, multicenter, randomized treatment trial of pregnant people with mild chronic hypertension. All patients with a postpartum follow-up assessment were included. The primary outcome was unplanned healthcare utilization, defined as unplanned postpartum clinic visits, Emergency Department or triage visits, or unplanned hospital admissions within six weeks postpartum. Differences in outcomes were compared between study groups (Active Group: blood pressure goal of<140/90 mm Hg, and Control Group: blood pressure goal of <160/105 mm Hg) and factors associated with outcomes were examined using logistic regression. RESULTS: A total of 2,293 patients were included with 1,157 (50.5%) in the active group and 1,136 (49.5%) in the control group. Rates of unplanned maternal postpartum health care utilization did not differ between treatment and control groups, (20.2% vs 23.3%, p=0.07, aOR 0.84, 95% CI 0.69-1.03. However, Emergency Department or triage/maternity evaluation unit visits were significantly lower in the Active group (10.2% vs 13.2%, p=0.03, aOR 0.76, 95% 0.58-0.99). Higher BMI at enrollment and cesarean delivery were associated with higher odds of unplanned postpartum healthcare utilization. CONCLUSION: While treatment of mild CHTN during pregnancy and postpartum was not significantly associated with overall unplanned healthcare resource utilization, it was associated with lower rates of postpartum Emergency Department and triage visits.

Effects of Antihypertensive Therapy During Pregnancy on Postpartum Blood Pressure Control.

OBJECTIVE: To compare differences in postpartum blood pressure (BP) control (BP below 140/90 mm Hg) for participants with hypertension randomized to receive antihypertensive treatment compared with no treatment during pregnancy. METHODS: This study was a planned secondary analysis of a multicenter, open-label, randomized controlled trial (The CHAP [Chronic Hypertension and Pregnancy] trial). Pregnant participants with mild chronic hypertension (BP below 160/105 mm Hg) were randomized into two groups: active (antihypertensive treatment) or control (no treatment unless severe hypertension, BP 160/105 mm Hg or higher). Study outcomes were BP control below 140/90 mm Hg (primary) and medication nonadherence based on a composite score threshold (secondary) at the 6-week postpartum follow-up visit. Participants without follow-up BP measurements were excluded from analysis of the BP control outcome. Participants without health care professional-prescribed antihypertensives at delivery were excluded from the analysis of the adherence outcome. Multivariable logistic regression was used to adjust for potential confounders. RESULTS: Of 2,408 participants, 1,684 (864 active, 820 control) were included in the analysis. A greater percentage of participants in the active group achieved BP control (56.7% vs 51.5%; adjusted odds ratio [aOR] 1.22, 95% CI, 1.00-1.48) than in the control group. Postpartum antihypertensive prescription was higher in the active group (81.7% vs 58.4%, P <.001), and nonadherence did not differ significantly between groups (aOR 0.81, 95% CI, 0.64-1.03). CONCLUSION: Antihypertensive treatment of mild chronic hypertension during pregnancy was associated with better BP control below 140/90 mm Hg in the immediate postpartum period.

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.

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.

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.