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

To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. 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. 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. 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. ClinicalTrials.gov, NCT02299414.

Sanusi AA ，Leach J ，Boggess K ，Dugoff L ，Sibai B ，Lawrence K ，Hughes BL ，Bell J ，Aagaard K ，Edwards RK ，Gibson KS ，Haas DM ，Plante L ，Metz TD ，Casey B ，Esplin S ，Longo S ，Hoffman MK ，Saade GR ，Hoppe KK ，Foroutan J ，Tuuli M ，Owens MY ，Simhan HN ，Frey H ，Rosen T ，Palatnik A ，Baker S ，August P ，Reddy UM ，Su EJ ，Krishna I ，Nguyen NA ，Norton ME ，Skupski D ，El-Sayed YY ，Ogunyemi D ，Galis ZS ，Harper L ，Ambalavanan N ，Geller NL ，Kuo HC ，Sinkey RG ，Librizzi R ，Pereira L ，Magann EF ，Habli M ，Williams S ，Mari G ，Pridjian G ，McKenna DS ，Parrish M ，Chang E ，Osmundson S ，Quinones J ，Szychowski JM ，Tita ATN ... -  《-》

Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis.

Chronic hypertension is associated with adverse perinatal outcomes, although the optimal treatment is unclear. The aim of this network metaanalysis was to simultaneously compare the efficacy and safety of antihypertensive agents in pregnant women with chronic hypertension. Medline, Scopus, CENTRAL, Web of Science, Clinicaltrials.gov, and Google Scholar databases were searched systematically from inception to December 15, 2019. Both randomized controlled trials and cohort studies were held eligible if they reported the effects of antihypertensive agents on perinatal outcomes among women with chronic hypertension. The primary outcomes were preeclampsia and small-for-gestational-age risk. A frequentist network metaanalytic random-effects model was fitted. The main analysis was based on randomized controlled trials. The credibility of evidence was assessed by taking into account within-study bias, across-studies bias, indirectness, imprecision, heterogeneity, and incoherence. Twenty-two studies (14 randomized controlled trials and 8 cohorts) were included, comprising 4464 women. Pooling of randomized controlled trials indicated that no agent significantly affected the incidence of preeclampsia. Atenolol was associated with significantly higher risk of small-for-gestational age compared with placebo (odds ratio, 26.00; 95% confidence interval, 2.61-259.29) and is ranked as the worst treatment (P-score=.98). The incidence of severe hypertension was significantly lower when nifedipine (odds ratio, 0.27; 95% confidence interval, 0.14-0.55), methyldopa (odds ratio, 0.31; 95% confidence interval, 0.17-0.56), ketanserin (odds ratio, 0.29; 95% confidence interval, 0.09-0.90), and pindolol (odds ratio, 0.17; 95% confidence interval, 0.05-0.55) were administered compared with no drug intake. The highest probability scores were calculated for furosemide (P-score=.86), amlodipine (P-score=.82), and placebo (P-score=.82). The use of nifedipine and methyldopa were associated with significantly lower placental abruption rates (odds ratio, 0.29 [95% confidence interval, 0.15-0.58] and 0.23 [95% confidence interval, 0.11-0.46], respectively). No significant differences were estimated for cesarean delivery, perinatal death, preterm birth, and gestational age at delivery. Atenolol was associated with a significantly increased risk for small-for-gestational-age infants. The incidence of severe hypertension was significantly lower when nifedipine and methyldopa were administered, although preeclampsia risk was similar among antihypertensive agents. Future large-scale trials should provide guidance about the choice of antihypertensive treatment and the goal blood pressure during pregnancy.

Bellos I ，Pergialiotis V ，Papapanagiotou A ，Loutradis D ，Daskalakis G ... -  《-》

Determining optimal timing of birth for women with chronic or gestational hypertension at term: The WILL (When to Induce Labour to Limit risk in pregnancy hypertension) randomised trial.

Chronic or gestational hypertension complicates approximately 7% of pregnancies, half of which reach 37 weeks' gestation. Early term birth (at 37 to 38 weeks) may reduce maternal complications, cesareans, stillbirths, and costs but may increase neonatal morbidity. In the WILL Trial (When to Induce Labour to Limit risk in pregnancy hypertension), we aimed to establish optimal timing of birth for women with chronic or gestational hypertension who reach term and remain well. This 50-centre, open-label, randomised trial in the United Kingdom included an economic analysis. WILL randomised women with chronic or gestational hypertension at 36 to 37 weeks and a singleton fetus, and who provided documented informed consent to "Planned early term birth at 38+0-3 weeks" (intervention) or "usual care at term" (control). The coprimary outcomes were "poor maternal outcome" (composite of severe hypertension, maternal death, or maternal morbidity; superiority hypothesis) and "neonatal care unit admission for ≥4 hours" (noninferiority hypothesis). The key secondary was cesarean. Follow-up was to 6 weeks postpartum. The planned sample size was 540/group. Analysis was by intention-to-treat. A total of 403 participants (37.3% of target) were randomised to the intervention (n = 201) or control group (n = 202), from 3 June 2019 to 19 December 2022, when the funder stopped the trial for delayed recruitment. In the intervention (versus control) group, losses to follow-up were 18/201 (9%) versus 15/202 (7%). In each group, maternal age was about 30 years, about one-fifth of women were from ethnic minorities, over half had obesity, approximately half had chronic hypertension, and most were on antihypertensives with normal blood pressure. In the intervention (versus control) group, birth was a median of 0.9 weeks earlier (38.4 [38.3 to 38.6] versus 39.3 [38.7 to 39.9] weeks). There was no evidence of a difference in "poor maternal outcome" (27/201 [13%] versus 24/202 [12%], respectively; adjusted risk ratio [aRR] 1.16, 95% confidence interval [CI] 0.72 to 1.87). For "neonatal care unit admission for ≥4 hours," the intervention was considered noninferior to the control as the adjusted risk difference (aRD) 95% CI upper bound did not cross the 8% prespecified noninferiority margin (14/201 [7%] versus 14/202 [7%], respectively; aRD 0.003, 95% CI -0.05 to +0.06), although event rates were lower-than-estimated. The intervention (versus control) was associated with no difference in cesarean (58/201 [29%] versus 72/202 [36%], respectively; aRR 0.81, 95% CI 0.61 to 1.08. There were no serious adverse events. Limitations include our smaller-than-planned sample size, and lower-than-anticipated event rates, so the findings may not be generalisable to where hypertension is not treated with antihypertensive therapy. In this study, we observed that most women with chronic or gestational hypertension required labour induction, and planned birth at 38+0-3 weeks (versus usual care) resulted in birth an average of 6 days earlier, and no differences in poor maternal outcome or neonatal morbidity. Our findings provide reassurance about planned birth at 38+0-3 weeks as a clinical option for these women. isrctn.com ISRCTN77258279.

Magee LA ，Kirkham K ，Tohill S ，Gkini E ，Moakes CA ，Dorling J ，Green M ，Hutcheon JA ，Javed M ，Kigozi J ，Mol BWM ，Singer J ，Hardy P ，Stubbs C ，Thornton JG ，von Dadelszen P ，WILL Trial Study Group ... -  《-》

Optimal treatment for women with acute hypertension in pregnancy; a randomized trial comparing intravenous labetalol versus nicardipine.

Blood pressure control in severe hypertension of pregnancy is crucial for mother and neonate. In absence of evidence, guidelines recommend either intravenous labetalol or nicardipine. We compared the effectiveness and safety of these two drugs in women with severe hypertension in pregnancy. We performed an open label randomized controlled trial. Women with a singleton pregnancy complicated by severe hypertension (systolic ≥ 160 mmHg and/or diastolic ≥ 110 mmHg) requiring intravenous antihypertensive treatment were randomized to intravenous labetalol or intravenous nicardipine. The primary outcome was a composite adverse neonatal outcome defined as severe Respiratory Distress Syndrome (RDS), Broncho Pulmonary Dysplasia (BPD), Intraventricular Hemorrhage (IVH) IIB or worse, Necrotizing Enterocolitis (NEC), or perinatal death defined as fetal death or neonatal death before discharge from the neonatal intensive care unit (NICU). Based on a power analysis, we estimated that 472 women (236 per group) needed to be included to detect a difference of 15% in the primary outcome with 90% power. The study was halted prematurely at 30 inclusions because of slow recruitment and trial fatigue. Between August 2018 and April 2022, we randomized 30 women of which 16 were allocated to intravenous nicardipine and 14 to intravenous labetalol. The composite adverse neonatal outcome was not significantly different between the two groups (25 % versus 43 % OR 0.28 (95 % CI 0.05-1.43), p = 0.12)). Respiratory distress syndrome occurred more often in the labetalol group than in the nicardipine group (42.9 % versus 12.5 %). Neonatal hypoglycemia occurred more often in the nicardipine group than in the labetalol group (31 % versus 7 %). Time until blood pressure control was faster in women treated with nicardipine than in women treated with labetalol (45 (15-150 min vs. 120 (60-127,5) min). In our prematurely halted small RCT, we were unable to provide evidence for the optimal choice of treatment for severe hypertension to improve neonatal outcome and/or to obtain faster blood pressure control. Differences in Respiratory distress syndrome and neonatal hypoglycemia between the groups might be the result of coincidental finding due to the small groups included in the study. A larger randomized trial would be needed to determine the safest and most efficacious (intravenous) therapy for severe hypertension in pregnancy. This study emphasizes the challenges of conducting a RCT for the optimal treatment for these women.

Bij de Weg JM ，de Boer MA ，Gravesteijn BY ，Hermes W ，Ganzevoort W ，van Bel F ，Willem Mol B ，de Groot CJM ... -  《-》

Amlodipine versus nifedipine ER for the management of postpartum hypertension: a noninferiority randomized controlled trial.

Postpartum hypertension is an increasingly prevalent problem and optimizing its treatment is imperative in reducing maternal morbidity and improving long-term health outcomes. Despite this, data on treatment of postpartum hypertension is limited. While most available studies focus on labetalol and nifedipine ER, these medications are not frequently used for hypertension treatment in the non-obstetric setting. As we aim to establish best practices for managing postpartum hypertension, use of more commonly encountered antihypertensives should be evaluated. To evaluate the use of amlodipine for the treatment of postpartum hypertension, as assessed by postpartum length of stay. In a pragmatic, randomized controlled noninferiority trial, patients were assigned to amlodipine or nifedipine ER for treatment of postpartum hypertension. The primary outcome was time from delivery until discharge with a noninferiority limit of 24 hours. A sample size of 132 was needed to achieve 80% power with a 2-tailed alpha of 0.05. Intent-to-Treat and Per Protocol analyses were performed. Prespecified secondary outcomes included the need for additional antihypertensives, side effects, medication discontinuation, breastfeeding satisfaction, and readmission rate. A post-hoc analysis of time from medication initiation until hospital discharge was also performed. From April 2021 to December 2022, 7618 patients were screened and 175 patients were randomized, with 132 meeting criteria for antihypertensive initiation. Baseline demographics were similar between groups. Amlodipine had a non-inferior length of stay compared to nifedipine ER (Intent-to-Treat Wilcoxon pseudo-median amlodipine=73.5 hours, nifedipine ER=72.0 hours, 95% CI -8.00 to 6.00). The remainder of analyses were performed only on the Per Protocol cohort. Time from medication initiation until hospital discharge was similar between groups (amlodipine=45.0 hours, nifedipine ER=45.5 hours, 95% CI -8.00 to 13.00). There were no differences in use of additional antihypertensives or patient-reported side effects or breastfeeding outcomes, but hypotension and tachycardia were less common with amlodipine use. Amlodipine was significantly less likely to be discontinued due to side effects (amlodipine n=0, nifedipine ER n=7 (10.1%), p=.02). Readmission rates were similar between groups. Amlodipine is noninferior to nifedipine ER for postpartum hypertension treatment, as defined by median length of postpartum stay. Rates of side effects were similar between groups, but there was a statistically significant difference in medication discontinuation rates. Clinicaltrials.gov, www. gov, NCT04790279 El resumen está disponible en Español al final del artículo.

Pratt K ，Lordo R ，Self S ，Carlson L ... -  《-》