Kumar Sailesh, Tarnow-Mordi William, Mol Ben W, Flenady Vicki, Liley Helen G, Badawi Nadia, Walker Susan, Hyett Jonathan, Seidler Anna Lene, Callander Emily, Simes John, O'Connell Rachel L
Mater Mothers' Hospital and Mater Research Institute-University of Queensland, Brisbane, Queensland, Australia.
National Health and Medical Research Council Stillbirth Centre for Research Excellence, Brisbane, Queensland, Australia.
JAMA. 2025 Jul 8;334(2):149-159. doi: 10.1001/jama.2025.7710.
Sildenafil citrate may increase uteroplacental blood flow. Its ability to reduce perinatal complications related to fetal hypoxia during labor is uncertain.
To compare the effectiveness of intrapartum maternal oral sildenafil citrate vs placebo in improving perinatal outcomes potentially related to intrapartum hypoxia in term pregnancies.
DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, multicenter, investigator-initiated, placebo-controlled randomized clinical trial including 3257 women was conducted in 13 Australian hospitals from September 6, 2021, to June 28, 2024. The last date of follow-up (28-day neonatal mortality) was July 26, 2024. Women aged 18 years or older with singleton or dichorionic twin pregnancies, planning vaginal birth at term by either spontaneous labor or induction of labor, were recruited.
Women were assigned to 50 mg oral sildenafil citrate every 8 hours up to 150 mg or equivalent placebo.
The primary composite outcome was intrapartum stillbirth, neonatal death, Apgar score less than 4 at 5 minutes (a score of <4 at 5 minutes is indicative of severe neonatal depression at birth, with scores ranging from 0 to 10), acidosis at birth (umbilical cord artery pH <7.0), hypoxic ischemic encephalopathy, neonatal seizures, neonatal respiratory support for greater than 4 hours, neonatal unit admission for greater than 48 hours, persistent pulmonary hypertension of the newborn, or meconium aspiration syndrome. Secondary outcomes were the individual components of the primary composite and emergency cesarean delivery or instrumental birth for intrapartum fetal distress.
A total of 3257 women were randomized to sildenafil citrate (n = 1626 women and 1634 infants) or placebo (n = 1631 women and 1641 infants). Mean (SD) maternal age and gestation at randomization were similar in both groups (31.7 [5.1] vs 31.5 [5.0] years and 39.5 [1.2] vs 39.5 [1.1] weeks, respectively). A total of 868 participants (53.4%) vs 874 participants (53.6%) were of Australia/New Zealand ethnicity and 315 participants (19.4%) vs 311 participants (19.1%) were of European ethnicity. Most participants were nulliparous (944 of 1624 [58.1%; 2 missing values] vs 966 of 1630 [59.3%; 1 missing value]). Induction of labor occurred in 1353 of 1621 women (83.5%) in the sildenafil citrate group and 1348 of 1627 women (82.9%) in the placebo group. The primary outcome occurred in 83 of 1625 women (5.1%) in the sildenafil citrate group and 84 of 1625 (5.2%) in the placebo group (relative risk, 1.02; 95% CI, 0.75-1.37). Sildenafil citrate had no significant effect on emergency cesarean delivery or instrumental vaginal birth for fetal distress (relative risk, 1.12; 95% CI, 0.98-1.29) or on any of the individual components of the primary outcome. Subgroup analyses showed no evidence of heterogeneity of treatment effect.
Sildenafil citrate did not result in a lower incidence of adverse perinatal outcomes potentially related to intrapartum hypoxia.
anzctr.org.au Identifier: ACTRN12621000231842.
枸橼酸西地那非可能会增加子宫胎盘血流量。其降低分娩期间与胎儿缺氧相关的围产期并发症的能力尚不确定。
比较分娩期产妇口服枸橼酸西地那非与安慰剂在改善足月妊娠分娩期缺氧可能相关的围产期结局方面的有效性。
设计、设置和参与者：这项务实的、多中心的、研究者发起的、安慰剂对照的随机临床试验纳入了3257名女性，于2021年9月6日至2024年6月28日在澳大利亚的13家医院进行。随访的最后日期（28天新生儿死亡率）为2024年7月26日。招募了年龄在18岁及以上、怀有单胎或双绒毛膜双胎妊娠、计划通过自然分娩或引产足月阴道分娩的女性。
将女性分为每8小时口服50毫克枸橼酸西地那非，最多150毫克或等效安慰剂。
主要复合结局为分娩期死产、新生儿死亡、5分钟时阿氏评分低于4分（5分钟时评分<4分表明出生时严重新生儿抑制，评分范围为0至10分）、出生时酸中毒（脐动脉pH<7.0）、缺氧缺血性脑病、新生儿惊厥、新生儿呼吸支持超过4小时、新生儿病房住院超过48小时、新生儿持续性肺动脉高压或胎粪吸入综合征。次要结局为主要复合结局的各个组成部分以及因分娩期胎儿窘迫进行的急诊剖宫产或器械助产。
共有3257名女性被随机分为枸橼酸西地那非组（n = 1626名女性和1634名婴儿）或安慰剂组（n = 1631名女性和1641名婴儿）。两组随机分组时的平均（标准差）产妇年龄和孕周相似（分别为31.7[5.1]岁对31.5[5.0]岁和39.5[1.2]周对39.5[1.1]周）。共有868名参与者（53.4%）对874名参与者（53.6%）为澳大利亚/新西兰族裔，315名参与者（19.4%）对311名参与者（19.1%）为欧洲族裔。大多数参与者为初产妇（1624名中的944名[58.1%；2个缺失值]对1630名中的966名[59.3%；1个缺失值]）。枸橼酸西地那非组1621名女性中有1353名（83..5%）进行了引产，安慰剂组1627名女性中有1348名（82.9%）进行了引产。枸橼酸西地那非组1625名女性中有83名（5.1%）出现主要结局，安慰剂组1625名中有84名（5.2%）出现主要结局（相对风险，1.02；95%CI，0.75 - 1.37）。枸橼酸西地那非对因胎儿窘迫进行的急诊剖宫产或器械阴道助产（相对风险，1.12；95%CI，0.98 - 1.29）或主要结局的任何单个组成部分均无显著影响。亚组分析未显示治疗效果存在异质性证据。
枸橼酸西地那非并未降低可能与分娩期缺氧相关的不良围产期结局的发生率。
anzctr.org.au标识符：ACTRN12621000231842。
