Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction A Randomized Clinical Trial
Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction A Randomized Clinical Trial
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DOI：
10.1001/jamanetworkopen.2020.5323
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发表时间：
2020-06-17
影响因子：
13.8
通讯作者：
Ganzevoort, Wessel
中科院分区：
文献类型：
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作者：
Pels, Anouk;Derks, Jan;Ganzevoort, Wessel
本随机临床试验探讨西地那非是否降低围产期死亡率或发病率的风险与安慰剂在儿童的孕妇有严重的早发性胎儿生长受限。问题西地那非是否降低围产期死亡率或发病率的风险在儿童的孕妇有严重的早发性胎儿生长受限？结果在这项随机临床试验中，包括216名孕妇，围产期死亡率或主要发病率没有统计学差异，发生在60.2%的参与者分配到西地那非与54.2%的那些分配到安慰剂的后代。西地那非组18.8%的新生儿发生肺动脉高压，安慰剂组5.1%的新生儿发生肺动脉高压，差异有统计学意义。这些研究结果表明，母亲西地那非治疗严重的早发性胎儿生长受限并没有降低围产儿死亡率或主要新生儿发病率的风险，但新生儿肺动脉高压增加observed.Importance严重早发性胎儿生长受限引起的胎盘功能障碍导致围产儿死亡率和新生儿发病率高。磷酸二酯酶5抑制剂西地那非抑制环磷酸鸟苷水解，从而激活一氧化氮的作用，并可能改善子宫胎盘功能和随后的围产期结局。目的探讨西地那非是否能降低围产儿死亡率或主要并发症。设计、设置和参与者本安慰剂对照随机临床试验于2015年1月20日至2018年7月16日在荷兰的10家三级转诊中心和1家综合医院进行。参与者包括妊娠20至30周的孕妇，严重胎儿生长受限，定义为胎儿腹围低于第三百分位数或估计胎儿体重低于第五百分位数，结合多普勒测量超出参考范围或母体高血压疾病。由于安全性问题，试验于2018年7月19日提前停止，而主要结局的获益不太可能。分析了2015年1月20日至2019年1月18日的数据。预先规定的主要分析是意向治疗分析，包括所有随机化受试者。干预措施参与者被随机分配到西地那非，25毫克，每天3次与安慰剂。主要结局和指标主要结局是出院前围产期死亡率或新生儿主要发病率的综合结果。结果在360名计划参与者中，共有216名孕妇被纳入，其中108名妇女被随机分配到西地那非组（随机化时的中位胎龄，24周5天[四分位距，23周3天至25周5天];平均[SD]估计胎儿体重，458 [160] g）和108名随机分配至安慰剂组的女性（中位胎龄，25周0天[四分位距，22周5天至26周3天];平均[SD]估计胎儿体重，464 [186] g）。2018年7月，由于担心西地那非可能导致新生儿肺动脉高压，该试验停止，而主要结局的获益不太可能。主要结局，围产期死亡率或主要新生儿发病率，发生在65名参与者（60.2%）分配到西地那非与58名参与者（54.2%）分配到安慰剂的后代（相对风险，1.11; 95%CI，0.88-1.40; P = 0.38）。肺动脉高压是监测安全性的重要预定结局，西地那非组16例新生儿（18.8%）vs安慰剂组4例新生儿（5.1%）发生肺动脉高压（相对风险，3.67; 95% CI，1.28-10.51; P = 0.008）。结论和相关性这些研究结果表明，产前母亲西地那非管理严重早发性胎儿生长受限并没有降低围产期死亡率或主要新生儿发病率的风险。结果表明，西地那非可能会增加新生儿肺动脉高压的风险。
This randomized clinical trial examines whether sildenafil reduces the risk of perinatal mortality or morbidity vs placebo in children of pregnant women with severe early onset fetal growth restriction.Question Does sildenafil reduce the risk of perinatal mortality or morbidity in children of pregnant women with severe early onset fetal growth restriction? Findings In this randomized clinical trial including 216 pregnant women, perinatal mortality or major morbidity was not statistically different and occurred in the offspring of 60.2% of participants allocated to sildenafil vs 54.2% of those allocated to placebo. Pulmonary hypertension occurred in 18.8% of neonates in the sildenafil group compared with 5.1% of neonates in the placebo group, which was statistically significantly different. Meaning These findings suggest that treatment of severe early onset fetal growth restriction by maternal sildenafil did not reduce the risk of perinatal mortality or major neonatal morbidity, but increased neonatal pulmonary hypertension was observed.Importance Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.