背景:胎儿生长受限与胎盘形成受损和子宫胎盘血流异常密切相关。一氧化氮供体如季戊四醇四硝酸酯是强血管扩张剂并保护内皮。最近,我们在一项随机对照试验研究中证明,对有风险的孕妇服用季戊四醇四硝酸酯后,胎儿生长受限或围产期死亡的相对风险降低了38%。妊娠中期子宫灌注受损。这项单中心研究的结果提示了以下假设:季戊四醇四硝酸酯可能对胎盘功能受损的妊娠具有二级预防作用。
目的:本研究旨在验证在一项多中心试验中,一氧化氮供体季戊四醇四硝酸酯减少妊娠中期胎盘灌注受损的孕妇胎儿生长受限和围产期死亡的假设。
方法:在这个多中心中,随机化,双盲,安慰剂对照试验,2个平行组的孕妇在妊娠19+0至22+6周时表现为平均子宫动脉搏动指数>95百分位数,随机分为50mgPentalong或安慰剂,每天两次。参与者根据他们的病史被分配到高或低风险组,然后随机分组,以固定的块长度按中心和风险组分层。主要疗效终点是围产期死亡或胎儿生长受限的复合结局。次要终点是新生儿和产妇结局参数。
结果:在2017年8月至2020年3月期间,317名参与者被纳入研究,307名参与者被分析。季戊四醇四硝酸酯组的主要结局的累积发生率为41.1%,安慰剂组为45.5%(未调整的相对风险,0.90;95%置信区间,0.69-1.17;调整后的相对风险,0.90;95%置信区间,0.69-1.17;P=.43)。次要结局,如早产(未调整的相对风险,0.73;95%置信区间,0.56-0.94;调整后的相对风险,0.73;95%置信区间,0.56-0.94;P=0.01)和妊娠高血压(未调整的相对风险,0.65;95%置信区间,0.46-0.93;调整后的相对风险,0.65;95%置信区间,0.46-0.92;P=0.01)减少。
结论:我们的研究未能显示季戊四醇四硝酸酯对妊娠中期子宫灌注受损的孕妇胎儿生长受限和围产期死亡的影响。季戊四醇四硝酸酯显着降低了次要结局参数,例如这些妊娠中早产和妊娠高血压的发生率。
Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis.
This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial.
In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters.
Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced.
Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.