先兆子痫仍然是孕产妇和新生儿发病和死亡的主要原因。生物合理性,令人信服的初步数据,一项初步临床试验支持普伐他汀预防先兆子痫的安全性和实用性.
我们先前报道了在高危孕妇中使用低剂量(10mg)普伐他汀的I期临床试验的结果。这里,我们报告了后续行动,在妊娠34+6周前需要分娩的先兆子痫孕妇中进行20mg普伐他汀与安慰剂的随机试验,目的是评估普伐他汀的安全性和药代动力学参数。
这是一个飞行员,多中心,失明,安慰剂对照,单例女性的随机试验,先兆子痫高风险的非异常妊娠。妊娠12+0至16+6周的女性被分配接受每日20mg普伐他汀剂量或口服安慰剂直至分娩。此外,在妊娠中期和妊娠中期以及产后4~6个月时进行稳态普伐他汀药代动力学研究.主要结局包括妊娠期间普伐他汀的母胎安全性和药代动力学参数。次要结局包括母体和脐带血化学以及母体和新生儿结局,包括先兆子痫和早产的发生率,分娩时的胎龄,和出生体重。
值得注意的是,10名接受普伐他汀的妇女和10名接受安慰剂的妇女完成了试验。两组间不良或严重不良事件发生率无显著差异,先天性异常,或母体和脐带血化学。最常见的副作用是头痛,其次是胃灼热和肌肉骨骼疼痛。我们报告了普伐他汀药代动力学参数,包括普伐他汀曲线下面积(给药间隔内的总药物暴露量),表观口腔清除率,半衰期,和其他人在怀孕期间,并将其与产后期间测量的值进行比较。在分娩时的大多数脐带和母体样本中,普伐他汀浓度低于测定的定量限。普伐他汀组的妊娠和新生儿结局更有利。所有新生儿都通过了脑干听觉诱发反应电位或类似的听力筛查测试。与每日10mg普伐他汀剂量相比,每日20mg剂量后的平均最大浓度和曲线下面积值高2倍以上。但明显的口腔间隙,半衰期,达到最大浓度的时间相似,这与先前报道的线性一致,普伐他汀在非妊娠受试者中的剂量独立药代动力学。
这项研究证实了普伐他汀在先兆子痫高危女性中的总体安全性和良好的妊娠结局。这种有利的风险-收益分析证明了一个更大的临床试验来评估普伐他汀预防先兆子痫的功效。在那之前,怀孕期间普伐他汀的使用仍在调查中。
Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia.
We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks\' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin.
This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight.
Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects.
This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.