Department of Obstetrics and Gynecology, the Ohio State University, Columbus, OH; Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX.
Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, Galveston, TX.
Am J Obstet Gynecol. 2021 Dec;225(6):666.e1-666.e15. doi: 10.1016/j.ajog.2021.05.018. Epub 2021 May 24.
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.
子痫前期仍然是孕产妇和新生儿发病率和死亡率的主要原因。生物学合理性、有力的初步数据以及一项试点临床试验支持普伐他汀用于预防子痫前期的安全性和实用性。
我们之前报告了使用低剂量（10mg）普伐他汀对高危孕妇进行的 I 期临床试验结果。在这里，我们报告了一项后续的、随机的 20mg 普伐他汀与安慰剂治疗有子痫前期史的孕妇的试验，这些孕妇需要在 34+6 孕周前分娩，目的是评估普伐他汀的安全性和药代动力学参数。
这是一项针对有单胎、非畸形妊娠且有子痫前期高危风险的孕妇的试点、多中心、盲法、安慰剂对照、随机试验。妊娠 12+0 至 16+6 周的孕妇每天口服 20mg 普伐他汀或安慰剂，直至分娩。此外，在妊娠第二和第三 trimester 以及产后 4 至 6 个月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婴安全性和药代动力学参数。次要结局包括母血和脐血化学物质以及母婴结局，包括子痫前期和早产的发生率、分娩时的孕龄和出生体重。
值得注意的是，10 名接受普伐他汀治疗的孕妇和 10 名接受安慰剂治疗的孕妇完成了试验。两组在不良或严重不良事件、先天性异常或母血和脐血化学物质方面无显著差异。头痛继以烧心和肌肉骨骼疼痛是最常见的副作用。我们报告了普伐他汀的药代动力学参数，包括普伐他汀的曲线下面积（一个给药间隔内的总药物暴露量）、表观口服清除率、半衰期等，这些参数在妊娠期间进行了测量，并与产后测量值进行了比较。在分娩时的大多数脐带和母血样本中，普伐他汀的浓度低于测定的定量下限。普伐他汀组的妊娠和新生儿结局更为有利。所有新生儿均通过了脑干听觉诱发电位或类似的听力筛查测试。与每日 10mg 普伐他汀相比，每日 20mg 普伐他汀的最大浓度和曲线下面积值增加了两倍以上，但表观口服清除率、半衰期和达到最大浓度的时间相似，这与非妊娠受试者中先前报道的普伐他汀线性、剂量无关的药代动力学一致。
本研究证实了普伐他汀在子痫前期高危孕妇中的总体安全性和良好的妊娠结局。这种有利的风险效益分析证明了更大规模的临床试验评估普伐他汀预防子痫前期的疗效是合理的。在那之前，普伐他汀在怀孕期间的使用仍处于研究阶段。
