Costantine Maged M, Cleary Kirsten, Hebert Mary F, Ahmed Mahmoud S, Brown Linda M, Ren Zhaoxia, Easterling Thomas R, Haas David M, Haneline Laura S, Caritis Steve N, Venkataramanan Raman, West Holly, D'Alton Mary, Hankins Gary
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
Columbia University, New York, NY.
Am J Obstet Gynecol. 2016 Jun;214(6):720.e1-720.e17. doi: 10.1016/j.ajog.2015.12.038. Epub 2015 Dec 23.
Preeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking.
As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia.
We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586).
Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile.
This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.
子痫前期约使3%-5%的妊娠复杂化，仍是孕产妇和新生儿发病及死亡的主要原因。它与成人心血管疾病有相似的致病机制以及许多风险因素。普伐他汀是一种亲水性的3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，临床前研究表明其可逆转与子痫前期相关的各种病理生理途径，这为其用于预防子痫前期提供了生物学合理性。然而，尚缺乏人体试验。
作为评估普伐他汀预防子痫前期效用的第一步，并经与美国食品药品监督管理局协商，我们开展了一项试点随机对照试验，目的是确定普伐他汀用于子痫前期高危孕妇时的安全性和药代动力学参数。
我们对单胎、无异常妊娠且有子痫前期高危因素的女性进行了一项试点、多中心、双盲、安慰剂对照的随机试验。妊娠12（0/7）至16（6/7）周的女性被分配至每日口服10 mg普伐他汀或安慰剂直至分娩。主要结局是孕期母婴安全性和普伐他汀的药代动力学参数。次要结局包括子痫前期和早产的发生率、分娩孕周、出生体重以及母体和脐血脂谱（clinicaltrials.gov标识符NCT01717586）。
10名分配至普伐他汀组和10名分配至安慰剂组的女性完成了试验。两组在研究药物副作用、先天性异常或其他不良或严重不良事件的发生率方面无差异。无孕产妇、胎儿或新生儿死亡。与产后相比，孕期普伐他汀的肾脏清除率显著更高。安慰剂组有4名受试者发生子痫前期，而普伐他汀组无。尽管普伐他汀降低了母体胆固醇浓度，但两组间脐血胆固醇浓度和婴儿出生体重并无差异。分娩时大多数脐血和母体普伐他汀血浆浓度低于检测方法的定量下限。使用普伐他汀与更有利的妊娠血管生成特征相关。
本研究提供了关于普伐他汀用于预防高危孕妇子痫前期的初步安全性和药代动力学数据。尽管数据是初步的，但在该队列中使用普伐他汀未发现可识别的安全风险。这种有利的风险效益分析证明在剂量递增的更大规模临床试验中使用普伐他汀是合理的。
