背景:己酸17-羟孕酮的有效性尚不清楚,因为试验提供了相互矛盾的结果。缺少有关给药剂量或药物浓度与分娩时胎龄之间关系的基本药理学研究,无法评估药物的有效性。
目的:评估17-羟基孕酮己酸酯的血浆浓度与早产率及早产胎龄之间的关系,并评估500毫克剂量的安全性。
方法:我们招募了两个先前有自发性早产的队列;一个队列(n=143)被随机分配给250mg或500mg17-羟孕酮己酸酯,第二组(n=16)接受250mg剂量的常规治疗.在妊娠26-30周时获得的17-羟基孕酮己酸酯的稳态谷血浆浓度与剂量相关,自发性早产率和妊娠长度的测量。还根据剂量评估了孕产妇和新生儿的安全性结果。
结果:使用250mg时,谷血浆浓度呈剂量比例增加(中位数=8.6ng/ml,n=66)和500mg(中位数=16.2ng/ml,n=55)剂量。在116名符合血液样本的参与者中,药物浓度与自发性早产率无关[OR(95CI)1.00(0.93-1.08)].然而,药物浓度和从第一次注射到分娩的时间间隔之间存在显著关系,(间隔A)[系数(95%CI)1.11(0.00-2.23,p=0.05)]和从26-30周抽血到分娩的间隔,(区间B)[系数(95%CI)1.56(0.25-2.87,p=0.02)。自发性早产率或妊娠长度的测量与剂量无关。注册后环扎会对所有药效学评估产生不利影响,因为它是自发性早产的有力预测因子[OR(95CI)4.03(1.24-13.19),p=0.021]以及两种妊娠长度的测量,区间A[系数(95CI)-14.9(-26.3-(-)3.4),p=0.011)]和区间B[系数(95CI)-15.9(-25.8-(-)5.9),p=0.002)]。初始宫颈长度与入组后环扎的风险显着相关[OR(95%CI)0.80(0.70-0.92),p=0.001]。两个给药组的孕产妇和新生儿安全结局相似。
结论:在这项药效学研究中,血浆己酸17-羟孕酮浓度的下降与早产时的胎龄显著相关,但与早产率无关.登记后环扎是自发性早产率的有力预测指标,和妊娠长度。初始宫颈长度预测了登记后环扎的风险。17-OHPC的500mg和250mg剂量的不良事件相似。
The effectiveness of 17-hydroxyprogesterone caproate is unclear as trials have provided conflicting results. With the absence of fundamental pharmacologic studies addressing dosing or the relationship between drug concentration and gestational age at delivery, the effectiveness of the medication cannot be evaluated.
This study aimed to evaluate the relationship between plasma concentrations of 17-hydroxyprogesterone caproate and preterm birth rates and gestational age at preterm delivery and to assess the safety of the 500-mg dose.
This study recruited 2 cohorts with previous spontaneous preterm birth; 1 cohort (n=143) was randomly assigned to either 250-mg or 500-mg 17-hydroxyprogesterone caproate, and the other cohort (n=16) was receiving the 250-mg dose for routine care. Steady-state trough plasma concentrations of 17-hydroxyprogesterone caproate obtained at 26 to 30 weeks of gestation were correlated to dose, spontaneous preterm birth rates, and measures of gestational length. Furthermore, maternal and neonatal safety outcomes were evaluated according to dose.
There was a dose proportional increase in trough plasma concentrations with the 250-mg (median, 8.6 ng/m; n=66) and 500-mg (median, 16.2 ng/mL; n=55) doses. In 116 compliant participants with blood samples, drug concentration was not related to the spontaneous preterm birth rate (odds ratio, 1.00; 95% confidence interval, 0.93-1.08). However, there was a significant relationship between drug concentration and both the interval from the first administration to delivery (interval A: coefficient, 1.11; 95% confidence interval, 0.00-2.23; P=.05) and the interval from the 26- to 30-week blood draw to delivery (interval B: coefficient, 1.56; 95% confidence interval, 0.25-2.87; P=.02). The spontaneous preterm birth rate or measures of gestational length were not related to dose. Postenrollment cerclage adversely affected all pharmacodynamic assessments because it was a powerful predictor of spontaneous preterm birth (odds ratio, 4.03; 95% confidence interval, 1.24-13.19; P=.021) and both measures of gestational length (interval A [coefficient, -14.9; 95% confidence interval, -26.3 to -3.4; P=.011] and interval B [coefficient, -15.9; 95% confidence interval, -25.8 to -5.9; P=.002]). Initial cervical length was significantly related to the risk of postenrollment cerclage (odds ratio, 0.80; 95% confidence interval, 0.70-0.92; P=.001). Maternal and neonatal safety outcomes were similar in both dosing groups.
In this pharmacodynamic study, trough plasma 17-hydroxyprogesterone caproate concentrations were significantly associated with gestational age at preterm birth but not with the preterm birth rate. Postenrollment cerclage was a powerful predictor of spontaneous preterm birth rate and gestational length. Initial cervical length predicted the risk of postenrollment cerclage. Adverse events were similar with the 500-mg and 250-mg doses of 17-hydroxyprogesterone caproate.