Vaginal progesterone vs intramuscular 17α‐hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth in singleton gestations: systematic review and meta‐analysis of randomized controlled trials

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Abstract
Objective: Randomized controlled trials (RCTs) have recently compared intramuscular 17α‐hydroxyprogesterone caproate (17‐OHPC) with vaginal progesterone for reducing the risk of spontaneous preterm birth (SPTB) in singleton gestations with prior SPTB. The aim of this systematic review and meta‐analysis was to evaluate the efficacy of vaginal progesterone compared with 17‐OHPC in prevention of SPTB in singleton gestations with prior SPTB.Methods: Searches of electronic databases were performed to identify all RCTs of asymptomatic singleton gestations with prior SPTB that were randomized to prophylactic treatment with either vaginal progesterone (intervention group) or intramuscular 17‐OHPC (comparison group). No restrictions for language or geographic location were applied. The primary outcome was SPTB < 34 weeks. Secondary outcomes were SPTB < 37 weeks, < 32 weeks, < 28 weeks and < 24 weeks, maternal adverse drug reaction and neonatal outcomes. The summary measures were reported as relative risk (RR) with 95% CI. Risk of bias for each included study was assessed.Results: Three RCTs (680 women) were included. The mean gestational age at randomization was about 16 weeks. Women were given progesterone until 36 weeks or delivery. Regarding vaginal progesterone, one study used 90 mg gel daily, one used 100 mg suppository daily and one used 200 mg suppository daily. All included RCTs used 250 mg intramuscular 17‐OHPC weekly in the comparison group. Women who received vaginal progesterone had significantly lower rates of SPTB < 34 weeks (17.5% vs 25.0%; RR, 0.71 (95% CI, 0.53–0.95); low quality of evidence) and < 32 weeks (8.9% vs 14.5%; RR, 0.62 (95% CI, 0.40–0.94); low quality of evidence) compared with women who received 17‐OHPC. There were no significant differences in the rates of SPTB < 37 weeks, < 28 weeks and < 24 weeks. The rate of women who reported adverse drug reactions was significantly lower in the vaginal progesterone group compared with the 17‐OHPC group (7.1% vs 13.2%; RR, 0.53 (95% CI, 0.31–0.91); very low quality of evidence). Regarding neonatal outcomes, vaginal progesterone was associated with a lower rate of neonatal intensive care unit admission compared with 17‐OHPC (18.7% vs 23.5%; RR, 0.63 (95% CI, 0.47–0.83); low quality of evidence). For the comparison of 17‐OHPC vs vaginal progesterone, the quality of evidence was downgraded for all outcomes by at least one degree due to imprecision (the optimal information size was not reached) and by at least one degree due to indirectness (different interventions).Conclusions: Daily vaginal progesterone (either suppository or gel) started at about 16 weeks' gestation is a reasonable, if not better, alternative to weekly 17‐OHPC injection for prevention of SPTB in women with singleton gestations and prior SPTB. However, the quality level of the summary estimates was low or very low as assessed by GRADE, indicating that the true effect may be, or is likely to be, substantially different from the estimate of the effect. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.Comparación entre la progesterona vaginal y el 17α‐hidroxiprogesterona caproato intramuscular para la prevención del parto pretérmino espontáneo recurrente en embarazos con feto único: revisión sistemática y metaanálisis de ensayos controlados aleatorios: RESUMENObjetivo: Recientemente se han realizado varios ensayos controlados aleatorios (ECA) que comparaban el caproato de 17α‐hidroxiprogesterona (17‐OHPC, por sus siglas en inglés) por vía intramuscular con la progesterona por vía vaginal para la reducción del riesgo de parto pretérmino espontáneo (PPTE) en embarazos con feto único de gestantes con historial de PPTE. El objetivo de esta revisión sistemática y metaanálisis fue evaluar la eficacia de la progesterona vaginal en comparación con la 17‐OHPC en la prevención de embarazos con feto único de gestantes con historial de PPTE.Métodos: Se realizaron búsquedas en bases de datos electrónicas para identificar todos los ECA con embarazos de feto único asintomáticos con historial de PPTE antes de ser asignados al azar a un tratamiento profiláctico, ya fuera con progesterona vaginal (grupo de intervención) o con 17‐OHPC intramuscular (grupo de control). No se aplicaron restricciones respecto al idioma o la ubicación geográfica. El resultado primario fue PPTE < 34 semanas. Los resultados secundarios fueron PPTE RCTs)对比了有自发性早产(spontaneous preterm birth,SPTB)既往史的单胎妊娠中肌肉注射17α‐已酸羟孕酮(intramuscular 17α‐hydroxyprogesterone caproate,17‐OHPC)与黄体酮阴道给药降低SPTB的风险。本篇系统回顾和meta分析的目的是评估在有SPTB既往史的单胎妊娠中黄体酮阴道给药对比17‐OHPC预防SPTB的疗效。方法: 检索电子数据库,查找关于有SPTB既往史的无症状单胎妊娠的所有RCTs,RCTs中将患者随机分为接受黄体酮阴道给药(干预组)或肌肉注射17‐OHPC(对照组)。对语言或地理位置无限制。主要结局为孕34周前发生SPTB。次要结局为孕37周前、孕32周前、孕28周前和孕24周前发生SPTB,母亲不良药物反应以及新生儿结局。综合检测结果以相对危险度(relative risk,RR)和95%CI表示。对每项纳入研究的偏倚风险进行评估。结果: 纳入3项RCTs(680例孕妇)。随机分组时平均孕周约为16周。给予孕妇黄体酮,直至孕36周或分娩。在黄体酮阴道给药组中,一项研究采用每日90 mg凝胶,一项采用每日100 mg栓剂,另外一项研究采用每日200 mg栓剂。对照组中,所有纳入的RCTs均采用每周250 mg 17‐OHPC肌肉注射。与17‐OHPC组孕妇相比,黄体酮阴道给药组孕妇孕34周前 [17.5%和25.0%;RR,0.71(95% CI,0.53 ~ 0.95);低质量证据]和孕32周前[8.9%和14.5%;RR,0.62(95% CI,0.40 ~ 0.94);低质量证据]SPTB的发生率明显较低。孕37周前、孕28周前和孕24周前SPTB的发生率无明显差异。黄体酮阴道给药组与17‐OHPC组比较,孕妇不良药物反应的发生率明显较低[7.1%和13.2%;RR,0.53(95% CI,0.31 ~ 0.91);极低质量证据]。在新生儿结局方面,与17‐OHPC组比较,黄体酮阴道给药组新生儿重症监护病房住院率较低[18.7%和23.5%;RR,0.63(95% CI,0.47 ~ 0.83);低质量证据]。对17‐OHPC和黄体酮阴道给药进行比较,所有结局的证据质量由于不精确降低至少一级(未达到最佳信息量),由于间接性至少降低一级(不同干预措施)。结论: 为了预防有SPTB既往史的单胎妊娠孕妇发生SPTB,在约孕16周时开始每日黄体酮阴道给药(栓剂或凝胶)是每周注射17‐OHPC的一项合理的,即使不是更好的替代方案。然而,根据GRADE,综合评估的质量水平较低或极低,表明真实的效果可能或很可能与估计的效果大不相同。

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