A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization
A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization
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DOI：
10.1093/humrep/deu194
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发表时间：
2014-10-01
影响因子：
6.1
通讯作者：
Soules, Michael
中科院分区：
文献类型：
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作者：
Baker, Valerie L.;Jones, Christopher A.;Soules, Michael
研究问题：当用于体外受精的黄体期支持时，新型皮下黄体酮水剂 (Proolutex (R)) 的持续妊娠率是否不低于阴道黄体酮 (Endometrin (R))？总结答案：在符合方案 (PP) 人群中，妊娠 12 周时每个卵母细胞取出的持续妊娠率在 Prolutex 和子宫内膜素（41.6 对比 44.4%），组间差异为 -2.8%（95% 置信区间 (CI) -9.7, 4.2），与皮下黄体期支持的非劣效性一致。 已知信息：黄体期支持已被明确证明可以提高接受体外受精 (IVF) 的女性的妊娠率。由于使用 hCG 会增加卵巢过度刺激综合征的风险，因此黄体酮已成为黄体期支持的首选治疗方法。 研究设计、规模、持续时间：这项前瞻性、开放标签、随机、对照、平行组、多中心、双臂、非劣效性研究在八个生育诊所进行。 2009 年 1 月至 6 月期间，共有 800 名女性入组，年龄 18-42 岁，BMI = 30 kg/m(2)，之前已完成 3 个辅助生殖技术 (ART) 周期，基线（第 2-3 天）FSH = 15 IU/L，并在美国 8 个中心（7 个私立中心，1 个学术中心）接受 IVF 治疗。 2011. 参与者/材料、地点、方法：总共 800 名接受 IVF 的女性在取出至少 3 个卵母细胞后被随机分配至皮下注射黄体酮水制剂（每日 25 毫克）或阴道黄体酮（每日 100 毫克 bid）。使用统计分析软件 (SAS (R)) 生成的随机化列表进行随机化，在每个中心招募 100 名患者。如果发生可行妊娠，则继续使用黄体酮治疗至妊娠 12 周。 主要结果和机会的作用：使用 PP 分析（包括所有接受胚胎移植的患者（Prolutex = 392；Endometrin = 390）），每次皮下黄体酮与阴道黄体酮提取的持续妊娠率分别为 41.6% 和 44.4%，组间差异为 22.8% (95% CI -9.7, 4.2)，与皮下注射黄体酮支持黄体期的非劣效性一致。此外，初始 β-hCG 阳性率（56.4% 皮下注射 vs 59.0% 阴道注射；95% CI -9.5, 4.3）、临床宫内妊娠伴胎儿心脏活动（42.6 vs 46.4%；95% CI -10.8, 3.2）、植入定义为孕囊数量除以移植胚胎数量（33.2 vs 46.4%）。 35.1%；95% CI -7.6，4.0）、活产（41.1 vs 43.1%；95% CI -8.9，4.9）和带回家婴儿（41.1 vs 42.6%；95% CI -8.4，5.4）具有可比性。两种制剂的耐受性良好，严重不良事件没有差异。对意向治疗人群的分析也表明，治疗组之间的任何结果均无差异。 局限性、注意原因：结论仅限于所研究的孕酮给药方案和本研究中检查的患者群体的治疗持续时间。研究结果的更广泛影响：对于因个人原因不愿使用阴道制剂或希望避免使用阴道制剂的接受 IVF 的女性来说，皮下注射孕酮代表了黄体期支持的新选择阴道或肌肉注射的副作用给药途径。研究资助/竞争利益：该研究由 Institut Biochimique SA (IBSA) 资助。 CAJ、BC、ST 和 CJ 是 IBSA 的员工。 FH 目前正在咨询 IBSA。试用注册号：NCT00828191。
STUDY QUESTION: Is the ongoing pregnancy rate with a new aqueous formulation of subcutaneous progesterone (Prolutex (R)) non-inferior to vaginal progesterone (Endometrin (R)) when used for luteal phase support of in vitro fertilization?SUMMARY ANSWER: In the per-protocol ( PP) population, the ongoing pregnancy rates per oocyte retrieval at 12 weeks of gestation were comparable between Prolutex and Endometrin (41.6 versus 44.4%), with a difference between groups of -2.8% (95% confidence interval (CI) -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support.WHAT IS KNOWN ALREADY: Luteal phase support has been clearly demonstrated to improve pregnancy rates in women undergoing in vitro fertilization (IVF). Because of the increased risk of ovarian hyperstimulation syndrome associated with the use of hCG, progesterone has become the treatment of choice for luteal phase support.STUDY DESIGN, SIZE, DURATION: This prospective, open-label, randomized, controlled, parallel-group, multicentre, two-arm, non-inferiority study was performed at eight fertility clinics. A total of 800 women, aged 18-42 years, with a BMI of = 30 kg/m(2), with,3 prior completed assisted reproductive technology ( ART) cycles, exhibiting baseline (Days 2-3) FSH of = 15 IU/L and undergoing IVF at 8 centres (seven private, one academic) in the USA, were enrolled from January 2009 through June 2011.PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 800 women undergoing IVF were randomized after retrieval of at least three oocytes to an aqueous preparation of progesterone administered subcutaneously (25 mgdaily) or vaginal progesterone (100 mg bid daily). Randomization was performed to enrol 100 patients at each site using a randomization list that was generated with Statistical Analysis Software (SAS (R)). If a viable pregnancy occurred, progesterone treatment was continued up to 12 weeks of gestation.MAIN RESULTS AND THE ROLE OF CHANCE: Using a PP analysis, which included all patients who received an embryo transfer (Prolutex = 392; Endometrin = 390), the ongoing pregnancy rate per retrieval for subcutaneous versus vaginal progesterone was 41.6 versus 44.4%, with a difference between groups of 22.8% (95% CI -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. In addition, rates of initial positive beta-hCG (56.4% subcutaneous versus 59.0% vaginal; 95% CI -9.5, 4.3), clinical intrauterine pregnancy with fetal cardiac activity (42.6 versus 46.4%; 95% CI -10.8, 3.2), implantation defined as number of gestational sacs divided by number of embryos transferred (33.2 versus 35.1%; 95% CI -7.6, 4.0), live birth (41.1 versus 43.1%; 95% CI -8.9, 4.9) and take-home baby (41.1 versus 42.6%; 95% CI -8.4, 5.4) were comparable. Both formulations were well-tolerated, with no difference in serious adverse events. Analysis with the intention-to-treat population also demonstrated no difference for any outcomes between the treatment groups.LIMITATIONS, REASONS FOR CAUTION: The conclusions are limited to the progesterone dosing regimen studied and duration of treatment for the patient population examined in this study.WIDER IMPLICATIONS OF THE FINDINGS: Subcutaneous progesterone represents a novel option for luteal phase support in women undergoing IVF who for personal reasons prefer not to use a vaginal preparation or who wish to avoid the side effects of vaginal or i.m. routes of administration.STUDY FUNDING/COMPETING INTERESTS: The study was funded by Institut Biochimique SA (IBSA). CAJ, BC, ST and CJ are employees of IBSA. FH currently consults for IBSA.TRIAL REGISTRATION NUMBER: NCT00828191.