Farquhar Cindy, Rombauts Luk, Kremer Jan Am, Lethaby Anne, Ayeleke Reuben Olugbenga
Department of Obstetrics and Gynaecology, University of Auckland, FMHS Park Road, Grafton, Auckland, New Zealand, 1003.
Monash IVF and Department of O&G, Monash University, 246 Clayton Rd, Melbourne, Australia.
Cochrane Database Syst Rev. 2017 May 25;5(5):CD006109. doi: 10.1002/14651858.CD006109.pub3.
Among subfertile women undergoing assisted reproductive technology (ART), hormone pills given before ovarian stimulation may improve outcomes.
To determine whether pretreatment with the combined oral contraceptive pill (COCP) or with a progestogen or oestrogen alone in ovarian stimulation protocols affects outcomes in subfertile couples undergoing ART.
We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, The Cochrane Central Register Studies Online, MEDLINE, Embase, CINAHL and PsycINFO. We also searched the reference lists of relevant articles and registers of ongoing trials.
Randomised controlled trials (RCTs) of hormonal pretreatment in women undergoing ART.
We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth or ongoing pregnancy and pregnancy loss.
We included 29 RCTs (4701 women) of pretreatment with COCPs, progestogens or oestrogens versus no pretreatment or alternative pretreatments, in gonadotrophin-releasing hormone (GnRH) agonist or antagonist cycles. Overall, evidence quality ranged from very low to moderate. The main limitations were risk of bias and imprecision. Most studies did not describe their methods in adequate detail. Combined oral contraceptive pill versus no pretreatmentWith antagonist cycles in both groups the rate of live birth or ongoing pregnancy was lower in the pretreatment group (OR 0.74, 95% CI 0.58 to 0.95; 6 RCTs; 1335 women; I = 0%; moderate quality evidence). There was insufficient evidence to determine whether the groups differed in rates of pregnancy loss (OR 1.36, 95% CI 0.82 to 2.26; 5 RCTs; 868 women; I = 0%; moderate quality evidence), multiple pregnancy (OR 2.21, 95% CI 0.53 to 9.26; 2 RCTs; 125 women; I = 0%; low quality evidence), ovarian hyperstimulation syndrome (OHSS; OR 0.98, 95% CI 0.28 to 3.40; 2 RCTs; 642 women; I = 0%, low quality evidence), or ovarian cyst formation (OR 0.47, 95% CI 0.08 to 2.75; 1 RCT; 64 women; very low quality evidence).In COCP plus antagonist cycles versus no pretreatment in agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (OR 0.89, 95% CI 0.64 to 1.25; 4 RCTs; 724 women; I = 0%; moderate quality evidence), multiple pregnancy (OR 1.36, 95% CI 0.85 to 2.19; 4 RCTs; 546 women; I = 0%; moderate quality evidence), or OHSS (OR 0.63, 95% CI 0.20 to 1.96; 2 RCTs; 290 women, I = 0%), but there were fewer pregnancy losses in the pretreatment group (OR 0.40, 95% CI 0.22 to 0.72; 5 RCTs; 780 women; I = 0%; moderate quality evidence). There were no data suitable for analysis on ovarian cyst formation.One small study comparing COCP versus no pretreatment in agonist cycles showed no clear difference between the groups for any of the reported outcomes. Progestogen versus no pretreatmentAll studies used the same protocol (antagonist, agonist or gonadotrophins) in both groups. There was insufficient evidence to determine any differences in rates of live birth or ongoing pregnancy (agonist: OR 1.35, 95% CI 0.69 to 2.65; 2 RCTs; 222 women; I = 24%; low quality evidence; antagonist: OR 0.67, 95% CI 0.18 to 2.54; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 0.63, 95% CI 0.09 to 4.23; 1 RCT; 42 women; very low quality evidence), pregnancy loss (agonist: OR 2.26, 95% CI 0.67 to 7.55; 2 RCTs; 222 women; I = 0%; low quality evidence; antagonist: OR 0.36, 95% CI 0.06 to 2.09; 1 RCT; 47 women; low quality evidence; gonadotrophins: OR 1.00, 95% CI 0.06 to 17.12; 1 RCT; 42 women; very low quality evidence) or multiple pregnancy (agonist: no data available; antagonist: OR 1.05, 95% CI 0.06 to 17.76; 1 RCT; 47 women; low quality evidence; gonadotrophins: no data available). Three studies, all using agonist cycles, reported ovarian cyst formation: rates were lower in the pretreatment group (OR 0.16, 95% CI 0.08 to 0.32; 374 women; I = 1%; moderate quality evidence). There were no data on OHSS. Oestrogen versus no pretreatmentIn antagonist or agonist cycles, there was insufficient evidence to determine whether the groups differed in rates of live birth or ongoing pregnancy (antagonist versus antagonist: OR 0.79, 95% CI 0.53 to 1.17; 2 RCTs; 502 women; I = 0%; low quality evidence; antagonist versus agonist: OR 0.88, 95% CI 0.51 to 1.50; 2 RCTs; 242 women; I = 0%; very low quality evidence), pregnancy loss (antagonist versus antagonist: OR 0.16, 95% CI 0.02 to 1.47; 1 RCT; 49 women; very low quality evidence; antagonist versus agonist: OR 1.59, 95% CI 0.62 to 4.06; 1 RCT; 220 women; very low quality evidence), multiple pregnancy (antagonist versus antagonist: no data available; antagonist versus agonist: OR 2.24, 95% CI 0.09 to 53.59; 1 RCT; 22 women; very low quality evidence) or OHSS (antagonist versus antagonist: no data available; antagonist versus agonist: OR 1.54, 95% CI 0.25 to 9.42; 1 RCT; 220 women). Ovarian cyst formation was not reported. Head-to-head comparisonsCOCP was compared with progestogen (1 RCT, 44 women), and with oestrogen (2 RCTs, 146 women), and progestogen was compared with oestrogen (1 RCT, 48 women), with an antagonist cycle in both groups. COCP in an agonist cycle was compared with oestrogen in an antagonist cycle (1 RCT, 25 women). Data were scant but there was no clear evidence that any of the groups differed in rates of live birth or ongoing pregnancy, pregnancy loss or other adverse events.
AUTHORS' CONCLUSIONS: Among women undergoing ovarian stimulation in antagonist protocols, COCP pretreatment was associated with a lower rate of live birth or ongoing pregnancy than no pretreatment. There was insufficient evidence to determine whether rates of live birth or ongoing pregnancy were influenced by pretreatment with progestogens or oestrogens, or by COCP pretreatment using other stimulation protocols. Findings on adverse events were inconclusive, except that progesterone pretreatment may reduce the risk of ovarian cysts in agonist cycles, and COCP in antagonist cycles may reduce the risk of pregnancy loss compared with no pretreatment in agonist cycles.
在接受辅助生殖技术（ART）的不育女性中，卵巢刺激前服用激素药丸可能会改善治疗结果。
确定在卵巢刺激方案中，联合口服避孕药（COCP）或单独使用孕激素或雌激素进行预处理是否会影响接受ART的不育夫妇的治疗结果。
我们检索了从数据库建立至2017年1月的以下数据库：Cochrane妇科与生育组专业注册库、Cochrane在线中央注册研究库、医学期刊数据库（MEDLINE）、荷兰医学文摘数据库（Embase）、护理学与健康领域数据库（CINAHL）和心理学文摘数据库（PsycINFO）。我们还检索了相关文章的参考文献列表和正在进行的试验注册库。
对接受ART的女性进行激素预处理的随机对照试验（RCT）。
我们采用了Cochrane推荐的标准方法程序。主要的综述结果是活产或持续妊娠以及妊娠丢失。
我们纳入了29项RCT（4701名女性），这些研究比较了在促性腺激素释放激素（GnRH）激动剂或拮抗剂周期中，使用COCP、孕激素或雌激素进行预处理与不进行预处理或采用其他预处理方法的效果。总体而言，证据质量从极低到中等不等。主要局限性在于偏倚风险和不精确性。大多数研究没有充分详细地描述其方法。
联合口服避孕药与不进行预处理
在两组的拮抗剂周期中，预处理组的活产或持续妊娠率较低（比值比[OR]0.74，95%置信区间[CI]0.58至0.95；6项RCT；1335名女性；I² = 0%；中等质量证据）。没有足够的证据来确定两组在妊娠丢失率（OR 1.36，95% CI 0.82至2.26；5项RCT；868名女性；I² = 0%；中等质量证据）、多胎妊娠率（OR 2.21，95% CI 0.53至9.26；2项RCT；125名女性；I² = 0%；低质量证据）、卵巢过度刺激综合征（OHSS；OR 0.98，95% CI 0.28至3.40；2项RCT；642名女性；I² = 0%，低质量证据）或卵巢囊肿形成率（OR 0.47，95% CI 0.08至2.75；1项RCT；64名女性；极低质量证据）方面是否存在差异。
在COCP加拮抗剂周期与激动剂周期不进行预处理的比较中，没有足够的证据来确定两组在活产或持续妊娠率（OR 0.89，95% CI 0.64至1.25；4项RCT；724名女性；I² = 0%；中等质量证据）、多胎妊娠率（OR 1.36，95% CI 0.85至2.19；4项RCT；546名女性；I² = 0%；中等质量证据）或OHSS发生率（OR 0.63，95% CI 0.20至1.96；2项RCT；290名女性，I² = 0%）方面是否存在差异，但预处理组的妊娠丢失较少（OR 0.40，95% CI 0.22至0.72；5项RCT；780名女性；I² = 0%；中等质量证据）。没有适合分析卵巢囊肿形成的数据。
一项在激动剂周期中比较COCP与不进行预处理的小型研究显示，两组在任何报告的结果上均无明显差异。
孕激素与不进行预处理
所有研究在两组中均采用相同的方案（拮抗剂、激动剂或促性腺激素）。没有足够的证据来确定在活产或持续妊娠率（激动剂：OR 1.35，95% CI 0.69至2.65；2项RCT；222名女性；I² = 24%；低质量证据；拮抗剂：OR 0.67，95% CI 0.18至2.54；1项RCT；47名女性；低质量证据；促性腺激素：OR 0.63，95% CI 0.09至4.23；1项RCT；42名女性；极低质量证据）、妊娠丢失率（激动剂：OR 2.26，95% CI 0.67至7.55；2项RCT；222名女性；I² = 0%；低质量证据；拮抗剂：OR 0.36，95% CI 0.06至2.09；1项RCT；47名女性；低质量证据；促性腺激素：OR 1.00，95% CI 0.06至17.12；1项RCT；42名女性；极低质量证据）或多胎妊娠率（激动剂：无可用数据；拮抗剂：OR 1.05，95% CI 0.06至17.76；1项RCT；47名女性；低质量证据；促性腺激素：无可用数据）方面是否存在差异。三项均使用激动剂周期的研究报告了卵巢囊肿形成情况：预处理组的发生率较低（OR 0.16，95% CI 0.08至0.32；374名女性；I² = 1%；中等质量证据）。没有关于OHSS的数据。
雌激素与不进行预处理
在拮抗剂或激动剂周期中，没有足够的证据来确定两组在活产或持续妊娠率（拮抗剂与拮抗剂：OR 0.79，95% CI 0.53至1.17；2项RCT；502名女性；I² = 0%；低质量证据；拮抗剂与激动剂：OR 0.88，95% CI 0.51至1.50；2项RCT；242名女性；I² = 0%；极低质量证据）、妊娠丢失率（拮抗剂与拮抗剂：OR 0.16，95% CI 0.02至1.47；1项RCT；49名女性；极低质量证据；拮抗剂与激动剂：OR 1.59，95% CI 0.62至4.06；1项RCT；220名女性；极低质量证据）、多胎妊娠率（拮抗剂与拮抗剂：无可用数据；拮抗剂与激动剂：OR 2.24，95% CI 0.09至53.59；1项RCT；22名女性；极低质量证据）或OHSS发生率（拮抗剂与拮抗剂：无可用数据；拮抗剂与激动剂：OR 1.54，95% CI 0.25至9.42；1项RCT；220名女性）方面是否存在差异。未报告卵巢囊肿形成情况。
直接比较
在两组均为拮抗剂周期的情况下，比较了COCP与孕激素（1项RCT，44名女性）以及与雌激素（2项RCT，146名女性），还比较了孕激素与雌激素（1项RCT，48名女性）。比较了激动剂周期中的COCP与拮抗剂周期中的雌激素（1项RCT，25名女性）。数据很少，但没有明确证据表明任何一组在活产或持续妊娠率、妊娠丢失率或其他不良事件方面存在差异。
在采用拮抗剂方案进行卵巢刺激的女性中，与不进行预处理相比，COCP预处理与较低的活产或持续妊娠率相关。没有足够的证据来确定活产或持续妊娠率是否受孕激素或雌激素预处理的影响，或受使用其他刺激方案的COCP预处理的影响。除了孕激素预处理可能降低激动剂周期中卵巢囊肿的风险，以及与激动剂周期不进行预处理相比，拮抗剂周期中的COCP可能降低妊娠丢失的风险外，关于不良事件的研究结果尚无定论。
