Bordewijk Esmée M, Ng Ka Ying Bonnie, Rakic Lidija, Mol Ben Willem J, Brown Julie, Crawford Tineke J, van Wely Madelon
Amsterdam UMC, University of Amsterdam, Center for Reproductive Medicine, Amsterdam, Netherlands, 1105 AZ.
University of Southampton, School of Human Development and Health, Southampton, UK, SO16 6YD.
Cochrane Database Syst Rev. 2020 Feb 11;2(2):CD001122. doi: 10.1002/14651858.CD001122.pub5.
Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions.
To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance.
We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies.
We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD.
Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes.
This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose.
AUTHORS' CONCLUSIONS: Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.
多囊卵巢综合征（PCOS）是一种常见病症，影响8%至13%的育龄妇女。过去，枸橼酸氯米芬（CC）曾是PCOS女性的一线治疗药物。根据新指南，来曲唑促排卵应作为一线治疗，但来曲唑的使用属于超说明书用药。因此，CC仍被广泛使用。约20%服用CC的女性不排卵。CC抵抗的女性可用促性腺激素或其他药物促排卵治疗。这些药物并非总能成功，可能耗时且会导致多胎妊娠和因过度反应而取消周期等不良事件。腹腔镜卵巢打孔术（LOD）是一种手术替代治疗方法。手术存在风险，如麻醉并发症、感染和粘连。
评估对于无排卵性多囊PCOS且CC抵抗的女性，LOD联合或不联合药物促排卵与单纯药物促排卵相比的有效性和安全性。
我们检索了Cochrane妇科与生育组（CGFG）试验注册库、CENTRAL、MEDLINE、Embase、PsycINFO、CINAHL以及截至2019年10月8日的两个试验注册库，并进行参考文献核对以及与研究作者和该领域专家联系以识别其他研究。
我们纳入了无排卵性PCOS且CC抵抗的女性的随机对照试验（RCT），这些试验比较了接受LOD联合或不联合药物促排卵与单纯药物促排卵、LOD联合辅助生殖技术（ART）与ART、LOD联合二次腹腔镜检查与期待治疗，或不同的LOD技术。
两位综述作者独立选择研究、评估偏倚风险、提取数据并使用GRADE方法评估证据质量。主要有效性结局是活产，主要安全性结局是多胎妊娠。妊娠、流产、卵巢过度刺激综合征（OHSS）、排卵、费用和生活质量是次要结局。
本次更新综述纳入38项试验（3326名女性）。证据质量极低至中等；主要局限性在于研究方法报告不佳，因偏倚风险（随机化和分配隐藏）以及缺乏盲法而降级。腹腔镜卵巢打孔联合或不联合药物促排卵与单纯药物促排卵相比汇总结果表明，与单纯药物促排卵相比LOD可能会使活产率略有降低（优势比（OR）0.71，95%置信区间（CI）0.54至0.92；9项研究，1015名女性；I² = 0%；低质量证据）。证据表明，如果单纯药物促排卵后的活产机会为42%，LOD后的机会将在28%至40%之间。仅限制于选择偏倚风险低的RCT的敏感性分析表明，治疗之间是否存在差异尚不确定（OR 0.90，95% CI 0.59至1.36；4项研究，415名女性；I² = 0%；低质量证据）。LOD可能会降低多胎妊娠率（Peto OR 0.34，95% CI 0.18至0.66；14项研究，1161名女性；I² = 2%；中等质量证据）。这表明，如果我们假设单纯药物促排卵后的多胎妊娠风险为5.0%，LOD后的风险将在0.9%至3.4%之间。仅限制于在LOD后随访女性6个月以及仅6个促排卵周期的RCT，活产结果与主要分析一致。治疗之间临床妊娠可能性可能几乎没有差异（OR 0.86，95% CI 0.72至1.03；21项研究，2016名女性；I² = 19%；低质量证据）。与单纯促排卵相比，LOD对流产的影响尚不确定（OR 1.11，95% CI 0.78至1.59；19项研究，1909名女性；I² = 0%；低质量证据）。OHSS是非常罕见的事件。LOD可能会降低OHSS（Peto OR 0.25，95% CI 0.07至0.91；8项研究，722名女性；I² = 0%；低质量证据）。单侧LOD与双侧LOD由于样本量小，证据质量不足以就活产得出结论（OR 0.83，95% CI 0.24至2.78；1项研究，44名女性；极低质量证据）。没有关于多胎妊娠的数据。由于证据质量和研究之间的巨大异质性，治疗之间临床妊娠的可能性尚不确定（OR 0.57，95% CI 0.39至0.84；7项研究，470名女性；I² = 60%，极低质量证据）。由于样本量小，证据质量不足以就流产得出结论（OR 1.02，95% CI 0.31至3.33；2项研究，131名女性；I² = 0%；极低质量证据）。其他比较由于缺乏证据和极低质量的数据，对于以下任何比较是否存在差异尚不确定：LOD联合体外受精（IVF）与IVF、LOD联合二次腹腔镜检查与期待治疗、单极LOD与双极LOD，以及调整热剂量与固定热剂量。
对于无排卵性PCOS且CC抵抗的女性，腹腔镜卵巢打孔联合或不联合药物促排卵与单纯药物促排卵相比可能会降低活产率。但仅限制于选择偏倚风险低的RCT的敏感性分析表明，由于估计存在不确定性，治疗之间是否存在差异尚不确定。中等质量证据表明LOD可能会减少多胎妊娠的数量。低质量证据表明治疗之间临床妊娠可能性可能几乎没有差异，与单纯促排卵相比，LOD对流产的影响尚不确定。LOD可能导致OHSS减少。对于单侧LOD与双侧LOD的分析，证据质量不足以就活产、临床妊娠或流产率得出结论。没有关于多胎妊娠的数据。
