Rizzuto Ivana, Behrens Renee F, Smith Lesley A
Gynaecology Oncology Department, East Suffolk and North Essex NHS Foundation Trust, Heath Road, Ipswich, Suffolk, UK, IP4 5PD.
Cochrane Database Syst Rev. 2019 Jun 18;6(6):CD008215. doi: 10.1002/14651858.CD008215.pub3.
This is an updated version of the original Cochrane Review published in the Cochrane Library in 2013 (Issue 8) on the risk of ovarian cancer in women using infertility drugs when compared to the general population or to infertile women not treated. The link between fertility drugs and ovarian cancer remains controversial.
To evaluate the risk of invasive ovarian cancer and borderline ovarian tumours in women treated with ovarian stimulating drugs for subfertility.
The original review included published and unpublished observational studies from 1990 to February 2013. For this update, we extended the searches from February 2013 to November 2018; we evaluated the quality of the included studies and judged the certainty of evidence by using the GRADE approach. We have reported the results in a Summary of findings table to present effect sizes across all outcome types.
In the original review and in this update, we searched for randomised controlled trials (RCTs) and non-randomised studies and case series including more than 30 participants.
At least two review authors independently conducted eligibility and 'Risk of bias' assessments and extracted data. We grouped studies based on the fertility drug used for two outcomes: borderline ovarian tumours and invasive ovarian cancer. We conducted no meta-analyses due to expected methodological and clinical heterogeneity.
We included 13 case-control and 24 cohort studies (an additional nine new cohort and two case-control studies), which included a total of 4,684,724 women.Two cohort studies reported an increased incidence of invasive ovarian cancer in exposed subfertile women compared with unexposed women. One reported a standardised incidence ratio (SIR) of 1.19 (95% confidence interval (CI) 0.54 to 2.25) based on 17 cancer cases. The other cohort study reported a hazard ratio (HR) of 1.93 (95% CI 1.18 to 3.18), and this risk was increased in women remaining nulligravid after using clomiphene citrate (HR 2.49, 95% CI 1.30 to 4.78) versus multiparous women (HR 1.52, 95% CI 0.67 to 3.42) (very low-certainty evidence). The slight increase in ovarian cancer risk among women having between one and three cycles of in vitro fertilisation (IVF) was reported, but this was not clinically significant (P = 0.18). There was no increase in risk of invasive ovarian cancer after use of infertility drugs in women with the BRCA mutation according to one cohort and one case-control study. The certainty of evidence as assessed using GRADE was very low.For borderline ovarian tumours, one cohort study reported increased risk in exposed women with an SIR of 3.61 (95% CI 1.45 to 7.44), and this risk was greater after treatment with clomiphene citrate (SIR 7.47, 95% CI 1.54 to 21.83) based on 12 cases. In another cohort study, the risk of a borderline ovarian tumour was increased, with an HR of 4.23 (95% CI 1.25 to 14.33), for subfertile women treated with IVF compared with a non-IVF-treated group with more than one year of follow-up. A large cohort reported increased risk of borderline ovarian tumours, with HR of 2.46 (95% CI 1.20 to 5.04), and this was based on 17 cases. A significant increase in serous borderline ovarian tumours was reported in one cohort study after the use of progesterone for more than four cycles (risk ratio (RR) 2.63, 95% CI 1.04 to 6.64). A case-control study reported increased risk after clomiphene citrate was taken, with an SIR of 2.5 (95% CI 1.3 to 4.5) based on 11 cases, and another reported an increase especially after human menopausal gonadotrophin was taken (odds ratio (OR) 9.38, 95% CI 1.66 to 52.08). Another study estimated an increased risk of borderline ovarian tumour, but this estimation was based on four cases with no control reporting use of fertility drugs. The certainty of evidence as assessed using GRADE was very low.However, although some studies suggested a slight increase in risks of ovarian cancer and borderline ovarian tumour, none provided moderate- or high-certainty evidence, as summarised in the GRADE tables.
AUTHORS' CONCLUSIONS: Since the last version of this review, only a few new relevant studies have provided additional findings with supporting evidence to suggest that infertility drugs may increase the risk of ovarian cancer slightly in subfertile women treated with infertility drugs when compared to the general population or to subfertile women not treated. The risk is slightly higher in nulliparous than in multiparous women treated with infertility drugs, and for borderline ovarian tumours. However, few studies have been conducted, the number of cancers is very small, and information on the dose or type of fertility drugs used is insufficient.
这是2013年发表于《考克兰系统评价数据库》第8期的关于使用不孕药物的女性患卵巢癌风险的原始考克兰综述的更新版本，该综述将使用不孕药物的女性与普通人群或未接受治疗的不孕女性进行了比较。生育药物与卵巢癌之间的联系仍存在争议。
评估接受卵巢刺激药物治疗不育症的女性发生浸润性卵巢癌和卵巢交界性肿瘤的风险。
原始综述纳入了1990年至2013年2月发表和未发表的观察性研究。本次更新将检索范围从2013年2月扩展至2018年11月；我们评估了纳入研究的质量，并使用GRADE方法判断证据的确定性。我们在“结果总结”表中报告了结果，以呈现所有结局类型的效应量。
在原始综述和本次更新中，我们检索了随机对照试验（RCT）、非随机研究以及包含30名以上参与者的病例系列。
至少两名综述作者独立进行了纳入标准和“偏倚风险”评估，并提取了数据。我们根据用于两种结局（卵巢交界性肿瘤和浸润性卵巢癌）的生育药物对研究进行了分组。由于预期的方法学和临床异质性，我们未进行荟萃分析。
我们纳入了13项病例对照研究和24项队列研究（另外9项新的队列研究和2项病例对照研究），共纳入4,684,724名女性。两项队列研究报告称，与未暴露的不育女性相比，暴露于不孕药物的不育女性浸润性卵巢癌发病率增加。一项研究基于17例癌症病例报告标准化发病率比（SIR）为1.19（95%置信区间（CI）0.54至2.25）。另一项队列研究报告风险比（HR）为1.93（95%CI 1.18至3.18），使用枸橼酸氯米芬后仍未孕的女性这一风险增加（HR 2.49，95%CI 1.30至4.78），而经产妇的风险比为1.52（95%CI 0.67至3.42）（极低确定性证据）。有报告称，进行1至3个周期体外受精（IVF）的女性卵巢癌风险略有增加，但这在临床上无显著意义（P = 0.18）。根据一项队列研究和一项病例对照研究，携带BRCA突变的女性使用不孕药物后浸润性卵巢癌风险未增加。使用GRADE评估的证据确定性非常低。
对于卵巢交界性肿瘤，一项队列研究报告暴露女性风险增加，SIR为3.61（95%CI 1.45至7.44），基于12例病例，使用枸橼酸氯米芬治疗后这一风险更高（SIR 7.47，95%CI 1.54至21.83）。在另一项队列研究中，与未接受IVF治疗且随访超过一年的组相比，接受IVF治疗的不育女性卵巢交界性肿瘤风险增加，HR为4.23（95%CI 1.25至14.33）。一项大型队列研究报告卵巢交界性肿瘤风险增加，HR为2.46（95%CI 1.20至5.04），基于17例病例。一项队列研究报告使用孕激素超过4个周期后浆液性卵巢交界性肿瘤显著增加（风险比（RR）2.63，95%CI 1.04至6.64）。一项病例对照研究报告服用枸橼酸氯米芬后风险增加，基于11例病例SIR为2.5（95%CI 1.3至4.5），另一项研究报告尤其是服用人绝经促性腺激素后风险增加（比值比（OR）9.38，95%CI 1.66至52.08）。另一项研究估计卵巢交界性肿瘤风险增加，但该估计基于4例病例，且无对照报告使用生育药物的情况。使用GRADE评估的证据确定性非常低。
然而，尽管一些研究表明卵巢癌和卵巢交界性肿瘤风险略有增加，但如GRADE表格总结的那样，没有一项研究提供中等或高确定性证据。
自本综述的上一版本以来，仅有少数新的相关研究提供了更多有支持证据的发现，表明与普通人群或未接受治疗的不育女性相比，使用不孕药物治疗不育症的女性患卵巢癌的风险可能略有增加。未生育的女性使用不孕药物后患卵巢癌和卵巢交界性肿瘤的风险略高于经产妇。然而，所开展的研究较少，癌症病例数量非常少，且关于使用的生育药物剂量或类型的信息不足。
