生育治疗与癌症：永恒的难题：系统评价与荟萃分析。

Fertility treatment and cancers-the eternal conundrum: a systematic review and meta-analysis.

机构信息

Division of Surgery and Cancer, Institute of Reproductive & Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London, UK.

Institute of Women's Health, University College London, London, UK.

出版信息

Hum Reprod. 2021 Mar 18;36(4):1093-1107. doi: 10.1093/humrep/deaa293.

STUDY QUESTION

Does fertility treatment (FT) significantly increase the incidence of breast, ovarian, endometrial or cervical cancer?

SUMMARY ANSWER

Overall, FT does not significantly increase the incidence of breast, ovarian or endometrial cancer and may even reduce the incidence of cervical cancer.

WHAT IS KNOWN ALREADY

Infertility affects more than 14% of couples. Infertility and nulliparity are established risk factors for endometrial, ovarian and breast cancer, yet the association with FT is more contentious.

STUDY DESIGN, SIZE, DURATION: A literature search was carried out using Cochrane Library, EMBASE, Medline and Google Scholar up to December 2019. Peer-reviewed studies stating cancer incidence (breast, ovarian, endometrial or cervical) in FT and no-FT groups were identified. Out of 128 studies identified, 29 retrospective studies fulfilled the criteria and were included (n = 21 070 337).

PARTICIPANTS/MATERIALS, SETTING, METHODS: In the final meta-analysis, 29 studies were included: breast (n = 19), ovarian (n = 19), endometrial (n = 15) and cervical (n = 13), 17 studies involved multiple cancer types and so were included in each individual cancer meta-analysis. Primary outcome of interest was cancer incidence (breast, ovarian, endometrial and cervical) in FT and no-FT groups. Secondary outcome was cancer incidence according to specific fertility drug exposure. Odds ratio (OR) and random effects model were used to demonstrate treatment effect and calculate pooled treatment effect, respectively. A meta-regression and eight sub-group analyses were performed to assess the impact of the following variables, maternal age, infertility, study size, outliers and specific FT sub-types, on cancer incidence.

MAIN RESULTS AND THE ROLE OF CHANCE

Cervical cancer incidence was significantly lower in the FT group compared with the no-FT group: OR 0.68 (95% CI 0.46-0.99). The incidences of breast (OR 0.86; 95% CI 0.73-1.01) and endometrial (OR 1.28; 95% CI 0.92-1.79) cancers were not found to be significantly different between the FT and no-FT groups. Whilst overall ovarian cancer incidence was not significantly different between the FT and no-FT groups (OR 1.19; 95% CI 0.98-1.46), separate analysis of borderline ovarian tumours (BOT) revealed a significant association (OR 1.69; 95% CI 1.27-2.25). In further sub-group analyses, ovarian cancer incidence was shown to be significantly higher in the IVF (OR 1.32; 95% CI 1.03-1.69) and clomiphene citrate (CC) treatment group (OR 1.40; 95% CI 1.10-1.77), respectively when compared with the no-FT group. Conversely, the incidences of breast (OR 0.75; 95% CI 0.61-0.92) and cervical cancer (OR 0.58; 95% CI 0.38-0.89) were significantly lower in the IVF treatment sub-group compared to the no-FT group.

LIMITATIONS, REASONS FOR CAUTION: The large, varied dataset spanning a wide study period introduced significant clinical heterogeneity. Thus, results have to be interpreted with an element of caution. Exclusion of non-English citations, unpublished work and abstracts, in order to ensure data accuracy and reliability was maintained, may have introduced a degree of selection bias.

WIDER IMPLICATIONS OF THE FINDINGS

The results for breast, ovarian, endometrial and cervical cancer are reassuring, in line with previously published meta-analyses for individual cancers but the association between IVF and CC treatment and an increase in ovarian cancer incidence requires additional work to understand the potential mechanism driving this association. In particular, focusing on (i) discriminating specific treatments effects from an inherent risk of malignancy; (ii) differential risk profiles among specific patient sub-groups (refractory treatment and obesity); and (iii) understanding the impact of FT outcomes on cancer incidence.

STUDY FUNDING/COMPETING INTEREST(S): This study did not receive any funding. The authors have no financial, personal, intellectual and professional conflicts of interest to declare.

PROSPERO REGISTRATION NUMBER

CRD42019153404.

研究问题

生育治疗（FT）是否会显著增加乳腺癌、卵巢癌、子宫内膜癌或宫颈癌的发病率？

总结答案

总体而言，FT 并不会显著增加乳腺癌、卵巢癌或子宫内膜癌的发病率，甚至可能降低宫颈癌的发病率。

已知事实

不孕症影响超过 14%的夫妇。不孕和未生育是子宫内膜癌、卵巢癌和乳腺癌的既定危险因素，但 FT 与之相关的争议更大。

研究设计、规模、持续时间：使用 Cochrane Library、EMBASE、Medline 和 Google Scholar 进行了文献检索，截至 2019 年 12 月。确定了在 FT 和非 FT 组中报告癌症发病率（乳腺癌、卵巢癌、子宫内膜癌或宫颈癌）的同行评审研究。从 128 项研究中，有 29 项回顾性研究符合标准并被纳入（n=21070337）。

参与者/材料、设置、方法：在最终的荟萃分析中，纳入了 29 项研究：乳腺癌（n=19）、卵巢癌（n=19）、子宫内膜癌（n=15）和宫颈癌（n=13），其中 17 项研究涉及多种癌症类型，因此被纳入每个单独的癌症荟萃分析。主要观察结果是 FT 和非 FT 组的癌症发病率（乳腺癌、卵巢癌、子宫内膜癌和宫颈癌）。次要观察结果是根据特定生育药物暴露的癌症发病率。使用比值比（OR）和随机效应模型分别展示治疗效果并计算汇总治疗效果。进行了荟萃回归和八个亚组分析，以评估以下变量（母亲年龄、不孕、研究规模、异常值和特定 FT 亚型）对癌症发病率的影响。

主要结果及其偶然性的作用

与非 FT 组相比，FT 组宫颈癌的发病率显著降低：OR 0.68（95%CI 0.46-0.99）。FT 和非 FT 组之间的乳腺癌（OR 0.86；95%CI 0.73-1.01）和子宫内膜癌（OR 1.28；95%CI 0.92-1.79）的发病率无显著差异。虽然总体卵巢癌的发病率在 FT 和非 FT 组之间无显著差异（OR 1.19；95%CI 0.98-1.46），但对交界性卵巢肿瘤（BOT）的单独分析显示存在显著关联（OR 1.69；95%CI 1.27-2.25）。在进一步的亚组分析中，与非 FT 组相比，IVF 和 CC 治疗组的卵巢癌发病率分别显著升高（OR 1.32；95%CI 1.03-1.69）和（OR 1.40；95%CI 1.10-1.77）。相反，与非 FT 组相比，IVF 治疗组的乳腺癌（OR 0.75；95%CI 0.61-0.92）和宫颈癌（OR 0.58；95%CI 0.38-0.89）的发病率显著降低。

局限性、谨慎原因：大型、多样化的数据集跨越了广泛的研究期，引入了显著的临床异质性。因此，结果必须谨慎解释。为了确保数据的准确性和可靠性，排除了非英语引用、未发表的工作和摘要，这可能引入了一定程度的选择偏倚。

研究结果的更广泛影响

乳腺癌、卵巢癌、子宫内膜癌和宫颈癌的结果令人放心，与之前发表的针对个别癌症的荟萃分析一致，但 IVF 和 CC 治疗与卵巢癌发病率增加之间的关联需要进一步研究以了解潜在的关联机制。特别是，需要关注：（i）区分特定治疗效果与恶性肿瘤的固有风险；（ii）特定患者亚组（难治性治疗和肥胖）的不同风险特征；（iii）了解 FT 结果对癌症发病率的影响。

研究资金/利益冲突：本研究没有获得任何资金。作者没有财务、个人、智力和专业利益冲突需要声明。

PROSPERO 注册号：CRD42019153404。