Luke Barbara, Brown Morton B, Missmer Stacey A, Spector Logan G, Leach Richard E, Williams Melanie, Koch Lori, Smith Yolanda R, Stern Judy E, Ball G David, Schymura Maria J
Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Hum Reprod. 2016 Jan;31(1):183-9. doi: 10.1093/humrep/dev288. Epub 2015 Nov 17.
How do the assisted reproductive technology (ART) outcomes of women presenting for ART after cancer diagnosis compare to women without cancer?
The likelihood of a live birth after ART among women with prior cancer using autologous oocytes is reduced and varies by cancer diagnosis but is similar to women without cancer when donor oocytes are used.
Premenopausal patients faced with a cancer diagnosis frequently present for fertility preservation.
STUDY DESIGN, SIZE, DURATION: Population-based cohort study of women treated with ART in NY, TX and IL, USA.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with their first ART treatment between 2004 and 2009 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database and linked to their respective State Cancer Registries based on name, date of birth and social security number. Years were rounded, i.e. year 1 = 6-18 months before treatment. This study used reports of cancer from 5 years, 6 months prior to treatment until 6 months after first ART treatment. Women who only presented for embryo banking were omitted from the analysis. The likelihood of pregnancy and of live birth with ART using autologous oocytes was modeled using logistic regression, with women without prior cancer as the reference group, adjusted for woman's age, parity, cumulative FSH dosage, infertility diagnosis, number of diagnoses, number of ART cycles, State of residency and year of ART treatment. Results of the modeling are reported as adjusted odds ratios (AORs) and (95% confidence intervals).
The study population included 53 426 women; 441 women were diagnosed with cancer within 5 years prior to ART cycle start. Mean (±SD) age at cancer diagnosis was 33.4 ± 5.7 years; age at start of ART treatment was 34.9 ± 5.8 for women with cancer compared with 35.3 ± 5.3 years for women without cancer (P = 0.03). Live birth rates among women using autologous oocytes differed substantially by cancer status (47.7% without cancer versus 24.7% with cancer, P < 0.0001), and cancer diagnosis (ranging from 53.5% for melanoma to 14.3% for breast cancer, P < 0.0001. The live birth rates among women using donor oocytes did not vary significantly by cancer status (60.4% for women with any cancer versus 64.5% for women without cancer), or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer). Women with breast cancer make up about one-third of all cancers in this cohort. Among women with breast cancer, 2.8% of the 106 women who underwent ART within 6 months of being diagnosed with cancer used donor oocytes compared with 34.8% of the 46 women who received ART treatment a longer time after being diagnosed with cancer (P < 0.0001). We conjecture that the former group were either unaware that they had cancer or decided to undergo ART therapy prior to cancer treatment. However, their live birth rate was only 11.7% compared with 28.8%, the overall live birth rate for all women with cancer using autologous oocytes (P < 0.0001). The live birth rate for women diagnosed with breast cancer more than 6 months before ART (23.3%) did not differ significantly from the overall live birth rate for cancer (P = 0.49). If this difference is substantiated by a larger study, it would indicate a negative effect of severe recent illness itself on ART success, rather than the poor outcome being only related to the destructive effects of chemotherapies on ovarian follicles. Alternatively, because of the short time difference between cancer diagnosis and ART treatment, these pre-existing cancers may have been detected due to the increased medical surveillance during ART therapy. In women who only used autologous oocytes, women with prior cancers were significantly less likely to become pregnant and to have a live birth than those without cancer (adjusted odds ratio (AOR): 0.34, [95% confidence interval (CI): 0.27, 0.42] and 0.36 [0.28, 0.46], respectively). This was also evident with specific cancer diagnoses: breast cancer (0.20 [0.13, 0.32] and 0.19 [0.11, 0.30], respectively), cervical cancer (0.36 [0.15, 0.87] and 0.33 [0.13, 0.84], respectively) and all female genital cancers (0.49 [0.27, 0.87] and 0.47 [0.25, 0.86], respectively). Of note, among women with cancer who became pregnant, their likelihood of having a live birth did not differ significantly from women without cancer (85.8 versus 86.7% for women using autologous oocytes, and 85.3 versus 86.9% for women using donor oocytes).
LIMITATIONS, REASONS FOR CAUTION: Women may not have been residents of the individual States for the entire 5-year pre-ART period, and therefore some cancers may not have been identified through this linkage. As a result, the actual observed number of cancers may be an underestimate. In addition, the overall prevalence is low due to the age distributions. Also, because we restricted the pre-ART period to 5 years prior, we would not have identified women who were survivors of early childhood cancers (younger than age 13 years at cancer diagnosis), or who had ART more than 5 years after being diagnosed with cancer. Additional analyses are currently underway evaluating live birth outcomes after embryo banking among women with cancer prior to ART, cycles which were excluded from the analyses in this paper. Future studies are planned which will include more States, as well as linkages to vital records to obtain information on spontaneous conceptions and births, to further clarify some of the issues raised in this analysis.
Since the live birth rates using donor oocytes were not reduced in women with a prior cancer, but were reduced with autologous cycles, this suggests that factors acting in the pre- or peri-conceptional periods may be responsible for the decline.
STUDY FUNDING/COMPETING INTERESTS: The study was funded by grant R01 CA151973 from the National Cancer Institute, National Institutes of Health, USA. B.L. is a research consultant for the Society for Assisted Reproductive Technology. All other authors report no conflict of interest.
癌症诊断后接受辅助生殖技术（ART）治疗的女性，其ART治疗结果与未患癌症的女性相比如何？
既往患癌女性使用自体卵母细胞进行ART后活产的可能性降低，且因癌症诊断而异，但使用供体卵母细胞时与未患癌症的女性相似。
面临癌症诊断的绝经前患者经常寻求生育力保存。
研究设计、规模、持续时间：基于美国纽约、德克萨斯州和伊利诺伊州接受ART治疗女性的人群队列研究。
参与者/材料、设置、方法：从辅助生殖技术协会诊所结果报告系统数据库中识别出2004年至2009年间首次接受ART治疗的女性，并根据姓名、出生日期和社会保障号码将其与各自的州癌症登记处相链接。年份进行了四舍五入，即第1年 = 治疗前6 - 18个月。本研究使用了从治疗前5年6个月至首次ART治疗后6个月的癌症报告。仅进行胚胎冷冻保存的女性被排除在分析之外。使用自体卵母细胞进行ART的妊娠和活产可能性采用逻辑回归模型进行分析，以未患癌症的女性作为参照组，并对女性年龄、产次、累积促卵泡生成素剂量、不孕诊断、诊断次数、ART周期数、居住州和ART治疗年份进行了调整。模型结果以调整后的优势比（AOR）和（95%置信区间）报告。
研究人群包括53426名女性；441名女性在ART周期开始前5年内被诊断患有癌症。癌症诊断时的平均（±标准差）年龄为33.4 ± 5.7岁；患癌女性开始ART治疗时的年龄为34.9 ± 5.8岁，未患癌症的女性为35.3 ± 5.3岁（P = 0.03）。使用自体卵母细胞的女性活产率因癌症状态存在显著差异（未患癌症者为47.7%，患癌者为24.7%，P < 0.0001），且因癌症诊断而异（从黑色素瘤的53.5%到乳腺癌的14.3%，P < 0.0001）。使用供体卵母细胞的女性活产率在癌症状态方面无显著差异（任何癌症女性为60.4%，未患癌症女性为64.5%），也不因癌症诊断而异（从乳腺癌的57.9%到内分泌癌的63.6%）。乳腺癌女性约占该队列所有癌症患者的三分之一。在乳腺癌女性中，106名在诊断癌症后6个月内接受ART治疗的女性中有2.8%使用了供体卵母细胞，而46名在诊断癌症较长时间后接受ART治疗的女性中有34.8%使用了供体卵母细胞（P < 0.0001）。我们推测前一组女性要么不知道自己患有癌症，要么在癌症治疗前决定接受ART治疗。然而，她们的活产率仅为11.7%，而所有使用自体卵母细胞的患癌女性的总体活产率为28.8%（P < 0.0001）。在ART治疗前6个月以上被诊断患有乳腺癌的女性的活产率（23.3%）与癌症总体活产率无显著差异（P = 0.49）。如果更大规模的研究证实了这种差异，这将表明近期严重疾病本身对ART成功率有负面影响，而不是不良结果仅与化疗对卵巢卵泡的破坏作用有关。或者，由于癌症诊断与ART治疗之间的时间差较短，这些先前存在的癌症可能是由于ART治疗期间医疗监测增加而被检测到的。在仅使用自体卵母细胞的女性中，既往患癌女性怀孕和活产的可能性显著低于未患癌症者（调整后的优势比（AOR）分别为：0.34，[95%置信区间（CI）：0.27，0.42]和0.36 [0.28，0.46]）。特定癌症诊断时也很明显：乳腺癌（分别为0.20 [0.13，0.32]和0.19 [0.11，0.30]）、宫颈癌（分别为0.36 [0.15，0.87]和0.33 [0.13，0.84]）以及所有女性生殖系统癌症（分别为0.49 [0.27，0.87]和0.47 [0.25，0.86]）。值得注意的是，在怀孕的患癌女性中，她们的活产可能性与未患癌症的女性无显著差异（使用自体卵母细胞的女性为85.8%对86.7%，使用供体卵母细胞的女性为85.3%对86.9%）。
局限性、注意事项：女性在ART治疗前的整个5年期间可能并非居住在各个州，因此一些癌症可能未通过这种关联被识别出来。因此，实际观察到的癌症数量可能被低估。此外，由于年龄分布的原因，总体患病率较低。而且，由于我们将ART治疗前的时间限制在5年之前，我们无法识别儿童期癌症幸存者（癌症诊断时年龄小于13岁）或癌症诊断后5年以上接受ART治疗的女性。目前正在进行额外的分析，评估ART治疗前患癌女性胚胎冷冻保存后的活产结局，这些周期在本文分析中被排除。计划开展的未来研究将包括更多州，以及与生命记录的关联，以获取关于自然受孕和出生的信息，以进一步阐明本分析中提出的一些问题。
由于既往患癌女性使用供体卵母细胞的活产率未降低，但自体周期的活产率降低，这表明在受孕前或受孕期间起作用的因素可能是导致下降的原因。
研究资金/利益冲突：本研究由美国国立卫生研究院国家癌症研究所的R0
