Spaan Mandy, Pontesilli Martina, van den Belt-Dusebout Alexandra W, Burger Curt W, van den Heuvel-Eibrink Marry M, Ravelli Anita C J, Goddijn Mariëtte, Lambalk Cornelis B, Roseboom Tessa J, van Leeuwen Flora E
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Epidemiology and Data Science, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
Hum Reprod Open. 2023 Jun 1;2023(3):hoad027. doi: 10.1093/hropen/hoad027. eCollection 2023.
Do children, adolescents, and young adults born after ART, including IVF, ICSI and frozen-thawed embryo transfer (FET), have an increased risk of cancer compared with children born to subfertile couples not conceived by ART and children from the general population?
After a median follow-up of 18 years, the overall cancer risk was not increased in children conceived by ART, but a slight risk increase was observed in children conceived after ICSI.
There is growing evidence that ART procedures could perturb epigenetic processes during the pre-implantation period and influence long-term health. Recent studies showed (non-)significantly increased cancer risks after ICSI and FET, but not after IVF.
A nationwide historical cohort study with prospective follow-up was carried out, including all live-born offspring from women treated with ART between 1983 and 2011 and subfertile women not treated with ART in one of the 13 Dutch IVF clinics and two fertility centers.
PARTICIPANTS/MATERIALS SETTING METHODS: Children were identified through the mothers' records in the Personal Records Database. Information on the conception method of each child was collected through the mother's medical record. In total, the cohort comprises 89 249 live-born children of subfertile couples, of whom 51 417 were conceived using ART and 37 832 were not (i.e. conceived naturally, through ovulation induction, or after IUI). Cancer incidence was ascertained through linkage with the Netherlands Cancer Registry for the period 1989-2019. Cancer risk in children conceived using ART was compared with risk in children born to subfertile couples but not conceived by ART (hazard ratio (HR)) and children from the general population (standardized incidence ratios (SIRs)).
In total, 358 cancers were observed after a median follow-up of 18 years. Overall cancer risk was not increased in children conceived using ART, when compared with the general population (SIR = 0.96, 95% CI = 0.81-1.12) or with children from subfertile couples not conceived by ART (HR = 1.06, 95% CI = 0.84-1.33). Compared with children from subfertile couples not conceived by ART, the use of IVF or FET was not associated with increased cancer risk, but ICSI was associated with a slight risk increase (HR = 1.58, 95% CI = 1.08-2.31). Risk of cancer after ART did not increase at older ages (≥18 years, HR = 1.26, 95% CI = 0.88-1.81) compared to cancer risk in children not conceived by ART.
The observed increased risk among children conceived using ICSI must be interpreted with caution owing to the small number of cases.
After a median follow-up of 18 years, children conceived using ART do not have an increased overall cancer risk. Many large studies with prolonged follow-up are needed to investigate cancer risk in (young) adults conceived by different types of ART. In addition, international pooling of studies is recommended to provide sufficient power to study risk of specific cancer sites after ART.
STUDY FUNDING/COMPETING INTERESTS: This work was supported by The Dutch Cancer Society (NKI 2006-3631) that funded the OMEGA-women's cohort, Children Cancer Free (KIKA; 147) that funded the OMEGA-I-II offspring cohort. The OMEGA-III offspring cohort was supported by a Postdoc Stipend of Amsterdam Reproduction & Development, and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD088393. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing interests.
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与未通过辅助生殖技术（ART）受孕的不育夫妇所生子女以及普通人群的子女相比，通过ART（包括体外受精（IVF）、卵胞浆内单精子注射（ICSI）和冻融胚胎移植（FET））出生的儿童、青少年和年轻成人患癌症的风险是否增加？
经过18年的中位随访，ART受孕儿童的总体癌症风险并未增加，但ICSI受孕儿童的风险略有增加。
越来越多的证据表明，ART程序可能会在植入前阶段扰乱表观遗传过程，并影响长期健康。最近的研究显示，ICSI和FET后癌症风险有（无）显著增加，但IVF后没有。
开展了一项全国性历史队列研究，并进行前瞻性随访，纳入1983年至2011年间接受ART治疗的女性所生的所有活产后代，以及荷兰13家IVF诊所和2家生育中心中未接受ART治疗的不育女性。
参与者/材料设置方法：通过个人记录数据库中的母亲记录识别儿童。通过母亲的病历收集每个孩子受孕方式的信息。该队列总共包括89249名不育夫妇的活产子女，其中51417名通过ART受孕，37832名未通过ART受孕（即自然受孕、通过促排卵或宫腔内人工授精（IUI）后受孕）。通过与荷兰癌症登记处1989年至2019年期间的数据链接确定癌症发病率。将ART受孕儿童的癌症风险与未通过ART受孕的不育夫妇所生子女的风险（风险比（HR））以及普通人群的子女的风险（标准化发病率（SIR））进行比较。
经过18年的中位随访，共观察到358例癌症。与普通人群相比（SIR = 0.96，95%可信区间 = 0.81 - 1.12），以及与未通过ART受孕的不育夫妇所生子女相比（HR = 1.06，95%可信区间 = 0.84 - 1.33），ART受孕儿童的总体癌症风险并未增加。与未通过ART受孕的不育夫妇所生子女相比，使用IVF或FET与癌症风险增加无关，但ICSI与风险略有增加有关（HR = 1.58，95%可信区间 = 1.08 - 2.31）。与未通过ART受孕的儿童相比，ART后癌症风险在较大年龄（≥18岁，HR = 1.26，9%可信区间 = 0.88 - 1.81）时并未增加。
由于病例数量较少，对于ICSI受孕儿童中观察到的风险增加必须谨慎解释。
经过中位18年的随访，ART受孕儿童的总体癌症风险并未增加。需要进行许多长期随访的大型研究来调查不同类型ART受孕的（年轻）成人的癌症风险。此外，建议进行国际研究汇总以提供足够的能力来研究ART后特定癌症部位的风险。
研究资金/利益冲突：这项工作得到了荷兰癌症协会（NKI 2006 - 3631）的支持，该协会资助了OMEGA - 女性队列；儿童无癌组织（KIKA；147）资助了OMEGA - I - II后代队列。OMEGA - III后代队列得到了阿姆斯特丹生殖与发育博士后奖学金以及美国国立卫生研究院尤妮斯·肯尼迪·施赖弗国家儿童健康与人类发展研究所（资助编号R01HD088393）的支持。内容仅由作者负责，不一定代表国立卫生研究院的官方观点。作者声明无利益冲突。
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