STUDY QUESTION Does the risk of childhood cancer following ARTs vary by sex? SUMMARY ANSWER In this registry-based study, some childhood cancers showed positive sex- and age-specific associations in children conceived using certain ART modalities, which were not evident in overall combined analyses. WHAT IS KNOWN ALREADY The relationship between ART and risk of childhood cancer has shown diverse outcomes in prior research. Studies examining whether there are sex differences in childhood cancer risk after ART conception are lacking. STUDY DESIGN, SIZE, DURATION This registry-based cohort study included all children born in Norway between 1984 and 2022 (n = 2 255 025), followed until 31 December 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS Children were identified via the Medical Birth Registry of Norway, and information was extracted on whether they were conceived via ART (defined as IVF/ICSI). Of the 2 255 025 children included in the study, 53 694 were ART-conceived. Birth records were linked to the Cancer Registry of Norway. Childhood cancer was defined as a cancer diagnosis according to the International Classification of Childhood Cancer Third Edition (ICCC-3) before the age of 18 years. Cox regression models were used to estimate the age- and sex-specific risk of cancer for ART-conceived children compared to children not conceived via ART. MAIN RESULTS AND THE ROLE OF CHANCE Among all children, 0.25% had a cancer diagnosis before the age of 18 years. The cumulative incidence of cancer was higher in children conceived by ART (IVF/ICSI) than in those not conceived via ART (21.5 vs 17.5 per 100 000 person-years, P = 0.04), and especially higher in boys conceived with ICSI or after cryopreserved embryo transfer. When combining all age groups, both sexes and all cancer types, there was little evidence of increased cancer risk with ART (adjusted hazard ratio (aHR) 1.13, 95% CI 0.94–1.36). However, differences were found when stratifying by age and sex. From age 5–9 years, ART-conceived children had a higher overall risk of cancer (aHR 1.53, 95% CI 1.06–2.20), with a slightly higher estimate in boys (aHR 1.73, 95% CI 1.09–2.74), than in girls (aHR 1.28, 95% CI 0.70–2.33). The risk was not higher up to age 5 years, or after age 10 years. In combined analyses, there was no overall increased risk after ICSI. When stratifying by sex, a higher risk was seen after ICSI for boys (aHR 1.69, 95% CI 1.18–2.42), but not for girls (aHR 0.65, 95% CI 0.37–1.16). The combined risk after cryopreservation (aHR 1.42, 95% CI 0.95–2.13) was driven by a higher risk in boys (aHR 1.79, 95% CI 1.09–2.94), while no evidence of an association was found in girls (aHR 1.01, 95% CI 0.50–2.03). No increased risk was seen with IVF or after fresh transfer for either boys or girls. LIMITATIONS, REASONS FOR CAUTION Childhood cancer is a rare outcome, and some analyses of cancer subtypes were likely underpowered. WIDER IMPLICATIONS OF THE FINDINGS Results from this large registry-based study suggest that addressing age- and sex-specific differences in the risk of childhood cancer following ART conception reveals increased risks for certain groups. Our findings require further study with consideration of possible underlying sex-specific mechanisms related to ART and different childhood cancers. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by: the Research Council of Norway through its Centres of Excellence Funding Scheme (project number 262700); the Norwegian Cancer Association (project number 244291); and the Norwegian Institute of Public Health. The funding agencies had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interests. TRIAL REGISTRATION NUMBER N/A.

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ART 受孕后儿童癌症风险的性别差异：一项基于登记的研究


研究问题 ART 后患儿童癌症的风险是否因性别而异？摘要答案 在这项基于登记的研究中，一些儿童癌症在使用某些 ART 方式受孕的儿童中显示出积极的性别和年龄特异性关联，这在整体联合分析中并不明显。已经知道的 ART 与儿童癌症风险之间的关系在之前的研究中显示出不同的结果。缺乏研究 ART 受孕后儿童癌症风险是否存在性别差异。研究设计、规模、持续时间 这项基于登记的队列研究包括 1984 年至 2022 年间在挪威出生的所有儿童 （n = 2 255 025），随访至 2023 年 12 月 31 日。参与者/材料、环境、方法 通过挪威医学出生登记处确定儿童，并提取有关他们是否通过 ART 受孕的信息（定义为 IVF/ICSI）。在纳入研究的 2 255 025 名儿童中，有 53 694 名是 ART 受孕的。出生记录与挪威癌症登记处相关联。根据国际儿童癌症分类第三版 （ICCC-3），儿童癌症被定义为 18 岁之前的癌症诊断。Cox 回归模型用于估计与未通过 ART 受孕的儿童相比，ART 受孕儿童的年龄和性别特异性癌症风险。主要结果和机会的作用在所有儿童中，0.25% 的儿童在 18 岁之前被诊断出患有癌症。通过 ART （IVF/ICSI） 受孕的儿童癌症累积发病率高于未通过 ART 受孕的儿童 （21.5 vs/100 000 人年，P = 0.04），尤其是使用 ICSI 受孕或冷冻保存胚胎移植后受孕的男孩。 当合并所有年龄组（包括性别和所有癌症类型）时，几乎没有证据表明 ART 会增加癌症风险（调整后的风险比 （aHR） 1.13,95% CI 0.94-1.36）。然而，在按年龄和性别分层时发现了差异。从 5-9 岁开始，ART 受孕儿童患癌症的总体风险更高 （aHR 1.53， 95% CI 1.06-2.20），男孩的估计值 （aHR 1.73， 95% CI 1.09-2.74） 略高于女孩 （aHR 1.28， 95% CI 0.70-2.33）。5 岁之前或 10 岁以后的风险不高。在综合分析中，ICSI 后总体风险没有增加。按性别分层时，ICSI 后男孩的风险更高 （aHR 1.69,95% CI 1.18-2.42），但女孩则没有 （aHR 0.65,95% CI 0.37-1.16）。冷冻保存后的综合风险 （aHR 1.42， 95% CI 0.95-2.13） 是由男孩的较高风险驱动的 （aHR 1.79， 95% CI 1.09-2.94），而女孩中没有发现关联的证据 （aHR 1.01， 95% CI 0.50-2.03）。IVF 或新鲜移植后，男孩或女孩的风险均未增加。局限性，谨慎的原因 儿童癌症是一种罕见的结果，一些对癌症亚型的分析可能把握度不足。研究结果的更广泛意义 这项基于注册的大型研究的结果表明，解决 ART 受孕后儿童癌症风险的年龄和性别特异性差异揭示了某些群体的风险增加。我们的研究结果需要进一步研究，同时考虑与 ART 和不同儿童癌症相关的可能潜在性别特异性机制。 研究资金/利益争夺 这项工作由以下机构资助： 挪威研究委员会通过其卓越中心资助计划（项目编号 262700）;挪威癌症协会（项目编号 244291）;以及挪威公共卫生研究所。资助机构在手稿的概念化、设计、数据收集、分析、出版决定或准备方面没有任何作用。作者声明没有利益冲突。试验注册号 N/A。