STUDY QUESTION Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

中文翻译：

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通过辅助生殖技术受孕的出生缺陷和儿童癌症的风险。


研究问题 生育状况、受孕方法与出生缺陷和儿童癌症的风险之间是否存在关联？摘要答案 儿童癌症风险有两个独立的组成部分：(i) 受孕方法和 (ii) 出生缺陷的存在、类型和数量。已知的情况 由于出生缺陷、癌症和 ART 同时发生的情况很少见，因此研究它们之间的关联具有挑战性。先前的研究表明，不孕症和辅助生殖技术与出生缺陷或癌症的风险增加有关，但受到样本量小和统计能力不足、未能调整或包括复数、定义和/或确定方法的差异等限制。缺乏有关 ART 治疗参数或跨越数十年的研究周期的信息，导致随着 ART 技术的改进而出现重大历史偏差。研究设计、规模、持续时间这是一项基于人群的队列研究，将 2004 年 1 月 1 日至 2017 年 12 月 31 日期间向辅助生殖技术协会临床结果报告系统 (SART CORS) 报告的 ART 周期联系起来，并在 2004 年至 2018 年期间实现了活产马萨诸塞州和北卡​​罗来纳州的活产率以及德克萨斯州和纽约州 2004 年至 2017 年的活产率。在与 ART 出生相同的时间段内选择了 10:1 的非 ART 出生样本。非 ART 兄弟姐妹是通过 ART 母亲的信息来识别的。非 ART 出生的孩子被归类为通过促排卵或宫腔内人工授精 (OI/IUI) 受孕的妇女所生的孩子，如果出生证明上有不孕不育治疗的指示，并且该妇女没有链接到 SART CORS；所有其他的都被归类为自然受孕。 参与者/材料、背景、方法 研究人群包括 165 125 名 ART 儿童、31 524 名非 ART 兄弟姐妹、12 451 名接受 OI/IUI 治疗的妇女所生的孩子以及 1 353 440 名自然受孕的孩子。所有研究儿童都与各自的州出生缺陷登记处相关联，以识别出生第一年内诊断出的主要缺陷。我们将患有重大缺陷的儿童分为染色体（即存在染色体缺陷，伴或不伴任何其他重大缺陷）或非染色体（即存在重大缺陷但没有染色体缺陷），或所有主要缺陷（染色体和非染色体），并计算每 1000 名儿童的比率。使用逻辑回归模型生成按受孕组（OI/IUI、非 ART 兄弟姐妹和按卵母细胞来源和胚胎状态进行 ART）划分的出生缺陷风险的调整优势比 (AOR) 和 95% CI，其中自然受孕儿童为参考，根据父亲和母亲的年龄进行调整；母亲的种族和民族、教育程度、体重指数、产次、糖尿病、高血压；以及复数、婴儿性别以及出生州和年份。所有研究儿童也都与各自的州癌症登记处有联系。 Cox 比例风险回归模型用于根据出生缺陷状态（包括缺陷的存在、缺陷的类型和数量）和受孕组来估计癌症的风险比 (HR) 和 95% CI。主要结果和机会的作用 共有 29 571 名单胎儿童 (2.0%) 和 3753 名双胞胎儿童 (3.5%) 患有严重出生缺陷（染色体或非染色体）。 使用自体卵母细胞进行 ART 受孕的儿童出现非染色体缺陷的风险增加，包括胚芽发育、心血管、胃肠道缺陷，以及泌尿生殖系统缺陷（仅限男性），AOR 范围为 1.22 至 1.85；自体新鲜组的儿童肌肉骨骼（AOR 1.28，95% CI 1.13，1.45）和口面部缺陷（AOR 1.40，95% CI 1.17，1.68）的风险也增加。在供体卵母细胞组中，从新鲜胚胎受孕的孩子在任何出生缺陷类别中的风险均没有增加，而从解冻胚胎受孕的孩子非染色体缺陷（AOR 1.20，95% CI 1.03，1.40）和胚芽发育缺陷的风险增加（ AOR 1.74，95% CI 1.14，2.65）。在自体新鲜组（HR 1.31，95% CI 1.08，1.59）和非 ART 兄弟姐妹（1.34，95% CI 1.02，1.76）中，ART 儿童患癌症的风险增加。 OI/IUI 组儿童（HR 2.15，95% CI 1.04，4.47）和非 ART 兄弟姐妹（HR 1.63，95% CI 1.02，2.61）患白血病的风险增加。在新鲜自体组（HR 1.68，95% CI 1.14，2.48）、新鲜供体组（HR 2.57，95% CI 1.04，6.32）和非 ART 兄弟姐妹中，ART 儿童患中枢神经系统肿瘤的风险增加（HR 1.84，95% CI 1.12，3.03）。自体新鲜组中的 ART 儿童患实体瘤的风险也增加（HR 1.39，95% CI 1.09，1.77）。共有127名儿童同时患有严重出生缺陷和癌症，其中53名儿童（42%）患有白血病。癌症风险有两个独立的组成部分：(i) 受孕方法（如上所述）和 (ii) 出生缺陷的存在、类型和数量。对于所有癌症和每种评估的类型来说，非染色体缺陷的存在会增加癌症风险，两种或多种缺陷的风险高于一种缺陷的风险。 染色体缺陷的存在与癌症风险密切相关（所有癌症的 HR 8.70，白血病的 HR 21.90），并且在染色体和非染色体缺陷同时存在时进一步升高（所有癌症的 HR 21.29，白血病的 HR 64.83，白血病的 HR 4.71）。胚胎肿瘤）。 2019 年，美国通过 ART 出生的 83,946 名儿童与自然受孕的儿童相比，这些风险意味着估计有 761 名儿童患有严重出生缺陷，31 名儿童患有癌症，以及 11 名儿童同时患有严重出生缺陷和癌症。局限性、注意事项 在 SART CORS 数据库中，无法区分胚胎冷冻方法（慢速冷冻与玻璃化冷冻），并且 ICSI 数据仅适用于新鲜胚胎 ART 组。在 OI/IUI 组中，无法区分所使用的非 ART 治疗类型，并且在 ART 和 OI/IUI 组中，无法获得有关不孕持续时间的数据。由于OI/IUI在出生证明上被低估，一些OI/IUI儿童可能被纳入自然受孕儿童中，这将减少所有组与自然受孕儿童之间的差异。研究结果的更广泛意义 ART 的使用与主要非染色体出生缺陷的风险增加有关。出生缺陷的存在与更大的癌症风险相关，这增加了 ART 组的基线风险。尽管这项研究没有显示因果关系，但这些发现表明，接受 ART 怀上的孩子、非 ART 兄弟姐妹以及所有有出生缺陷的孩子都应该受到更密切的监测，以了解随后的癌症发展情况。 研究经费/竞争利益 该项目得到国家儿童健康和人类发展研究所 R01 HD084377 拨款的支持。内容仅由作者负责，并不一定代表国家儿童健康和人类发展研究所、国立卫生研究院或任何提供数据的州卫生部的官方观点。 MLE 为 Ro、Hannah、Dadi、Sandstone 和 Underdog 提供咨询服务； SSMR 主席；和 SMRU 董事会成员。其余作者报告没有利益冲突。试用注册号 不适用。