Pooled Analysis of Cancer in Children after Assisted Reproductive Technologies

描述（由申请人提供）：随着生育年龄的增加，不孕症的频率沿着增加，使辅助生殖技术（ART）成为世界各地非常普及的方法。虽然有报道称，ART后怀孕的儿童围产期死亡率、多胎妊娠、低出生体重和畸形的风险增加，但很少有研究分析与这些技术相关的长期癌症负担。儿童期癌症发病率可能增加，这与实验室操作配子引起的印记疾病或表观遗传因素的发展有关，和/或在接受ART的妇女中大量使用不孕药物。然而，年轻时癌症的罕见性使得个体研究的力量非常有限。 该项目的目的是通过对现有的已发表和未发表的队列研究进行汇总分析，评估ART与儿童癌症之间的关联。该项目的终点是ART后出生的儿童中所有类型的癌症的发展。已经确定了对ART后出生的儿童进行随访的研究人员，并进行了初步联系。一些调查人员已经同意参与数据共享和分析。 为了比较暴露队列中的癌症发病率与一般人群中儿童的癌症发病率，将通过将国家、年龄和性别特异性癌症发病率应用于暴露队列来计算预期病例;将计算标准化发病率比（SIR）。将对研究间的异质性和入选偏倚进行统计学评估。 这项研究提供的结果将增加关于ART长期安全性的知识;事实上，如果这项大型分析没有记录癌症增加，那么ART的长期安全性将得到有力支持。如果在ART后出生的儿童中发现癌症风险高于一般人群，则可以设计关于基因印记和表观遗传因素的分子研究，以及关于ART前给予母亲激素治疗的详细研究，以了解这种风险增加的原因。 如果没有观察到癌症风险增加，本研究提供的结果将非常有助于评估辅助生殖技术（ART）的长期安全性。如果在ART后出生的儿童中发现癌症风险高于一般人群，则有必要采取行动。在可能采取的战略中，有必要深入研究这种风险增加的可能原因，如母亲的激素治疗，基因印迹，基因甲基化，以便计划改变不孕症的临床方法。 目前的汇总分析已经建立了一个研究者网络，这将为ART后出生的儿童人群的任何未来分子研究提供独特的机会。

DESCRIPTION (provided by applicant): The increasing frequency of infertility disorders along with the increasing age of parenthood makes Assisted Reproductive Technologies (ART) a very diffuse method all over the world. Although an increased risk in perinatal mortality, multiple pregnancies, low birth weight and malformations in children conceived after ART has been reported, few studies have analyzed the long-term cancer burden associated with such techniques. A possible increase in childhood cancer incidence has been suggested, and has been related to the development of imprinting disorders or epigenetic factors induced by the laboratory manipulation of gametes, and/or the large use of infertility drugs in women who undergo ART. However, the rarity of cancer at young ages makes the power of individual studies very limited. The aim of the proposed project is to evaluate the association between ART and childhood cancer by performing a pooled analysis of existing cohort studies, both published and unpublished. The endpoint of the project is development of cancer of all types in children born after ART. Investigators that have follow up data on children born after ART have been identified, and an initial contact has been made. Several investigators have already agreed to participate in data sharing and analysis. In order to compare cancer incidence in the exposed cohort with cancer incidence in children from the general population, expected cases will be calculated by applying national-, age- and sex-specific cancer rates to the exposed cohort; Standardized Incidence Ratios (SIR) will be calculated. Heterogeneity between studies and inclusion bias will be assessed statistically. The results provided by this study will add knowledge on the long term safety of ART; in fact, if no cancer increase will be documented by this large analysis, then the long-term safety of ART will be strongly supported. If a higher cancer risk will be found in children born after ART than in the general population, molecular studies on gene imprinting and epigenetic factors can be designed, as well as detailed studies on hormonal treatments administered to the mothers before ART, in order to understand the reasons for this increased risk. The results provided by this study will be very useful to assess the long term safety of Assisted Reproductive Technologies (ART) if no increased risk of cancer will be observed. If a higher cancer risk will be found in children born after ART than in the general population, actions will be necessary. Among the possible strategies to be undertaken, it will be necessary to deeply study the possible reasons for this increased risk, such as hormonal treatment for mothers, gene imprinting, gene methylation, in order to plan changes in the clinical approach to infertility. The present pooled analysis has created a network of investigators who will be a unique opportunity for any future molecular study in the population of children born after ART.