Pooled Analysis of Cancer in Children after Assisted Reproductive Technologies

描述(申请人提供)：随着父母年龄的增加，不孕不育疾病的发生率越来越高，使得辅助生殖技术(ART)成为一种在世界各地非常普及的方法。尽管ART术后围产期死亡率、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此类技术相关的长期癌症负担。儿童癌症发病率可能增加，这与实验室操纵配子引起的印记障碍或表观遗传因素的发展有关，和/或接受抗逆转录病毒治疗的妇女大量使用不孕药。然而，癌症在年轻时很罕见，这使得个人研究的力量非常有限。 拟议项目的目的是通过对已发表和未发表的现有队列研究进行汇集分析，来评估抗逆转录病毒治疗与儿童癌症之间的联系。该项目的终点是在ART后出生的儿童中发展所有类型的癌症。已经确定了对接受抗逆转录病毒治疗后出生的儿童进行跟踪数据的调查人员，并进行了初步联系。几名调查人员已经同意参与数据共享和分析。 为了将暴露人群中的癌症发病率与普通人群中儿童的癌症发病率进行比较，将通过对暴露人群适用国家、年龄和性别特定癌症发病率来计算预期病例；将计算标准化发病率比率(SIR)。研究之间的异质性和纳入偏倚将进行统计评估。 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，如果这项大型分析不会证明癌症增加，那么ART的长期安全性将得到强有力的支持。如果发现抗逆转录病毒治疗后出生的孩子患癌症的风险高于普通人群，可以设计关于基因印记和表观遗传因素的分子研究，以及关于抗逆转录病毒治疗前母亲接受激素治疗的详细研究，以了解风险增加的原因。 如果没有观察到癌症风险的增加，这项研究提供的结果将对评估辅助生殖技术(ART)的长期安全性非常有用。如果在接受抗逆转录病毒治疗后出生的儿童中发现比普通人群更高的癌症风险，就必须采取行动。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、基因印记、基因甲基化，以便计划改变不孕不育的临床方法。 目前的汇集分析创建了一个研究人员网络，他们将是未来在ART后出生的儿童群体中进行任何分子研究的独特机会。

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between ART and childhood cancer by performing a pooled analysis of existing cohort studies, both published and unpublished.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.