Nested case-control study of maternal herpes viruses in relation to gastroschisis

描述（由申请人提供）：腹裂是一种先天性腹壁缺陷，出生时肠道和其他器官位于体外，具有严重的手术和医疗后果。腹裂从其他出生缺陷中脱颖而出，因为它具有低复发风险，最常发生在年轻母亲的后代中，在过去几十年中患病率一直在增加，有时会发生在集群中。虽然吸烟，高酒精摄入量和非法药物的使用在年轻母亲中更常见，并与腹裂风险有关，但它们并不能解释与母亲年龄的强烈负相关关系。腹裂的流行病学特征表明，一种感染因子可能在发育途径中。已知某些感染因子会导致出生缺陷，但腹裂尚未被确定为先天性感染表型的一部分。我们已经确定了四种发生模式与腹裂的流行病学特征相匹配的感染因子：EB病毒、单纯疱疹病毒2型、巨细胞病毒和沙眼衣原体。然而，目前缺乏一个明确的生物学机制，通过这些感染性病原体可以破坏胎儿发育，产生孤立的腹裂缺陷。因此，我们提出了这个探索性的项目，以快速有效地确定这些感染因子是否与腹裂相关，以及是否有必要进行大规模的临床研究来探索生物学机制。这项探索性研究的目的将通过芬兰产妇队列中的巢式病例对照研究简单有效地实现。已在170多万例妊娠中储存了孕早期母体血清样本，其中包括约401例受腹裂影响的妊娠。两个对照组将按母亲年龄与每个病例匹配。在妊娠早期（腹裂发生时）原发性或复发性感染的血清学证据将在病例组和对照组之间进行比较，考虑匹配因素，出生年份，地理区域，产次，体重指数，吸烟和维生素D。使用孕早期血清样本来测量感染状态克服了回顾性母体报告的挑战，这种回顾性母体报告已用于大多数先前腹裂危险因素的研究。这一探索性项目具有巨大的潜力，可以开发腹裂研究的新轨迹，从而了解其发病机制，解释强烈的逆母体年龄关联和随时间推移而增加的患病率，并预防腹裂。由于孕早期血清样本捕获了大多数出生缺陷的病因相关时间范围，因此该开发项目可能会刺激许多出生缺陷的新研究议程。

DESCRIPTION (provided by applicant): Gastroschisis, a congenital abdominal wall defect where the bowel and other organs are outside of the body at birth, has substantial surgical and medical consequences. Gastroschisis stands out from other birth defects in that it has a low recurrence risk, occurs most often in the offspring of younger mothers, has been increasing in prevalence over the past several decades, and sometimes occurs in clusters. Although cigarette smoking, high alcohol intake, and illicit drug use are more common in young mothers and have been linked to gastroschisis risk, they do not account for the strong inverse relation with maternal age. The epidemiologic characteristics of gastroschisis suggest an infectious agent may be in the developmental pathway. Certain infectious agents are known to cause birth defects, but gastroschisis has not been identified as part of a congenital infection phenotype. We have identified four infectious agents with patterns of occurrence that match the epidemiologic profile of gastroschisis: Epstein-Barr virus, herpes simplex virus 2, cytomegalovirus, and Chlamydia trachomatis. However, a clear biological mechanism through which these infectious agents could disrupt fetal development to produce the isolated gastroschisis defect is lacking at present. Thus, we propose this exploratory project, to quickly and efficiently identify whether these infectious agents are associated with gastroschisis and whether a large-scale, clinically-oriented study is warranted to explore biologic mechanisms. The aims of this exploratory study will be achieved simply and efficiently by a nested case-control study within the Finnish Maternity Cohort. First trimester maternal serum samples have been banked on over 1.7 million pregnancies, including approximately 401 gastroschisis-affected pregnancies. Two controls will be matched to each case by maternal age. Serologic evidence of primary or recurrent infection during early gestation (when gastroschisis develops) will be compared between cases and controls, taking the matching factors, birth year, geographic region, parity, body mass index, smoking, and vitamin D into account. The use of first trimester serum samples to measure infection status overcomes the challenge of retrospective maternal report that has been used in the majority of previous studies of risk factors for gastroschisis. This exploratory project has enormous potential to develop a new trajectory of gastroschisis research, which could lead to knowledge of its pathogenesis, to an explanation of the strong inverse maternal age association and increasing prevalence over time, and to prevention. Because first trimester serum samples capture the etiologically relevant time frame for most birth defects, this developmental project could spur new research agendas for many birth defects.