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

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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.