PROJECT SUMMARY Aberrations in reproductive function may be a harbinger of future health. Recent studies demonstrate associations between infertility and future risk of cardiometabolic disease and mortality in studies of both males and females. To date, most studies examining the association between fertility and long- term health have been retrospective with limited data on individuals at the beginning of their fertility attempts, making it difficult to assess causality. Further examination of the intersection of reproductive and somatic health has implications for millions around the world. In the current proposal, we will combine two interrelated and ongoing prospective cohorts of couples trying to conceive to examine the association between fertility and future health. Launched in Denmark in 2007, Snart-Gravid.dk (SG; translates to `soon pregnant') is a prospective internet-based preconception cohort of female pregnancy planners. In 2011, the study began enrolling male partners and was renamed Snart-Foraeldre.dk (SF; translates to `soon parents'). Pregnancy Study Online (PRESTO) is an ongoing prospective cohort study of couples residing in the U.S. or Canada. Modeled on the SG/SF cohorts and initiated in 2013. With a combined total of more than 39,000 participants, the SG/SF (>18,000) and PRESTO (>21,000) cohorts provide the ideal data to answer questions about the influence of fertility on future health outcomes. Comprehensive data have been collected for both members of the couple during the preconception and perinatal periods. In this application, we propose to extend follow-up of participants for up to 20 years and collect additional clinical data in all cohorts (e.g., via registry linkage in Denmark; and via questionnaire re-contact and medical record validation in PRESTO) to evaluate the following specific aims: 1) Evaluate extent to which TTP and SAB predict cardiometabolic disorders (e.g., incident hypertension, hyperlipidemia, type 2 diabetes), 2) Evaluate extent to which TTP and SAB predict subsequent immune disorders. 3) Assess extent to which TTP and SAB predict subsequent weight gain in the PRESTO cohort. An infertility evaluation creates an opportunity to identify and intervene regarding an individual's future health risk, which could be modified by early recognition and/or prevention of disease depending on the association. Establishing an association between reproductive and future health could be a “game changer” if care is shifted to early prevention for those at risk and treatment for those already affected. The current proposal will fill important gaps in the literature on the extent to which fertility serves as a marker of future health and will create opportunities for primary prevention of diseases in mid-life.