PROJECT SUMMARY/ABSTRACT Despite prevalent anecdotal reports, the impact of SARS-CoV-2 infection or vaccination on menorrhagia and menstrual regularity has not been investigated. COVID-19 disease has impacted millions, while stay-at-home orders and heightened stress have impacted billions. Menorrhagia, menstrual irregularity, and chronic pelvic pain (with or without endometriosis) are known to increase in severity when challenged with stress, unraveling of personal coping mechanisms, or diminished access to healthcare – all of which occurred during the COVID- 19 pandemic. To successfully assess changes in menstrual and gynecologic characteristics attributable to SARS-CoV-2 infection or vaccination, it is critical to compare post-infection or post-vaccination menstruation and pelvic symptoms to that person’s pre-exposure menstruation and also to compare menstruation among those who have been infected or vaccinated to those who have not, accounting for pandemic impacts that may vary by individual social or economic frailty and mental health. Answering these critical questions with scientific rigor in existing research cohort populations is responsive to Notice of Special Interest (NOSI) to Encourage Administrative Supplement Applications to Investigate COVID-19 Vaccination and Menstruation (NOT-HD-21- 035). Our Parent R01 funding focuses on infertility and long-term health outcomes within the Harvard Cohorts, primarily within the Nurses’ Health Study II. While the current age range of NHSII cohort does not accommodate menstrual-change focused discovery, our team and infrastructure also include leaders and resources from the Nurses’ Health Study 3 (NHS3; age 19-51 years at baseline) that began in 2010 and the Growing Up Today Study (GUTS) that began in 1996 (current age 24-39 years). A year-long series of COVID-19 pandemic surveys were launched in April 2020. Baseline COVID-19 surveys were completed by 40% (N=11,976) of female NHS3 participants among whom 80% of responders are frontline healthcare providers and 41% (N=4,681) of female GUTS participants among whom 22% of responders are frontline healthcare providers. Within these two harmonized cohorts, we will confirm if 1) SARS-CoV-2 infection or 2) vaccination are associated with incident or worsened menorrhagia, menstrual irregularity or pelvic pain compared to pre-pandemic, pre-infection, or pre- vaccination menstrual characteristics and compared to those who have neither been infected nor vaccinated; and 3) increase in COVID-19 pandemic-related distress (e.g. depression, anxiety, social isolation, economic peril) will be associated with incident or increased severity of menorrhagia, menstrual cycle irregularity, or chronic pelvic pain – independent of SARS-CoV-2 infection or vaccination. While many are scrambling to assemble research teams and establish de novo human data and sample collection, which will yield uncertain deliverables, small samples sizes, and often reliance on fully de-identifi...