The goal of this clinical trial is to evaluate whether daily oral metformin extended-release (metformin-XR), taken prior to pregnancy, can reduce the risk and severity of Hyperemesis Gravidarum (HG)-a severe nausea and vomiting condition in pregnancy-in individuals aged 18-49 who have experienced HG in a previous pregnancy and are trying to conceive. Researchers also aim to better understand which individuals may respond well-or poorly-to metformin based on biological and clinical characteristics. The main questions this study aims to answer are: 1. Is metformin-XR acceptable and well-tolerated when taken by non-pregnant individuals who have had HG in a previous pregnancy and are currently trying to conceive? 2. How safe and tolerable is metformin-XR when taken at increasing doses over 8 weeks and continued through early pregnancy (or for up to 12 months if pregnancy does not occur)? 3. Among those who become pregnant during the study, does pre-pregnancy metformin-XR use reduce the risk of HG coming back and lower the severity of nausea and vomiting symptoms? 4. How does pre-pregnancy metformin-XR use affect pregnancy outcomes, postpartum health, and newborn health and development? 5. Are there specific genetic, biomarker, demographic, or clinical features that predict whether someone is likely to benefit from metformin-XR or experience side effects that lead them to stop taking it? Researchers will compare a metformin treatment group to a survey-only group (comparator) to see if metformin-XR is associated with improved outcomes, including reduced HG recurrence and better maternal and neonatal health indicators. Participants will: Complete online questionnaires before pregnancy, during early pregnancy, and postpartum (Treatment group only) Take daily metformin-XR and attend three brief study visits (Treatment group only) Undergo blood draws at specified timepoints to assess safety and biological response
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Adherence to Escalating Doses of Metformin-XR
Timeframe: Baseline to 8 weeks after treatment initiation
Tolerability and Safety of Metformin-XR
Timeframe: Baseline through treatment completion (up to 12 months after treatment initiation or 2 weeks after confirmed pregnancy, whichever comes first)
Hyperemesis Gravidarum (HG) Recurrence and Severity
Timeframe: From confirmed pregnancy through 12 weeks of gestation
Pregnancy & Neonatal Outcomes: Incidence of Pregnancy Complications
Timeframe: From confirmed pregnancy through delivery
Pregnancy & Neonatal Outcomes: Delivery Characteristics
Timeframe: At delivery
Pregnancy & Neonatal Outcomes: Assessment of Peripartum Events
Timeframe: From confirmed pregnancy to 6 months postpartum
Pregnancy & Neonatal Outcomes: Maternal Postpartum Depression
Timeframe: From birth to 6 months postpartum
Pregnancy & Neonatal Outcomes: Maternal Postpartum Anxiety
Timeframe: From birth to 6 months postpartum
Pregnancy & Neonatal Outcomes: Maternal Postpartum Quality of Life
Timeframe: From birth to 6 months postpartum
Pregnancy & Neonatal Outcomes: Neonatal Health Status
Timeframe: At delivery
Pregnancy & Neonatal Outcomes: Child Developmental Status
Timeframe: From birth to 6 months postpartum (with optional follow up until the end of the 5-year study period)
Indicators of Metformin Response: Genetic Factors
Timeframe: Once at baseline
Indicators of Metformin Response: Circulating Biomarker Levels
Timeframe: Once at baseline, once when participant reaches highest tolerated metformin dose (up to week 8), and once at pregnancy confirmation in participants who conceive
Indicators of Metformin Response: Demographic Characteristics
Timeframe: At baseline