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
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
224
Participants in the Treatment Arm will receive oral extended-release metformin (metformin-XR) 1x daily with an evening meal starting prior to conception. Daily dosing will begin at 500 mg and increase gradually over an 8 week period (+500mg every 2 weeks, as tolerated) to a maximum tolerated dose of up to 2,000 mg. Treatment at highest tolerated dose will continue until either 2 weeks after a positive pregnancy test or 12 months from treatment start, whichever comes first. Participants will attend 3 clinic visits and provide blood samples at baseline, after dose escalation, and during early pregnancy to assess biomarker levels and genetic characteristics. Daily dosing, adherence, and side effects are recorded via MyCap; clinical visits include vital signs, PUQE-24/HELP scores, and blood draws (CBC, creatinine, genotyping, biomarker levels). Postpartum surveys include a metformin treatment \& HG outcomes survey (REDCap) and additional measures (PES, MAPP-QOL, EPDS, PSAS, and ASQ-3).
Adherence to Escalating Doses of Metformin-XR
Proportion of participants in the Treatment Arm who reach and maintain each target dose level during the 8-week dose-escalation period, as recorded via MyCap survey entries.
Time frame: Baseline to 8 weeks after treatment initiation
Tolerability and Safety of Metformin-XR
Number and severity of treatment-related adverse events and dose-limiting toxicities experienced by participants during the 8-week dose-escalation period and maintenance phase. Safety assessed by participant report, clinical evaluations, and laboratory results.
Time frame: 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
Incidence and severity of HG in subsequent pregnancy, assessed using validated tools (Pregnancy-Unique Quantification of Emesis (PUQE-24), HyperEmesis Level Prediction (HELP) Score) and pregnancy experience survey responses.
Time frame: From confirmed pregnancy through 12 weeks of gestation
Pregnancy & Neonatal Outcomes: Incidence of Pregnancy Complications
Proportion of participants who experience predefined pregnancy complications (e.g., gestational diabetes, preeclampsia, gestational hypertension). Data will be abstracted from medical records and study surveys.
Time frame: From confirmed pregnancy through delivery
Pregnancy & Neonatal Outcomes: Delivery Characteristics
Proportion of participants with a favorable delivery outcome, defined as live birth at ≥37 weeks gestation. Delivery outcome will be abstracted from medical records and study surveys.
Time frame: At delivery
Pregnancy & Neonatal Outcomes: Assessment of Peripartum Events
Peripartum events will be evaluated using the validated Peripartum Events Scale (PES). PES score will be evaluated via medical record abstraction. The lowest possible PES score is zero, with higher scores corresponding to more stressful labor and delivery experiences.
Time frame: From confirmed pregnancy to 6 months postpartum
Pregnancy & Neonatal Outcomes: Maternal Postpartum Depression
Maternal mental health will be assessed using the Edinburgh Postnatal Depression Scale (EPDS). The EPDS range is 0-30, with higher scores corresponding to more severe depressive symptoms.
Time frame: From birth to 6 months postpartum
Pregnancy & Neonatal Outcomes: Maternal Postpartum Anxiety
Maternal mental health will be assessed using the Postpartum-Specific Anxiety Scale (PSAS). The PSAS range is 51-204, with higher scores corresponding to greater postpartum-specific anxiety.
Time frame: From birth to 6 months postpartum
Pregnancy & Neonatal Outcomes: Maternal Postpartum Quality of Life
Maternal postpartum quality of life will be assessed using the validated Maternal Postpartum Quality of Life (MAPP-QOL) Questionnaire. The MAPP-QOL possible total score range is 38-228, with higher scores corresponding to better quality of life.
Time frame: From birth to 6 months postpartum
Pregnancy & Neonatal Outcomes: Neonatal Health Status
Proportion of neonates who experience an adverse neonatal outcome, defined as the presence of at least one predefined adverse neonatal event, including but not limited to low birth weight (\<2500 grams), preterm birth (\<37 weeks gestation), admission to a neonatal intensive care unit (NICU), or low 5-minute Apgar score (\<7). Data will be obtained from medical record abstraction and study surveys.
Time frame: At delivery
Pregnancy & Neonatal Outcomes: Child Developmental Status
Child development will be assessed before 6 months postpartum using the validated Ages and Stages Questionnaires, Third Edition (ASQ-3). Optionally, every 6 months up to year 5 (study completion), participants will have the opportunity to complete an additional ASQ-3 assessment corresponding to their child's age to report long-term child outcomes.
Time frame: 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
Genotyping of variants associated with HG risk (e.g., rs1058587/GDF15, rs9312688/IGFBP7, rs12790159/PGR, and rs10948901/GFRAL) to explore their association with metformin response and pregnancy outcomes.
Time frame: Once at baseline
Indicators of Metformin Response: Circulating Biomarker Levels
Measurement of biomarker (e.g., GDF15, IGFBP7) concentrations at three timepoints in the Treatment Arm (baseline, after dose escalation, and during early pregnancy) to explore the role of each as a predictive biomarker for HG and metformin response.
Time frame: 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
Demographic information will be collected via initial study survey and qualitatively analyzed for associations with HG and metformin response.
Time frame: At baseline
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