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NCT Number: NCT07129473

Hyperemesis Gravidarum Risk Reduction With Metformin

The goal of this clinical trial is to evaluate whether daily oral metformin extended-release (metformin-XR), taken prior to and in early 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 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 an 8-week titration period and continued through early pregnancy (or for up to 12 months after reaching maintenance dose 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, no study drug) 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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Key information

Conditions

Hyperemesis Gravidarum Female Urogenital Diseases and Pregnancy Complications Morning Sickness Nausea Pathological Conditions, Signs and Symptoms Pregnancy Complications Signs and Symptoms Signs and Symptoms, Digestive Urogenital Diseases Vomiting

Age range

18 year–49 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

The Morning Sickness & HG Clinic, Birmingham, Alabama, United States

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Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Ages 18-49
  • HG in prior pregnancy (clinical criteria: intravenous (IV) fluid treatment)
  • Trying to conceive
  • Treatment Arm: willing to refrain from trying to conceive during their metformin dose titration period and before 2 weeks at maximum tolerated dose (up to 8 weeks total). Will use birth control or contraceptive device until maintenance dose.
  • Under care of a personal OB/GYN or willing to establish care with a personal OB/GYN before study start
  • Ownership of a personal scale (or willingness to obtain one for study use)
  • Willing to participate in a trial that includes daily use of an oral agent prior to pregnancy
  • Treatment Arm: residing in California/Alabama
  • Treatment Arm: normal blood panel (CBC) (e.g., white count, hemoglobin, platelets all within the normal range)
  • Treatment Arm: normal to mildly decreased creatinine levels (estimated GFR > 60 mL/min/1.73m²)
  • Survey/Comparator Arm: not currently taking metformin and do not plan to take metformin prior to pregnancy
  • Able and willing to provide written informed consent prior to initiation of any study procedures.
  • Demonstrates understanding of the study objectives, requirements, potential risks, and willingness to comply with study procedures and follow-up.
  • English speaking
  • Regular cycles

Exclusion criteria

  • Allergic or adverse reaction to metformin-XR
  • Thalassemia
  • Cirrhosis and/or hepatic impairment
  • Decompensated heart failure
  • Daily/regular use of medications/substances (tobacco, cyclobenzaprine, cannabis, escitalopram, sertraline, other SSRIs, Lasix)
  • Treatment Arm: Use of insulin, sulfonylureas, meglitinides, or other blood sugar altering medication
  • Assisted Reproductive Technology
  • Excess alcohol consumption (> 7 standard drinks per week on average)
  • Pregnant
  • Not trying to conceive
  • Treatment Arm: Residing outside California/Alabama
  • Treatment Arm: abnormal blood panel (CBC) (e.g., white count or platelets not within the normal range)
  • Treatment Arm: abnormal creatinine levels (estimated GFR < 60 mL/min/1.73m² excluded from the study, signs of kidney disease)
  • Treatment Arm: current metformin use
  • Survey/Comparator Arm: current metformin use or plans to take metformin prior to pregnancy
  • Any medical/surgical condition that the investigator feels would compromise the participant's participation in the study
  • Not able and willing to provide written informed consent prior to initiation of any study procedures.
  • Does not demonstrate understanding of the study objectives, requirements, potential risks, and willingness to comply with study procedures and follow-up.
  • Not english speaking
  • Irregular cycles
  • Not willing to refrain from trying to conceive/use birth control or contraceptive device until maintenance dose.

Treatment and study plan

Metformin Extended Release Oral Tablet

Drug

Participants in the Treatment Arm will receive oral extended-release metformin (metformin-XR) once daily with an evening meal starting prior to conception. Daily dosing will begin at 500 mg and increase gradually over an 8-week period (+500 mg every 2 weeks, as tolerated, with increases, holds, or reductions based on symptom severity) to a maximum dose of 2,000 mg. Treatment at highest tolerated dose will continue until 2 weeks after positive pregnancy test or 12 months after cessation of birth control/contraceptive device. 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. Postpartum surveys include a metformin treatment & HG outcomes survey (REDCap) and additional measures (PES, MAPP-QOL, EPDS, PSAS, and ASQ-3).

Primary outcomes

  1. Adherence to Escalating Doses of Metformin-XR

    Time frame: Baseline to 8 weeks after treatment initiation

    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.

  2. Tolerability and Safety of Metformin-XR

    Time frame: Baseline through treatment completion (up to 12 months after maintenance dose following cessation of birth control/contraceptive device or 2 weeks after confirmed pregnancy, whichever comes first)

    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.

  3. Hyperemesis Gravidarum (HG) Recurrence and Severity

    Time frame: From confirmed pregnancy through 12 weeks of gestation

    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.

  4. Pregnancy & Neonatal Outcomes: Incidence of Pregnancy Complications

    Time frame: From confirmed pregnancy through delivery

    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.

  5. Pregnancy & Neonatal Outcomes: Delivery Characteristics

    Time frame: At delivery

    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.

  6. Pregnancy & Neonatal Outcomes: Assessment of Peripartum Events

    Time frame: From confirmed pregnancy to 6 months postpartum

    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.

  7. Pregnancy & Neonatal Outcomes: Maternal Postpartum Depression

    Time frame: From birth to 6 months postpartum

    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.

  8. Pregnancy & Neonatal Outcomes: Maternal Postpartum Anxiety

    Time frame: From birth to 6 months postpartum

    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.

  9. Pregnancy & Neonatal Outcomes: Maternal Postpartum Quality of Life

    Time frame: From birth to 6 months postpartum

    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.

  10. Pregnancy & Neonatal Outcomes: Neonatal Health Status

    Time frame: At delivery

    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.

  11. Pregnancy & Neonatal Outcomes: Child Developmental Status

    Time frame: From birth to 6 months postpartum (with optional follow up until the end of the 5-year study period)

    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.

  12. Indicators of Metformin Response: Genetic Factors

    Time frame: Once at baseline

    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.

  13. Indicators of Metformin Response: Circulating Biomarker Levels

    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

    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.

  14. Indicators of Metformin Response: Demographic Characteristics

    Time frame: At baseline

    Demographic information will be collected via initial study survey and qualitatively analyzed for associations with HG and metformin response.

Study contacts

Contact information is provided by the study sponsor or research team.

Andrew Housholder, MD, FACEP

CONTACT

205-772-9595

Marlena Fejzo, PhD

CONTACT

[email protected]

310-383-3581

Sponsors and collaborators

Lead sponsor

University of Southern California

Other

Collaborators

  • The Morning Sickness & HG Clinic

Registry information

Important dates

Study start
2026
Primary completion
2031
Study completion
2031
First posted
Aug 19, 2025
Registry last updated
Jul 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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