EMERGE Mothers and Kids: a longitudinal cohort study of mothers and children enrolled in the randomized placebo-controlled trial of metformin in women with GDM (EMERGE): study protocol

Abstract

Background

Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with increased risks of adverse perinatal outcomes and with long-term metabolic and cardiovascular consequences for both mother and child. The original EMERGE randomized controlled trial (RCT) evaluated the effectiveness of early metformin in addition to usual care in women with GDM on glycemic control and perinatal outcomes. The primary objective of the EMERGE Mothers and Kids study is to evaluate long-term maternal cardiometabolic health and child anthropometric and neurodevelopmental outcomes following participation in the EMERGE trial.

Methods

This is a prospective, observational longitudinal cohort follow-up study of women and their children previously enrolled in the EMERGE trial (NCT06327191). Participants are invited to attend a follow-up visit in a single-site hospital-based clinical research setting at the Clinical Research Facility Galway, Ireland. Key inclusion criteria are women and their children who participated in the EMERGE trial and consent to follow-up. Key exclusion criteria include participants who did not provide consent for future follow-up studies. The planned follow-up sample is a pragmatic convenience sample of up to 321 mother–child pairs. A single follow-up visit will be conducted up to 6 years after the index pregnancy. Maternal assessments include anthropometric data, glucose tolerance, and metabolic parameters. Child assessments include growth metrics, adiposity measured via skinfold thickness, and neurodevelopmental status assessed through validated questionnaires. Additional data on quality of life, mental health, breastfeeding, and health economics will also be collected.

Discussion

This study aims to provide insights into the long-term safety and efficacy of metformin use during pregnancy, addressing the evidence gap in maternal cardiometabolic outcomes after metformin-treated GDM while also assessing child anthropometric and neurodevelopmental outcomes.

Trial registration

ClinicalTrials.gov NCT06327191. Registered on November 21, 2023. First planned enrollment in this follow-up study: July 2024. Trial record available at https://clinicaltrials.gov/study/NCT06327191.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-026-09703-6.

Background

Gestational diabetes mellitus (GDM) is a common metabolic disorder defined by glucose intolerance that develops during pregnancy in women without pre-existing diabetes [1]. Worldwide, an estimated 19.7% of women in 2024 were affected by hyperglycemia during pregnancy, with 79.2% of cases attributed to GDM [2]. Consistent with global estimates, GDM affects approximately 12.4% of pregnancies in Ireland [3]. However, these estimates vary depending on screening practices and diagnostic criteria used [4]. Beyond its acute impact, GDM represents a critical risk marker for future cardiometabolic disease in both mother and child. Poorly controlled hyperglycemia independently increases the risk of cesarean delivery and pre-eclampsia for the mother and exposes the fetus to excess growth, neonatal hypoglycemia, hyperbilirubinemia, birth injury, preterm birth, and intensive care unit (NICU) admission [5]. Typically, the glucose intolerance abates after delivery, while the metabolic imprint of GDM persists [6]. Long-term follow-up studies suggest that up to 60% of affected women develop type 2 diabetes mellitus (T2DM) later in life [7]. GDM is also associated with increased risks of hypertension [8], dyslipidemia [9], coronary artery calcification [10], and chronic kidney disease [11]. Similarly, offspring exposed to GDM in utero are more likely to develop adiposity [12], glucose intolerance [13], hypertension [14], and neurocognitive disorders [15] when followed up during childhood and adolescence.

Metformin has emerged as a promising therapeutic option for GDM, offering maternal benefits over insulin, including significantly reduced gestational weight gain without increasing the risk of serious perinatal complications, as demonstrated in the landmark Metformin in Gestational Diabetes (MiG) and EMERGE trials [16, 17]. These advantages, together with its low cost and oral administration, have led to widespread use in pregnancy. However, whether these short-term gains translate into long-term cardiometabolic benefits or risks remains uncertain for both mother and child. This uncertainty is particularly important in GDM, which represents an insulin-resistant pregnancy phenotype associated with high long-term maternal risk of T2DM, metabolic syndrome, hypertension, and dyslipidemia, despite long-term post-trial maternal follow-up after metformin-exposed GDM pregnancies remains limited. Follow-up studies after metformin treatment for GDM have provided important but heterogeneous evidence on longer-term offspring outcome. In the MiG TOFU program, early follow-up showed no difference in overall body fat at 2 years, although differences in fat distribution were reported [18], and later follow-up at 7 to 9 years showed broadly similar metabolic outcomes overall [19], with subgroup differences in anthropometric measures across centers. In addition, a 9-year follow-up of offspring from Finnish randomized controlled trials (RCTs) comparing metformin and insulin reported similar growth and glucose metabolism, with some differences in lipid profile between exposure groups [20]. By contrast, meta-analytic evidence has reported lower birthweight with postnatal catch-up growth and higher body mass index (BMI) in mid-childhood among metformin-exposed offspring [21]. More recently, a systematic review and meta-analysis including 18 studies reported that metformin-exposed children had comparable BMI to non-exposed peers at the oldest age of follow-up reported, with a modest increase in BMI at 1–3 years that was no longer evident at 3–6 or 6–11 years, and no clear differences in overweight, obesity, or waist circumference [22]. Similarly, a meta-analysis of neurodevelopmental outcomes up to 14 years found no association between in utero metformin exposure and neurodevelopmental delay, or adverse motor and cognitive outcomes in childhood [23]. Although these data are reassuring for offspring safety, they also emphasize the need for dedicated longitudinal studies with robust maternal phenotyping and parallel child follow-up in well-characterized GDM cohorts. Preclinical models support a role for metformin in fetal metabolic programming through AMP-activated protein kinase (AMPK) activation, placental mTOR inhibition, and epigenetic remodeling of key developmental pathways [24, 25]. In the absence of robust longitudinal human data, the long-term safety and efficacy of prenatal metformin exposure remain unresolved, underscoring the rationale for follow-up studies such as EMERGE Mothers and Kids (EMK).

The EMERGE study took place between 2017 and 2022 [17]. A total of 535 pregnancies in 510 women with GDM were randomized in a 1:1 ratio to receive either metformin (up to 2500 mg daily) or placebo, in addition to usual care including medical nutrition counseling, physical activity, and insulin therapy, as required. The EMERGE trial reported that early metformin in addition to usual care was not superior to placebo plus usual care for the composite primary outcome of insulin initiation or fasting laboratory glucose ≥5.1 mmol/L at week 32 or 38, with a risk ratio (RR) of 0.89 (95% CI 0.78–1.02; p = 0.13). However, women in the metformin group had less gestational weight gain compared to the placebo group, and women in the metformin group were 25% less likely to require insulin. Children born to mothers exposed to metformin had a significant reduction in macrosomia (>4 kg) and large for gestational age (LGA). Regarding neonatal anthropometrics, the only difference between groups was a statistically significant difference of −0.7 cm in crown-heel length between the metformin group and the placebo group, the clinical significance of which is unclear.

EMERGE Mothers and Kids (EMK) is a longitudinal follow-up study of the EMERGE trial participants and their offspring. The primary aim of the EMK study is to determine whether metformin use during pregnancy leads to an improvement in both maternal and child cardiometabolic health at up to 6 years following the diagnosis of GDM. Recruitment is currently underway.

Objectives

The primary objective of the EMERGE Mothers and Kids study is to assess whether treatment with metformin during pregnancy in women with GDM, compared to placebo, is associated with long-term risk, up to 6 years postpartum, of (a) disorders of glucose metabolism; (b) metabolic syndrome; (c) overweight and obesity; (d) hypertension; and (e) alterations in lipid profiles.

The primary objective for children in this follow-up study is to determine whether in utero exposure to metformin is associated with adiposity at follow-up, as measured by BMI, anthropometric parameters, and skinfold thickness.

The secondary objectives for mothers are to assess the associations of GDM and its treatment with (a) breastfeeding duration beyond 12 weeks postpartum; (b) maternal mental health; (c) health-related quality of life (QoL); (d) dietary intake patterns; (e) physical activity patterns; and (f) self-reported economic burden of GDM care and treatment.

The secondary objectives for children are to identify predictors of childhood adiposity and to investigate associations between maternal GDM, metformin exposure, and neurodevelopmental outcomes including (a) autism spectrum disorder (ASD); (b) attention-deficit/hyperactivity disorder (ADHD); and (c) higher executive functioning.

Exploratory objectives include the identification of novel biomarkers in the prediction of future metabolic risk, including plasma glycated CD59 and extracellular vesicle signatures from maternal samples.

Study design

The EMERGE Mothers and Kids study is a longitudinal prospective cohort study of women and their offspring who participated in the EMERGE RCT, a phase III, randomized, double-blind, placebo-controlled trial. In the original EMERGE RCT, participants were randomized in a 1:1 ratio to metformin or placebo, using minimization to balance maternal BMI (≤30 vs >30 kg/m²) and history of GDM, with a fixed block size of 4. Allocation was performed through a secure interactive web-based randomization system after eligibility confirmation, ensuring allocation concealment [17].

Methods

Study setting

This is a single-site follow-up study conducted in a hospital-based outpatient research setting at the Clinical Research Facility Galway, based at Galway University Hospital and University of Galway.

Eligibility criteria

Eligible participants are women and their children who participated in the EMERGE trial. The follow-up cohort comprises mother–child pairs re-contacted from a well-characterized trial population of women with singleton pregnancies and GDM originally recruited in two centers in Ireland, with baseline maternal, pregnancy, and neonatal data available from the original trial, and who had provided permission to be contacted for follow-up. Exclusion criteria include participants who did not provide consent for further follow-up studies.

Informed consent

Participants will be asked to provide consent for both themselves and their child, and written informed consent will be obtained from each participant by a trained investigator or sub-investigator prior to any follow-up assessments. The study will be explained using the approved Participant Information Leaflet (PIL), and participants will have the opportunity to ask questions before providing consent. As the consent leaflets are written in English, a translator service provides for any participant who requires help with consent. Participants will be asked if they agree to further use of their data even if they choose to withdraw from the study at a later stage. They will also be asked to provide permission for relevant data to be shared with members of the research team at the University of Galway and, where applicable, with future research collaborators. This study involves the collection of biological specimens for ancillary studies, including biomarker and extracellular vesicle analysis. Patients and the public were not formally involved in the design, conduct, or reporting of this follow-up study.

A copy of the consent form is attached as Additional file 1.

Interventions

This study is a non-interventional observational follow-up study, and no intervention is administered as part of the follow-up study. In the original EMERGE RCT, women were allocated in a 1:1 ratio to metformin (up to 2500 mg daily) or placebo, in addition to usual care. In EMK, no new treatment or comparator arms are introduced, and analyses will compare follow-up outcomes according to the original EMERGE treatment allocation (metformin versus placebo), consistent with the post-trial observational follow-up design. Following completion of the original EMERGE trial, participants received usual clinical care through their treating healthcare teams, and no protocol-directed post-trial treatment was provided as part of EMK. Blood sampling is performed at the single follow-up visit as part of the study assessments, including venous sampling for the 75-g oral glucose tolerance test (OGTT) and routine laboratory tests and, where consent is provided, additional aliquots from the same venipuncture are stored for biobanking. Participants are permitted to continue prescribed medications prior to study visits, except lipid-lowering medications or glucose-lowering agents which are to be discontinued 72 h prior to site visit, for the purpose of standardizing metabolic assessments and reducing acute treatment-related confounding of biochemical and OGTT results, where considered clinically appropriate by the investigator. Where applicable, the decision to stop insulin is made on a case-by-case basis by the investigator.

Provisions for post-trial care

As this is a non-interventional, observational follow-up study, no post-trial care is required or planned. Participants continue to receive routine clinical care under local health service provision.

Outcomes

Outcomes are assessed at the single EMK follow-up visit. Relevant historical variables from the original EMERGE trial database and medical records are used for longitudinal comparisons where applicable. Detailed methods for outcomes assessment, including timing of assessments and data sources, are described in the Study procedures section.

Co-primary maternal outcomes

• Diagnosis of T2DM or pre-diabetes (based on 75-g OGTT and hemoglobin A1c (HbA1c), with ADA criteria [26] and cut-offs specified in the Study procedures section)

• Occurrence of metabolic syndrome (defined using prespecified criteria detailed in the Study procedures section) [27]

• Overweight or obesity status (based on BMI, categorized using World Health Organization (WHO) criteria detailed in the Study procedure section) [28]

• Presence of hypertension (based on blood pressure assessment and/or antihypertensive treatment, as specified in the Study procedures section)

• Associations between GDM diagnosis, sum of fasting, 1-h, and 2-h glucose z-scores after 75-g load, insulin sensitivity indices assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), derived from fasting glucose and fasting insulin [29], and lipid levels, at 24–32 weeks’ gestation with lipid levels 3–6 years postpartum

Primary child outcome

• Presence of overweight or obesity, classified using prespecified age- and sex-appropriate BMI-based criteria

Secondary maternal outcomes

• Breastfeeding duration beyond 12 weeks postpartum

• Mental health status (assessed via Edinburgh Postnatal Depression Scale, EPDS) [30]

• Quality of life status (assessed via SF-12 questionnaire) [31]

• Dietary intake (assessed via Food Frequency Questionnaire, FFQ) [32]

• Physical activity (assessed via 7-point validated questionnaire) [33]

• Self-reported economic burden and healthcare utilization

Secondary child outcomes

• Neurodevelopmental status, including (1) ASD assessed via Social Responsiveness Scale-2 (SRS-2) questionnaire (children >2.5 years) [34] and Quantitative Checklist for Autism in Toddlers (Q-chat) questionnaire (children <2.5 years) [35]; (2) ADHD assessed via ADHD-5 questionnaire (children >5 years) [36] and ADHD-IV questionnaire (children <5 years) [37]

• Executive function (assessed via the Behaviour Rating Inventory of Executive Function, BRIEF-2 questionnaire) [38]

The ASD and ADHD questionnaires are used as validated screening tools to identify children at increased risk of neurodevelopmental difficulties, and findings will be interpreted accordingly rather than as clinical diagnoses.

Primary and secondary maternal and child outcomes are detailed in Table 1.

Table 1.

Summary of primary and secondary endpoints in the EMK follow-up study

Outcome category		Endpoint	Time-point	Measurement/instrument
Primary	Maternal	Diagnosis of T2DM or pre-diabetes	Single EMK follow-up visit (3–6 years postpartum)	75-g OGTT (mmol/L) and HbA1c (mmol/mol) [26]
		Metabolic syndrome	Single EMK follow-up visit (3–6 years postpartum)	Presence of 3 or more of the following factors: • Fasting glucose >5.6 mmol/L or diagnosis of T2DM • HDL-C <1.29 mmol/L or drug treatment for low HDL cholesterol • TG >1.7 mmol/L or drug treatment for elevated TG • Waist circumference >80 cm • Hypertension with a blood pressure >130/85 mmHg or drug treatment for hypertension [27]
		Overweight or obesity	Single EMK follow-up visit (3–6 years postpartum)	Overweight or obesity status categorized from BMI (kg/m2) using WHO criteria [28]
		Hypertension	Single EMK follow-up visit (3–6 years postpartum)	Blood pressure >130/85 mmHg or drug treatment for hypertension
		Associations between GDM diagnosis, pregnancy glucose z-score sum, insulin sensitivity, and lipids (pregnancy to follow-up)	EMERGE pregnancy assessments (24–32 weeks’ gestation) and single EMK follow-up visit (3–6 years postpartum)	EMERGE 75-g OGTT glucose values used to derive pregnancy glucose z-score sum; fasting glucose and insulin for HOMA-IR [29]; fasting lipids (total cholesterol, LDL-C, HDL-C, TG) at follow-up (mmol/L; HOMA-IR index)
	Child	Overweight or obesity	Single EMK follow-up visit (3–6 years postpartum)	Age- and sex-appropriate BMI-based classification (BMI, kg/m2), reported as categorical overweight/obesity status [28]
Secondary	Maternal	Breastfeeding duration beyond 12 weeks postpartum	Single EMK follow-up visit (3–6 years postpartum)	Historical postpartum self-report
	Maternal	Mental health status	Single EMK follow-up visit (3–6 years postpartum)	EPDS [30]
	Maternal	Quality of life status	Single EMK follow-up visit (3–6 years postpartum)	SF-12 [31]
	Maternal	Dietary intake	Single EMK follow-up visit (3–6 years postpartum)	FFQ [32]
	Maternal	Physical activity	Single EMK follow-up visit (3–6 years postpartum)	7-point validated questionnaire [33]
	Maternal	Self-reported economic burden and healthcare utilization	Single EMK follow-up visit (3–6 years postpartum)	Self-report
	Child	Neurodevelopmental status	Single EMK follow-up visit (3–6 years postpartum)	• ASD screening assessed via SRS-2 questionnaire (kids >2.5 years) [34] and Q-chat questionnaire (kids <2.5 years) [35] • ADHD screening assessed via ADHD-5 questionnaire (kids >5 years) [36] and ADHD-IV questionnaire (kids <5 years [37]
	Child	Executive function	Single EMK follow-up visit (3–6 years postpartum)	BRIEF-2 [38]

T2DM type 2 diabetes mellitus, EMK EMERGE Mothers and Kids, OGTT oral glucose tolerance test, ADA American Diabetes Association, HbA1c hemoglobin A1c, LDL-C low-density lipoprotein, HDL-C high-density lipoprotein cholesterol, TG triglycerides, WHO World Health Organization, GDM gestational diabetes mellitus, BMI body mass index, HOMA-IR Homeostatic Model Assessment of Insulin Resistance, EPSD Edinburgh Postnatal Depression Scale, SF-12 Short-Form Health Survey-12, FFQ Food Frequency Questionnaire, ASD autism spectrum disorder, ADHD attention-deficit/hyperactivity disorder, SRS-2 Social Responsiveness Scale-2, Q-chat Quantitative Checklist for Autism in Toddlers, BRIEF-2 Behaviour Rating Inventory of Executive Function

Health economic analysis

A trial-based economic evaluation will be conducted by the Health Economic and Policy Analysis (HEPA) group at the University of Galway. Cost-effectiveness and cost-utility analyses will compare metformin plus usual care versus usual care alone, adopting a healthcare provider perspective. Outcomes will be expressed as costs per quality-adjusted life year (QALY) gained, derived from the SF-12 questionnaire [39]. Incremental cost-effectiveness ratios (ICERs) will be calculated and sensitivity analyses performed in line with Health Information and Quality Authority (HIQA) guidance.

Participant timeline

Recruitment for the EMK follow-up study commenced in July 2024 and will continue until May 2026. Eligible participants are invited to attend a single follow-up visit at the Clinical Research Facility, University of Galway, together with their offspring. A sample timeline is depicted in Fig. 1.

Fig. 1.

SPIRIT participant timeline for the EMERGE trial and EMK follow-up. ^aOther procedures include eligibility confirmation, informed consent, study ID verification, and review of relevant EMERGE and medical record data

Study procedures

Data are collected during a single scheduled follow-up visit in the morning, with mothers attending in the fasting state for blood sampling and metabolic assessment.

For longitudinal analyses, key variables available from the original EMERGE trial may include maternal clinical and metabolic data during pregnancy, treatment allocation, and pregnancy and neonatal outcomes, which will be compared with corresponding maternal and child follow-up measures where applicable.

For mothers, relevant comorbidities are recorded including psychiatric disorders (e.g., anxiety, depression), cardiovascular disease, polycystic ovary syndrome, thyroid dysfunction, hypercholesterolemia, essential hypertension, T2DM or pre-diabetes, and any long-standing medical condition requiring treatment. All current medications are recorded via interview and/or medical record review. For children, historical data on prematurity, neonatal hypoglycemia, birth trauma, brain injury, severe illness, and assessments of ASD or ADHD are collected from the EMERGE trial database and/or medical records. Maternal disorders of glucose metabolism are evaluated at the follow-up visit using a 75-g OGTT and HbA1c. Cutoffs for disorders of glucose metabolism are defined according to ADA criteria [26], with diabetes diagnosed as fasting plasma glucose ≥7.0 mmol/L, and/or 2-h plasma glucose ≥11.1 mmol/L during the 75-g OGTT, and/or HbA1c ≥48 mmol/mol. Impaired fasting glucose is defined as fasting plasma glucose 5.6 to 6.9 mmol/L, and impaired glucose tolerance as 2-h plasma glucose 7.8 to 11.0 mmol/L. Other laboratory tests include maternal fasting lipids, including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) reported in mmol/L, fasting insulin and c-peptide (pmol/L), urea (mmol/L), creatinine (mmol/L), alanine transaminase (ALT, U/L), aspartate transaminase (AST, U/L), c-reactive protein (CRP, mg/L), and uric acid (mmol/L). Maternal bio-bank samples for future biomarker analysis, including glycated CD59 and extracellular vesicle profiling, are also collected with consent. Standardized measurements are obtained for both mother and child, including blood pressure and heart rate using calibrated instruments, weight in kilograms, height in meters, and BMI as kg/m². Maternal BMI is categorized according to WHO standards [28]: underweight, <18.5 kg/m²; normal, 18.5–24.9 kg/m²; overweight, 25–29.9 kg/m²; obese, >30 kg/m². For mothers, waist circumference is taken using a tape measure halfway between the hip bone and the lowest rib, approximately 5 cm above the umbilicus. Metabolic syndrome is defined as the presence of 3 or more of the following risk factors in women: fasting glucose >5.6 mmol/L or diagnosed T2DM; HDL-C of <1.29 mmol/L or drug treatment for low HDL-C; TG level of >1.7 mmol/L or drug treatment for elevated TG; waist circumference of >80 cm (given the predominantly Caucasian cohort); or hypertension with a blood pressure of >130/85 mmHg or drug treatment for hypertension [27]. For children, head circumference, neck circumference, left upper arm circumference, and abdominal circumference at the umbilicus are all taken using a tape measure. All body circumferences are measured in centimeters. For children only, triceps, subscapular, and supra-iliac skinfold thickness are measured in millimeters using a caliper. Child overweight and obesity are determined from follow-up anthropometric measurements using prespecified age- and sex-appropriate BMI-based criteria [28].

During the site visit, maternal participants also complete questionnaires regarding their health and the health of their child (listed in Appendix A). All blood samples, anthropometric measurements, and questionnaire responses are collected by the study investigators, a research nurse, or a clinical research associate, using standardized study procedures and calibrated instruments where applicable. Participants and study staff are not blinded as to the participants’ treatment allocation in the EMERGE trial, as unblinding already occurred upon completion of EMERGE.

Sample size

Given that this study is a longitudinal follow-up of a completed randomized trial cohort, the sample size is pragmatic and will consist of a convenience sample of all eligible EMERGE mother–child pairs who can be re-contacted and consent to follow-up. Based on an anticipated follow-up retention rate of approximately 60%, which is considered realistic for a long-term mother–child follow-up study and consistent with expected attrition in similar cohorts, we expect to include up to 321 pairs, with analyses primarily focused on estimation and hypothesis generation rather than formal hypothesis testing based on prespecified power. For women who participated in EMERGE on more than one occasion, only the first pregnancy will be included in the EMK follow-up cohort. To assess potential attrition bias, baseline characteristics from the original EMERGE trial will be compared between participants who attend the follow-up visit and those who are lost to follow-up or decline participation.

Recruitment

All participants from the EMERGE trial who consented to follow-up are contacted by post, phone, or e-mail. Invitation letters and consent forms are issued in advance of the study visit. Participants are invited to attend a single follow-up visit in a hospital-based clinical research setting at the Clinical Research Facility Galway, based at Galway University Hospitals and the University of Galway.

Assignment of interventions: allocation

In this follow-up study, there is no intervention to assign. Upon completion of the EMERGE trial, participants were formally unblinded, and treatment allocation is now known to both participants and research staff conducting EMK study visits.

Data collection and management

Plans for assessment and collection of outcomes

Data are collected during a single scheduled site visit using study-specific electronic case report forms (eCRFs). All data are entered by trained research staff into a secure, password-protected electronic database, maintained by the University of Galway, and designed to ensure data quality and participant confidentiality. Participants are identified using a study-specific ID code/number assigned at the time of enrollment in the EMERGE trial. Source documents include EMERGE trial data, hospital medical records, laboratory results, physical assessment forms, and self-reported questionnaires. Data entry follows a predefined data management plan, and validation rules are embedded in the system to flag out-of-range values for verification. Data quality is further supported by routine review for completeness and consistency, with verification against source documents where applicable to resolve missing, inconsistent, or implausible entries. The study complies with Good Clinical Practice (GCP) and General Data Protection Regulation (GDPR) guidelines, and all identifiable information is securely stored in accordance with institutional policy.

Plans to promote participant and complete follow-up

To maximize follow-up rates, participants are contacted in advance to confirm availability, sent reminder communications, and offered flexible appointment times to facilitate attendance with their offspring. Reminder phone calls and emails are used to support adherence. For participants unable to attend in person, a minimum dataset will be collected remotely where possible (e.g., questionnaires, self-reported outcomes), including data on the child provided that maternal consent is obtained. Any protocol deviations are recorded using a dedicated form, and participants are rescheduled at the earliest convenience. Withdrawal and loss to follow-up are documented in accordance with GCP standards.

Confidentiality

Participant data are de-identified using unique study codes. Personal identifiers are stored separately in a secure, access-controlled location. All staff are trained in confidentiality and data protection procedures. Only authorized members of the study team have access to identifiable information. Data are anonymized prior to any data sharing or publication.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use

Maternal blood samples are collected at the follow-up visit for current laboratory evaluation and are not discarded after analysis because, where consent is provided, they are stored for future biomarker and molecular analyses. Sample storage and retention are managed under the institutional biobanking governance framework at the University of Galway and Galway University Hospital, in accordance with ethical approval and applicable data protection requirements. Planned analyses include assays for glycated CD59 and extracellular vesicle signatures. Samples are processed and stored using temperature-controlled systems at Galway University Hospital and the Clinical Research Facility, University of Galway. All samples are labeled with study-specific participant IDs to ensure traceability and confidentiality.

Statistical methods

Statistical methods for primary and secondary outcomes

Statistical analysis will be performed using R software version 4.5.0. For primary endpoints, data will be summarized as means and standard deviations if normally distributed, or as medians and interquartile ranges (IQR) if not normally distributed. Differences between groups will be assessed using independent t-tests for normally distributed variables and Mann-Whitney U test for non-normally distributed variables. Categorical data will be analyzed using the chi-square test to compare the two groups. Multivariable analysis will be performed using multiple logistic regression to examine associations between glycemic status and cardiovascular risk factors and appropriate linear regression approaches for continuous outcomes, adjusting for relevant confounders. Post-trial medication use, including glucose-lowering therapies initiated after completion of the original EMERGE trial, breastfeeding exposure, and other postnatal factors captured in the study assessments will also be considered as potential confounders in multivariable models and sensitivity analyses, where appropriate. Potential attrition bias will be assessed by comparing baseline characteristics from the original EMERGE trial between participants who attend the follow-up visit and those who are lost to follow-up or decline participation.

Results will be reported as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). The significance level will be set at 0.05.

For secondary endpoints, including questionnaire-based outcomes in mothers and children, comparisons between the metformin and placebo groups will be performed using appropriate statistical methods based on data distribution. For child outcomes, age at follow-up will be considered in analyses where relevant, including the use of age- and sex-appropriate classifications and covariate adjustment as appropriate to the endpoint. The health economic evaluation will be conducted by the Health Economic and Policy Analysis (HEPA) group at the University of Galway.

Given the number of maternal and child outcomes, analyses are primarily exploratory and focused on estimation and hypothesis generation. Results will be interpreted with appropriate caution for multiplicity, with emphasis on effect sizes and confidence intervals. Where multiple tests are performed within the same outcome domain, adjustment for multiple comparisons will be applied as appropriate, and both adjusted and unadjusted results will be reported.

Interim analyses

No interim analyses are planned for this follow-up study.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data

All analyses will be performed on an intention-to-treat basis, according to the original randomization group. For missing data, an initial assessment will identify the likely mechanism (missing completely at random, missing at random, or missing not at random). A suitable multiple imputation strategy will then be employed to determine the sensitivity of missing data on the inference gleaned from the final model.

Plans to give access to the full protocol, participant-level dataset, and statistical code

The full study protocol and statistical code will be made publicly available at the time of publication in a recognized open repository. De-identified participant-level data and the data dictionary will be deposited in a controlled-access repository after completion and publication of the primary and secondary manuscripts arising from the EMK study. Data access will be granted on reasonable request for bona fide research purposes following review of the request and completion of a data sharing agreement, in accordance with ethical approval, GDPR, and institutional data protection policies.

Oversight and monitoring

The study is carried out at the Clinical Research Facility at the University of Galway. Oversight of study activities, including data collection and regulatory compliance, is managed in accordance with institutional policies and under the direction of the chief investigator. The sponsor provides support and oversight as per Good Clinical Practice (GCP) standards.

Composition of the data monitoring committee, its role and reporting structure

Given the non-interventional nature of this follow-up study, a formal Data Monitoring Committee (DMC) is not required. Study oversight, including data integrity and participant safety, is managed by the study team and sponsor in accordance with standard institutional procedures.

Adverse event reporting and harms

Due to the observational design and minimal risk involved, adverse events are not anticipated. However, any unsolicited or spontaneously reported adverse events related to study participation (e.g., venipuncture complications) will be documented and managed by the study investigators.

Frequency and plans for auditing trial conduct

Trial monitoring visits are carried out according to the trial monitoring plan and are independent from the trial investigators.

Plans for communicating important protocol amendments to relevant parties

Any substantial protocol amendments, including changes to eligibility criteria, outcomes, and study procedures, will be submitted to the Galway Clinical Research Ethics Committee for approval prior to implementation. Approved amendments will also be communicated to the study sponsor, registered in the trial registry (ClinicalTrials.gov), and shared with investigators and study participants where relevant. A revised protocol version will be archived and referenced in subsequent study reports and publications.

Dissemination plans

Study results will be submitted for publication in peer-reviewed journals and presented at national and international conferences in the fields of diabetes, endocrinology, and public health. A plain-language summary will be shared with participants who express interest in receiving study results. Findings will also be disseminated through the National Clinical Trial Network (CTN) in Diabetes, and relevant national stakeholders, including healthcare providers and policymakers. No publication restrictions apply. Professional writers will not be employed in the writing of results.

Discussion

The EMK study represents one of the most comprehensive long-term follow-up investigations of a randomized trial of metformin in GDM. The EMK study was designed as a single-visit follow-up study to enable standardized assessment of mother–child pairs from a completed trial cohort while minimizing participant burden. This study is uniquely positioned to provide valuable insight into the long-term impact of in utero exposure to metformin on both maternal and child cardiometabolic and neurodevelopmental outcomes. In this context, child overweight/obesity and adiposity were prioritized as primary child outcomes because they are clinically relevant early indicators of cardiometabolic health in offspring of mothers with GDM and can be assessed consistently at follow-up in this cohort. Conducting longitudinal research presents practical challenges, including participant retention, biological sampling in mothers, and scheduling dual mother–child assessments. Use of standardized procedures, trained research staff, and integrated biobanking enhances the quality and reproducibility of findings. Importantly, the study design minimizes participant risk, and the insights generated may help shape future GDM management and prevention strategies. Limitations include the single-country setting and the demographic characteristics of the cohort, which may influence how the findings are interpreted across different settings.

Clinical and preclinical evidence on the long-term effects of metformin in GDM

Despite the increasing use of metformin in GDM, its long-term safety and efficacy remain under investigation, particularly in relation to maternal cardiometabolic risk and offspring development. Follow-up of children born to mothers with GDM who participated in the MiG trial revealed no differences in total body fat at 2 years, but subtle shifts in fat distribution were noted, including increased subcutaneous fat in the upper limbs and trunk, potentially reflecting a more favorable fat partitioning [18].

In the Auckland arm of the 9-year MiG follow-up, metformin-exposed children displayed higher BMI, mid-upper arm and waist circumferences, and total fat mass, whereas no such differences were observed in the Adelaide cohort [19], underscoring the influence of maternal metabolic status and gestational weight gain on treatment effects. Beyond the MiG cohorts, data from other clinical settings support the safety of metformin in pregnancy. Observational studies in GDM pregnancies indicate no increased risk of congenital anomalies or neurodevelopmental impairment, with comparable outcomes in cognitive and motor development at 2 years and similar IQ scores during childhood between metformin- and insulin-exposed offspring [40–42].

Recent pooled analyses have provided broadly reassuring results, showing no clear long-term signal for increased overall adiposity, overweight risk, or waist circumference among metformin-exposed offspring compared with non-exposed children, while also providing reassuring data on cognitive, motor, and broader neurodevelopmental outcomes up to 14 years of age [22, 23].

In pregnancies complicated by polycystic ovary syndrome (PCOS), longitudinal studies have reported higher BMI z-scores and obesity risk in metformin-exposed children at 4 [43] and up to 10 years of age [44]. Additional studies noted increased fasting glucose and systolic blood pressure [45], as well as higher weight and BMI at 1 year [46]. Although these studies suggest potential sex- and phenotype-specific susceptibilities, interpretation is limited by small sample sizes, heterogeneous populations, and confounding by indication.

From a mechanistic standpoint, metformin has been shown to cross the placenta and reach the fetal circulation at concentrations comparable to maternal levels [47]. Whether this reflects equilibrium between compartments or selective accumulation in fetal tissues remains unclear and deserves further investigation.

Experimental studies have demonstrated that metformin modulates fetal metabolic programming via activation of AMP-activated protein kinase (AMPK) and inhibition of mTOR, pathways that regulate cellular growth and nutrient sensing [24]. Additionally, alterations in mitochondrial bioenergetics, folate-mediated one-carbon metabolism, and the fetal epigenetic landscape have been documented, particularly in hepatic and adipose tissues [24]. These changes may persist into postnatal life, influencing adipocyte differentiation, hepatic metabolism, and insulin signaling. Notably, animal models highlight divergent outcomes based on maternal phenotype. In lean mouse dams, metformin exposure has been associated with lower birthweight, increased adiposity, and insulin resistance when offspring were later exposed to high-fat diets. In contrast, in obese dams, male offspring exposed to metformin exhibited reduced fat mass and improved metabolic outcomes [25]. Taken together, current evidence underscores the complexity of long-term metformin effects in GDM, shaped by maternal phenotype, fetal sex, and postnatal environment. The EMERGE Mothers and Kids study is uniquely positioned to address these uncertainties by integrating clinical, metabolic, and neurodevelopmental assessments up to 6 years after exposure, offering crucial insight into the intergenerational impact of metformin therapy in pregnancy.

Reporting guidelines

This protocol was written in adherence with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Guidelines 2013 [48].

Trial status

This protocol corresponds to version 3.0, 03 May 2024. Recruitment for the EMERGE Mothers and Kids follow-up study began in July 2024 and is expected to continue until May 2026.

Abbreviations

ADHD

Attention-deficit/hyperactivity disorder

ALT

Alanine transaminase

AMPK

AMP-activated protein kinase

aOR

Adjusted odds ratio

AST

Aspartate transaminase

ASD

Autism spectrum disorder

BMI

Body mass index

BRIEF-2

Behaviour Rating Inventory of Executive Function

CD59

Cluster of differentiation 59

CI

Confidence interval

CRP

C-reactive protein

CTN

Clinical Trial Network

DMC

Data Monitoring Committee

eCRF

Electronic case report form

EMK

EMERGE Mothers and Kids

EMERGE

Evaluating Metformin in Gestational Diabetes

EPDS

Edinburgh Postnatal Depression Scale

FFQ

Food Frequency Questionnaire

GCP

Good Clinical Practice

GDM

Gestational diabetes mellitus

GDPR

General Data Protection Regulation

GDRC

Galway Diabetes Research Centre

HbA1c

Hemoglobin A1c

HDL

High-density lipoprotein

HEPA

Health Economic and Policy Analysis

HOMA-IR

Homeostatic Model Assessment of Insulin Resistance

HIQA

Health Information and Quality Authority

HRB

Health Research Board

IADPSG

International Association of Diabetes and Pregnancy Study Groups

ICERs

Incremental cost-effectiveness ratios

IQ

Intelligence quotient

IQR

Interquartile range

LGA

Large for gestational age

LDL

Low-density lipoprotein

MiG

Metformin in Gestational Diabetes

mTOR

Mechanistic target of rapamycin

NICU

Neonatal intensive care unit

OGTT

Oral glucose tolerance test

Q-Chat

Quantitative Checklist for Autism in Toddlers

QALY

Quality-adjusted life year

QoL

Quality of life

PCOS

Polycystic ovary syndrome

PIL

Participant Information Leaflet

RCT

Randomized controlled trial

RR

Risk ratio

SD

Standard deviation

SF-12

12-Item Short Form Survey

SRS-2

Social Responsiveness Scale-2

TG

Triglycerides

T2DM

Type 2 diabetes mellitus

WHO

World Health Organization

Authors’ contributions

FD, AE, AS, DD, and MOD devised the concept for this trial and RS, FD, AE, CN, AS, DD, and MOD wrote the protocol. AAI, MF, and PG provided input on planned statistical and economic analysis respectively. POS will oversee biochemical analysis of laboratory samples. All authors revised the manuscript. All authors approved the final version of the manuscript and are accountable for the integrity of the work.

Funding

The study is sponsored by the University of Galway. Funding was provided by Merck Healthcare KGaA, Darmstadt, Germany.

Data availability

The study protocol and statistical code will be made publicly available at the time of publication. De-identified participant-level data and the data dictionary will be deposited in a recognized controlled-access repository and made available for research purposes only after completion and publication of the primary and secondary manuscripts arising from the EMK study, in accordance with ethical approval, GDPR, and institutional policies.

Declarations

Ethics approval and consent to participate

The study received ethical approval from the Galway Clinical Research Ethics Committee. Written informed consent was obtained at the time of original enrollment and reaffirmed at the follow-up visit (reference number CA 3024).

Consent for publication

This manuscript does not contain any individual person’s data in any form. Consent for publication is therefore not applicable. Results will be published in peer-reviewed journals and presented at international conferences.

Competing interests

The authors declare no competing interests. The study received funding from Merck Healthcare KGaA, Darmstadt, Germany, which had no involvement in the design, analysis, or reporting of the study.