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

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 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 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study protocol Roberta Scairati, Christine Newman, Alberto Alvarez-Iglesias, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7632300/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Apr, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version 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 glycaemic control and perinatal outcomes. The EMERGE Mothers and Kids study is a longitudinal follow-up of the EMERGE trial participants, designed to investigate the long-term metabolic, cardiovascular, and neurodevelopmental outcomes in mothers and their offspring. Methods This is a prospective, observational cohort study of participants and their children from the EMERGE trial (NCT06327191). 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 and its potential impact on the long term maternal and child health outcomes, contributing to evidence-based management of GDM. Trial registration: ClinicalTrials.gov; Identifier: NCT06327191 Gestational diabetes mellitus Metformin Pregnancy Long-term follow-up Randomized controlled trial Figures Figure 1 ADMINISTRATIVE INFORMATION Title 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) Trial Registration EMERGE RCT: NCT06327191, registered 21/11/2023 https://clinicaltrials.gov/study/NCT06327191?cond=gestational%20diabetes&term=emerge&rank=1 Protocol Version EMERGE Mothers and Kids protocol version 4.0 (3 rd May 2024) is currently in use Author details FD, AE, AS, DD, 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 provided oversight on planned biochemical analysis. All authors revised the manuscript. All authors approved the final version of the manuscript and are accountable for the integrity of the work. Role of sponsor and funder The sponsor (University of Galway, phone 0035391 524411) and funder (Merck Healthcare KGaA, Darmstadt, Germany) had no role in the study design, collection, management, analysis, and interpretation of data, writing of the report, or the decision to submit the manuscript for publication. 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 hyperglycaemia 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 caesarean 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 for the offspring remains uncertain. Follow-up studies comparing in utero exposure to metformin versus insulin have reported conflicting outcomes, ranging from similar childhood adiposity and metabolic profiles ( 18 ) to evidence of lower birthweight with postnatal catch-up growth and increased body mass index (BMI) in mid-childhood ( 19 ). Preclinical models support a role for metformin in fetal metabolic programming through AMPK activation, placental mTOR inhibition, and epigenetic remodeling of key developmental pathways ( 20 , 21 ). 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 & Kids (EMK). The EMERGE Randomized Controlled Trial (RCT) took place between 2017–2022 ( 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 primary outcome (fasting glucose > 5.1mmol/L at gestational weeks 32 or 38 or insulin initiation) was not significantly different between the two groups. 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 (> 4kg) 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 & 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 for is currently underway. OBJECTIVES The primary objective of the EMERGE Mother 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 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 body mass index (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; (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. This protocol was written in adherence with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Guidelines 2013 ( 22 ). STUDY DESIGN The EMERGE Mother and Kids study is a cohort study of women and their offspring who participated in the EMERGE RCT, a phase III, randomized, double-blind, placebo-controlled trial. METHODS Study Setting This study will take place at the Clinical Research Facility, Galway University Hospital and University of Galway. Eligibility Criteria Inclusion criteria include women and their children who participated in the EMERGE trial and gave permission for consent to 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. A copy of the consent form is attached as Additional file 1. Interventions No intervention is administered as part of the follow-up study. This study is a non-interventional observational follow-up, and no new treatment or comparator arms are introduced. 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 hours prior to site visit. 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 Primary maternal outcomes: Diagnosis of T2DM or pre-diabetes Occurrence of metabolic syndrome Overweight or obesity status Presence of hypertension Associations between GDM diagnosis, sum of fasting, 1-hour, and 2-hour glucose z-scores after 75-g load, insulin sensitivity, and lipid levels at 24–32 weeks’ gestation with lipid levels 3-6 years postpartum. Primary child outcome: Presence of overweight or obesity Secondary maternal outcomes: Breastfeeding duration beyond 12 weeks postpartum Mental health status (assessed via Edinburgh Postnatal Depression Scale, EPDS) Quality of life status (assessed via SF-12 questionnaire) Dietary intake (assessed via Food Frequency Questionnaire (FFQ)) Physical activity (assessed via 7-point validated questionnaire) Self-reported economic burden and healthcare utilisation Secondary child outcomes: Neurodevelopmental status, including 1) ASD assessed via Social Responsiveness Scale-2 (SRS 2) questionnaire (kids >2.5 years), and Quantitative Checklist for Autism in Toddlers (Q-chat) questionnaire (kids 5 years) and ADHD-IV questionnaire (kids <5 years) Executive function (assessed via the Behaviour Rating Inventory of Executive Function, BRIEF-2 questionnaire) 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. 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 EMERGE Mothers and Kids follow-up study commenced in June 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 figure 1. Study procedures Data are collected during the scheduled follow-up visit. Following informed consent, a detailed review of maternal and child medical history is performed. 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 hypoglycaemia, birth trauma, brain injury, severe illness, and diagnoses (or assessments) of ASD or ADHD are collected from the EMERGE trial database and/or medical records. Maternal disorders of glucose metabolism are evaluated using a 75-g oral glucose tolerance test (OGTT) and haemoglobin A1c (HbA1c). Cutoffs for diabetes, impaired fasting glucose and impaired glucose tolerance are defined according to ADA criteria (23). Other laboratory tests include maternal fasting lipids (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides (TG)), fasting insulin, fasting c-peptide, urea, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), c-reactive protein (CRP) and uric acid. 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/m 2 . Maternal BMI is categorized according to World Health Organization (WHO) standards: underweight, 30 kg/m 2 . For mothers, waist circumference is taken using a tape measure half-way 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 diabetes; high density lipoprotein (HDL) cholesterol of 1.7 mmol/L or drug treatment for elevated triglycerides; 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. 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. 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, body measurements and questionnaire responses are collected by the study investigators, research nurse, or clinical research associate, all of whom have received standardized training in the study procedures. 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 The target sample size includes 321 participants pairs, representing a realistic estimate of the number of mother-child pairs expected to return for further assessment as detailed in this study. This projection is based on a follow-up rate of approximately 60%, in line with other studies of similar sized populations. The original EMERGE RCT enrolled a total of 535 pregnancies in 510 women. For women who participated on more than one occasion in EMERGE, only the first pregnancy will be included. 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. 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 enrolment 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. 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, the study team offers flexible scheduling options and reminder communications. Participants are contacted in advance to confirm availability 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 future biomarker and molecular analyses. These include assays for glycated CD59, and extracellular vesicle signatures. These samples are frozen and stored in the CRF, University of Galway. Samples are processed and stored at the laboratory in Galway University Hospital using temperature-controlled systems. All samples are labelled 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 glycaemic status and cardiovascular risk factors, adjusting for relevant confounders. 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. The health economic evaluation will be conducted by the Health Economic and Policy Analysis (HEPA) group at the University of Galway. 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 Requests for access to the full protocol, de-identified participant-level dataset, and statistical code will be considered on reasonable request, subject to approval by the study sponsor, chief investigator, and relevant ethical oversight committees. Data sharing will adhere to 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 policy makers. No publication restrictions apply. Professional writers will not be employed in the writing of results. DISCUSSION The EMERGE Mothers and Kids (EMK) study represents one of the most comprehensive long-term follow-up investigations of a randomized trial of metformin in GDM. 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. 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. 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 two years, but subtle shifts in fat distribution were noted, including increased subcutaneous fat in the upper limbs and trunk, potentially reflecting a more favourable fat partitioning (24). 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 (18), 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 two years and similar IQ scores during childhood between metformin- and insulin-exposed offspring (25–27). 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 (28) and up to 10 years of age (29). Additional studies noted increased fasting glucose and systolic blood pressure (30), as well as higher weight and BMI at one year (31). 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 (32). Whether this reflects equilibrium between compartments or selective accumulation in fetal tissues remain 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 (20). Additionally, alterations in mitochondrial bioenergetics, folate-mediated one-carbon metabolism, and the fetal epigenetic landscape have been documented, particularly in hepatic and adipose tissues (20). 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 (21). 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. Trial Status This protocol corresponds to Version 3.0, 03 May 2024. Recruitment for the EMERGE Mothers and Kids follow-up study began in June 2024 and is expected to continue until May 2026. List of 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; 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; 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; LDL, Low-Density Lipoprotein; 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; SF-12, 12-Item Short Form Survey; SRS 2, Social Responsiveness Scale-2; TG, Triglycerides; T2DM, Type 2 Diabetes Mellitus; WHO, World Health Organization. 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 enrolment 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. Availability of data and materials We plan to grant public access to the full protocol; requests for access to the full protocol, de-identified participant-level data, and statistical code will be considered upon reasonable request and subject to approval by the study steering committee and ethical committee. Competing interests The authors declare no competing interests. The study received funding from the Merck Healthcare KGaA, Darmstadt, Germany, which had no involvement in the design, analysis, or reporting of the study. Funding The study is sponsored by the University of Galway. Funding was provided by Merck Healthcare KGaA, Darmstadt, Germany. Authors’ contributions FD, AE, AS, DD, 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. Acknowledgements We wish to acknowledge all the participants in the EMERGE study and the staff at the Clinical Research Facility in University of Galway. References World Health Organization. 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Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus Insulin for the Treatment of Gestational Diabetes. N Engl J Med. 2008;8(19):2003–15. Dunne F, Newman C, Alvarez-Iglesias A, Ferguson J, Smyth A, Browne M, et al. Early Metformin in Gestational Diabetes. JAMA. 2023;330(16):1547. Rowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7–9 years of age. BMJ Open Diabetes Res Care. 2018;6(1):e000456. Tarry-Adkins JL, Aiken CE, Ozanne SE. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis. PLoS Med. 2019;16(8):e1002848. McEvoy RP, Newman C, Egan AM, Dunne FP. A narrative review of metformin in pregnancy: Navigating benefit and uncertainty. Diabetes Obes Metab. 2025;27(S3):16–30. Salomäki H, Vähätalo LH, Laurila K, Jäppinen NT, Penttinen AM, Ailanen L, et al. Prenatal Metformin Exposure in Mice Programs the Metabolic Phenotype of the Offspring during a High Fat Diet at Adulthood. PLoS ONE. 2013;8(2):e56594. Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346(jan08 15):e7586–7586. ElSayed NA, Aleppo G, Bannuru RR, et al. 15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47:S282–94. Rowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU). Diabetes Care. 2011;34(10):2279–84. Deussen AR, Louise J, Dodd JM. Childhood follow-up of the GRoW randomized trial: Metformin in addition to dietary and lifestyle advice for pregnant women with overweight or obesity. Pediatr Obes. 2023;18(1). Wouldes TA, Battin M, Coat S, Rush EC, Hague WM, Rowan JA. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Arch Dis Child Fetal Neonatal Ed. 2016;101(6):F488–93. Greger HK, Hanem LGE, Østgård HF, Vanky E. Cognitive function in metformin exposed children, born to mothers with PCOS – follow-up of an RCT. BMC Pediatr. 2020;20(1):60. Hanem LGE, Stridsklev S, Júlíusson PB, Salvesen Ø, Roelants M, Carlsen SM, et al. Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs. J Clin Endocrinol Metab. 2018;103(4):1612–21. Hanem LGE, Salvesen Ø, Juliusson PB, Carlsen SM, Nossum MCF, Vaage MØ, et al. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5–10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc Health. 2019;3(3):166–74. Rø TB, Ludvigsen HV, Carlsen SM, Vanky E. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest. 2012;72(7):570–5. Carlsen SM, Martinussen MP, Vanky E. Metformin’s Effect on First-Year Weight Gain: A Follow-up Study. Pediatrics. 2012;130(5):e1222–6. Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83(5):1575–8. Supplementary Files SPIRITchecklistCN.docx Cite Share Download PDF Status: Published Journal Publication published 20 Apr, 2026 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 12 Feb, 2026 Reviewers agreed at journal 15 Jan, 2026 Reviewers invited by journal 15 Jan, 2026 Editor assigned by journal 07 Oct, 2025 First submitted to journal 23 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7632300","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":575357746,"identity":"b6821c62-97d0-4b6b-a6fb-3c353abf5a37","order_by":0,"name":"Roberta Scairati","email":"","orcid":"","institution":"Health Research Board Clinical Research Facility Galway: HRB Clinical Research Facility","correspondingAuthor":false,"prefix":"","firstName":"Roberta","middleName":"","lastName":"Scairati","suffix":""},{"id":575357747,"identity":"b3bc5852-5804-42e9-be06-bd96b2978cb3","order_by":1,"name":"Christine 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1","display":"","copyAsset":false,"role":"figure","size":104208,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSPIRIT participant timeline\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7632300/v1/34b6f3881894c59d46ed9b1d.jpg"},{"id":107928451,"identity":"9d0ffd19-a13f-41e5-82f3-ae075e1b3574","added_by":"auto","created_at":"2026-04-27 16:10:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":335032,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7632300/v1/5c6b107c-12ed-4b37-8bcb-8aeee0356031.pdf"},{"id":100697989,"identity":"718a7d98-7ad7-495e-b917-064b9efee790","added_by":"auto","created_at":"2026-01-20 15:19:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":39354,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklistCN.docx","url":"https://assets-eu.researchsquare.com/files/rs-7632300/v1/c4e604ee742696d12243e3a6.docx"}],"financialInterests":"","formattedTitle":"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","fulltext":[{"header":"ADMINISTRATIVE INFORMATION","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"631\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTitle\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eEMERGE 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)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrial Registration\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eEMERGE RCT: NCT06327191, registered 21/11/2023\u003c/p\u003e\n \u003cp\u003ehttps://clinicaltrials.gov/study/NCT06327191?cond=gestational%20diabetes\u0026amp;term=emerge\u0026amp;rank=1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eProtocol Version\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eEMERGE Mothers and Kids protocol version 4.0 (3\u003csup\u003erd\u003c/sup\u003e May 2024) is currently in use\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eFD, AE, AS, DD, 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 provided oversight on planned biochemical analysis. All authors revised the manuscript. All authors approved the final version of the manuscript and are accountable for the integrity of the work.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 243px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRole of sponsor and funder\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 387px;\"\u003e\n \u003cp\u003eThe sponsor (University of Galway, phone 0035391 524411) and funder (Merck Healthcare KGaA, Darmstadt, Germany) had no role in the study design, collection, management, analysis, and interpretation of data, writing of the report, or the decision to submit the manuscript for publication.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"BACKGROUND","content":"\u003cp\u003eGestational diabetes mellitus (GDM) is a common metabolic disorder defined by glucose intolerance that develops during pregnancy in women without pre-existing diabetes (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Worldwide, an estimated 19.7% of women in 2024 were affected by hyperglycaemia during pregnancy, with 79.2% of cases attributed to GDM (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Consistent with global estimates, GDM affects approximately 12.4% of pregnancies in Ireland (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). However, these estimates vary depending on screening practices and diagnostic criteria used (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). 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 caesarean 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 (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Typically, the glucose intolerance abates after delivery, while the metabolic imprint of GDM persists (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Long-term follow-up studies suggest that up to 60% of affected women develop type 2 diabetes mellitus (T2DM) later in life (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). GDM is also associated with increased risks of hypertension (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), dyslipidemia (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), coronary artery calcification (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and chronic kidney disease (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Similarly, offspring exposed to GDM in utero are more likely to develop adiposity (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), glucose intolerance (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), hypertension (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), and neurocognitive disorders (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) when followed up during childhood and adolescence.\u003c/p\u003e \u003cp\u003eMetformin 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 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). 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 for the offspring remains uncertain. Follow-up studies comparing in utero exposure to metformin versus insulin have reported conflicting outcomes, ranging from similar childhood adiposity and metabolic profiles (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) to evidence of lower birthweight with postnatal catch-up growth and increased body mass index (BMI) in mid-childhood (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Preclinical models support a role for metformin in fetal metabolic programming through AMPK activation, placental mTOR inhibition, and epigenetic remodeling of key developmental pathways (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). 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 \u0026amp; Kids (EMK).\u003c/p\u003e \u003cp\u003eThe EMERGE Randomized Controlled Trial (RCT) took place between 2017\u0026ndash;2022 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). 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 primary outcome (fasting glucose\u0026thinsp;\u0026gt;\u0026thinsp;5.1mmol/L at gestational weeks 32 or 38 or insulin initiation) was not significantly different between the two groups. 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 (\u0026gt;\u0026thinsp;4kg) and large for gestational age (LGA). Regarding neonatal anthropometrics, the only difference between groups was a statistically significant difference of \u0026minus;\u0026thinsp;0.7 cm in crown-heel length between the metformin group and the placebo group, the clinical significance of which is unclear.\u003c/p\u003e \u003cp\u003eEMERGE Mothers \u0026amp; 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 for is currently underway.\u003c/p\u003e"},{"header":"OBJECTIVES","content":"\u003cp\u003eThe primary objective of the EMERGE Mother 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 e) alterations in lipid profiles.\u003c/p\u003e \u003cp\u003eThe 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 body mass index (BMI), anthropometric parameters and skinfold thickness.\u003c/p\u003e \u003cp\u003eThe 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; (f) self-reported economic burden of GDM care and treatment.\u003c/p\u003e \u003cp\u003eThe 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.\u003c/p\u003e \u003cp\u003eExploratory 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.\u003c/p\u003e \u003cp\u003eThis protocol was written in adherence with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Guidelines 2013 (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSTUDY DESIGN\u003c/h2\u003e \u003cp\u003eThe EMERGE Mother and Kids study is a cohort study of women and their offspring who participated in the EMERGE RCT, a phase III, randomized, double-blind, placebo-controlled trial.\u003c/p\u003e \u003c/div\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will take place at the Clinical Research Facility, Galway University Hospital and University of Galway.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria include women and their children who participated in the EMERGE trial and gave permission for consent to follow-up. Exclusion criteria include participants who did not provide consent for further follow up studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA copy of the consent form is attached as Additional file 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo intervention is administered as part of the follow-up study. This study is a non-interventional observational follow-up, and no new treatment or comparator arms are introduced. 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 hours prior to site visit. Where applicable, the decision to stop insulin is made on a case-by-case basis by the investigator.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary maternal outcomes:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDiagnosis of T2DM or pre-diabetes\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eOccurrence of metabolic syndrome\u003c/li\u003e\n \u003cli\u003eOverweight or obesity status\u003c/li\u003e\n \u003cli\u003ePresence of hypertension\u003c/li\u003e\n \u003cli\u003eAssociations between GDM diagnosis, sum of fasting, 1-hour, and 2-hour glucose z-scores after 75-g load, insulin sensitivity, and lipid levels at 24–32 weeks’ gestation with lipid levels 3-6 years postpartum.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary child outcome:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePresence of overweight or obesity\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary maternal outcomes:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eBreastfeeding duration beyond 12 weeks postpartum\u003c/li\u003e\n \u003cli\u003eMental health status (assessed via Edinburgh Postnatal Depression Scale, EPDS)\u003c/li\u003e\n \u003cli\u003eQuality of life status (assessed via SF-12 questionnaire)\u003c/li\u003e\n \u003cli\u003eDietary intake (assessed via Food Frequency Questionnaire (FFQ))\u003c/li\u003e\n \u003cli\u003ePhysical activity (assessed via 7-point validated questionnaire)\u003c/li\u003e\n \u003cli\u003eSelf-reported economic burden and healthcare utilisation\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary child outcomes:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eNeurodevelopmental status, including 1) ASD assessed via Social Responsiveness Scale-2 (SRS 2) questionnaire (kids \u0026gt;2.5 years), and Quantitative Checklist for Autism in Toddlers (Q-chat) questionnaire (kids \u0026lt;2.5 years); 2) ADHD assessed via ADHD-5 questionnaire (kids \u0026gt;5 years) and ADHD-IV questionnaire (kids \u0026lt;5 years)\u003c/li\u003e\n \u003cli\u003eExecutive function (assessed via the Behaviour Rating Inventory of Executive Function, BRIEF-2 questionnaire)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eHealth Economic Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 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. Incremental cost-effectiveness ratios (ICERs) will be calculated and sensitivity analyses performed in line with Health Information and Quality Authority (HIQA) guidance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecruitment for the EMERGE Mothers and Kids follow-up study commenced in June 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 figure 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy procedures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are collected during the scheduled follow-up visit. Following informed consent, a detailed review of maternal and child medical history is performed. 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 hypoglycaemia, birth trauma, brain injury, severe illness, and diagnoses (or assessments) of ASD or ADHD are collected from the EMERGE trial database and/or medical records. Maternal disorders of glucose metabolism are evaluated using a 75-g oral glucose tolerance test (OGTT) and haemoglobin A1c (HbA1c). Cutoffs for diabetes, impaired fasting glucose and impaired glucose tolerance are defined according to ADA criteria (23). Other laboratory tests include maternal fasting lipids (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides (TG)), fasting insulin, fasting c-peptide, urea, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), c-reactive protein (CRP) and uric acid. 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/m\u003csup\u003e2\u003c/sup\u003e. Maternal BMI is categorized according to World Health Organization (WHO) standards: underweight, \u0026lt;18.5 kg/m\u003csup\u003e2\u003c/sup\u003e; normal, 18.5–24.9 kg/m\u003csup\u003e2\u003c/sup\u003e; overweight, 25–29.9 kg/m\u003csup\u003e2\u003c/sup\u003e; obese, \u0026gt;30 kg/m\u003csup\u003e2\u003c/sup\u003e. For mothers, waist circumference is taken using a tape measure half-way 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 \u0026gt;5.6 mmol/L or diagnosed diabetes; high density lipoprotein (HDL) cholesterol of \u0026lt;1.29 mmol/L or drug treatment for low HDL cholesterol; triglyceride level of \u0026gt;1.7 mmol/L or drug treatment for elevated triglycerides; waist circumference of \u0026gt;80 cm (given the predominantly Caucasian cohort); or hypertension with a blood pressure of \u0026gt;130/85 mmHg or drug treatment for hypertension. 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the site visit, maternal participants also complete questionnaires regarding their health and the health of their child (listed in Appendix A). All blood samples, body measurements and questionnaire responses are collected by the study investigators, research nurse, or clinical research associate, all of whom have received standardized training in the study procedures. 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe target sample size includes 321 participants pairs, representing a realistic estimate of the number of mother-child pairs expected to return for further assessment as detailed in this study. This projection is based on a follow-up rate of approximately 60%, in line with other studies of similar sized populations. The original EMERGE RCT enrolled a total of 535 pregnancies in 510 women. For women who participated on more than one occasion in EMERGE, only the first pregnancy will be included.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePlans for assessment and collection of outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData 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 enrolment 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. 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePlans to promote participant \u0026nbsp;and complete follow-up\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo maximize follow-up rates, the study team offers flexible scheduling options and reminder communications. Participants are contacted in advance to confirm availability 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipant 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMaternal blood samples are collected at the follow-up visit for current laboratory evaluation and future biomarker and molecular analyses. These include assays for glycated CD59, and extracellular vesicle signatures. These samples are frozen and stored in the CRF, University of Galway. Samples are processed and stored at the laboratory in Galway University Hospital using temperature-controlled systems. All samples are labelled with study-specific participant IDs to ensure traceability and confidentiality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSTATISTICAL METHODS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical 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 glycaemic status and cardiovascular risk factors, adjusting for relevant confounders. Results will be reported as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). The significance level will be set at 0.05.\u003c/p\u003e\n\u003cp\u003eFor 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. The health economic evaluation will be conducted by the Health Economic and Policy Analysis (HEPA) group at the University of Galway.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo interim analyses are planned for this follow-up study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant-level dataset, and statistical code\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRequests for access to the full protocol, de-identified participant-level dataset, and statistical code will be considered on reasonable request, subject to approval by the study sponsor, chief investigator, and relevant ethical oversight committees. Data sharing will adhere to GDPR and institutional data protection policies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComposition of the data monitoring committee, its role and reporting structure\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAdverse event reporting and harms\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFrequency and plans for auditing trial conduct\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrial monitoring visits are carried out according to the trial monitoring plan and are independent from the trial investigators.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePlans for communicating important protocol amendments to relevant parties\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDissemination plans\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy 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 policy makers. No publication restrictions apply. Professional writers will not be employed in the writing of results.\u0026nbsp;\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe EMERGE Mothers and Kids (EMK) study represents one of the most comprehensive long-term follow-up investigations of a randomized trial of metformin in GDM. 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. Conducting longitudinal research presents practical challenges, including participant retention, biological sampling in mothers, and scheduling dual mother\u0026ndash;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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical and preclinical evidence on the long-term effects of metformin in GDM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite 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 two years, but subtle shifts in fat distribution were noted, including increased subcutaneous fat in the upper limbs and trunk, potentially reflecting a more favourable fat partitioning (24).\u003c/p\u003e\n\u003cp\u003eIn 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 (18), 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 two years and similar IQ scores during childhood between metformin- and insulin-exposed offspring (25\u0026ndash;27). 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 (28) and up to 10 years of age (29). Additional studies noted increased fasting glucose and systolic blood pressure (30), as well as higher weight and BMI at one year (31). Although these studies suggest potential sex- and phenotype-specific susceptibilities, interpretation is limited by small sample sizes, heterogeneous populations, and confounding by indication.\u003c/p\u003e\n\u003cp\u003eFrom a mechanistic standpoint, metformin has been shown to cross the placenta and reach the fetal circulation at concentrations comparable to maternal levels (32). Whether this reflects equilibrium between compartments or selective accumulation in fetal tissues remain unclear and deserves further investigation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExperimental 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 (20). Additionally, alterations in mitochondrial bioenergetics, folate-mediated one-carbon metabolism, and the fetal epigenetic landscape have been documented, particularly in hepatic and adipose tissues (20). 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 (21). 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.\u003c/p\u003e"},{"header":"Trial Status","content":"\u003cp\u003eThis protocol corresponds to Version 3.0, 03 May 2024. Recruitment for the EMERGE Mothers and Kids follow-up study began in June 2024 and is expected to continue until May 2026.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eADHD, 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; 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; 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; LDL, Low-Density Lipoprotein; 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; SF-12, 12-Item Short Form Survey; SRS 2, Social Responsiveness Scale-2; TG, Triglycerides; T2DM, Type 2 Diabetes Mellitus; WHO, World Health Organization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study received ethical approval from the Galway Clinical Research Ethics Committee. Written informed consent was obtained at the time of original enrolment and reaffirmed at the follow-up visit (reference number CA 3024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript does not contain any individual person\u0026rsquo;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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe plan to grant public access to the full protocol; requests for access to the full protocol, de-identified participant-level data, and statistical code will be considered upon reasonable request and subject to approval by the study steering committee and ethical committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests. The study received funding from the Merck Healthcare KGaA, Darmstadt, Germany, which had no involvement in the design, analysis, or reporting of the study.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is sponsored by the University of Galway. Funding was provided by Merck Healthcare KGaA, Darmstadt, Germany.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFD, AE, AS, DD, 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe wish to acknowledge all the participants in the EMERGE study and the staff at the Clinical Research Facility in University of Galway.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World Health Organization guide- line. 2013 [Available from:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://apps.who.int/iris/bitstream/handle/10665/85975/WHO_NMH_MND_13.2_eng.pdf;jsessionid=9FCF790BB60B3564DE5C0CDEC58E3E86?sequence=1\u003c/span\u003e\u003cspan address=\"https://apps.who.int/iris/bitstream/handle/10665/85975/WHO_NMH_MND_13.2_eng.pdf;jsessionid=9FCF790BB60B3564DE5C0CDEC58E3E86?sequence=1\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e].\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInternational Diabetes Federation. IDF Diabetes Atlas. 11th ed. Brussels, Belgium: International Diabetes Federation. 2025. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://diabetesatlas.org\u003c/span\u003e\u003cspan address=\"https://diabetesatlas.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Sullivan EP, Avalos G, O\u0026rsquo;Reilly M, Dennedy MC, Gaffney G, Dunne F. Atlantic Diabetes in Pregnancy (DIP): the prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia. 2011;54(7):1670\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogdanet D, O\u0026rsquo;Shea P, Lyons C, Shafat A, Dunne F. The Oral Glucose Tolerance Test\u0026mdash;Is It Time for a Change?\u0026mdash;A Literature Review with an Emphasis on Pregnancy. J Clin Med. 2020;9(11):3451.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMetzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991\u0026ndash;2002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcIntyre HD, Catalano P, Zhang C, Desoye G, Mathiesen ER, Damm P. Gestational diabetes mellitus. Nat Rev Dis Primers. 2019;5(1):47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNoctor E. Type 2 diabetes after gestational diabetes: The influence of changing diagnostic criteria. World J Diabetes. 2015;6(2):234.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTobias DK, Hu FB, Forman JP, Chavarro J, Zhang C. Increased Risk of Hypertension After Gestational Diabetes Mellitus. Diabetes Care. 2011;34(7):1582\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChodick G, Tenne Y, Barer Y, Shalev V, Elchalal U. Gestational diabetes and long-term risk for dyslipidemia: a population-based historical cohort study. BMJ Open Diabetes Res Care. 2020;8(1):e000870.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGunderson EP, Sun B, Catov JM, Carnethon M, Lewis CE, Allen NB, et al. Gestational Diabetes History and Glucose Tolerance After Pregnancy Associated With Coronary Artery Calcium in Women During Midlife. Circulation. 2021;143(10):974\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeharier O, Shoham-Vardi I, Pariente G, Sergienko R, Kessous R, Baumfeld Y, et al. Gestational Diabetes Mellitus Is a Significant Risk Factor for Long-Term Maternal Renal Disease. J Clin Endocrinol Metab. 2015;100(4):1412\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLowe WL, Lowe LP, Kuang A, Catalano PM, Nodzenski M, Talbot O, et al. Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study. Diabetologia. 2019;62(4):598\u0026ndash;610.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScholtens DM, Kuang A, Lowe LP, Hamilton J, Lawrence JM, Lebenthal Y, et al. Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal Glycemia and Childhood Glucose Metabolism. Diabetes Care. 2019;42(3):381\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTam WH, Ma RCW, Ozaki R, Li AM, Chan MHM, Yuen LY, et al. In Utero Exposure to Maternal Hyperglycemia Increases Childhood Cardiometabolic Risk in Offspring. Diabetes Care. 2017;40(5):679\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiang AH, Wang X, Martinez MP, Walthall JC, Curry ES, Page K, et al. Association of Maternal Diabetes With Autism in Offspring. JAMA. 2015;313(14):1425.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus Insulin for the Treatment of Gestational Diabetes. N Engl J Med. 2008;8(19):2003\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDunne F, Newman C, Alvarez-Iglesias A, Ferguson J, Smyth A, Browne M, et al. Early Metformin in Gestational Diabetes. JAMA. 2023;330(16):1547.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRowan JA, Rush EC, Plank LD, Lu J, Obolonkin V, Coat S, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7\u0026ndash;9 years of age. BMJ Open Diabetes Res Care. 2018;6(1):e000456.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTarry-Adkins JL, Aiken CE, Ozanne SE. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis. PLoS Med. 2019;16(8):e1002848.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcEvoy RP, Newman C, Egan AM, Dunne FP. A narrative review of metformin in pregnancy: Navigating benefit and uncertainty. Diabetes Obes Metab. 2025;27(S3):16\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalom\u0026auml;ki H, V\u0026auml;h\u0026auml;talo LH, Laurila K, J\u0026auml;ppinen NT, Penttinen AM, Ailanen L, et al. Prenatal Metformin Exposure in Mice Programs the Metabolic Phenotype of the Offspring during a High Fat Diet at Adulthood. PLoS ONE. 2013;8(2):e56594.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346(jan08 15):e7586\u0026ndash;7586.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElSayed NA, Aleppo G, Bannuru RR, et al. 15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes\u0026mdash;2024. Diabetes Care. 2024;47:S282\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRowan JA, Rush EC, Obolonkin V, Battin M, Wouldes T, Hague WM. Metformin in Gestational Diabetes: The Offspring Follow-Up (MiG TOFU). Diabetes Care. 2011;34(10):2279\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeussen AR, Louise J, Dodd JM. Childhood follow-up of the GRoW randomized trial: Metformin in addition to dietary and lifestyle advice for pregnant women with overweight or obesity. Pediatr Obes. 2023;18(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWouldes TA, Battin M, Coat S, Rush EC, Hague WM, Rowan JA. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes. Arch Dis Child Fetal Neonatal Ed. 2016;101(6):F488\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreger HK, Hanem LGE, \u0026Oslash;stg\u0026aring;rd HF, Vanky E. Cognitive function in metformin exposed children, born to mothers with PCOS \u0026ndash; follow-up of an RCT. BMC Pediatr. 2020;20(1):60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanem LGE, Stridsklev S, J\u0026uacute;l\u0026iacute;usson PB, Salvesen \u0026Oslash;, Roelants M, Carlsen SM, et al. Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs. J Clin Endocrinol Metab. 2018;103(4):1612\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHanem LGE, Salvesen \u0026Oslash;, Juliusson PB, Carlsen SM, Nossum MCF, Vaage M\u0026Oslash;, et al. Intrauterine metformin exposure and offspring cardiometabolic risk factors (PedMet study): a 5\u0026ndash;10 year follow-up of the PregMet randomised controlled trial. Lancet Child Adolesc Health. 2019;3(3):166\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026oslash; TB, Ludvigsen HV, Carlsen SM, Vanky E. Growth, body composition and metabolic profile of 8-year-old children exposed to metformin in utero. Scand J Clin Lab Invest. 2012;72(7):570\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarlsen SM, Martinussen MP, Vanky E. Metformin\u0026rsquo;s Effect on First-Year Weight Gain: A Follow-up Study. Pediatrics. 2012;130(5):e1222\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005;83(5):1575\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gestational diabetes mellitus, Metformin, Pregnancy, Long-term follow-up, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-7632300/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7632300/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePregnancies 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 glycaemic control and perinatal outcomes. The EMERGE Mothers and Kids study is a longitudinal follow-up of the EMERGE trial participants, designed to investigate the long-term metabolic, cardiovascular, and neurodevelopmental outcomes in mothers and their offspring.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a prospective, observational cohort study of participants and their children from the EMERGE trial (NCT06327191). 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.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study aims to provide insights into the long-term safety and efficacy of metformin use during pregnancy and its potential impact on the long term maternal and child health outcomes, contributing to evidence-based management of GDM.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov; Identifier: NCT06327191\u003c/p\u003e","manuscriptTitle":"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","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-20 12:42:57","doi":"10.21203/rs.3.rs-7632300/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2026-02-12T20:52:57+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-01-16T04:54:52+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-16T04:30:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-07T09:37:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-09-23T10:41:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9582a429-ff66-4953-b556-b6454f25b91d","owner":[],"postedDate":"January 20th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T16:07:34+00:00","versionOfRecord":{"articleIdentity":"rs-7632300","link":"https://doi.org/10.1186/s13063-026-09703-6","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-04-20 15:57:53","publishedOnDateReadable":"April 20th, 2026"},"versionCreatedAt":"2026-01-20 12:42:57","video":"","vorDoi":"10.1186/s13063-026-09703-6","vorDoiUrl":"https://doi.org/10.1186/s13063-026-09703-6","workflowStages":[]},"version":"v1","identity":"rs-7632300","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7632300","identity":"rs-7632300","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}