Life-course management of gestational diabetes mellitus: A narrative review

Abstract

BACKGROUND

Gestational diabetes mellitus (GDM) has emerged as a global public health challenge, fueled by increasing maternal age, rising obesity rates, and lifestyle shifts. It is linked to substantial short- and long-term health risks for both mothers and their offspring, offering a critical opportunity for intergenerational prevention of metabolic disorders.

AIM

To synthesize current evidence on the pathophysiology, diagnosis, management, complications, and individualized treatment strategies of GDM.

METHODS

We conducted a narrative review in accordance with PRISMA guidelines. PubMed, Scopus, Web of Science, and EMBASE were searched for English-language articles (2017-2025) using terms such as “GDM”, “pregnancy”, “insulin resistance”, and “maternal outcomes”. After removing duplicates, 512 records were screened; 102 full texts were assessed for eligibility, and 55 studies were included based on methodological quality, clinical relevance, and alignment with the review objectives.

RESULTS

GDM results from a complex interplay among progressive insulin resistance, β-cell dysfunction, immune dysregulation, and placental inflammation. Emerging evidence indicates that hyperglycemia before formal diagnosis can impair fetal programming via epigenetic mechanisms. GDM increases a mother’s risk of developing type 2 diabetes mellitus seven- to tenfold and raises the incidence of cardiovascular disease, preeclampsia, and cesarean delivery. Offspring are at higher risk of macrosomia, neonatal hypoglycemia, and future metabolic and cardiovascular disorders. Lifestyle modification remains the cornerstone of therapy and, when necessary, can be supplemented with pharmacologic agents such as metformin or insulin. Postpartum follow-up, breastfeeding support, and preconception counseling are vital to long-term metabolic health.

CONCLUSION

GDM requires precision-based, life-course care. Future priorities include early risk detection, biomarker validation, unified diagnosis, and culturally sensitive interventions to improve maternal-child outcomes.

Key Words: Gestational diabetes mellitus; Insulin resistance; Pregnancy; Fetal programming; Type 2 diabetes mellitus; Precision medicine; Epigenetics; Postpartum follow-up; Life-course management; Public health

Core Tip: This narrative review explores the latest evidence on gestational diabetes mellitus (GDM), emphasizing its pathophysiology, clinical management, and long-term cardiometabolic consequences. It highlights the role of early hyperglycemia, epigenetic fetal programming, and GDM heterogeneity. The review advocates for precision medicine, life-course management, and context-sensitive postpartum care. It also outlines structural barriers to follow-up in low-resource settings and provides a roadmap for individualized prevention strategies aimed at interrupting intergenerational disease transmission.

INTRODUCTION

Gestational diabetes mellitus (GDM) is currently the most common metabolic disorder of pregnancy. It affects approximately 14%-25% of pregnancies worldwide, amounting for more than 18 million births each year[1-3]. The rising incidence of GDM parallels global trends in maternal obesity, sedentary lifestyles, and delayed childbearing[4-6].

Clinically, GDM is associated with a broad spectrum of adverse perinatal outcomes, including preeclampsia, cesarean section, macrosomia, neonatal hypoglycemia, and respiratory distress syndrome[7-9]. In the long term, GDM contributes to increased risks of type 2 diabetes mellitus (T2DM) and cardiovascular disease in mothers, as well as obesity and metabolic syndrome in their offspring[10-12].

Over the past two decades, the prevalence of GDM has risen substantially—from under 5% in some high-income countries to over 25% in certain regions of Asia and the Middle East—driven by changing diagnostic criteria and shifting population risk profiles[13,14]. Adoption of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria—endorsed by the World Health Organization (WHO) and the American Diabetes Association (ADA)—has increased reported GDM diagnoses by up to 75% in some regions[15]. However, this expansion has sparked debate over potential overdiagnosis, particularly when applied in early pregnancy without robust clinical trial validation[16,17].

Despite broad international endorsement of these criteria, substantial variability persists in screening practices, diagnostic thresholds, and timing across countries, hindering efforts toward standardized global management[18,19]. Moreover, GDM is increasingly recognized as a heterogeneous, temporally dynamic disorder rather than a single disease entity. Emerging classification models that consider variations in insulin sensitivity, β-cell function, genetic predisposition, and gestational timing may facilitate more precise, tailored interventions[20,21]. However, most current clinical guidelines continue to rely on uniform diagnostic cutoffs and standardized treatment protocols.

This narrative review synthesizes the latest advances across seven key domains: Pathophysiology, epidemiology, diagnostic methodologies, clinical management, maternal-fetal outcomes, molecular insights, and public health perspectives. By integrating recent scientific developments and addressing ongoing controversies, we aim to support a shift toward risk-stratified, individualized care for GDM.

MATERIALS AND METHODS

This narrative review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to ensure methodological transparency and rigor. A comprehensive literature search was performed across four major databases—PubMed, EMBASE, Web of Science, and Scopus—to identify peer-reviewed articles published between January 2017 and March 2025. The search strategy combined Medical Subject Headings and free-text terms, including: “gestational diabetes mellitus”, “GDM”, “pregnancy”, “hyperglycemia”, “insulin resistance”, “epigenetics”, and “maternal outcomes”.

All references were imported into EndNote for deduplication and screening. After removing 130 duplicate records, 512 unique articles remained and were screened by title and abstract. Full-text review was conducted for 102 studies that met the preliminary inclusion criteria. Of these, 47 articles were excluded due to methodological limitations, insufficient relevance, or incomplete outcome data. A total of 55 studies were ultimately included in the qualitative synthesis based on scientific quality, clinical significance, and relevance to the review objectives.

Although this review was informed by PRISMA principles to improve methodological transparency and reporting quality, it does not constitute a systematic review. No meta-analysis was conducted, and the review protocol was not registered in PROSPERO or any other database. The primary objective was to provide a comprehensive narrative synthesis of current evidence, rather than a quantitative aggregation or statistical evaluation. The full study selection process is presented in Figure 1.

Figure 1 PRISMA flow diagram outlining the study selection process. A total of 642 records were identified through database searching. After removal of 130 duplicates, 512 records underwent title and abstract screening. Of these, 102 full-text articles were assessed for eligibility, resulting in 55 studies included in the final qualitative synthesis.

RESULTS

Pathophysiology of GDM

Hormone-induced insulin resistance: GDM develops when the physiological insulin resistance of pregnancy exceeds the compensatory capacity of maternal pancreatic β-cells, resulting in hyperglycemia[21,22]. Normally, placental hormones—including human placental lactogen, estrogen, progesterone, and placental growth hormone—induce insulin resistance to redirect maternal nutrients toward fetal growth[23,24]. In GDM, this adaptation becomes maladaptive. Insulin sensitivity can decline by up to 80%, particularly in overweight or obese women, whose preexisting insulin resistance and impaired β-cell function exacerbate metabolic dysregulation[1,4].

Adipose tissue dysfunction and inflammatory mediators: Dysfunctional adipose tissue plays a pivotal role in GDM pathogenesis. Adipocyte hypertrophy and immune cell infiltration foster chronic low-grade inflammation, characterized by elevated levels of TNF-α, interleukin-6 (IL-6), and C-reactive protein (CRP). These inflammatory cytokines impair insulin signaling through serine phosphorylation of insulin receptor substrate-1 (IRS-1) and suppression of GLUT4 expression[25-27]. At the placental level, inflammation disrupts trophoblast invasion, alters nutrient transport, and contributes to fetal overgrowth and macrosomia[9,28].

Adipokine imbalance: GDM is characterized by disrupted adipokine secretion, with elevated leptin concentrations and reduced adiponectin levels. This imbalance decreases insulin sensitivity, impairs β-cell function, and aggravates placental dysfunction, thereby exacerbating hyperglycemia[1,26].

β-cell dysfunction and failure of compensation: Central to GDM is β-cell dysfunction, including impaired insulin secretion, lipotoxicity-induced apoptosis, and failure of β-cell mass expansion. Unlike physiological pregnancy, where β-cell proliferation meets increased metabolic demands, women with GDM demonstrate inadequate functional adaptation[29,30].

Genetic and epigenetic susceptibility: Genetic studies have identified both T2DM-shared (e.g., GCK, CDKAL1, and HNF1A) and GDM-specific variants associated with placental function and neuroendocrine regulation[31]. Epigenetic modifications—including altered DNA methylation of leptin, SLC6A4, ADIPOQ, and GLUT1/3 in fetal tissues—suggest a mechanism for intergenerational transmission of metabolic risk[32].

Metabolomic and lipid dysregulation: Metabolomic profiling in GDM has revealed elevated levels of branched-chain amino acids and triglycerides, which contribute to insulin resistance and fetal overgrowth independently of maternal body mass index (BMI)[7,9]. These signatures may serve as biomarkers for GDM subtypes and predictors of adverse outcomes.

Oxidative stress and cellular injury: Oxidative stress is a hallmark of GDM pathophysiology. Hyperglycemia, elevated free fatty acids, and advanced glycation end products activate inflammatory pathways via Toll-like receptor signaling and NF-κB activation. This leads to reactive oxygen species generation, causing β-cell and endothelial damage[33]. GDM placentas exhibit diminished antioxidant defenses and increased vulnerability to oxidative injury, impairing angiogenesis and exacerbating fetal complications[26,34].

Immune dysregulation: Recent research implicates immune dysregulation in GDM, including shifts in regulatory T cell (Treg)/Th17 balance, polarization of macrophages toward a proinflammatory M1 phenotype, and abnormal galectin expression in maternal serum and placental tissue. These findings highlight a complex interplay among immune, endocrine, and metabolic systems in GDM pathogenesis[26,28].

Summary: The pathophysiology of GDM involves a multifaceted network of hormonal, inflammatory, metabolic, and immunologic disruptions. Figure 2 presents an integrative schematic summarizing these mechanisms, including placental hormone influence, adipose-derived inflammation, oxidative stress, and epigenetic modifications. This complexity underlines the necessity for personalized diagnostic and therapeutic approaches in GDM management.

Figure 2 Pathophysiology of gestational diabetes mellitus: A multi-pathway model. This diagram illustrates the multifactorial pathophysiology of gestational diabetes mellitus. Placental hormones—including human placental lactogen, estrogen, and placental growth hormone—progressively induce insulin resistance to support fetal nutrient supply. In susceptible women with insufficient β-cell compensation, this adaptive mechanism fails, resulting in maternal hyperglycemia. Simultaneously, adipose tissue dysfunction—characterized by macrophage infiltration, elevated proinflammatory cytokines [e.g., tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)], and decreased GLUT4 expression—further aggravates insulin resistance. Oxidative stress and mitochondrial dysfunction contribute to β-cell apoptosis and impaired insulin secretion. Epigenetic modifications, such as altered DNA methylation [e.g., decreased GLUT1 and increased leptin (LEP)] and dysregulated mRNAs (e.g., downregulated miR-29a and upregulated miR-98), are implicated in fetal metabolic programming and may perpetuate transgenerational cardiometabolic risk. Blue blocks - core insulin-glucose axis: Placental hormones, increased insulin resistance, inadequate β-cell compensation, and maternal hyperglycemia. Orange blocks - adipose inflammation and insulin resistance: Elevated TNF-α, elevated IL-6, reduced GLUT4 expression, and adipose tissue dysfunction. Yellow blocks - oxidative stress and mitochondrial dysfunction: Increased reactive oxygen species and β-cell apoptosis. Purple blocks - epigenetic mechanisms: Altered DNA methylation (e.g., decreased GLUT1 and increased LEP) and dysregulated miRNAs. TNF-α: Tumor necrosis factor alpha; IL-6: Interleukin-6; GLUT4: Glucose transporter type 4; ROS: Reactive oxygen species; LEP: Leptin; miR: MicroRNA.

Epidemiology of GDM

Global burden and trends: The global prevalence of GDM is steadily increasing, representing a major public health challenge. According to the International Diabetes Federation, hyperglycemia affects approximately 14% of pregnancies worldwide, with over 80% attributed to GDM—equivalent to nearly one in six live births each year[1]. Based on standardized IADPSG diagnostic criteria and the universal 75-g oral glucose tolerance test (OGTT), Wang et al[13] reported a global, age- and practice-adjusted GDM prevalence of 14.0%.

Regional disparities: Considerable interregional variation exists. The Middle East and North Africa region reports the highest prevalence at 27.6%, followed by Southeast Asia (20.8%), the Western Pacific (14.7%), and Africa (14.2%). In contrast, North America and Europe report relatively lower rates of 7.1% and 7.8%, respectively[13].

Within-region and country-level variability: Even within regions, GDM prevalence is highly heterogeneous. For example, among 24 European countries, the average prevalence is 10.9%, yet country-specific estimates range from 1.8% in Sweden to 66.1% in Moldova[6]. In Asia, prevalence ranges from 1.2% to nearly 50%, influenced by ethnic background, urbanization levels, and diagnostic protocols[18].

National trends—case examples: In mainland China, GDM prevalence increased 3.5-fold between 1999 and 2012, reaching 14.8% under pooled IADPSG data, with urban areas reporting higher rates than rural counterparts[12]. In Taiwan, prevalence rose from 7.6% in 2004 to 13.4% in 2015, with the highest rates observed among women aged ≥ 41 and in the eastern and southern regions[14]. In the United States, GDM prevalence increased by 78%—from 4.6% in 2006 to 8.2% in 2016—with steeper rises among Asian women and those of lower socioeconomic status[35].

Diagnostic criteria and detection: The rising burden of GDM is partially attributed to evolving diagnostic criteria. The adoption of the IADPSG thresholds has driven a marked increase in case detection—for instance, a 3.5-fold rise in Australia between 2010 and 2019[18]. While these criteria enhance sensitivity, they may also elevate false positive rates and increase clinical workload, prompting discussion on threshold calibration.

Recurrence and predictors: GDM recurrence remains a significant clinical concern. Meta-analyses estimate a pooled recurrence rate of 47.6%, with higher rates observed among African American, Latina, and Asian populations[10]. Risk factors for recurrence include advanced maternal age, elevated pre-pregnancy BMI, prior insulin therapy, interpregnancy weight gain, and elevated OGTT values in prior pregnancies.

Early-onset GDM and screening debates: Recent studies suggest that up to 70% of GDM cases may present in early pregnancy, particularly under more sensitive diagnostic criteria[16]. However, the accuracy of early screening remains contentious. For instance, the threshold of fasting plasma glucose (FPG) ≥ 5.1 mmol/L may yield excessive false positives in certain populations. As a result, some experts advocate for revised cut-offs (e.g., FPG ≥ 5.5 mmol/L) to avoid overtreatment.

Summary and public health relevance: The global rise, geographic heterogeneity, and high recurrence of GDM underscore the necessity for region-specific screening strategies and individualized, risk-adapted care models. As maternal age and obesity continue to escalate worldwide, the burden of GDM is projected to grow—particularly in low- and middle-income countries, where healthcare infrastructure may be inadequate to manage its long-term cardiometabolic sequelae.

Screening and diagnostic criteria for GDM

Lack of global consensus: The screening and diagnosis of GDM remain subjects of ongoing debate, largely due to the lack of a universally accepted standard. Prominent international organizations—including the IADPSG, the ADA, the WHO, and the American College of Obstetricians and Gynecologists (ACOG)—have each proposed differing diagnostic approaches, contributing to global variation in clinical practice.

Diagnostic approaches: The IADPSG and WHO recommend a one-step 75-g OGTT, typically performed between 24 and 28 weeks of gestation. A diagnosis of GDM is made if any of the following plasma glucose values are met or exceeded: FPG ≥ 5.1 mmol/L (92 mg/dL); 1-hour plasma glucose ≥ 10.0 mmol/L (180 mg/dL); 2-hour plasma glucose ≥ 8.5 mmol/L (153 mg/dL)[15,18,22].

In contrast, the ACOG continues to endorse the two-step approach. The initial screening involves a 50-g glucose challenge test (GCT), administered without fasting. A plasma glucose level ≥ 140 mg/dL one-hour post-load prompts a follow-up 100-g OGTT. GDM is diagnosed if two or more of the following values are abnormal: Fasting ≥ 95 mg/dL (5.3 mmol/L); 1-hour ≥ 180 mg/dL (10.0 mmol/L); 2-hour ≥ 155 mg/dL (8.6 mmol/L); 3-hour ≥ 140 mg/dL (7.8 mmol/L)[24,30].

These differing criteria have led to substantial variation in GDM prevalence across populations, complicating international efforts to standardize care. A comparative summary of these diagnostic strategies is presented in Table 1.

Table 1 Summary of diagnostic thresholds for gestational diabetes mellitus according to different guidelines.

Guideline	Test type	Timing	Fasting threshold (mg/dL)	1-hour	2-hour	Diagnosis criteria
IADPSG	75-g OGTT	24-28 weeks	≥ 92	≥ 180	≥ 153	Any one abnormal
ADA	75-g OGTT	24-28 weeks	≥ 95	≥ 180	≥ 155	Any two abnormal
ACOG	50-g GCT + 100-g OGTT	24-28 weeks	≥ 95	≥ 180	≥ 155	Two-step approach
WHO	75-g OGTT	24-28 weeks	≥ 92	-	≥ 153	Any one abnormal

Thresholds are presented in both mmol/L and mg/dL. A diagnosis of gestational diabetes mellitus is established when one or more values exceed the cut-off in the one-step approach, or when two or more values exceed the cut-offs in the two-step approach. ADA: American diabetes association; IADPSG: International Association of Diabetes and Pregnancy Study Groups; ACOG: American College of Obstetricians and Gynecologists; WHO: World Health Organization; OGTT: Oral glucose tolerance test; GCT: Glucose challenge test.

One-step vs two-step debate: The one-step diagnostic method has been widely adopted in countries such as China and Australia. However, its implementation has resulted in a 2-3-fold increase in GDM diagnoses, raising concerns about overdiagnosis, increased healthcare costs, and limited evidence of improved maternal or neonatal outcomes[14,36,37].

Randomized controlled trials—including the ScreenR2GDM and GEMS studies—reported no significant differences between the one-step and two-step approaches in terms of reducing large-for-gestational-age (LGA) births, cesarean delivery, or neonatal complications. However, the one-step method resulted in a greater proportion of women receiving treatment[1,21].

National and contextual variations: In response to the above-mentioned findings, several national guidelines—including those from Korea and Taiwan—allow for either approach based on resource availability, clinical infrastructure, and feasibility[14,36]. Tailoring screening strategies to local health system capacity may improve implementation and equity.

Timing and threshold considerations: Most international guidelines recommend GDM screening between 24 and 28 weeks of gestation. However, early screening in high-risk individuals—such as those with obesity, prior GDM, or a family history of diabetes—is increasingly being explored. Despite this, early-pregnancy FPG levels show limited sensitivity. Recent proposals suggest raising the diagnostic threshold (e.g., from 5.1 to 5.5 mmol/L) to minimize false positives and prevent unnecessary interventions[16,26].

Universal vs selective screening: Universal screening has been shown to identify more cases of GDM, especially in regions with a high prevalence. In contrast, selective screening based on risk factors may miss 35%-47% of cases[1,13]. In low-resource settings, the International Federation of Gynecology and Obstetrics (FIGO) recommends the use of handheld, plasma-calibrated glucometers as a cost-effective alternative for diagnosis[38].

Emerging diagnostic tools: Advances in molecular diagnostics and omics-based approaches offer promising tools for early risk prediction and subtype identification.

Biomarkers such as β-muricholic acid, urinary metabolites, and inflammatory proteins [e.g., sex hormone-binding globulin (SHBG), CRP, and IL-6] have demonstrated high predictive performance (area under the curve > 0.95)[10,26].

Polygenic risk scores, immune gene panels (e.g., FABP4 and CXCL10), and metabolomic subtyping strategies may facilitate precision diagnosis and personalized interventions[20,28].

Controversies and future directions: Despite the broad international endorsement of IADPSG criteria by major organizations such as the WHO, ADA, and FIGO, ongoing controversies remain regarding their cost-effectiveness, psychological impact, and actual clinical benefit. Achieving global consensus will require harmonization of diagnostic thresholds, improved risk stratification models, and the development of adaptable, context-specific screening protocols.

Risk factor stratification for GDM

Maternal age: Advanced maternal age is one of the most consistently recognized non-modifiable risk factors for GDM. Women aged ≥ 35 years have up to a 4-fold higher risk than those < 25 years[2,8,12]. In Asian populations, the risk increases by approximately 12.7% for each year beyond age 18[30]. A large-scale European study reported a 2.14-fold higher prevalence of GDM among women aged ≥ 30 years compared to younger counterparts[6].

Adiposity and gestational weight gain: Prepregnancy overweight and obesity are the most modifiable and impactful risk factors for GDM. Obesity (BMI ≥ 30 kg/m²) is associated with a 6.8-fold higher risk. Overweight status (BMI 25-29.9 kg/m²) confers a 2.3-fold increased risk[6,8]. Each unit increase in BMI is linked to a 9%-12% higher risk of LGA infants or macrosomia[7]. Excessive gestational weight gain, particularly during the second trimester, significantly elevates GDM risk—especially in older or overweight women[2].

Family and obstetric history: Personal or familial history of metabolic or obstetric complications markedly increases the risk of developing GDM. A family history of diabetes is associated with as much as a 3.6-fold increase in GDM risk. A prior diagnosis of GDM is the strongest predictor of recurrence, with an odds ratio of approximately 21.1 and a recurrence rate ranging from 29% to 84%[8,10]. Other obstetric factors associated with elevated GDM risk include multiparity, prior macrosomia, stillbirth, preterm birth, and pregestational smoking. Polycystic ovary syndrome (PCOS), due to its association with chronic insulin resistance, approximately doubles the risk of developing GDM[1,30]. Table 2 outlines clinically relevant risk tiers and corresponding screening recommendations to support risk-adapted screening protocols in various healthcare settings.

Table 2 Risk stratification framework for gestational diabetes mellitus screening.

Risk level	Key characteristics	Recommended screening approach
High	BMI ≥ 30 kg/m², prior GDM, strong family history, PCOS	Early OGTT (< 20 weeks), repeat at 24-28 weeks
Moderate	BMI 25-29.9 kg/m², age ≥ 30 years, non-White ethnicity	Standard OGTT at 24-28 weeks
Low	BMI < 25 kg/m², age < 25 years, no risk factors	Routine screening or selective as per policy

High-risk individuals may benefit from early screening, ideally before 24 weeks of gestation, to enable timely diagnosis and intervention. BMI: Body mass index; GDM: Gestational diabetes mellitus; PCOS: Polycystic ovary syndrome; OGTT: Oral glucose tolerance test.

Lifestyle and sociodemographic factors: Sociodemographic and behavioral factors play a substantial role in GDM risk. Low socioeconomic status, physical inactivity, and sedentary behavior of ≥ 4 hours per day are independently associated with increased GDM risk[12,35]. Seasonal patterns (e.g., winter conception), urban living, and residence in economically aged communities have also been linked to higher prevalence[14].

Pronounced ethnic disparities: South and East Asian, Hispanic, and African American women exhibit higher GDM prevalence. However, progression to T2DM following GDM may occur more frequently among White and Black women[39].

Dietary and environmental factors: Nutritional patterns, micronutrient status, and lifestyle behaviors significantly shape insulin sensitivity and GDM risk. Diets rich in processed foods, saturated animal fats, and added sugars contribute to GDM pathogenesis. Conversely, low-glycemic index (GI) and high-fiber diets have been shown to enhance insulin sensitivity and reduce GDM risk. Additional contributors include vitamin D deficiency, chronic psychological stress, and poor sleep quality, which are associated with impaired glucose regulation and heightened metabolic risk[25,30].

Genetic and epigenetic risk: Genetic predisposition and epigenetic changes contribute to GDM susceptibility and may drive intergenerational metabolic risk transmission. Genetic susceptibility loci such as TCF7 L2, MTNR1B, and CDKAL1 are strongly associated with GDM and T2DM. Polygenic risk scores have demonstrated predictive value for GDM, particularly when integrated with clinical or metabolic risk factors[9,20]. Epigenetic modifications—including placental DNA methylation, altered microRNA (miRNA) expression, and exosome-mediated signaling—may influence both maternal metabolic adaptations and fetal programming, contributing to intergenerational transmission of metabolic risk[29,32].

Summary: A comprehensive risk stratification model for GDM should incorporate three key domains: (1) Non-modifiable factors: Maternal age, genetic predisposition, ethnicity, and obstetric history; (2) Modifiable factors: Pre-pregnancy BMI, physical activity, dietary quality, and micronutrient status; and (3) Molecular and epigenetic markers: Genetic polymorphisms, DNA methylation, and miRNA profiles. Such an integrative framework facilitates earlier identification of high-risk women, enabling personalized screening schedules and targeted preventive interventions.

Current management strategies for GDM

To support clinical implementation, a simplified algorithm depicting the diagnostic and therapeutic workflow for GDM is presented in Figure 3.

Figure 3 Stepwise clinical algorithm for the diagnosis and management of gestational diabetes mellitus. This flowchart outlines a standardized care pathway from initial screening—via oral glucose tolerance testing (OGTT) at 24-28 weeks—to postpartum follow-up. Lifestyle intervention constitutes the cornerstone of treatment, while pharmacologic therapy (primarily insulin, with metformin as an alternative) is initiated if glycemic targets are not met within 10-14 days. Postpartum OGTT and ongoing metabolic surveillance are essential to mitigate future risks of type 2 diabetes mellitus and cardiovascular disease. Blue blocks: Diagnostic and monitoring checkpoints (e.g., OGTT at 24-28 weeks, 10-14 days reassessment). Gray-blue blocks: Lifestyle and non-pharmacologic interventions (e.g., medical nutrition therapy, exercise, and glycemic control). Orange blocks: Persistent hyperglycemia (e.g., glycemia uncontrolled). Yellow blocks: Pharmacologic therapy and delivery planning (e.g., insulin initiation, intrapartum glucose targets). Pale-pink blocks: Intrapartum management and delivery timing considerations. Pale-gray blocks: Postpartum surveillance (e.g., OGTT at 6-12 weeks, annual screening every 1-3 years). GDM: Gestational diabetes mellitus; OGTT: Oral glucose tolerance test.

Lifestyle and nutritional therapy: Lifestyle intervention is the first-line treatment for GDM. Medical nutrition therapy, individualized to caloric and metabolic needs, generally includes: Carbohydrates: 40%-50% of daily intake (≥ 175 g/day); Fats: 20%-35%, favoring unsaturated sources; and Proteins: 10%-35%, derived from lean sources. Approximately 70%-85% of GDM cases are successfully managed through dietary modification and exercise[22,40]. Moderate physical activity—such as 30 minutes per day of walking or resistance training—improves insulin sensitivity and glycemic control. Postprandial walking and at-home cycling are particularly effective strategies[5,12].

Glucose monitoring and glycemic targets: Blood glucose monitoring guides therapy adjustments and predicts pregnancy outcomes. ADA 2024 recommended targets[22,24] are shown in Table 3. Monitoring modalities include: Self-monitoring of blood glucose; Clinic-based testing; Continuous glucose monitoring (promising for type 1 diabetes and those under evaluation for GDM[21]; and Pharmacologic therapies (if lifestyle measures fail to achieve target glycemia within 10-14 days, then pharmacologic treatment is initiated).

Table 3 Glycemic targets for pregnant women according to American Diabetes Association 2024 guidelines.

Time point	Target glucose (mg/dL)
Fasting	< 95
1 hour postprandial	< 140
2 hours postprandial	< 120

Values are based on capillary whole blood or plasma glucose measurements.

First-line therapy: Insulin remains the gold standard for efficacy and fetal safety. Oral alternatives include metformin (preferred due to lower neonatal hypoglycemia rates compared to glyburide) and glyburide (crosses the placenta; associated with higher risk of neonatal hypoglycemia). Emerging concerns exist over the long-term effects of metformin, with evidence suggesting increased BMI in offspring at 7-9 years of age[32]. Experimental therapies (e.g., GLP-1 receptor agonists and DPP-4 inhibitors) are under investigation for postpartum T2DM prevention[1], but are not approved for patients during pregnancy.

Recent advances and controversies: Key developments in GDM management include distinct strategies for early GDM (< 20 weeks) due to low reproducibility of early OGTT results[21]. IADPSG diagnostic controversy includes increased detection but no clear neonatal outcome benefit[15]. Biomarker-based prediction efforts include: (1) Proteins: SHBG, FABP4, GDF-15, and adiponectin; (2) MiRNAs: MiR-222 and miR-223; and (3) Insulin resistance indices: HOMA-IR and metabolomic subtypes[7,9]. Precision medicine models for GDM risk prediction and tailored care are actively being evaluated[21,28].

Intrapartum and postpartum management: Intrapartum care includes: (1) Hourly glucose monitoring; (2) Maintaining blood glucose between 4.0 and 7.0 mmol/L; and (3) Using insulin or glucose infusions as required[38]. Postpartum care includes: (1) Discontinuing insulin unless hyperglycemia persists; (2) Administering a 75-g OGTT at 6-12 weeks postpartum; and (3) Scheduling long-term screening every 1-3 years[22]. Breastfeeding is associated with a 30%-50% reduction in maternal T2DM risk and supports β-cell preservation[36]. The postpartum period represents a crucial window for T2DM prevention[21].

Patient education and health system considerations: Effective patient communication is essential for adherence and outcomes. Identified barriers include: (1) Cultural mismatches in dietary guidance; (2) Overmedicalization of pregnancy; and (3) Fragmented multidisciplinary care pathways[37]. Proposed solutions include: (1) Telehealth-based dietary and glycemic counseling; (2) One-day comprehensive GDM clinics; and (3) Multilingual education and structured behavior-change interventions[12,41].

Genetics and epigenetics of GDM

GDM is increasingly recognized not merely as a transient metabolic adaptation of pregnancy but as a complex, polygenic disorder with epigenetic regulation. While it shares numerous susceptibility loci with T2DM, GDM also involves pregnancy-specific genetic and regulatory mechanisms.

Genetic susceptibility: Many genetic loci implicated in GDM are also linked to T2DM, underscoring a shared pathophysiological basis centered on insulin resistance and β-cell dysfunction. Genome-wide association studies (GWAS) have identified the following key genes[23]: (1) MTNR1B (rs10830963): Elevates fasting glucose and impairs insulin secretion; (2) CDKAL1, GCK, KCNQ1, and TCF7 L2: Crucial regulators of β-cell function; (3) IRS-1 (rs1801278): Affects insulin receptor signaling pathways; and (4) FTO, MC4R, APOA5, and LDLR: Obesity-related genes frequently co-associated with dyslipidemia in GDM.

These findings position GDM within a broader metabolic continuum that overlaps with T2DM, while also reflecting unique gestational influences, particularly involving placental signaling. The functional implications of key GDM-associated genetic loci are summarized in Figure 4, highlighting the overlap with type 2 diabetes and the mechanistic relevance of insulin signaling, β-cell function, and metabolic regulation.

Figure 4 Genetic loci associated with gestational diabetes mellitus and their mechanistic roles in disease pathogenesis. This diagram maps the key gestational diabetes mellitus-associated genes to their molecular functions. MTNR1B and IRS-1 regulate glucose metabolism and insulin signaling. CDKAL1 and TCF7 L2 impair β-cell proliferation and insulin synthesis. Obesity-related genes such as FTO and APOA5 contribute to gestational weight gain and metabolic dysregulation, reinforcing the polygenic basis of gestational diabetes mellitus. GDM: Gestational diabetes mellitus; T2DM: Type 2 diabetes mellitus.

Epigenetic reprogramming: Maternal hyperglycemia induces stable, tissue-specific DNA methylation changes in both maternal and fetal compartments. Placental targets include HOOK2, RDH12, COPS8, and PIK3R5—genes linked to nutrient sensing and metabolic signaling. Fetal genes include: MEST, NR3C1, and TNFRSF1B—associated with glucocorticoid response and inflammation. These epigenetic alterations persist into cord blood and have been associated with increased insulin resistance and dysregulated lipid metabolism in offspring[23,42]. Furthermore, oxidative stress and low-grade inflammation observed in GDM may amplify these epigenetic lesions, enhancing the risk of long-term metabolic dysregulation[43].

MiRNAs: MiRNAs serve as post-transcriptional regulators and show dysregulated expression profiles in GDM. Downregulated miRNAs include: MiR-132, miR-29a, and miR-222—affect insulin sensitivity and trophoblast function. Upregulated miRNAs include: MiR-16-5p, miR-20a-5p, and miR-98—linked to β-cell stress, placental inflammation, and neurodevelopmental changes. Several miRNAs show strong predictive potential (area under the curve > 0.80), making them promising candidates for early diagnosis[23,26]. Several miRNAs exhibit altered expression profiles in GDM and are linked to critical targets involved in metabolic regulation and inflammation (Figure 5).

Figure 5 Regulatory network of dysregulated microRNAs in gestational diabetes mellitus. This network diagram illustrates experimentally validated interactions between dysregulated miRNAs, their molecular targets, and their physiological impacts—including insulin resistance, β-cell dysfunction, and placental adaptation.

Metabolomics: Metabolomic profiling has identified several biomarkers elevated in GDM: (1) 2-Hydroxybutyrate, an indicator of insulin resistance and oxidative stress; and (2) Choline, which plays a role in hepatic lipid metabolism and fetal neurodevelopment. Animal and human studies suggest that maternal diet and GDM exposure modulate epigenetic marks in key regulators (e.g., adiponectin, leptin, and PPARG), predisposing offspring to long-term metabolic disorders[9].

These molecular and epigenetic alterations provide a mechanistic bridge between maternal GDM exposure and long-term offspring outcomes. A conceptual summary of this gene-to-phenotype axis is illustrated in Figure 6.

Figure 6 Conceptual pathway from genetic and epigenetic factors to offspring risk in gestational diabetes mellitus. This conceptual diagram links maternal genetic predisposition (e.g., MTNR1B and IRS-1), epigenetic alterations (e.g., DNA methylation of MEST and PIK3R5; dysregulation of miR-29a and miR-223), and transgenerational metabolic outcomes such as obesity, insulin resistance, and type 2 diabetes mellitus in offspring.

Translational barriers: Despite the promise of omics-based biomarkers in GDM risk stratification and prediction, major translational barriers remain: (1) Lack of population-specific standardization of cut-off thresholds; (2) Absence of clinical validation in prospective settings; and (3) Cost, accessibility, and technical feasibility in routine obstetric care. To bridge the gap from bench to bedside, future efforts must focus on multicenter prospective trials and the development of harmonized, scalable biomarker platforms[9,20].

Complications of GDM

GDM is increasingly recognized not merely as a transient pregnancy complication but as a sentinel event that predicts long-term metabolic and cardiovascular morbidity. Suboptimal glycemic control during pregnancy poses serious risks to both maternal and neonatal outcomes, with sequelae that extend well beyond delivery.

Maternal complications: Inadequately managed GDM is associated with increased risks of preeclampsia, preterm labor, excessive gestational weight gain, cesarean delivery, and postpartum hemorrhage[24,30].

The most consequential long-term complication for mothers is T2DM: Women with prior GDM have an approximately 10-fold increased risk of developing T2DM. It was estimated that 30%-50% will convert to T2DM within 5-10 years postpartum, with conversion risk modulated by ethnicity, residual β-cell function, and lifestyle factors[24,30]. Beyond metabolic disease, GDM is also an independent risk factor for cardiovascular complications, including hypertension, coronary artery disease, stroke, and congestive heart failure[44].

Emerging evidence suggests that maternal diabetes may induce lasting alterations in fetal cardiometabolic programming through epigenetic and developmental pathways, thereby increasing lifelong cardiovascular risk[45]. These associations remain robust even after adjusting for subsequent T2DM, underscoring GDM as a distinct marker of elevated cardiovascular risk.

Fetal and neonatal complications: Intrauterine exposure to maternal hyperglycemia profoundly disrupts fetal metabolic homeostasis. Key perinatal complications include: Macrosomia (15%-45% prevalence); Neonatal hypoglycemia; Respiratory distress syndrome (RDS); Birth trauma (e.g., shoulder dystocia); and Stillbirth and perinatal mortality[24,30].

Macrosomia—defined as birth weight > 4000 g—is among the most consistent neonatal consequences and is associated with an increased risk of labor complications and surgical delivery. Neonatal hypoglycemia typically presents within hours after birth due to persistent fetal hyperinsulinemia, a compensatory response to transplacental glucose overload. If prolonged, it may impair neurodevelopment.

Long-term offspring outcomes: Exposure to GDM in utero predisposes offspring to a spectrum of adverse long-term outcomes, including childhood and adolescent obesity, impaired glucose tolerance, early-onset T2DM, dyslipidemia and hypertension, and premature cardiovascular disease[46].

These observations support the Developmental Origins of Health and Disease (DOHaD) paradigm, in which intrauterine hyperglycemia induces placental dysfunction, perturbs adipokine/cytokine signaling, and drives epigenetic alterations (e.g., DNA methylation and miRNA dysregulation), together shaping lifelong cardiometabolic risk trajectories[45].

Key supporting evidence includes: HAPO-FUS (10-14 years) and EPOCH (12-15 years) cohorts show increased central adiposity, impaired glucose tolerance, and insulin resistance among GDM-exposed offspring[46,47]. A meta-analysis of 32 studies (over 3.3 million offspring) confirmed that in utero exposure to GDM significantly increases the risk of obesity (odds ratio [OR] = 1.57), type 2 diabetes (OR = 4.5), and multiple components of metabolic syndrome, including elevated blood pressure, BMI, triglycerides, and LDL cholesterol levels[48]. Danish national registry data report an approximately 29% increase in early adulthood cardiovascular events in GDM-exposed individuals[49].

Public health implications of GDM

GDM has evolved from a clinical obstetric issue into a pressing global public health concern. Its far-reaching consequences include adverse maternal and neonatal outcomes, long-term metabolic disease, intergenerational transmission of cardiometabolic risk, and increased strain on healthcare systems. Addressing GDM requires coordinated, multi-tiered strategies embedded within national and global maternal health agendas.

Global burden and rising prevalence: The global prevalence of GDM continues to escalate, driven by rising maternal age, obesity, and sedentary lifestyles. In South and Southeast Asia, GDM is now a major contributor to maternal and perinatal morbidity, potentially reversing progress in reducing stillbirths and congenital anomalies. South Asia bears some of the world's highest stillbirth rates—up to 25.15 per 1000 Live births—a burden exacerbated by undiagnosed or poorly managed GDM[50]. In many low- and middle-income countries, GDM surveillance is inadequate, with limited population-based prevalence data, low screening coverage, and fragmented care delivery systems[14,51]. These realities emphasize the need to integrate GDM into national maternal health frameworks, particularly in resource-limited contexts where the potential for intervention is greatest.

Cardiometabolic sequelae and chronic disease prevention: GDM is a powerful predictor of future chronic disease in both mothers and offspring. It is associated with a 7-10-fold increased risk of developing T2DM within 5-10 years postpartum, and elevated lifetime risks of stroke, myocardial infarction, heart failure, and metabolic syndrome[22,44].

Importance of structured long-term follow-up: Guidelines have recommended a 75-g OGTT at 4-12 weeks postpartum, and regular metabolic screening every 1-3 years, stratified by individual risk level[6]. Furthermore, GDM exposure in utero is now firmly associated with intergenerational risk transmission. Offspring of mothers with GDM face increased likelihood of obesity, insulin resistance, and early-onset T2DM[14].

Policy recommendations and preventive strategies: To translate the evidence into action, Table 4 summarizes multilevel strategies recommended across the GDM continuum, from preconception to postpartum care.

Table 4 Multilevel policy recommendations for the prevention and management of gestational diabetes mellitus.

Level	Strategic action
Preconception	Promote weight optimization and screen high-risk women[2]
Antenatal	Implement universal OGTT screening in high-burden regions[14]
Postpartum	Ensure OGTT follow-up, breastfeeding support, and metabolic surveillance[44]
Health system	Harmonize diagnostic criteria and integrate GDM into chronic disease frameworks[6]

This table outlines strategic interventions across each stage of care, reinforcing the importance of aligning clinical guidelines with public health infrastructure to reduce the lifelong burden of gestational diabetes mellitus. GDM: Gestational diabetes mellitus; OGTT: Oral glucose tolerance test.

Data gaps and health equity considerations: Gaps in diagnostic standardization and surveillance impede global policy efforts. Within Europe, national GDM prevalence ranges from 1.8% to 66.1%, reflecting variability in screening strategies and diagnostic thresholds[6]. Vulnerable populations—including women with low socioeconomic status, ethnic minorities, and those with limited healthcare access—face both higher GDM prevalence and lower rates of postpartum follow-up[2,50]. Addressing these disparities requires equity-focused health system reform. Universal access to timely diagnosis, culturally appropriate care, and sustained follow-up is essential to mitigate both the clinical and societal impact of GDM.

Practical barriers to postpartum follow-up: Despite the well-established risks of T2DM and cardiovascular disease following GDM, postpartum follow-up and long-term preventive care remain grossly inadequate in many healthcare systems—especially in low-resource or underserved populations. Qualitative evidence from Nagraj et al[52] highlights key barriers at both the patient and provider levels. Women often lack awareness of the long-term consequences of GDM and do not perceive the need for continued monitoring unless symptomatic. Meanwhile, healthcare providers cite fragmented referral systems, insufficient integration between obstetric and primary care, and limited provider training as persistent obstacles to continuity of care.

Sinha et al[53] further identified logistical and psychosocial barriers, including lack of childcare, transportation difficulties, postpartum exhaustion, and ambiguous provider communication. Importantly, the study also recognized several facilitators that could be leveraged to improve adherence—such as strong provider recommendations, automated reminder systems, culturally tailored education, and pre-scheduled follow-up appointments.

These qualitative insights are corroborated by large-scale retrospective data. In a 2023 analysis by D’Amico et al[54], less than 20% of women with a history of GDM received diabetes-related care in primary care settings within six months postpartum, and only one-third completed the standard six-week postpartum visit. The study found that breakdowns in structured referral pathways contributed significantly to care gaps.

Collectively, these findings underscore the urgent need for integrated care models that bridge obstetric and primary care, particularly for at-risk populations. Strategies such as telehealth follow-up, community health worker engagement, electronic referral tracking, and patient-centered education may help close the implementation gap and mitigate the long-term cardiometabolic burden associated with GDM.

Fetal impact and complications of GDM

GDM exerts profound effects on fetal development, encompassing immediate perinatal complications as well as long-term cardiometabolic consequences. These outcomes are primarily mediated by maternal hyperglycemia and resultant fetal hyperinsulinemia, with growing evidence pointing to epigenetic mechanisms that program disease risk in later life.

Macrosomia and neonatal morbidity: Macrosomia is a hallmark feature of GDM, observed in approximately 15%-45% of affected pregnancies. A systematic review by Mistry et al[50] found that 6 out of 8 studies confirmed a strong association between GDM and macrosomia, with incidence rates as high as 28%. This overgrowth is primarily driven by fetal hyperinsulinemia and is associated with a higher risk of LGA infants and birth trauma, including shoulder dystocia. GDM also increases the likelihood of neonatal hypoglycemia, RDS, and admission to neonatal intensive care units (NICU). Even in treated pregnancies, these risks persist[16,26,30]. Interestingly, the Treatment of Booking Gestational Diabetes Mellitus pilot trial found that although early GDM treatment reduced the incidence of LGA births, it was paradoxically associated with an increased rate of NICU admissions, primarily due to a higher prevalence of small-for-gestational-age (SGA) neonates[16].

Congenital anomalies: Although GDM is typically diagnosed after the period of organogenesis, it is associated with an increased risk of congenital anomalies, likely due to undiagnosed preexisting insulin resistance and β-cell dysfunction.

A large United States national cohort (n > 29 million) found that GDM was linked to a 28% increase in overall congenital anomaly risk (relative risk [RR] = 1.28)[51]. Specific associations include: Cyanotic congenital heart disease (RR = 1.50); Hypospadias (RR = 1.29); Cleft lip/palate (RR = 1.28-1.40); Down syndrome (RR = 1.38); and Spina bifida (RR = 1.13).

These findings suggest that GDM, even when diagnosed later in pregnancy, may reflect a latent pathophysiological state with developmental consequences.

Stillbirth and growth restriction: GDM contributes not only to fetal overgrowth but also to intrauterine growth restriction and stillbirth. In one study, the stillbirth rate in the GDM group was 4.8% compared to 0% in the control group (P = 0.02)[50]. These adverse outcomes may result from placental vasculopathy, chronic fetal acidosis, and subclinical maternal inflammation. This dual risk of overgrowth and restriction reflects the heterogeneous and dynamic nature of GDM’s impact on fetal development.

Long-term cardiometabolic programming: In utero exposure to maternal hyperglycemia has enduring effects on the offspring’s metabolic health. Findings from the HAPO-FUS and EPOCH cohorts show that GDM-exposed children are at significantly increased risk for obesity (increased by 54%), insulin resistance (increased by 50%), and cardiovascular disease (1.42-fold increase in adulthood)[11]. In addition, studies by Plows et al[25] and Alejandro et al[30] reinforce these findings, reporting increased rates of childhood obesity, impaired glucose tolerance, and early-onset T2DM.

Epigenetic and predictive markers: GDM-associated fetal programming is mediated, in part, by epigenetic changes, including: DNA methylation in insulin-related genes; Altered expression of adipokines such as leptin and adiponectin; and Mitochondrial stress in placental and fetal hepatic tissue[11]. These molecular changes may underpin long-term disease susceptibility and highlight opportunities for early prediction and intervention. Emerging clinical tools, such as fetal abdominal circumference assessment at 24-28 weeks, may help personalize glycemic targets and reduce fetal overgrowth risk. However, standardized guidelines for their application are still lacking[36].

Maternal and lifespan risks associated with GDM

GDM is increasingly recognized as a sentinel marker of future cardiometabolic disease for both mother and child. Far from being a transient gestational complication, GDM signals heightened lifetime risk, necessitating proactive long-term surveillance and preventive care strategies. Figure 7 depicts the longitudinal trajectory of metabolic and cardiovascular risk associated with GDM, which affects both maternal and offspring health across the lifespan. This figure underscores the intergenerational consequences of in utero hyperglycemia and the urgency of early intervention.

Figure 7 Life-course impact of gestational diabetes mellitus. This schematic illustrates the parallel health trajectories of mothers and their offspring following exposure to gestational diabetes mellitus (GDM). Maternal risks include progression to type 2 diabetes mellitus (T2DM) [relative risk (RR) = 7-10], cardiovascular disease (RR = 1.98), and NAFLD. Offspring face increased risks of neonatal complications, childhood obesity (54% higher), insulin resistance, and adult-onset cardiovascular disease (RR = 1.42). Central drivers include DOHaD-based fetal programming, persistent epigenetic alterations, and transgenerational metabolic stress. Blue blocks: Maternal life stages (GDM → postpartum → T2DM/CVD/NAFLD). Orange blocks: Offspring trajectory (neonatal → childhood → adult metabolic disease). Purple blocks: Epigenetic memory (e.g., increased LEP methylation, decreased miR-29a, and increased miR-98). Light-purple blocks: DOHaD hypothesis - epigenetic basis of lifelong risk. Gray box: Quantified risks - e.g., +54% childhood obesity; T2DM RR: 7-10 ×. RR: Relative risk; T2DM: Type 2 diabetes mellitus; CVD: Cardiovascular disease; NAFLD: Non-alcoholic fatty liver disease; DOHaD: Developmental Origins of Health and Disease; LEP: Leptin; miR: MicroRNA.

Pregnancy-associated maternal complications: Short-term maternal complications of GDM include: (1) Preeclampsia, which occurs in over 20% of GDM pregnancies[50]; (2) Cesarean delivery: Data are mixed, with some studies showing higher rates[50]; and (3) Gestational hypertension and mental health: No significant differences between early vs deferred treatment groups in the TOBOGM trial[17].

Postpartum progression to T2DM: GDM is a strong predictor of future T2DM: (1) Incidence: 30%-60% conversion within 5-10 years[30,36]; (2) Relative risk: 7-10-fold increase[11,25]; (3) Pooled meta-analysis: RR = 8.92 (95%CI: 7.84-10.14)[39]; (4) Ethnic disparities: Asian women convert at higher rates, even with similar BMI[36]; and (5) Screening: OGTT remains more sensitive than FPG for detecting early β-cell dysfunction[36].

Long-term cardiometabolic morbidity: Even in the absence of T2DM, women with a history of GDM are at increased risk of: (1) Hypertension, dyslipidemia, and CVD; (2) Non-alcoholic fatty liver disease (NAFLD); and (3) Chronic kidney disease and diabetic retinopathy[11].

Postpartum obesity and intergenerational risk: Prepregnancy obesity and GDM have synergistic effects: Women with both conditions are more likely to retain excess postpartum weight and develop hypertension, T2DM, and CVD[4]. Their offspring face higher risks of central adiposity, insulin resistance, and early-onset metabolic disease[46,47,55].

Offspring outcomes and developmental programming: Offspring of GDM pregnancies exhibit: (1) +54% risk of childhood obesity; (2) A 1.42-fold increased risk of cardiovascular events by age 35-40[11]; and (3) Persistent risks independent of BMI, pointing to epigenetic reprogramming as a key mechanism[21,32].

Neurodevelopmental and epigenetic sequelae: Beyond cardiometabolic risk, GDM-exposed offspring may be at increased risk of ADHD (RR = 2.00) and autism spectrum disorder (RR = 1.48), especially in cases involving maternal obesity or pharmacologic treatment[32]. Epigenetic changes in genes like HNF4A and RREB1 are observed in cord blood, supporting intergenerational transmission of metabolic dysfunction[36].

Protective role of lactation and missed preventive opportunities: Lactation offers significant metabolic benefits, yet postpartum care gaps limit its long-term preventive potential. Lactation lowers maternal T2DM risk by 30%-50% and supports β-cell function[36]. Breastfeeding mothers show 40% greater β-cell preservation four years postpartum. However, many women report a discontinuity of care after delivery[37], representing a critical missed opportunity for long-term prevention and education.

A consolidated overview of maternal and offspring risks is provided in Table 5. GDM is not merely a pregnancy-related diagnosis—it is a powerful early warning signal of lifelong cardiometabolic risk. Comprehensive postpartum care should incorporate structured long-term follow-up, patient education, lactation support, and early pediatric interventions. These strategies are essential to disrupting the intergenerational cycle of diabetes and cardiovascular disease and improving outcomes across the life-course.

Table 5 Comparative overview of maternal and offspring risks associated with gestational diabetes mellitus.

Risk domain	Maternal impact	Offspring impact
T2DM	7- to 10-fold increased risk within 10 years	Increased insulin resistance
Cardiovascular disease	A 2-fold increased risk (even without T2DM)	Early-onset CVD, hypertension
Weight trajectory	Higher postpartum weight retention	Higher adiposity and central fat distribution
Epigenetic programming	Persistent inflammation, β-cell stress	Altered methylation of insulin signaling genes
Preventive leverage	Breastfeeding, early screening	Healthy lifestyle education, pediatric monitoring

This table summarizes the long-term health risks faced by women with a history of gestational diabetes mellitus and their offspring, highlighting key domains such as diabetes, cardiovascular disease, obesity trajectories, epigenetic programming, and preventive opportunities. T2DM: Type 2 diabetes mellitus; CVD: Cardiovascular disease.

DISCUSSION

Clinical implications

GDM has evolved from a narrowly defined obstetric condition into a major public health concern at the intersection of global epidemics of obesity, T2DM, and cardiovascular disease. Emerging evidence supports a paradigm shift toward longitudinal, individualized, and prevention-focused models of care.

Clinical gaps and implementation challenges: Several barriers impede optimal GDM management in routine clinical practice: (1) Heterogeneity of interventions: Variation in nutritional counseling, physical activity protocols, and lack of cultural tailoring limits the generalizability and scalability of effective interventions[5]; (2) Inconsistent screening: Diagnostic discrepancies between IADPSG, ADA, and WHO guidelines lead to variable case detection and inconsistent care planning[15]; and (3) Poor postpartum follow-up: Despite clear guidelines, the rate of postpartum OGTT completion remains unacceptably low—particularly among underserved populations and in low-resource settings[41].

Priority clinical insights: Evidence-based strategies targeting modifiable risks and surveillance can guide more effective, individualized GDM care: (1) Integrating regular physical activity into routine prenatal care: Enhancing insulin sensitivity and supporting weight control, and reducing risk of neonatal complications[5]; (2) Adopting multifactorial risk stratification: Maternal age ≥ 30, high BMI, tobacco use, and family history of diabetes should be considered[8]; and (3) Lifelong surveillance for high-risk groups: Asian, obese, and older women require annual screening, as elevated T2DM risk persists years after delivery[21].

System-level and policy implications: The rising global burden of GDM reflects broader shifts in demography and health behavior. Key drivers include delayed childbearing, rapid urbanization, and increasing maternal obesity prevalence[2,50]. Policy imperatives include: (1) Preconception weight optimization initiatives; (2) Global harmonization of diagnostic thresholds and screening timelines; and (3) Health system funding for structured postpartum care transitions, including long-term metabolic surveillance.

Summary of clinical recommendations: Based on the reviewed evidence, Table 6 consolidates key clinical recommendations across care domains, providing a framework for comprehensive GDM management from screening to postpartum follow-up.

Table 6 Summary of clinical recommendations for gestational diabetes mellitus management across the care continuum.

Domain	Clinical recommendation
Prenatal care	Integrate structured lifestyle guidance into routine visits
Screening	Employ early risk-based screening using BMI, age, ethnicity, and history
Postpartum	Ensure OGTT at 6-12 weeks and initiate annual T2DM risk surveillance
Education	Improve cultural and psychosocial sensitivity in patient communication
Health systems	Standardize GDM diagnosis globally; expand access and continuity of care

This framework synthesizes key action points for optimizing gestational diabetes mellitus management at every stage—from early detection to postnatal transition—anchored in prevention, personalization, and system-wide integration. GDM: Gestational diabetes mellitus; OGTT: Oral glucose tolerance test; T2DM: Type 2 diabetes mellitus.

GDM care must transcend glycemic control and embrace a life-course strategy targeting both maternal and intergenerational cardiometabolic risk. A proactive, multidisciplinary approach—rooted in risk stratification, continuity of care, and equity—will be essential for translating knowledge into lasting clinical and public health impact.

Prevention of GDM recurrence

Recurrent GDM affects up to 84% of high-risk women, amplifying cumulative maternal-fetal complications and entrenching intergenerational metabolic vulnerability[10]. Preventive strategies must be stratified by risk phenotype and initiated early—ideally in the postpartum or preconception periods. To visualize the temporally stratified approach for GDM recurrence prevention, Figure 8 presents a comprehensive timeline incorporating postpartum, preconception, and early pregnancy strategies based on individual risk profiles.

Figure 8 Timeline-based strategy for preventing recurrence of gestational diabetes mellitus. This infographic illustrates a phased intervention model spanning postpartum to early pregnancy. Above the central timeline are stage-specific strategies: Postpartum (e.g., weight management and lactation), preconception (e.g., nutrition and screening), and early pregnancy [e.g., early oral glucose tolerance test (OGTT) and targeted therapy]. Bariatric surgery is considered for morbidly obese women (body mass index ≥ 35 kg/m²) with prior recurrence. Light-blue: Lifecycle stages. Deep-blue: Postpartum recovery (e.g., lactation and weight control). Yellow: Health promotion (e.g., physical activity and screening). Purple: Early medical interventions (e.g., early OGTT). Orange: Surgical option pathway (e.g., bariatric surgery for body mass index ≥ 35 kg/m²). OGTT: Oral glucose tolerance test; BMI: Body mass index.

Current limitations: Most trials have failed to prevent GDM recurrence due to: (1) Delayed intervention (initiated mid-pregnancy, after key metabolic windows); (2) Absence of phenotype-based stratification (e.g., insulin-resistant vs lean GDM); and (3) Lack of pharmacologic efficacy: Neither metformin nor probiotics have consistently reduced recurrence[10].

Proven preventive strategies: Timely lifestyle or surgical interventions can substantially reduce GDM recurrence, particularly in high-risk women: (1) Early lifestyle intervention: In the RADIEL trial (Finland), lifestyle intervention was initiated before 20 weeks in women with prior GDM and/or obesity. The outcome was a significant reduction in recurrence (adjusted P = 0.044)[10]; (2) Prepregnancy bariatric surgery: This was associated with a 77% reduction in GDM recurrence (OR = 0.23; 95%CI: 0.15-0.36); and (3) Considerations: Micronutrient deficiency and SGA risk should be considered[10].

Clinical implementation matrix: To inform evidence-based prevention strategies, Table 7 summarizes the effectiveness of current GDM recurrence interventions based on clinical evidence.

Table 7 Summary of clinical strategies for preventing gestational diabetes mellitus recurrence.

Strategy	Effectiveness	Comments
Preconception lifestyle	++	Strongest evidence, cost-effective
Mid-late pregnancy lifestyle	-	Typically implemented too late for meaningful metabolic benefit
Metformin	-	No proven preventive effect
Probiotics	-	Promising but inconsistent
Bariatric surgery	+++	Consider for BMI ≥ 35 kg/m² and failed lifestyle efforts

Effectiveness ratings are qualitative (+ to +++), based on current clinical trial data and expert consensus. BMI: Body mass index.

Recommendations: Targeted, phenotype-informed strategies and early action are essential to prevent GDM recurrence and optimize maternal-fetal outcomes: (1) Identifying high-risk women early (prior GDM, age ≥ 35 years, and BMI ≥ 25 kg/m²); (2) Initiating lifestyle intervention preconceptionally; (3) Stratifying by GDM phenotype to distinguish insulin-resistant subtypes; (4) Considering surgery: For BMI ≥ 35 kg/m² with recurrent GDM; and (5) Promoting multidisciplinary care: Obstetrics, endocrinology, and primary care teams should be linked.

Controversies and evidence gaps: Unresolved issues in screening, pharmacotherapy, biomarkers, and global criteria hinder consensus and limit progress in GDM management.

Early screening uncertainty: Although early-onset GDM (< 20 weeks) comprises up to 70% of cases, current FPG thresholds (e.g., ≥ 5.1 mmol/L) have low specificity and predictive value[17]. Early treatment (e.g., in TOBOGM trial) reduced LGA but increased SGA births, raising safety concerns: (1) Long-term safety of pharmacologic therapy: Metformin is associated with a higher childhood BMI at 7-9 years[32,36]. Glyburide is Associated with increased neonatal hypoglycemia risk due to placental transfer; (2) Lack of standardized precision tools: Biomarkers such as SHBG, FABP4, GDF-15, and miRNAs (e.g., miR-222 and miR-223) are promising but remain unincorporated in clinical practice due to validation and standardization challenges[9,20,26]; (3) Ambiguous management of early-onset GDM: Clear protocols are currently lacking. Risk may be higher, but treatment thresholds are extrapolated from later gestation data[21]; and (4) Inconsistent global diagnostic criteria: Prevalence varies from < 2% to > 60% across regions due to differing criteria (e.g., IADPSG, WHO, and ADA), impeding unified care delivery[13,18].

Future directions: To address the above gaps, researchers should conduct stratified RCTs by GDM phenotype, follow metformin-exposed offspring for long term, validate predictive biomarkers across ethnicities and assays, develop region-specific, standardized diagnostic models, and integrate ethics and health equity into national policy reform.

Summary: To synthesize the core findings and ongoing debates in GDM research and management, we provide a concise tabular summary (Table 8) outlining current clinical standards, key controversies, and recommended directions for future investigation across three major domains: Screening timing, pharmacologic treatment, and epigenetics. GDM recurrence is both foreseeable and preventable—yet remains under-addressed in standard clinical care. Early, risk-adapted interventions—spanning postpartum, preconception, and early gestation—represent the most effective window for disrupting the intergenerational transmission of diabetes and associated cardiometabolic risks.

Table 8 Summary of key clinical and research dimensions in gestational diabetes mellitus.

Dimension	Current standard	Controversies	Recommended research
Screening timing	24-28 weeks OGTT	Early screening utility unclear	TOBOGM and similar RCTs
Pharmacologic treatment	Insulin; Metformin (optional)	Long-term safety of metformin	Childhood follow-up & mechanistic studies
Epigenetics	Not routinely applied	Inconsistent miRNA & methylation data	Multicenter validation & standardization

This visual framework synthesizes current clinical guidelines, areas of uncertainty, and priorities for future research across critical domains in gestational diabetes mellitus care. OGTT: Oral glucose tolerance test; RCTs: Randomized controlled trials.

CONCLUSION

GDM is an escalating global health concern with wide-reaching implications for maternal, fetal, and intergenerational metabolic health. While adoption of the IADPSG criteria has enhanced screening standardization and early detection, it has also raised important concerns regarding overdiagnosis, healthcare burden, and uncertain long-term benefit[15,21]. Clinical trials such as ACHOIS and TOBOGM demonstrate that timely intervention reduces neonatal complications like macrosomia and respiratory distress syndrome; however, improvements in maternal outcomes, particularly hypertensive disorders, remain modest[17]. The maternal burden of GDM extends far beyond pregnancy. Women with prior GDM face a 7-10-fold increased risk of progressing to T2DM, especially those of Asian descent or with overweight/obesity[30,36]. Simultaneously, fetal exposure to maternal hyperglycemia initiates epigenetic reprogramming and metabolic dysregulation, increasing long-term risk for obesity, insulin resistance, and cardiometabolic disease[11,32]. A paradigm shift is urgently needed from pregnancy-limited care to a life-course prevention framework. This entails: (1) Establishing integrated care pathways spanning preconception to postpartum; (2) Embedding risk-based screening into routine antenatal care; and (3) Expanding access to postpartum surveillance, lactation support, and behavioral interventions, particularly in high-risk and under-resourced populations. To transform the management and prevention of GDM, the following areas warrant urgent investigation: (1) Stratified, multiethnic RCTs to test early, phenotype-specific interventions; (2) Refinement of GDM classification through metabolic subtyping (e.g., insulin resistance vs β-cell dysfunction); (3) Determination of optimal timing for intervention: Preconception, first trimester, or universal 24-28-week screening; (4) Validation of molecular biomarkers (e.g., SHBG, FABP4, miR-223, and miR-29a) for early risk prediction and monitoring; and (5) Long-term evaluation of pharmacologic safety, including metformin and GLP-1 receptor agonists in pregnancy.

GDM exemplifies the critical link between reproductive and metabolic health, providing a unique opportunity to implement precision medicine strategies that interrupt the cycle of chronic disease transmission across generations. To fully harness this potential, clinical care models must evolve—driven by translational research, harmonized international guidelines, and a firm commitment to equity, prevention, and personalized care.