Glycated hemoglobin and risk stratification in gestational diabetes: An editorial perspective

Abstract

The diagnosis of gestational diabetes mellitus (GDM) is based on an oral glucose tolerance test (OGTT) performed according to the Carpenter-Coustan or the International Association of Diabetes and Pregnancy Study Groups criteria. Although universally recommended, the OGTT has limitations, including logistical challenges, poor reproducibility, and inability to detect antecedent glycemic exposure. These shortcomings have prompted interest in alternative markers such as glycated hemoglobin (HbA1c), alone or in combination with fasting plasma glucose. The established role of HbA1c, however, remains limited to ruling out pregestational diabetes in the first trimester. Additionally, elevated values in early pregnancy that do not reach diagnostic thresholds for diabetes may help identify women at risk of developing GDM and related complications. Currently, HbA1c is not used to diagnose GDM at 24-28 weeks because it underestimates maternal glycemia due to pregnancy-related hematologic changes. Emerging evidence indicates that elevated HbA1c at this gestational age independently predicts adverse perinatal outcomes beyond GDM status itself. While OGTT remains the standard for diagnosing GDM, this editorial explores the current evidence on the possible role of HbA1c as a complementary tool for risk stratification. HbA1c ≥ 5.9% (41 mmol/mol) appears to identify women at increased risk of adverse outcomes in both early and late pregnancy. However, prospective studies are needed before HbA1c can be integrated into risk-based care pathways.

Key Words: Risk stratification; Pregnancy glycemic biomarkers; Early gestational dysglycemia; Postpartum diabetes risk; Large-for-gestational age; Macrosomia

Core Tip: Glycated hemoglobin (HbA1c) is unreliable for diagnosing gestational diabetes mellitus (GDM) because pregnancy alters red cell turnover and induces hematologic variability, yet rising evidence suggests it may still offer prognostic value. Early-pregnancy HbA1c above 5.9% predicts later GDM, while mid- and late-pregnancy values above 5.7-5.9 percent correlate with fetal overgrowth, hypertensive disorders, cesarean delivery, and postpartum dysglycemia. Although not a replacement for the oral glucose tolerance test, HbA1c may help identify women at heightened metabolic risk. More studies are needed before HbA1c can be integrated into risk-stratification algorithms for GDM care.

This editorial refers to “Role of fasting glucose and glycated hemoglobin for gestational diabetes mellitus diagnosis: A prospective study” by Molina-Vega et al, 2026; https://doi.org/10.4239/wjd.v17.i1.112882.

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INTRODUCTION

Pregnancy is associated with a progressive rise in insulin resistance, driven by placental hormones and amplified by maternal adiposity. As pregnancy advances, maternal glucose sensitivity may decline by 40%-80%, leading to higher postprandial glucose levels to facilitate transplacental nutrient transfer[1]. Because insulin resistance peaks in mid- to late gestation, gestational diabetes mellitus (GDM) screening using an oral glucose tolerance test (OGTT) is performed at 24-28 weeks. GDM is defined as hyperglycemia first identified during pregnancy, with glucose levels above normal but not meeting the thresholds for overt diabetes[2].

Though OGTT is the recommended test for diagnosing GDM, it requires fasting, is time-intensive, involves multiple blood samples, and many women do not tolerate the oral glucose load[3]. Glycated hemoglobin (HbA1c) has been explored as an alternative to the OGTT, but its sensitivity is low, and a substantial proportion of women with GDM have HbA1c values within the normal or near-normal range[4-6]. Though HbA1c is not a substitute for OGTT, early and late-pregnancy HbA1c predicts adverse outcomes, including fetal overgrowth, cesarean delivery, and hypertensive disorders[5,7,8].

In this edition, a study published in World Journal of Diabetes by Molina-Vega et al[9] reconfirm that an alternative criteria employed during the coronavirus disease 2019 pandemic, based on fasting glucose and/or HbA1c, have low sensitivity for detecting GDM and cannot replace the OGTT. The criteria, however, identified women who tested negative on the standard OGTT but had a high-risk profile, including obesity and a history of delivery of neonates with macrosomia. This group showed a significantly higher likelihood of delivering large-for-gestational-age (LGA) babies. This raises the important question of whether HbA1c may have a role in risk stratification in GDM. In this editorial, we review and briefly discuss the current evidence to explore that possibility.

LITERATURE SEARCH STRATEGY

We assessed the literature by searching the commonly used biomedical databases, including PubMed and EMBASE. Search terms included “glycated haemoglobin” or “HbA1c” in combination with “gestational diabetes”, “pregnancy”, and “pregnancy outcomes”. We reviewed the observational studies, randomized controlled trials, and systematic reviews and meta-analyses published till November 2025 that examined HbA1c in relation to GDM and pregnancy outcomes. As this is an editorial, studies were selected based on relevance to clinical practice rather than strict methodological criteria.

LIMITATIONS OF HBA1C IN PREGNANCY

HbA1c is systematically underestimated during pregnancy due to pregnancy-induced physiologic anemia and accelerated red blood cell turnover. Pregnancy causes a 40%-50% expansion of plasma volume and increases erythropoiesis, shortening the red blood cell lifespan from 120 days to 90-100 days. This results in a younger red blood cell population with lower HbA1c content circulating at any given time, causing HbA1c to be artificially low[10]. The effect of anemia on HbA1c could be biphasic, with values appearing falsely low in the first trimester and artificially high later on. This could be attributed to hemodilution and faster red cell turnover in early pregnancy, but later on, iron deficiency can prolong red cell lifespan and falsely elevate HbA1c levels[11].

A longitudinal study by Edelson et al[12], which tracked pregnancies with risk factors for GDM, validated the above findings. The results showed that mean OGTT glucose levels increased significantly between the 10-15 and 24-30 weeks, while HbA1c levels decreased during this period. The discrepancy in HbA1c and mean OGTT glucose in the 1^st trimester was 1.2 mg/dL (0.07 mmol/L). The discrepancy widened to 13.2 mg/dL (0.73 mmol/L) between 24 and 30 weeks[12]. Additionally, the availability and affordability of HbA1c vary across countries and health-care settings. Ethnic differences, hemoglobinopathies, and hemolytic anemia can all lead to discordance in HbA1c[6].

HBA1C IS UNRELIABLE FOR THE DIAGNOSIS OF GDM

The Hyperglycemia and Adverse Pregnancy Outcome study compared HbA1c and OGTT at 24-32 weeks’ gestation. Findings indicate that glucose measures showed a stronger association than HbA1c with key neonatal outcomes, including birth weight, skinfold thickness, and percent body fat above the 90^th percentile. Fasting and 1-hour glucose values also had significant associations with cord C-peptide levels. In fully adjusted models, effect sizes for HbA1c were lower for both birth weight and elevated cord C-peptide, reinforcing its limited value as a predictor compared with glucose measures[4].

GDM primarily occurs due to pregnancy-induced insulin resistance on the background of underlying beta-cell dysfunction[13]. The OGTT directly measures glycemic response to a glucose load and captures postprandial excursions that drive fetal hyperinsulinemia and adverse outcomes. HbA1c, in contrast, reflects an average over preceding weeks and is influenced by pregnancy-related changes in red cell turnover, hemodilution, and iron status, making it an unreliable marker of glycemia during gestation[14].

ROLE OF HBA1C IN EARLY PREGNANCY

HbA1c is primarily used to screen for pregestational overt diabetes in early pregnancy[15]. The American Diabetes Association also suggests that HbA1c ≥ 5.9% (41 mmol/mol) is indicative of early abnormal glucose metabolism and may identify pregnancies at higher risk of preeclampsia, macrosomia, shoulder dystocia, perinatal death, and subsequent GDM[2]. However, despite its value in risk prediction, the benefit of early intervention at this HbA1c threshold remains unproven.

Elevated HbA1c in early pregnancy can predict incident GDM at 24-28 weeks[16]. A study by Saravanan et al[17] demonstrated that early-pregnancy HbA1c levels could reduce the number of OGTTs needed in three cohorts from India, Kenya, and the United Kingdom. The rule-in thresholds identified were 5.4% (36 mmol/mol) in India, 6.0% (42 mmol/mol) in Kenya, and 5.6% (38 mmol/mol) in the United Kingdom. A systematic review and meta-analysis including 16 studies with a total of 43627 women reported that an early pregnancy HbA1c > 5.7% (39 mmol/mol) had the strongest association with adverse pregnancy outcomes, including pre-eclampsia, LGA births, macrosomia, and preterm delivery[18].

Although higher HbA1c levels in early pregnancy below the diagnostic range for diabetes predict GDM and adverse outcomes, current international guidelines do not endorse HbA1c as a threshold for intervention because of insufficient evidence. Studies have reported threshold values in the range of 5.25% (33 mmol/mol) to 6.0% (42 mmol/mol), with positive predictive values varying widely from 0.13 to 0.74[16].

The benefits of treatment in early GDM have not been proven conclusively. The Treatment of Booking Gestational Diabetes Mellitus trial showed a modest reduction in adverse neonatal outcomes primarily due to lower rates of neonatal respiratory distress. Subgroup analyses suggest that early treatment in women with milder abnormalities may increase the risk of small-for-gestational-age[19]. Many women diagnosed with early GDM had a regression of hyperglycemia by mid-pregnancy[20]. Systematic reviews have not demonstrated consistent benefit, indicating that early treatment is unlikely to help all women and may need to be targeted[21].

HBA1C AS AN ADDITIONAL PROGNOSTIC MARKER AT 24-28 WEEKS

The American Diabetes Association recommends maintaining HbA1c below 6%-6.5% (42-48 mmol/mol) in pregnancies with preexisting diabetes, as observational data suggests fetal risk is lowest below this level[15]. In the Hyperglycemia and Adverse Pregnancy Outcome cohort, HbA1c showed correlations with several adverse pregnancy outcomes. Higher maternal HbA1c levels were associated with increased rates of LGA infants, primary cesarean delivery, and elevated cord C-peptide. For example, individuals in the highest HbA1c category [≥ 5.8% (40 mmol/mol)] had a 2.72 times higher likelihood of having a birth weight > 90^th percentile than those in the lowest category [< 4.5% (37 mmol/mol)]. However, these associations were weaker than those seen with OGTT glucose values and lost significance once glucose measures were included in the model[4].

Several other studies indicate that the HbA1c levels at 24-28 weeks correlate with adverse pregnancy outcomes. Analysis of a retrospective cohort of 3098 pregnancies showed that the likelihood of LGA [odds ratio (OR) 2.7], macrosomia (OR 3.5), cesarean delivery (OR 3.6), and hypertensive disorders (OR 2.6) was significantly higher above HbA1c ≥ 5.9% (41 mmol/mol)[7]. Individuals with obesity and GDM have higher rates of preeclampsia, cesarean delivery, macrosomia, and neonatal intensive care admission, with both elevated body mass index (BMI) and higher HbA1c being independent predictors[22]. In a retrospective study, higher HbA1c at 24-28 weeks was associated with increased risks of macrosomia, pregnancy-induced hypertension, preterm birth, and primary cesarean delivery. These associations varied by maternal age, pregestational BMI, and gestational weight gain, indicating that baseline maternal characteristics modify risk[5].

HbA1c levels measured in late pregnancy also serve as a predictor of persistent glucose intolerance and future risk of type 2 diabetes mellitus (T2DM). Women with HbA1c ≥ 5.4% (36 mmol/mol) are 5.5-6.1 times more likely to develop T2DM after pregnancy, making it a useful marker for long-term diabetes risk stratification. Early identification of these high-risk women can guide lifestyle interventions and close monitoring to prevent or delay the onset of T2DM[23,24].

CAN HBA1C HELP IN RISK STRATIFICATION IN GDM?

Current evidence indicates that HbA1c ≥ 5.7% (39 mmol/mol) in early pregnancy marks an increased risk of later GDM, hypertensive disorders, fetal malformations, and postpartum dysglycemia[18]. Additionally, values ≥ 5.7% (39 mmol/mol) in late pregnancy correlate with several adverse maternal and neonatal outcomes[5,7,14]. HbA1c ≥ 5.9% (41 mmol/mol) at 24-28 weeks is linked to failure of lifestyle therapy, earlier insulin requirement, and impaired beta-cell function[7,9]. Higher late-pregnancy HbA1c also predicts persistent postpartum glucose intolerance and future T2DM[23,24]. Additionally, an early pregnancy HbA1c of 5.9%-6.4% (41-47 mmol/mol) was associated with a higher 5 year incidence of T2DM (63% vs 6.4%) compared with women who developed GDM later but had HbA1c < 5.9%. Risk increased progressively, reaching a hazard ratio of 16.7 at HbA1c 6.2%-6.4%[25].

Most guidelines restrict the use of HbA1c to identify or follow overt or preexisting diabetes, rather than for diagnosing milder degrees of dysglycemia and GDM[26-29]. However, the recent 2025 Australasian Diabetes in Pregnancy Society consensus have included HbA1c in the diagnostic pathway[30]. The guideline recommends first trimester HbA1c testing in women with risk factors for hyperglycemia in pregnancy. An HbA1c ≥ 6.5% (≥ 48 mmol/mol) should be treated as overt diabetes in pregnancy. Women with prior gestational diabetes or HbA1c 6.0%-6.4% (42-47 mmol/mol) should undergo a 75 g oral glucose tolerance test before 20 weeks, preferably between 10 and 14 weeks.

Thus emerging data highlights the potential utility of HbA1c for risk stratification, but its susceptibility to ethnic variation and to hematologic changes underlines the need for cautious interpretation. Well designed, prospective studies across diverse populations, with careful consideration of anemia and iron status, are needed to support the integration of HbA1c into risk-based approaches for GDM care.

WHAT THE STUDY BY MOLINA-VEGA ET AL ADDS

The study by Maria Molina-Vega et al[9] evaluated 354 singleton pregnancies to assess the utility of alternative diagnostic criteria, defined as a fasting plasma glucose ≥ 95 mg/dL (5.3 mmol/L) and/or HbA1c ≥ 5.7% (39 mmol/mol), by comparing them against the standard 100-g OGTT. The alternative criteria demonstrated high specificity (91.2%) but low sensitivity (25.0%) relative to the OGTT, with a positive predictive value of 45.4%, and a negative predictive value of 80.6%. Using OGTT as the reference standard, receiver operating characteristic analysis demonstrated modest discriminatory ability of fasting plasma glucose [area under curve (AUC) 0.664, 95% confidence interval (CI): 0.592-0.736], HbA1c (AUC 0.647, 95%CI: 0.578-0.716), or their combination (AUC 0.681, 95%CI: 0.613-0.750), thereby reconfirming the limited role of HbA1c-based criteria in the diagnosis of GDM.

The criteria additionally identified a high-risk group of women whose OGTT results were negative but met the alternative criteria. The prevalence of pregestational obesity was 70.8% in this group, whereas it was 28.3% among women who were positive only on OGTT. The group had a high prevalence of LGA newborns (29.4%), comparable to pregnancies that were OGTT positive, and significantly higher than those negative by both criteria (12.4%). Univariate logistic analysis suggested that positive alternative criteria were associated with LGA newborns; however, in multivariate analysis, only history of macrosomia and pregestational BMI remained independently associated. Though OGTT remains the diagnostic gold standard, in this study, HbA1c-based criteria identified a subgroup that would have been missed by OGTT alone, suggesting a potential role for HbA1c in risk stratification or as an adjunct to OGTT. However, the study is limited by a relatively small sample size and restricted population representation.

CONCLUSION

Although HbA1c is not recommended as a standalone diagnostic test for GDM, available data suggest that certain thresholds may help identify women at increased metabolic risk. Early pregnancy HbA1c values around 5.9% (41 mmol/mol) predict later GDM, while levels above 5.7%-5.9% (39-41 mmol/mol) at 24-28 weeks correlate with several maternal and neonatal complications. Higher HbA1c also signals the need for insulin requirement and a greater likelihood of postpartum dysglycemia. These findings suggest that HbA1c could play a role in risk stratification. Additionally, it remains to be determined whether HbA1c-based criteria identify high-risk pregnancies not captured by OGTT. Interpretation must account for anemia, iron deficiency, and ethnic variation, all of which independently affect HbA1c. Population-specific cut-offs may be necessary, especially in regions with high rates of GDM, nutritional anemia, and hemoglobinopathies. The current evidence supports re-examining HbA1c as part of a broader, multifactorial risk assessment rather than a diagnostic tool, with a clear need for well-designed studies to define how best to integrate it into pregnancy care.