Gestational diabetes mellitus poses significant maternal and fetal health risks worldwide. Clinicians continue to seek accessible biomarkers that can identify high-risk pregnancies before conventional testing windows. Recently, researchers examined the utility of NLR in gestational diabetes as a cost-effective marker derived from routine complete blood counts. While systemic inflammation drives insulin resistance during pregnancy, the definitive diagnostic capacity of this inflammatory ratio remains uncertain.

Pathophysiological Rationale of NLR in Gestational Diabetes

Pregnancy induces dynamic immunological shifts that support fetal development while preserving maternal defense. However, excessive low-grade systemic inflammation can impair beta-cell compensation and exacerbate insulin resistance. Neutrophils act as primary responders in acute and chronic inflammatory cascades, releasing proteolytic enzymes and reactive oxygen species. In contrast, lymphocytes modulate regulatory pathways and maintain immune tolerance. An elevated neutrophil-to-lymphocyte ratio reflects heightened innate immune activation coupled with relative adaptive immune suppression. Consequently, investigators hypothesized that this hematologic balance could signal metabolic dysfunction before hyperglycemia manifests. Because complete blood counts represent routine antenatal care, calculating this ratio requires no additional venipuncture or expense. Therefore, clinicians find the parameter attractive for early gestational screening. Furthermore, metabolic endotoxemia and maternal adipose inflammation stimulate continuous neutrophil recruitment into vascular beds. This vascular stress interferes with glucose transporter signaling and worsens postprandial glucose excursions. Nevertheless, physiological leukocytosis normally occurs during gestation, complicating the interpretation of inflammatory indices. Thus, clinicians must distinguish between expected pregnancy-induced hematologic adaptations and true pathologic inflammation when evaluating maternal risk profiles. Accordingly, establishing verified baseline thresholds is vital before adopting this metric in clinical workflows.

Diagnostic Accuracy of NLR Across Gestational Trimesters

A systematic review and meta-analysis synthesized data from eleven studies and twelve datasets to evaluate clinical accuracy. All included investigations utilized the oral glucose tolerance test as the definitive reference standard. In the first trimester, pooled sensitivity reached 0.702, whereas pooled specificity was only 0.426. The summary area under the curve measured 0.694, indicating poor discriminative power for early risk stratification. Consequently, first-trimester testing misclassifies many healthy pregnant women as high risk. In the second trimester, diagnostic accuracy improved modestly. Specifically, pooled sensitivity reached 0.665, pooled specificity achieved 0.644, and the summary area under the curve rose to 0.798. Furthermore, exploratory analyses of studies using cutoffs of 3.0 or less demonstrated higher area under the curve values of 0.845 in early pregnancy and 0.850 in mid-pregnancy. However, investigators did not formally test subgroup differences, limiting statistical confidence in these threshold observations. Additionally, wide confidence intervals across studies underscore substantial diagnostic variability. Therefore, while second-trimester testing exhibits better discriminatory ability than first-trimester assessments, neither trimester achieves the diagnostic accuracy necessary for independent clinical decision-making. These findings confirm that the biomarker cannot replace standard biochemical testing.

Methodological Limitations and Index-Test Bias in Existing Evidence

Despite encouraging preliminary findings, critical appraisal reveals profound methodological flaws across published literature. Most notably, all included studies carried a high risk of index-test bias due to post hoc threshold selection. Researchers frequently selected cutoff points that maximized sensitivity and specificity within their specific datasets. Consequently, these data-driven cutoffs artificially inflated reported diagnostic accuracy. Furthermore, seven of the eleven studies employed retrospective case-control designs rather than prospective cohort structures. Case-control methodologies inherently introduce selection bias and distort predictive accuracy by overestimating disease discrimination. Additionally, the meta-analysis revealed substantial statistical and clinical heterogeneity among datasets. Variations in maternal age, gestational age at sampling, body mass index, and ethnic risk contributed significantly to this observed variance. Laboratory analytical methods also varied, including differences in automated hematology analyzers and sample handling techniques. Moreover, few studies accounted for confounding inflammatory conditions, such as asymptomatic urinary tract infections, periodontal disease, or gestational hypertensive disorders. Therefore, the lack of rigorous methodological standardization prevents researchers from establishing a universally reliable reference interval. These substantial limitations emphasize why clinicians cannot translate current findings into clinical practice.

Clinical Implications for Obstetric and Endocrine Practice

In clinical obstetrics and endocrinology, timely identification of glycemic intolerance is crucial to prevent adverse outcomes. Maternal hyperglycemia increases the risks of macrosomia, birth trauma, preeclampsia, and emergency cesarean deliveries. However, based on current systematic evidence, practitioners must not utilize this hematologic ratio as a standalone diagnostic instrument. Furthermore, it should never replace the established oral glucose tolerance test. Nevertheless, the ratio may serve as an adjunctive risk marker within multimodal stratification pathways. When clinicians evaluate high-risk women, an elevated ratio might prompt heightened vigilance and reinforced lifestyle guidance. For instance, obstetricians might recommend earlier dietary modifications, physical exercise, and closer weight tracking when early inflammatory signals align with traditional risk factors. These traditional factors include maternal age, family history of type 2 diabetes, polycystic ovary syndrome, and elevated pre-pregnancy body mass index. Additionally, combining hematologic inflammatory markers with biochemical measures like fasting plasma glucose or glycosylated hemoglobin could potentially refine early prediction models. However, clinicians must avoid initiating medical therapy solely on elevated white cell ratios. Premature interventions based on unvalidated surrogate markers generate unnecessary patient anxiety and maternal distress.

Future Directions and Prospective Validation Requirements

Bridging the gap between translational biomarker research and clinical implementation demands rigorous future investigation. First, researchers must conduct large, multicenter prospective cohort studies across ethnically diverse pregnant populations. These investigations must pre-specify diagnostic cutoff values before data collection rather than deriving thresholds retrospectively. Moreover, independent external validation cohorts are mandatory to confirm reproducible diagnostic sensitivity and specificity. Standardizing pre-analytical sample collection protocols and reporting blood cell counts precisely will also minimize laboratory-induced variability. Furthermore, researchers should explore whether longitudinal changes in inflammatory ratios offer better prognostic insight than isolated single-point measurements. Tracking serial inflammatory trends from the first through the second trimester may better reflect evolving beta-cell stress and placental endocrine activity. Additionally, health economic analyses should evaluate whether incorporating hematologic ratios into tiered screening algorithms yields cost-effective reductions in maternal morbidity. Machine learning algorithms that integrate hematologic parameters with clinical risk scores, maternal lipidomics, and placental biomarkers could further enhance early risk discrimination. Until these high-quality prospective studies provide definitive validation, professional guidelines should continue emphasizing standardized oral glucose tolerance testing as the gold standard for gestational diabetes diagnosis.

Can the neutrophil-to-lymphocyte ratio replace the oral glucose tolerance test?

No, the neutrophil-to-lymphocyte ratio cannot replace the oral glucose tolerance test. Current evidence demonstrates that the ratio lacks sufficient sensitivity and specificity to function as an independent diagnostic test. The oral glucose tolerance test directly evaluates dynamic maternal carbohydrate metabolism and remains the international reference standard. Relying solely on hematologic ratios would result in unacceptable rates of missed diagnoses and false-positive results, compromising maternal and fetal care.

Why is there no universal cutoff value for this inflammatory ratio?

There is no universally accepted cutoff because published studies relied on post hoc statistical analyses. Investigators selected arbitrary thresholds that optimized diagnostic accuracy within their specific study cohorts. Consequently, reported cutoff values varied widely across different centers. Moreover, maternal gestational age, race, body mass index, and physiological leukocytosis influence leukocyte counts significantly. Without prospective validation using prespecified thresholds across large populations, clinical guidelines cannot establish a definitive diagnostic threshold.

How can obstetricians utilize this ratio in current clinical practice?

Obstetricians may consider this ratio as an adjunctive indicator rather than a diagnostic tool. When calculated from routine antenatal complete blood counts, elevated values may highlight patients with elevated baseline systemic inflammation. Clinicians can integrate this finding with conventional risk factors like maternal age and pre-pregnancy obesity. This comprehensive assessment encourages early dietary counseling, lifestyle intervention, and strict adherence to scheduled screening, without altering standardized diagnostic testing pathways.

Disclaimer: This content is for informational and educational purposes only... Refer to the latest local and national guidelines for clinical practice.

References

1. Chen L et al. Adjunctive screening and risk stratification performance of neutrophil-to-lymphocyte ratio for gestational diabetes mellitus: A systematic review and meta-analysis. Biomol Biomed. 2026 Sep 28. doi: 10.17305/bb.2026.14713. PMID: 42804757.
2. Zhao Y, Sun X, Yuan L, Zhang M. A prospective cohort study on the association between neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and gestational diabetes mellitus in Chinese pregnant women. Front Endocrinol (Lausanne). 2025;16:1356789.
3. Yilmaz H, Celik HT, Namuslu M, Inan O, Onaran Y, Karakurt F. Benefits of the neutrophil-to-lymphocyte ratio for the prediction of gestational diabetes mellitus in pregnant women. Exp Clin Endocrinol Diabetes. 2014;122(1):39-43.