Associations of Systemic Immune-Inflammation Index and Systemic Inflammation Response Index with Maternal Gestational Diabetes Mellitus: Evidence from a Prospective Birth Cohort Study
Gestational diabetes mellitus (GDM) is a significant health concern during pregnancy, affecting approximately 16.70% of pregnant women globally. It is associated with adverse perinatal outcomes such as preterm labor, preeclampsia, cesarean section, macrosomia, and birth defects. Furthermore, women with GDM face an increased risk of developing type 2 diabetes mellitus (T2DM), metabolic syndrome, cardiovascular disease, and malignancies postpartum. Their offspring are also more susceptible to glucose irregularities and obesity throughout their lives. With the rising prevalence of pre-pregnancy obesity and delayed childbearing age, the health implications of GDM are expected to impact an expanding population. Identifying risk factors and understanding the underlying mechanisms of GDM are crucial for its prevention.
Inflammation has recently emerged as a focal point in GDM research. Studies have established correlations between GDM and various inflammatory mediators, including interleukins (ILs) and tumor necrosis factor-α (TNF-α). Additionally, individual inflammatory indicators from routine blood tests, such as white blood cell (WBC), neutrophil (Neut), lymphocyte (Lymph), monocyte (Mono), and platelet (PLT) counts, have been linked to GDM. Derived indices like the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have also been explored. However, most studies have been limited by small sample sizes, case-control or cross-sectional designs, and a focus on mid-to-late gestation indices, leaving early trimester indices understudied.
The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) are novel indices that reflect the body’s chronic immune-inflammatory state. The SII is calculated as Neut count × PLT count / Lymph count, while the SIRI is calculated as Neut count × Mono count / Lymph count. These indices have been associated with cardiovascular diseases, neoplasms, diabetes, and metabolic syndrome. Compared to the NLR and PLR, the SII and SIRI provide a more comprehensive measure of immune-inflammatory status by incorporating multiple cell types. However, few studies have examined the associations between these indices and GDM. This study aimed to investigate the relationships between first-trimester SII and SIRI and the development of GDM in a large prospective birth cohort.
The study was conducted at Beijing Obstetrics and Gynecology Hospital from February 2018 to December 2020. Pregnant women in their first trimester were recruited, and baseline SII and SIRI values were derived from routine clinical blood tests. Participants were grouped into quartiles based on their SII or SIRI values. GDM was diagnosed using a 75-g, 2-hour oral glucose tolerance test (OGTT) at 24–28 weeks of gestation, following the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Logistic regression was used to analyze the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between SII, SIRI, and GDM risk.
Among the 28,124 women included in the study, the average age was 31.8 years, and 15.76% (4,432/28,124) developed GDM. Higher SII and SIRI quartiles were associated with increased GDM rates. For the SII, GDM rates ranged from 12.26% in the lowest quartile to 20.10% in the highest quartile. Similarly, for the SIRI, rates increased from 11.92% to 19.31% across quartiles. The ORs for GDM risk in the second, third, and fourth SII quartiles were 1.09, 1.21, and 1.39, respectively. For the SIRI, the ORs were 1.24, 1.41, and 1.64, respectively. These associations remained consistent in subgroup and sensitivity analyses.
The study’s findings suggest that elevated SII and SIRI levels in the first trimester are independent risk factors for GDM. Chronic low-grade inflammation, as reflected by these indices, may play a pivotal role in the pathogenesis of GDM. The SII and SIRI provide a more comprehensive measure of systemic inflammation compared to traditional indices like the NLR and PLR, making them promising markers for assessing GDM risk.
The study also explored potential mechanisms linking inflammation to GDM. Neutrophil overactivation in GDM patients can lead to the release of reactive oxygen species and neutrophil extracellular traps (NETs), contributing to insulin resistance (IR). Regulatory T cells (Tregs) in non-GDM patients inhibit proinflammatory responses, but Tregs are functionally impaired in GDM patients. Platelets, activated by inflammation, may also indirectly reflect the inflammatory state. The SII and SIRI, which incorporate Neut, Lymph, Mono, and PLT counts, offer a holistic view of systemic immune inflammation, highlighting their potential role in GDM development.
The study’s strengths include its large sample size, prospective design, and comprehensive adjustment for confounders such as pre-pregnancy BMI, history of GDM, and blood glucose and lipid levels. However, limitations include its single-center design, which may limit generalizability, and the lack of data on other inflammatory markers like interleukin-6 and C-reactive protein. Additionally, the study did not explore the mechanistic roles of SII or SIRI-associated blood cells in GDM pathophysiology.
In conclusion, this study provides robust epidemiological evidence that elevated SII and SIRI levels in early pregnancy are associated with an increased risk of GDM. These indices serve as valuable markers for assessing systemic inflammation and identifying women at higher risk of developing GDM. Maintaining appropriate levels of immune inflammation during pregnancy may help mitigate GDM risk. Further research is needed to validate these findings and elucidate the underlying mechanisms of SII and SIRI in GDM.
doi.org/10.1097/CM9.0000000000003236
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