In this study, the correlation between GDM and novel inflammatory markers were analyzed using the representative US NHANES database. The results showed that SII, LMR, NLR and PLR were significantly associated with GDM, and these associations became more significant after adjusting for all covariates. LMR was positively associated with the risk of GDM, with the risk of GDM in the highest quartile of LMR being 1.78 times higher than that in the lowest quartile of pregnant women, while NLR, PLR, and SII were negatively associated with GDM, and our subgroup analyses suggested the stability of these findings.
To the best of our knowledge, this is the largest study to analyze the correlation between GDM and novel inflammatory markers up to now. SII, LMR, NLR, and PLR are novel inflammatory markers that have attracted much attention in recent years, and they are the combination of neutrophil counts, lymphocyte counts, platelet counts, and monocyte counts in the complete blood count, reflecting the state of immune inflammation better than a single source of blood counts. SII was initially used as a prognostic indicator of outcome in cancer patients, and is a novel marker of systemic immune inflammation, which has been widely used in the study of endocrine abnormalities, heart failure, myocardial infarction in the elderly, hepatic fibrosis, hyperlipidaemia, etc[13–15, 22, 26]. A prospective observational study in 2023 found that SII levels were higher in women with GDM than in healthy women, which is consistent with the findings of the present study, and also suggests that SII is useful in the prediction of GDM, and could be an adjunctive tool in the prediction of GDM[27]. A retrospective study of 467 pregnant women was conducted by Seval, which not only found that SII levels were higher in women with GDM than in healthy women, but also found that SII levels were significantly higher in the late than the early stages of pregnancy[28]. Wang concluded that NLR is a stable biomarker that reflects the systemic inflammatory response of the body, which is important for the diagnosis of cardiovascular and cerebrovascular diseases. Both Yildiz and Ning Han found that NLR levels were higher in patients with GDM than in healthy women[27, 29], which was consistent with our findings. NLRP3 and its effector molecules (Caspase-1, IL-1β, IL-18) were higher in women with GDM than in healthy women, potentially suggesting that GDM is a chronic inflammatory state[29]. It has also been shown that LMR and PLR can be used as prognostic indicators for cervical cancer patients with high accuracy, and the inclusion of LMR and PLR to routinely assess and monitor cancer conditions will better guide clinicians to adopt personalized treatments and improve patient prognosis[30]. Tumour development is largely influenced by the level of inflammation. Inflammatory markers can reflect the balance between tumour and inflammation in the body, and have also been proposed as predictors of tumour recurrence[30, 31]. Taken together, SII, LMR, NLR, and PLR have all been suggested to be closely associated with a variety of inflammatory diseases and are crucial in assessing disease prognosis.
The 75g oral glucose tolerance test has been used to diagnose gestational diabetes mellitus, which typically manifests between 24 and 28 weeks of pregnancy[32]. To lower the risk of GDM for both mother and fetus, it is imperative to look for indicators that can be utilized for early detection and screening of the disease[33, 34]. Prior to the diagnosis of GDM, both mother and fetus may have been exposed to a high-glucose environment to different degrees. Numerous perinatal conditions, including gestational diabetes, pre-eclampsia, and preterm labor, have been linked to intestinal dysbiosis and inflammation[35]. According to certain research. Insulin resistance and malfunctioning β-cells in the pancreas are closely linked to the development of GDM. Furthermore, endolipin and lipocalin are involved in the pathophysiology of GDM and are connected to the metabolism of glucose. Pregnant women with GDM have higher levels of endolipin and lower levels of lipocalin than normal pregnant women, which are related to oxidative stress and inflammation, and prolonged inflammatory stimulation may lead to the expression of aberrant insulin signaling pathways. Some studies have also shown that GDM patients have increased expression of both Toll-like receptor 4 (TLR4) and inflammatory cytokines, and NLRP3 levels are abnormally elevated in diabetic rats[36]. Among them, IL-1 is an inflammatory factor closely related to GDM and insulin resistance. And soybean isolate protein could attenuate the TLR4/NF-κB inflammatory pathway and reduce blood glucose level in GDM patients[37]. TGF-β is one of the most important inflammatory cytokines related to pregnancy and plays an important role in hormone secretion and embryonic development during pregnancy[38], and TGF-β induces GDM and pre-eclampsia. In GDM patients, the expression of IL-6, IL-1β, and TNF-α was elevated, which can inhibit the expression of GLUT-1, GLUT-4, GLUT-9, affect the insulin signaling pathway and promote the development of GDM[39]. Oxidative stress plays a prominent role in the pathological mechanisms of metabolic diseases, and the increase of glucose and lipids can promote reactive oxygen species production, which in turn affects insulin secretion signaling and promotes pancreatic β-cell apoptosis. And studies have shown that patients with GDM have elevated levels of oxidative stress, with significant elevations in thiobarbituric acid reactive substances, lipid hydroperoxide, malondialdehyde, and xanthine oxidase[40]. A prospective study has shown a positive correlation between the TyG index[41], which is a composite of glycaemia and lipids, and GDM risk, as compared to a single glycaemic index. 2024 The TyG index is a more accurate measure of the body's inflammation than is glucose, Lipids better reflect the inflammatory state of the body, is a factor that has been studied in many cardiovascular diseases in recent years, and may be used as a predictor of type 2 diabetes mellitus[42].
Some studies have shown that leukocytes, neutrophils, lymphocytes, monocytes and NLR in early pregnancy are clinically relevant in identifying individuals at high risk of GDM. Suheyla Gorar concluded that leukocyte and platelet counts are positively associated with the risk of GDM. Our study also confirms previous findings that GDM is associated with inflammatory markers. Its specific pathological mechanism is related to oxidative stress, which can induce GDM progression by mediating inflammatory responses, stimulating NF-κβ signaling and producing inflammatory factors such as TNF-α[43]. It is worth mentioning that pro-inflammatory factors can in turn impair insulin signaling and damage pancreatic β-cell function. Pro-inflammatory diets can increase the risk of GDM and pre-eclampsia[44], whereas multi-nutrient therapies have shown positive effects on improving endocrine abnormalities in GDM and may be associated with NF-κβ factors. Micro RNAs have an important role in the pathogenesis and therapeutic targets of GDM[45]. GDM patients have high levels of micro RNA-222 and micro RNA-17-5p, which are involved in insulin resistance and inflammatory signalling pathways to varying degrees. It has been suggested that micro RNA-17-5p/Mfn1/2/NF-κβ is a novel key target pathway for the treatment of GDM[46], and micro RNAs can also be used to predict the risk of GDM and its complications. However, further studies on the predictive value of micro RNA for GDM are still needed[47].
It has to be admitted that our study has some limitations. Firstly, this study is a cross-sectional study, which cannot accurately derive the causal relationship between GDM and novel inflammatory markers. Second, the diagnosis of GDM is still dependent on participants' self-report due to the lack of test data for 75g OGTT in the NHANES database. However, researchers from NHANES told participants that their positive answers to RHQ162 should exclude diabetes known before pregnancy during the interview questionnaires. What’s more, previous studies have shown the validity of using this self-reported GDM as definition of diagnosis[18–20, 48]. Third, although our study corrected for the interference of some common confounders, we could not exclude the interference of other confounders.