Associations of systemic immune-inflammation index and systemic inflammation response index with maternal gestational diabetes mellitus: Evidence from a prospective birth cohort study

Abstract

Background:

The role of inflammation in the development of gestational diabetes mellitus (GDM) has recently become a focus of research. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI), novel indices, reflect the body’s chronic immune-inflammatory state. This study aimed to investigate the associations between the SII or SIRI and GDM.

Methods:

A prospective birth cohort study was conducted at Beijing Obstetrics and Gynecology Hospital from February 2018 to December 2020, recruiting participants in their first trimester of pregnancy. Baseline SII and SIRI values were derived from routine clinical blood results, calculated as follows: SII = neutrophil (Neut) count × platelet (PLT) count/lymphocyte (Lymph) count, SIRI = Neut count × monocyte (Mono) count/Lymph count, with participants being grouped by quartiles of their SII or SIRI values. Participants were followed up for GDM with a 75-g, 2-h oral glucose tolerance test (OGTT) at 24–28 weeks of gestation using the glucose thresholds of the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Logistic regression was used to analyze the odds ratios (ORs) (95% confidence intervals [CIs]) for the the associations between SII, SIRI, and the risk of GDM.

Results:

Among the 28,124 women included in the study, the average age was 31.8 ± 3.8 years, and 15.76% (4432/28,124) developed GDM. Higher SII and SIRI quartiles were correlated with increased GDM rates, with rates ranging from 12.26% (862/7031) in the lowest quartile to 20.10% (1413/7031) in the highest quartile for the SII (P_trend <0.001) and 11.92–19.31% for the SIRI (P_trend <0.001). The ORs (95% CIs) of the second, third, and fourth SII quartiles were 1.09 (0.98–1.21), 1.21 (1.09–1.34), and 1.39 (1.26–1.54), respectively. The SIRI findings paralleled the SII outcomes. For the second through fourth quartiles, the ORs (95% CIs) were 1.24 (1.12–1.38), 1.41 (1.27–1.57), and 1.64 (1.48–1.82), respectively. These associations were maintained in subgroup and sensitivity analyses.

Conclusion:

The SII and SIRI are potential independent risk factors contributing to the onset of GDM.

Introduction

Gestational diabetes mellitus (GDM) poses a significant threat to maternal and neonatal health during pregnancy, with a global prevalence of 16.70% among pregnant women.^[1] GDM is associated with an increased risk of adverse perinatal outcomes, including preterm labor, preeclampsia, cesarean section, macrosomia, and birth defects.^[2,3,4] Longitudinally, women with GDM are at an elevated risk for developing type 2 diabetes mellitus (T2DM), metabolic syndrome, cardiovascular disease (CVD), and malignancies postpartum.^[5,6] Moreover, their offspring exhibit increased susceptibility to glucose irregularities and obesity throughout childhood, adolescence, and adulthood.^[7,8] With the postponement of marriage and childbearing age, coupled with the increasing prevalence of pre-pregnancy obesity and overweight caused by poor lifestyle and dietary structure, the health implications of GDM are expected to affect an expanding population of pregnant women and their progeny. Therefore, identifying risk factors and elucidating the etiology of GDM are imperative to prevent it.

The underlying pathophysiologic mechanisms driving the development of GDM have not yet been fully clarified.^[9] The involvement of inflammation in the development of GDM has emerged as a focal point of recent research.^[10] Prior research has established a correlation between GDM or T2DM and various inflammatory mediators, including interleukins (ILs) and tumor necrosis factor-α (TNF-α).^[11,12] Beyond the aforementioned inflammatory mediators, research has identified correlations between GDM and individual inflammatory indicators obtained from routine clinical blood tests, such as white blood cell (WBC), neutrophil (Neut), lymphocyte (Lymph), monocyte (Mono), and platelet (PLT) counts. Several studies have also examined the relationship between GDM and derived indices calculated based on two indicators: the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR).^{[13,14,15,16,17,18]} One systematic review revealed a significantly greater NLR in GDM pregnancies than in non-GDM controls, with noted heterogeneity among the studies.^[15] Another systematic review also observed a greater PLR in pregnant women diagnosed with GDM than in pregnant women without GDM, albeit the difference was not statistically significant.^[16] Nevertheless, a significant proportion of past studies have utilized case–control or cross-sectional designs and are characterized by fairly limited sample sizes. Furthermore, the majority of these studies have focused on analyzing inflammatory indices in the mid-to-late stages of gestation (post-20 weeks), with early trimester indices receiving minimal consideration.

The systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI) are novel indices recently identified to reflect the body’s chronic systemic immune-inflammatory status. The SII and SIRI were calculated as follows: SII = Neut count × PLT count/Lymph count, SIRI = Neut count × Mono count/Lymph count. Hu et al^[19] first proposed these indices in 2014, and both indices are associated with cardiovascular and neoplastic diseases^[20,21,22] as well as with diabetes and metabolic syndrome.^[23,24] Compared with the NLR and PLR, which only consider the proportions of two types of cells at the same time, the SII and SIRI take into account the impact of several indicators such as Neut, Lymph, Mono, and PLT, and offer a more holistic measure of the body’s immune-inflammatory status. However, there is a paucity of studies that have assessed the associations between the SII or SIRI and GDM. Further evidence is needed from prospective studies with larger samples examining routine clinical inflammatory factors and GDM. Therefore, this study aimed to investigate the relationships of maternal first-trimester SII and SIRI with the development of GDM based on a birth cohort study located in Beijing, China.

Methods

Ethical approval

The study was carried out according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University (approval No. 2018-KY-003-02). All individual participants provided informed consent for participating this study.

Participants and study design

A single-center prospective cohort study design was employed. The cohort study enrolled pregnant women who underwent prenatal registration at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, from February 2018 to December 2020 and who had taken part in the China Birth Cohort Study (CBCS).^[25] The inclusion criteria for pregnant women in the present study were as follows: (1) singleton pregnancy; (2) absence of preconception diabetes or fasting blood glucose (FBG) levels below 7.0 mmol/L at the initial prenatal visit; (3) no prior history of chronic diseases that could impact hematologic assessments; (4) negative serostatus for hepatitis B, hepatitis C, syphilis, and human immunodeficiency virus; (5) no experience of cold or fever during the first trimester; and (6) no use of medication that could influence hematologic or lipid profiles during pre- or early pregnancy.

All participants completed a baseline questionnaire evaluating pre- and early pregnancy risk factors, which included sociodemographic data such as age, ethnicity, education level, occupation, and body measurements. Data on previous pregnancies (including the number, complications, and outcomes) and current pregnancy details (such as the conception method and fetus count) were also collected. Subsequent sections inquired about health status before and during early pregnancy, covering reported illnesses or medications, lifestyle habits, and vitamin consumption, especially folic acid and multivitamin use.

Longitudinal follow-up assessments were performed during mid-pregnancy, late pregnancy, and postpartum, coinciding with routine prenatal examinations at gynecology and obstetrics hospitals. Corresponding maternal and fetal data were collected through in-person interviews utilizing structured questionnaires at each follow-up point. In addition, by matching the database with the discharge diagnosis data on the first page of the hospital medical records system, the outcomes of mothers and infants in the cohort were passively followed up. Data regarding maternal and neonatal outcomes during pregnancy (including various pregnancy complications such as GDM) and documented pregnancy outcomes (encompassing birth defects and occurrences of induced labor) were also collected.

Laboratory measurements

Morning fasting venous blood samples from all participants were collected during routine clinical examinations. All specimens underwent full anticoagulation and were analyzed within 1 h of collection. Routine blood measurements (including WBC, Neut, Mono, Lymph, PLT, and red blood cell [RBC] counts) were performed using an automated hematology analyzer in the hospital’s clinical laboratory department. All operations were conducted strictly according to the instrument’s standard operating procedures. Other clinical laboratory measurements—including triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and FBG level—were also measured in accordance with standard operating procedures.

Oral glucose tolerance test (OGTT) and GDM diagnosis

The GDM diagnosis involved a one-step OGTT at 24–28 weeks of gestation. The OGTT protocol was as follows: an FBG sample was collected following 8–10 h of fasting (0 h); subsequently, the participants ingested 75 g of glucose, and blood samples were drawn at 1 h and 2 h post-ingestion. GDM diagnosis was confirmed when one or more blood glucose readings exceeded the established OGTT threshold values—FBG >5.1 mmol/L or blood glucose >10 mmol/L at the first hour and >8.5 mmol/L at the second hour—according to the guidelines of the International Association of Diabetes and Pregnancy Study Groups (IADPSG).^[26] In addition, data from case diagnosis system of the hospital were used to supplement and verify the clinical diagnoses of the cohort of pregnant women in terms of pregnancy comorbidities and pregnancy outcomes. For pregnant women who could not be identified in the case diagnosis system, telephone follow-up was used to obtain their pregnancy outcomes.

Statistical analysis

Pre-pregnancy body mass index (BMI) was calculated by dividing weight in kilograms by the square of height in meters. Folic acid supplementation was defined as the intake of folic acid preparations, either alone or in combination, within three months prior to pregnancy and during early pregnancy. This included continuous consumption for at least one week at a minimum frequency of five days per week, with a dosage of no less than 400 units per day. Multivitamin supplementation was defined as the intake of vitamin preparations, either alone or in combination, within three months prior to pregnancy and during early pregnancy. This included continuous consumption for at least one week at a minimum frequency of five days per week, with a dosage of no less than 400 units per day. The gestational age of the fetus was determined based on the date of the last menstrual period (LMP) or ultrasound measurements during the first trimester. Gestational periods from 6 weeks to 13⁺⁶ weeks were classified as the first trimester. The SII and SIRI were calculated as follows: SII = Neut count × PLT count/Lymph count, SIRI = Neut count × Mono count/Lymph count. The participants were stratified into quartiles following the methods of other studies on the SIRI and SII correlations with non-GDM diseases. Baseline characteristics across quartiles of the SII or SIRI were analyzed using the chi-squared test for categorical variables and the Kruskal–Wallis test for continuous variables. Directed acyclic graph (DAG) analysis was utilized to examine the confounding factors influencing the associations among the SII, SIRI, and GDM. The Cochran–Armitage test was employed to assess trends in the associations between increasing quartiles of the SII or SIRI and GDM incidence rates. Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the incidence of GDM across quartiles of the SII or SIRI, with the first quartile serving as the reference category. We employed restricted cubic spline (RCS) analysis in the multivariate logistic regression model to explore the non-linear relationships among the continuous SII, SIRI, and GDM, with four knots. Subgroup and interaction analyses were performed based on the SII, SIRI, and GDM influencing factors. Heterogeneity in subgroup associations were tested by incorporating multiplicative interaction terms into the models and employing likelihood ratio tests. Sensitivity analyses was performed by excluding the following participants: those with a history of GDM due to an increased risk of recurrence, those whose OGTT results were outside the recommended gestational range of 24–28 weeks, and those whose specific OGTT values were unavailable.

Results

Baseline participant characteristics

Of the 36,256 pregnant women who were initially enrolled, 35,743 completed the baseline questionnaire after 513 requested to withdrawal from the study. Adherence to the inclusion criteria led to the exclusion of 3931 participants, leaving 31,812 individuals to establish the study’s baseline cohort. Within this group, 2115 women lacked the necessary hematological test results for the SII or SIRI calculations. Furthermore, 1065 women had miscarriages or underwent induced labor prior to undergoing the OGTT, and 508 were lost to follow-up. Ultimately, the study included a total of 28,124 participants [Figure 1]. Among 28,124 pregnant women, 26,095 (92.79%) underwent OGTT at Beijing Obstetrics and Gynecology Hospital, while 2029 (7.21%) did so at external hospitals, with specific OGTT values unavailable. The incidence of GDM in the 2029 participants was based on diagnoses in hospital records and questionnaire surveys via face-to-face or telephone interviews.

Figure 1.

Flowchart of the study investigating associations between SII, SIRI and maternal GDM. FBG: Fasting blood glucose; GDM: Gestational diabetes mellitus; OGTT: Oral glucose tolerance test; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index.

The average age of the 28,124 pregnant women included in the present study was 31.8 ± 3.8 years. The mean pre-pregnancy BMI was 21.80 ± 3.48 kg/m². The prevalence of overweight and obesity among the participants was 15.41% (4335/28,124) and 4.69% (1320/28,124), respectively. Of the total cohort, 53.46% (15,035/28,124) were in their first pregnancy, and 5.61% (1579/28,124) had pregnancies resulting from assisted reproductive techniques (ART). The prevalence of smoking, alcohol consumption, menstrual irregularity, GDM history, lack of folic acid supplementation, and lack of multivitamin supplementation were 3.09% (869/28,124), 4.92% (1384/28,124), 17.26% (4853/28,124), 2.39% (673/28,124), 10.81% (3041/28,124), and 22.87% (6432/28,124), respectively [Table 1]. DAG analysis revealed that baseline covariates such as age at pregnancy, ethnicity, education level, annual family income, pre-pregnancy BMI, smoking status, alcohol consumption, menstrual regularity, first pregnancy, history of GDM, mode of conception, multivitamin supplementation, RBC count, and FBG, TG, LDL-c, and HDL-c levels were potential confounding factors that may have influenced the associations among the SII, SIRI, and GDM [Supplementary Figure 1, http://links.lww.com/CM9/C92].

Table 1.

Baseline characteristics of pregnant women in the study investigating associations between SII, SIRI and maternal GDM.

Characteristics	Total (N = 28,124)
Age at pregnancy (years)	31.79 ± 3.84
Age at pregnancy
<35 years	21,476 (76.36)
≥35 years	6648 (23.64)
Ethnicity
Han	25,967 (92.33)
Others	2157 (7.67)
Education level
Below college	5860 (20.84)
Undergraduate/college	15,378 (54.68)
Postgraduate or higher	6886 (24.48)
Annual family income
<100,000 CNY	3156 (11.22)
100,000–200,000 CNY	7684 (27.32)
200,000–400,000 CNY	10,303 (36.63)
>400,000 CNY	6981 (24.82)
Pre-pregnancy BMI (kg/m2)	21.80 ± 3.48
Pre-pregnancy BMI
<18.5 kg/m2	3391 (12.06)
18.5–23.9 kg/m2	19,078 (67.84)
24.0–27.9 kg/m2	4335 (15.41)
≥28.0 kg/m2	1320 (4.69)
Smoking
No	27,255 (96.91)
Yes	869 (3.09)
Alcohol consumption
No	26,740 (95.08)
Yes	1384 (4.92)
Menstrual regularity
Irregularity	4853 (17.26)
Regularity	23,271 (82.74)
First pregnancy
No	13,089 (46.54)
Yes	15,035 (53.46)
History of GDM
No	27,451 (97.61)
Yes	673 (2.39)
Mode of conception
Natural pregnancy	26,545 (94.39)
ART	1579 (5.61)
Folic acid supplementation
No	3041 (10.81)
Yes	25,083 (89.19)
Multivitamin supplementation
No	6432 (22.87)
Yes	21,692 (77.13)
Blood count parameters
SII	790.86 ± 312.70
SIRI	1.33 ± 0.66
NLR	3.18 ± 1.03
PLR	134.97 ± 37.70
WBC (×109/L)	8.35 ± 1.92
Neut (×109/L)	5.87 ± 1.62
Lymph (×109/L)	1.93 ± 0.48
Mono (×109/L)	0.41 ± 0.12
PLT (×109/L)	248.81 ± 52.79
RBC (×1012/L)	4.29 ± 0.34
First-trimester FBG (mmol/L)	4.65 ± 0.35
First-trimester blood lipids
TC (mmol/L)	4.22 ± 0.69
TG (mmol/L)	1.08 ± 0.48
HDL-c (mmol/L)	1.51 ± 0.29
LDL-c (mmol/L)	2.23 ± 0.59

Data are shown as n (%) or mean ± SD. ART: Assisted reproductive techniques; BMI: Body mass index; FBG: Fasting blood glucose; GDM: Gestational diabetes mellitus; HDL-c: High-density lipoprotein cholesterol; LDL-c: Low-density lipoprotein cholesterol; Lymph: Lymphocytes; Mono: Monocytes; Neut: Neutrophils; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; PLT: Platelets; RBC: Red blood cell; SD: Standard deviation; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; TC: Total cholesterol; TG: Triglyceride; WBC: White blood cell.

Baseline participant characteristics according to quartiles of the SII and SIRI

Different quartiles of both SII and SIRI exhibit distinct distributions of baseline factors, including age at pregnancy, education level, annual family income, pre-pregnancy BMI, menstrual regularity, mode of conception, and first-trimester laboratory measurements of WBC, Neut, Lymph, Mono, PLT, RBC counts, FBG, TG, and LDL-c levels (all P <0.05). Additionally, SIRI quartiles also show variations in ethnicity, smoking status, and first pregnancy, while SII quartiles show variations in history of GDM and multivitamin supplementation [Supplementary Tables 1 and 2, http://links.lww.com/CM9/C92].

OGTT results and incidence rate of GDM by quartiles of the SII and SIRI

Abnormal blood glucose levels during the OGTT at 0-h, 1-h, and 2-h intervals showed increased abnormal rates from the first to fourth quartiles of both the SII and SIRI (all P_trend <0.001) [Table 2]. Consequently, women in the higher quartiles of the SII or SIRI experienced increased incidence rates of GDM. Specifically, the GDM rates for the first through fourth quartiles of the SII were 12.26% (862/7031), 14.22% (1000/7031), 16.46% (1157/7031), and 20.10% (1413/7031), respectively (P_trend <0.001). For the SIRI quartiles, the rates rose from 11.92% (840/7045) in the first quartile to 19.31% (1351/6995) in the fourth quartile, demonstrating a trend analogous to that observed in the SII quartiles (P_trend <0.001) [Supplementary Figure 2, http://links.lww.com/CM9/C92].

Table 2.

OGTT results by quartiles of the first-trimester SII and SIRI.

Items	Q1	Q2	Q3	Q4	Z	Ptrend values*
SII
0-h glucose					9.933	<0.001
<5.1 mmol/L	6293 (95.93)	6220 (95.01)	6112 (93.80)	5957 (92.04)
≥5.1 mmol/L	267 (4.07)	327 (4.99)	404 (6.20)	515 (7.96)
1-h glucose					9.586	<0.001
<10.0 mmol/L	6161 (93.92)	6069 (92.70)	5954 (91.38)	5794 (89.52)
≥10.0 mmol/L	399 (6.08)	478 (7.30)	562 (8.62)	678 (10.48)
2-h glucose					9.331	<0.001
<8.5 mmol/L	6127 (93.40)	6041 (92.27)	5929 (90.99)	5760 (89.00)
≥8.5 mmol/L	433 (6.60)	506 (7.73)	587 (9.01)	712 (11.00)
SIRI
0-h glucose					8.702	<0.001
<5.1 mmol/L	6299 (95.98)	6203 (94.54)	6094 (93.78)	5986 (92.48)
≥5.1 mmol/L	264 (4.02)	358 (5.46)	404 (6.22)	487 (7.52)
1-h glucose					9.352	<0.001
<10.0 mmol/L	6174 (94.07)	6070 (92.52)	5919 (91.09)	5815 (89.83)
≥10.0 mmol/L	389 (5.93)	491 (7.48)	579 (8.91)	658 (10.17)
2-h glucose					9.243	<0.001
<8.5 mmol/L	6147 (93.66)	6043 (92.10)	5878 (90.46)	5789 (89.43)
≥8.5 mmol/L	416 (6.34)	518 (7.90)	620 (9.54)	684 (10.57)

Data are shown as n (%). Data analysis was based on 26,095 pregnant women with complete OGTT test values. ^*Cochran–Armitage trend test. OGTT: Oral glucose tolerance test; Q: Quartile; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index, SII: Q₁ (<570), Q₂ (570–736), Q₃ (737–951), Q₄ (≥952), SIRI: Q₁ (<0.88), Q₂ (0.88–1.19), Q₃ (1.20–1.62), Q₄ (≥1.63).

Associations between the first-trimester SII and SIRI and GDM risk

A significant non-linear association was observed between the SII and SIRI and the risk of GDM as determined by RCS analysis, which implied a positive association between SII or SIRI and the risk of GDM. Higher systemic inflammation levels, as reflected by increased SII or SIRI indices, are associated with an increased risk of GDM [Supplementary Figure 3, http://links.lww.com/CM9/C92].

The participants were also categorized into quartiles based on their baseline SII and SIRI. Those in the higher quartiles of the SII demonstrated an incrementally increased risk of GDM compared to those in the lowest quartile, with the risk rising by 9% (OR = 1.09, 95% CI: 0.98–1.21), 21% (OR = 1.21, 95% CI: 1.09–1.34), and 39% (OR = 1.39, 95% CI: 1.26–1.54), respectively (P_trend <0.001). The results were adjusted for a multitude of variables, including age at pregnancy, ethnicity, education level, annual family income, pre-pregnancy BMI, smoking status, alcohol consumption, menstrual regularity, first pregnancy, history of GDM, mode of conception, multivitamin supplementation, first-trimester laboratory measurements of RBC counts, and FBG, TG, LDL-c, and HDL-c levels. Likewise, compared with those of participants in the lowest quartile of the SIRI, the ORs from the second to highest quartiles of the SIRI were 1.24 (1.12–1.38), 1.41 (1.27–1.57), and 1.64 (1.48–1.82), suggesting a gradual increase in risk (P_trend <0.001) [Table 3]. The findings from tertile-based grouping matched the quartile results [Supplementary Table 3, http://links.lww.com/CM9/C92]. When treated as a continuous variable, GDM risk rose by 4% (OR = 1.04, 95% CI: 1.03–1.05) for each 100-unit increase in the SII and by 28% (OR = 1.28, 95% CI: 1.22–1.35) for each unit increase in the SIRI [Supplementary Table 4, http://links.lww.com/CM9/C92].

Table 3.

Association between the first-trimester SII, SIRI and risk of GDM.

Items	Q1	Q2	Q3	Q4	χ2	Ptrend values
SII
GDM, n (+/–)	862/6169	1000/6031	1157/5874	1413/5618
Rates (%)	12.26	14.22	16.46	20.10
OR (95% CI)*	1.00	1.19 (1.08–1.31)	1.41 (1.28–1.55)	1.80 (1.64–1.97)	173.98	<0.001
OR (95% CI)†	1.00	1.10 (1.00–1.22)	1.26 (1.14–1.39)	1.51 (1.37–1.66)	80.50	<0.001
OR (95% CI)‡	1.00	1.09 (0.98–1.21)	1.21 (1.09–1.34)	1.39 (1.26–1.54)	45.02	<0.001
SIRI
GDM, n (+/–)	840/6205	1054/6041	1187/5802	1351/5644
Rates (%)	11.92	14.86	16.98	19.31
OR (95% CI)*	1.00	1.29 (1.17–1.42)	1.51 (1.37–1.66)	1.77 (1.61–1.94)	154.97	<0.001
OR (95% CI)†	1.00	1.26 (1.14–1.40)	1.41 (1.28–1.56)	1.66 (1.51–1.83)	108.30	<0.001
OR (95% CI)‡	1.00	1.24 (1.12–1.38)	1.41 (1.27–1.57)	1.64 (1.48–1.82)	95.05	<0.001

BMI: Body mass index; CI: Confidence interval; FBG: Fasting blood glucose; GDM: Gestational diabetes mellitus; HDL-c: High-density lipoprotein cholesterol; LDL-c: Low-density lipoprotein cholesterol; OR: Odds ratio; Q: Quartile; RBC: Red blood cell; SII: Systemic immune-inflammation index; SIRI: Systemic inflammation response index; TC: Total cholesterol; TG: Triglyceride; SII: Q₁ (<570), Q₂ (570–736), Q₃ (737–951), Q₄ (≥952), SIRI: Q₁ (<0.88), Q₂ (0.88–1.19), Q₃ (1.20–1.62), Q₄ (≥1.63). ^*Unadjusted. ^†Adjusted for age at pregnancy, ethnicity, education level, annual family income, pre-pregnancy BMI, smoking, alcohol consumption, menstrual regularity, first pregnancy, history of GDM, mode of conception, multivitamin supplementation. ^‡Additionally adjusted for laboratory measurements of RBC counts, FBG, TG, LDL-c, and HDL-c levels in the first trimester.

Subgroup and interaction analyses examining the associations between the first-trimester SII and SIRI and GDM risk

Subgroup analysis demonstrated that the SII and SIRI were positively correlated with the risk of GDM in pregnant women across diverse traits of baseline exposure; namely, the risk of GDM increased concomitantly with the rise in the SII or SIRI across all subgroups. The findings of the interaction analysis indicated that FBG levels in early pregnancy were interactively associated with the SIRI (P_{for interaction} = 0.019), whereas no interaction was noted between the SII, SIRI and other measures of baseline exposure (all P_{for interaction} >0.05) [Supplementary Figures 4 and 5, http://links.lww.com/CM9/C92].

Sensitivity analysis for the associations between the first-trimester SII and SIRI and GDM risk

Participants with a history of GDM (673 participants), those whose OGTT values were unavailable (2029 participants), and those whose OGTT was unavailable and conducted outside the 24–28-week gestational range (2349 participants) were further excluded. Pregnant women in the second to fourth quartiles of the SII and SIRI maintained trend of an increased risk of developing GDM [Supplementary Table 5, http://links.lww.com/CM9/C92].

Discussion

Based on this prospective birth cohort study involving 28,124 pregnant women, this study documented an increased risk for GDM in participants with elevated first-trimester SII and SIRI. Notably, all of these associations were maintained in subgroup and sensitivity analyses. To our knowledge, this prospective birth cohort study comprehensively assess the impact of the SII and SIRI on the risk of developing GDM, thus providing solid epidemiological evidence for the potential role of chronic systemic immune inflammation, as represented by the SII or SIRI in the pathogenesis of GDM.

Pregnant women with GDM exhibited significantly greater blood cell parameters (including WBC, Neut, Lymph, Mono, and PLT in early or mid-gestation) than healthy women. Chronic low-grade inflammation is a major cause of insulin resistance (IR), which is the main pathogenesis of GDM.^[27,28] WBC (including Neut, Lymph, and Mono) are immunoinflammatory cells of interest according to routine clinical blood tests. PLT-related markers may indirectly reflect the inflammatory state given that inflammation can trigger vascular injury and dysfunction, leading to PLT activation and aggregation. Elevated WBC counts are an important risk factor for IR.^[29] In addition, pregnant women with GDM display significantly greater blood cell parameters such as WBC, Neut, Lymph, or PLT at early or mid-gestation than healthy women.^{[13,14,18,30,31]} Our results are consistent with previous findings suggesting that increased activation of circulating immune-inflammatory cells could be associated with glucose metabolism disorders in pregnant women.

The NLR is an index that evaluates inflammation and immune status based on Neut and Lymph calculations, and the PLR is an immunoinflammatory index rooted in PLT count and Lymph calculations. Based on a cohort study involving 28,124 pregnant women, we observed that those with GDM exhibited increased NLR, while PLR were not significantly elevated in this group [Supplementary Table 6, http://links.lww.com/CM9/C92]. To date, several case–control and cross-sectional studies have examined the relationships between GDM and the NLR as well as between GDM and the PLR.^{[15,16,30,32,33,34]} The majority of these studies imply that pregnancies complicated by GDM show higher NLR than pregnancies complicated by non-GDM controls, although some studies have reported contradictory outcomes. Furthermore, two recent systematic reviews published in 2021 reported a greater NLR in GDM pregnancies than in non-GDM controls, with noted heterogeneity among the studies.^[15,16] One of the aforementioned systematic reviews noted a greater PLR in pregnant women diagnosed with GDM than that in pregnant women without GDM, albeit without a statistically significant difference (P = 0.065).^[16] Our results on the relationship between the NLR and GDM are consistent with those of two previous meta-analyses. Our study on PLR and GDM, similar to the meta-analysis of Dr. Kamran’s team, did not find significantly greater PLR in pregnant women with GDM. More studies are required to further verify the relationship between the PLR and GDM.

The SII and SIRI are novel indicators of systemic immune-inflammatory status. The SII is calculated by aggregating Neut, Lymph, and PLT counts and reflects the body’s overall immune-inflammatory state. Similarly, the SIRI is derived by analyzing Neut, Mono, and Lymph counts and serves as a vital indicator of this state. The SII, SIRI, NLR, and PLR are used to assess inflammation and immune status, each of which offers distinct advantages; however, the SII and SIRI often provide more comprehensive insights than the NLR and PLR. Unlike the NLR and PLR, which assess only two cell types, the SII and SIRI incorporate three cell types, offering a more detailed reflection of the body’s immune-inflammatory state. Furthermore, the SII emphasizes PLT-related immune processes, whereas the SIRI includes Mono counts, enhancing its ability to reflect immune regulatory responses. An elevated SII or SIRI has been associated with the development and progression of diseases such as coronary heart disease, metabolic syndrome, and tumors.^[20,23,35] In T2DM patients, significant correlations have been identified between the SII or SIRI and glucose regulation.^[24,36] Given the similar pathogenesis of GDM and T2DM, the SII and SIRI, which are comprehensive indicators, may also be related to impaired glucose metabolism.

In our prospective cohort study of 28,124 individuals, women with GDM displayed significantly greater SII and SIRI values. Additionally, our results showed that increased first-trimester inflammation levels, as measured by the SII or SIRI, correlated with higher abnormal glucose levels during the OGTT (at 0 h, 1 h, and 2 h, respectively) and elevated GDM rates. The dose–response relationships between the first-trimester SII or SIRI and GDM risk were further analyzed. Women in the second, third, and fourth quartiles for the SII or SIRI faced increased GDM risk compared to those in the first quartile. These findings imply that higher SII or SIRI values significantly increase the risk of GDM. Our research uniquely examined the link between maternal SII and SIRI—novel markers of systemic inflammation—and GDM risk in a prospective cohort. Furthermore, compared to the NLR and PLR, the SII and SIRI were more strongly correlated with GDM risk. The SII and SIRI, as novel indicators of inflammation and immune status, may serve as promising indices to assess comprehensive immune-inflammatory levels in clinical settings.

Several studies have posited potential explanations for the underlying mechanisms through which the SII or SIRI increase the risk of GDM. Pregnant women with GDM and elevated TNF-α levels may suffer from neutrophil overactivation.^[28] This process can generate excess reactive oxygen species and stimulate the formation of neutrophil extracellular traps (NETs), leading to the release of neutrophil elastase.^[37,38] Released neutrophil elastase can degrade insulin receptor substrate 1, thereby contributing to the development of IR.^[38] Furthermore, regulatory T cells (Tregs) in non-GDM patients inhibit proinflammatory responses, whereas Tregs are functionally impaired in GDM patients.^[39] Inflammation can precipitate vascular injury and dysfunction as well as stimulate PLT activation and aggregation. Consequently, PLT may also indirectly reflect the inflammatory state.^[40] The SII and SIRI are comprehensive indices manifesting the body’s immune-inflammatory state, considering the impacts of Neut, Lymph, Mono, and PLT. Systemic immune inflammation may play a pivotal role in the development of GDM, with the SII and SIRI serving as significant clinical indicators.

Our findings merit consideration for several reasons. A primary strength of our study is the provision of novel insights into the relationships among emerging inflammatory indices, the SII and SIRI, and GDM. An additional advantage of our study is the inclusion of a substantial cohort of 28,124 pregnant women in the first trimester, and the vast majority were able to complete consistent follow-ups in subsequent trimesters (second and third) at the same institution because our hospital ensures high compliance among its patients. This facilitated our investigation of the correlation between the SII and SIRI in the early trimester and GDM risk using a prospective birth cohort study design. Additionally, we considered a wide range of confounders—including macro-epidemiological and micro-laboratory testing variables, such as pre-pregnancy BMI, history of GDM, and measurements of blood glucose and lipids—which further contributed to the robustness of our study.

Nevertheless, our study has several limitations. First, this was a single-center cohort study, which limits the generalizability of our findings. Second, in the initial cohort of pregnant women who met the inclusion criteria, baseline SII and SIRI data were missing for 2115 patients, and 508 recorded GDM outcomes were unavailable at follow-up. These missing data could impact our findings; however, the relatively small percentage and results of the sensitivity analysis suggest that such influence might be minimal. Furthermore, we did not explore the potential associations between the SII or SIRI and other inflammatory markers (such as interleukin-6 and C-reactive protein) due to their unavailability in this cohort. Additionally, this clinical study failed to provide insights into the mechanistic roles of the SII or SIRI-associated blood cells in the pathophysiology of GDM. Compared to well-known indicators such as FBG,^[41] the associations between the SII or SIRI and GDM are somewhat moderate. Our findings indicate that the SII and SIRI are associated with an increased risk of GDM. Whether the SII and SIRI can serve as effective markers for early pregnancy screening of GDM patients requires additional research. As this study represents the initial exploratory phase, further research is crucial to validate our results and elucidate the underlying mechanisms of the SII and SIRI in GDM.

In sum, in this study, we have demonstrated an increased incidence of GDM in pregnant women exhibiting elevated SII and SIRI during early pregnancy. Elevated SII and SIRI serve as independent risk factors contributing to the onset of GDM, providing robust epidemiological evidence for the potential role of chronic systemic inflammation, indicated by the SII and SIRI, in the pathogenesis of GDM. Our findings underscore the importance of maintaining appropriate levels of immune inflammation during pregnancy to mitigate the risk of developing GDM.

Acknowledgments

We appreciate the contribution of all pregnant women who participated in this birth cohort study. We are also grateful to all the medical staff of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, responsible for disease diagnosis, questionnaire collection, biological sample collection, and laboratory testing.

Funding

This study was supported by the Capital’s Funds for Health Improvement and Research (No. 2024-2G-2118), the National Key Research and Development Program of China (No. 2016YFC1000100), the Leading Talents in the Construction Project of High Level Public Health Technical Talents in Beijing (No. 20221003), the “Green Seedling” Youth Program by the Beijing Hospitals Authority (No. QML20231402), and the Young Elite Scientist Sponsorship Program by the Beijing Association for Science and Technology (No. BYESS2022200).

Conflicts of interest

None.

Data availability

The datasets generated and analyzed during the study are not publicly available due to privacy considerations for the participants included in the study. However, they are available from the corresponding author upon reasonable request.

Supplementary Material

cm9-138-729-s001.pdf ^{(788.3KB, pdf)}