Preplanned Studies: Hematological Parameters in the First Trimester and the Risk of Gestational Diabetes Mellitus — Beijing, China, 2017–2020

Gestational diabetes mellitus (GDM) is a prevalent high-risk disorder during pregnancy, increasing the risk of adverse pregnancy outcomes (1). Previous studies have documented that abnormalities in hematological cells reflect the increasing level of maternal immune dysregulation and viscosity, which may play a role in the pathophysiology of GDM (2-3). However, reports of the association between several hematological parameters in early pregnancy and GDM are equivocal. Although some epidemiological studies have demonstrated a positive association between red blood cell (RBC) (4), white blood cell (WBC) (5), or hemoglobin (Hb) (6) in early pregnancy and GDM, inconsistent results were observed in other studies (7). To our knowledge, previous studies have not included certain novel immune blood parameters, such as the neutrophil-lymphocyte ratio (NLR). We conducted a retrospective study and used adjusted logistic regression models to assess the association between increased hematological parameters in early pregnancy and incident GDM, collecting data from the Haidian District Maternal and Child Health Care Hospital on pregnant women between 2017 and 2020. All analyses were performed using the R software (version 4.1.2；R Foundation for Statistical Computing, Vienna, Austria). The results showed that a quartile increment in Hb, RBC, WBC, platelet (PLT), neutrophils (NEU), NLR, and systemic immune-inflammation index (SII) was positively associated with GDM incident (P_trend<0.05) after multivariable adjustment.

This retrospective cohort study was conducted among 29,570 reproductive-aged women with singleton pregnancies who were registered in the obstetric archives between January 2017 and April 2020 and completed their routine prenatal visits in the Maternal and Child Health Care Hospital of Haidian District, Beijing. After excluding participants with chronic diseases (e.g., hypertension, diabetes, or chronic nephritis), infectious diseases [e.g., syphilis, clap, or acquired immune deficiency syndrome (AIDS)], missing values of hematological parameters before 13 gestational weeks, or women who did not undergo a standard oral glucose tolerance test (OGTT) at 24 to 28 gestational weeks, a total of 5,529 participants were finally included (Supplementary Figure S1).

Hematological parameters included blood cell counts [RBC, PLT, and WBC, including neutrophil (NEU) and lymphocyte (LYM)] and hemoglobin concentration, which were tested from fasting blood samples collected in the first trimester and immediately stored at 4–8 °C for 24 h. We further calculated NLR and SII [(neutrophil × platelet)/lymphocyte], indicating the degree of individual inflammatory burden (8). Both NLR and SII reflect the balance of adaptive immune and inflammatory factors in the human body. Physical examinations, previous obstetric history, laboratory parameters, and diagnoses were extracted from the electronic medical record system. Information on physical examinations contained height and weight.

GDM was diagnosed if at least one value of plasma glucose concentration was equal to or exceeded the thresholds of 5.1, 10.0, and 8.5 mmol/L for fasting, 1 h, and 2 h post-glucose load values, respectively, after performing a 75 g OGTT at gestational 24–28 weeks according to the Guidelines for Diagnosis and Treatment of Diabetes in Pregnancy (2014) in China (9). We further distinguished the impact of three subtypes of GDM: isolated fasting hyperglycemia (GDM-IFH), isolated post-load hyperglycemia (GDM-IPH), and combined hyperglycemia (GDM-CH) (10). This study used age-adjusted and multivariable-adjusted logistic regression models to examine the associations between hematological parameters and GDM. The odds ratio (OR) and 95% confidence interval (CI) of having GDM were used to quantify the association. We categorized participants into four groups based on quartile cutoff values of hematological parameters. A linear trend was tested by recoding individual hematological parameters as a continuous variable into the regression model. To provide clinical recommendation (11), the normal ranges of RBC, Hb, WBC, PLT, NEU, and LYM in the first trimester were defined as 3.42–4.55 (×10¹²/L), 116–139 (g/L), 5.7–13.6 (×10⁹/L), 174–391 (×10⁹/L), 3.61–10.19 (×10¹²/L), and 1.1–3.6 (×10¹²/L), respectively. All the regression models were adjusted for the following covariates: age (categorical, <30, ≥30), gestational week (categorical, <9, ≥9), parity (categorical, 0, ≥1), body mass index (BMI) before 20 gestational weeks (categorical, <18.5, 18.5–23.9, 24.0–27.9, ≥28.0), history of adverse pregnancy outcomes (categorical, have, not have), and fasting blood glucose (categorical, <6.1, ≥6.1). All analyses were conducted using R software 4.1.2, and two-sided P<0.05 values were considered statistically significant.

Among the 5,529 participants, 1,017 incident GDM cases (18.4%, including 503 GDM-IPH, 339 GDM-IFH, and 175 GDM-CH) were identified. Table 1 shows the baseline characteristics of the pregnant women. The median age of participants was 31 (29 to 34) years, and the median gestational week at enrollment was 12.01. Participants with GDM were more likely to be older, parous, have an abnormal pregnancy history, and have higher levels of fasting plasma glucose and BMI in the first trimester (P<0.05). The hematological parameters in the first trimester, including RBC, Hb, WBC, PLT, LYM, NEU, NLR, and SII, were higher in GDM than in non-GDM women (P<0.05). Results from multivariable-adjusted logistic regressions revealed that, compared with the first quartile, the odds ratios (95% CI) of GDM across the highest quartile of NEU, WBC, RBC, Hb, SII, NLR, and PLT were 1.87 (1.53, 2.29), 1.81 (1.48, 2.21), 1.56 (1.28, 1.91), 1.52 (1.26, 1.84), 1.51 (1.24, 1.84), 1.42 (1.17, 1.74), and 1.36 (1.12, 1.67), respectively (all P_trend<0.01, Table 2). For GDM subtypes, increased risks of GDM-IFH, GDM-IPH, and GDM-CH were associated with an increase in RBC, WBC, and NEU count. Elevated LYM, rather than SII or NLR, was only significantly associated with GDM-CH. In addition, Hb and PLT were only significantly associated with GDM-IPH (Table 3). In summary, the results verified that a high level of each hematological parameter was a significant predictor of GDM. According to clinical classification, the risk for GDM was significantly increased with higher WBC [OR=2.03 (1.21, 3.31) for WBC ≥13.7×10¹²/L], NEU [OR=2.01 (1.33, 2.98) for NEU ≥10.2×10¹²/L], RBC [OR=1.55 (1.28, 1.87) for RBC ≥4.56×10¹²/L], and Hb [OR=1.7 (1.34, 2.14) for Hb ≥140 g/L] levels in the first trimester (Supplementary Table S1).