First‐trimester blood urea nitrogen and risk of gestational diabetes mellitus

Abstract Prior studies indicated that urea increased insulin resistance and higher blood urea nitrogen (BUN) was associated with incident diabetes mellitus. However, it remains unclear whether BUN during the first trimester of pregnancy increases risk of gestational diabetes mellitus (GDM). We aimed to investigate the association between first‐trimester BUN and risk of incident GDM. We conducted a prospective, multicenter cohort study of pregnant women. A total of 13 448 eligible pregnant women with measured first‐trimester BUN levels were included in this analysis. Logistic regression analysis was used to estimate the relationship between BUN and GDM. Discrimination and reclassification for GDM by BUN were analysed. A total of 2973 (22.1%) women developed GDM. Compared with the lowest quartile of BUN, the third and fourth quartiles were associated with increased risk of GDM (adjusted odds ratios 1.21 [95% CI 1.07‐1.37] and 1.50 [95% CI 1.33‐1.69], respectively, P for trend <.001). The addition of BUN to conventional factor model improved discrimination (C statistic 0.2%, P = .003) and reclassification (net reclassification index 14.67%, P < .001; integrated discrimination improvement 0.12%, P < .001) for GDM. In conclusion, higher BUN concentrations during the first trimester of pregnancy were associated with increased risk of GDM, suggesting that BUN could be a potential predictor for GDM.

Chronic kidney disease (CKD) has become a worldwide public health problem and is commonly characterized by insulin resistance. 6,7 It has been shown that CKD and diabetes share similar pathological mechanisms. 8 Blood urea nitrogen (BUN) is conventionally considered as a parameter to evaluate renal function and had been reported to be associated with cardiovascular events and mortality in various pathophysiological conditions. 9,10 Prior experimental studies suggested that increased levels of urea might induce insulin resistance and suppress insulin secretion both in vitro and in vivo. Recently, epidemiological evidence from the US Department of Veterans Affairs databases provided the evidence that higher levels of BUN were associated with increased risk of incident diabetes mellitus among people without diabetes 11 and increased risk of insulin use in patients with diabetes. 12 However, whether BUN during the first trimester of pregnancy increases risk of incident GDM remains unknown. Hence, we aim to explore the relationship between first-trimester BUN and GDM in a larger cohort of pregnant women.

| Participants
The multicenter cohort study was conducted in ten hospitals and fifteen community healthcare centres of Kunshan, Jiangsu Province, China, from January 2015 to December 2017. The aims of this cohort study were to identify first-trimester predictors of adverse pregnancy outcome. Pregnant women receiving prenatal care at participating hospitals or healthcare centres were invited to participate in this cohort. Women 14-40 years old were included, and exclusion criteria were without first-trimester data of BUN, receiving first prenatal care after 14 weeks, drug and/or alcohol abuse and uncontrolled endocrine disease. Finally, a total of 13 448 women were eligible for this analysis.
The study was approved by the Ethics Committee of Maternal and Child Health Hospital of Kunshan, and written informed consent was obtained from all study participants.  Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) of GDM for upper quartiles (Q2-Q4) compared to the lowest quartile (Q1) and for 1-SD increment of logarithm-transformed BUN levels. The multivariate-adjusted models included maternal age, education, gravidity, parity, baseline BMI, gestational weight gain, systolic BP, baseline FPG, white blood cell (WBC), haemoglobin and eGFR. A receiver operating characteristic (ROC) curve was further configured to explore cut-off point of first-trimester BUN that optimally predicted GDM. In addition, spline regression models were used to examine the shape of the association between BUN and GDM by fitting a restricted cubic spline function and 4 knots (5th, 35th, 65th and 95th percentiles). 15 Sensitivity analysis was conducted to test the robustness of our results by excluding participants with low eGFR (<90 mL/min per 1.73 m 2 ). In subgroup analyses, we conducted multivariable models to examine effect modification by maternal age, gravidity, baseline BMI, gestational weight gain, systolic BP, WBC and haemoglobin. The interaction between BUN and interested factors was tested by the likelihood ratio test of models with interaction terms.

| Statistical analyses
Furthermore, C statistic, category-free net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to evaluate the improvement of discrimination and reclassification by adding first-trimester BUN to conventional risk factors model. 16 Two-tailed P < .05 was considered to be statistically significant. All statistical analyses were conducted by SAS statistical software (version 9.4).

| Baseline characteristics
The present analysis included a total of 13 448 women, mean age of whom was 27.63 ± 4.09 years, and the median serum BUN concentration was 2.91 mmol/L (IQR, 2.40-3.50 mmol/L). The baseline characteristics are presented in Table 1. Compared with the participants with lower BUN levels, those with higher BUN levels tended to be older, had higher proportion of gravidity (≥2), senior high school, higher levels of gestational weight gain, FPG, haemoglobin, serum creatinine and eGFR, but had lower levels of BMI and diastolic BP, and lower proportion of junior middle school or below. Multiple-adjusted spline regression models suggested a linear association between BUN levels and GDM (P for linearity <0.001; Figure 1). Note: Data given as mean ± SD, mean (IQR) or n (%).

TA B L E 1 Characteristics of participants according to serum blood urea nitrogen quartiles
Abbreviations: BMI, body mass index; BP, blood pressure; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; WBC, white blood cell.
In the sensitivity analyses, further exclusion of participants with low eGFR (<90 mL/min per 1.73 m 2 ) did not change the association between BUN and GDM (Table 3). Similar significant associations between high BUN and GDM were observed in all subgroups (Table 4).
Statistical tests for interactions between BUN and these interesting factors on outcome were not significant (all P > .05).

| Discrimination and reclassification of BUN
Discrimination and reclassification for GDM by BUN are shown in Table 5. Adding BUN to the conventional model significantly improved C statistic by 0.2% (P = .003), category-free NRI by 14.67% (P < .001) and IDI by 0.12% (P < .001) for GDM.

| D ISCUSS I ON
In this multicenter cohort study, we observed a dose-response association between higher first-trimester BUN and an increased risk of developing GDM, even after adjustment for potential con- Our results extended this information specifically to pregnant women population and provided epidemiologic evidence to support the relationship between BUN and developing GDM. In the present study, we found that a higher level of first-trimester BUN was significantly asso-

| CON CLUS IONS
Our results indicated that higher concentrations of BUN during the first trimester of pregnancy were positively and independently associated with increased risk of GDM. Adding BUN to conventional risk factors significantly improved risk prediction for GDM, suggesting that first-trimester BUN could be a potential predictor for GDM.