The relationship between advanced glycation end products and gestational diabetes: A systematic review and meta-analysis

INTRODUCTION: Gestational Diabetes Mellitus (GDM) is a condition in which women without history of diabetes experience hyperglycemia during pregnancy, especially at the second and third trimesters. In women who have had GDM, an elevated body mass index (BMI) may have a substantial impact for persistent hyperglycemia in their lives after gestation. Beyond hyperglycemia, increased local oxidative stress directly promotes the formation of Advanced Glycation End-products (AGEs). Hence, this systematic review and meta-analysis was aimed to determine the relationship between the level of AGEs and/or related metabolic biomarkers with GDM. METHODS: Literature search was carried out through visiting electronic databases, indexing services, and directories including PubMed/MEDLINE (Ovid(®)), EMBASE (Ovid(®)), google scholar and WorldCat to retrieve studies without time limit. Following screening and eligibility evaluation, relevant data were extracted from included studies and analyzed using Rev-Man 5.3 and STATA 15.0. Inverse variance method with random effects pooling model was used for the analysis of outcome measures at 95% confidence interval. Hedge’s adjusted g statistics was applied to calculate the standardized mean difference (SMD) to consider the small sample bias. Besides, meta-regression, meta-influence, and publication bias analyses were conducted. The protocol has been registered on PROSPERO with ID: CRD42020173867. RESULTS: A total of 16 original studies were included for the systematic review and meta-analysis. Compared with women with pregnant controls, the level of AGE was significantly higher in women with GDM (SMD [95% CI] = 2.26 [1.50‒3.02], Z = 5.83, P < 0.00001; I(2) = 97%, P< 0.0001). The BMI was also significantly higher in women with GDM (SMD [95% CI] = 0.97 [0.33‒1.62], Z = 2.98, P = 0.003) compared to controls. Regarding specific and related metabolic biomarkers, there was higher level of HOMA-IR (SMD [95% CI] = 0.39 [0.22–0.55], Z = 4.65, P < 0.0001, after sensitivity analysis) and HbA1c (SMD [95% CI] = 0.58 [0.03‒1.12], Z = 2.07, P = 0.04, after sensitivity analysis) in gestational diabetic women. Subgroup analyses indicated that studies conducted in Asia and Europe, at third trimester of pregnancy and blood/plasma AGE samples showed a significant difference in AGE level among women with GDM compared to pregnant controls. What is more, meta-regression with the sample size (regression coefficient (Q) = -0.0092, P = 0.207) and year of publication (Q = 0.0035, P = 0.984) suggested that the covariates had no significant effect on the heterogeneity. CONCLUSION: The study indicated that there was a strong relationship between AGE and GDM. Besides, the BMI and other specific biomarkers showed a significant difference between the two groups indicating the high risk of developing long-standing type 2 diabetes and its complications in gestational diabetic women. Early detection of these biomarkers may play a pivotal role in controlling postpartum diabetic complications.