Table 2.
General characteristics of the eligible studies included in the present systematic review and meta-analysis.
| Authors (Country) | Group Characteristics | GDM diagnosis made by | Assay for RBP4 | Unit | Data measured at (weeks of gestation) | Key outcome(s) |
|---|---|---|---|---|---|---|
| Abetew DF et al., 2013 (41), (United States) | GDM (N = 173, age = 34.15 ± 4.56); Controls (N = 187, age = 32.95 ± 4.32) | ADA | ELISA (Catalog number DRB400, Quantikine TM, R&D Systems, Minneapolis, MN, United States) | μg/mL | 16 | The mean serum RBP4 level was significantly higher among GDM cases than controls. There was modest evidence of a positive association of early pregnancy elevated RBP4 concentration with increased GDM risk, particularly among women of advanced age. |
| Chan TF et al., 2007 (42), (Taiwan) | GDM (N = 20, age = 32.7 ± 5, BMI = 26.1 ± 4.7); Controls (N = 20, age = 32.7 ± 5, BMI = 25.9 ± 2.9) | NDDG | ELISA (Immundiagnostik AG, Bensheim, Germany) | ng/mL | 24–28, upon delivery | Serum RBP4 concentrations at glucose challenge test were significantly higher in the GDM group than in the healthy control group. BMI was significantly correlated to serum RBP4 concentrations by multiple linear regression analysis. |
| Chen and Du, 2011 (31), (China) | GDM (Obesity: age = 32 ± 4.8, normal weight: age = 31.7 ± 3.5, N = 52); Controls (Obesity: age = 28.4 ± 3.1, normal weight: age = 28.3 ± 3, N = 46) | N/A | ELISA | μg/L | 37–39 | Serum RBP4 levels were higher in obese pregnant women than in non-obese women. RBP4 levels in GDM with obesity were higher than in other groups. |
| Du M et al., 2016 (43), (China) | GDM (N = 38, age = 28.79 ± 4.04); Controls (N = 38, age = 28.92 ± 3.02) | NDDG | ELISA (R&D Company, United States) | μg/mL | 37–42 | RBP4 levels were higher in women with GDM. In healthy controls, RBP4 concentrations were positively correlated with HOMA-IR and TG. |
| Du X et al., 2019 (44), (China) | GDM (N = 194, age = 31.71 ± 3.63); Controls (N = 67, age = 31 ± 3.43) | FIGO | ELISA (R&D Systems in the United States of America) | μg/mL | 24–28, 37–40 | RBP4 levels were significantly higher in the GDM group compared to control group. RBP4 is related to GDM, and its levels increase with the increase of gestational weeks. |
| Ping F et al., 2012 (45), (China) | GDM (N = 488); GIGT (N = 235); NGT (N = 582); Normal (GCT−) (N = 290) | ADA | ELISA (Phoenix, Belmont, CA, United States EK-028-28) | μg/mL | 13–15, 24–28 | The estimated indices of IR gradually increased from NGT to GDM. RBP4 mRNA expression in adipose tissue of GDM patients was significantly increased. |
| Francis E et al., 2020 (39), (United States) | GDM (N = 107, age = 30.5 ± 5.7); Controls (N = 214, age = 30.4 ± 5.4) | Carpenter-Coustan | Quantikine Human RBP4 Immunoassay (R&D Systems) | N/A | 10–14, 15–26, 23–31, 33–39 | Adipokines, including FABP4, chemerin, and sOB-R may be implicated in the pathogenesis of GDM, with significant associations detected approximately 10–18 weeks before typical GDM screening. Chemerin and RBP4 were associated with a worse lipid profile. |
| Fruscalzo A et al., 2015 (32), (Italy) | GDM (iGDM: age = 33.55 ± 4.06, dGDM: age = 33.43 ± 4.03) (N = 32); Controls (AGA: age = 37.18 ± 4.44, LGA: age = 32.85 ± 3.47) (N = 64) | IADPSG | Non-commercial ELISA using polyclonal rabbit anti-human antibodies (Biozol, Eching, Germany) | 11–13 | GDM patients were characterised by reduced RBP4 compared to controls. | |
| Gashlan H et al., 2017 (46), (Saudi Arabia) | GDM (N = 51, age = 32.4 ± 0.98, BMI = 33.8 ± 1.01); Controls (N = 37, age = 34 ± 1.52, BMI = 33.4 ± 0.81) | WHO | Assay from Elabscience Company (Wuhan, China) | ng/mL | 2nd trimester, 3rd trimester | RBP4 was significantly decreased in GDM compared to control and was significantly correlated with IR in the GDM group only. |
| Gorkem U et al., 2016 (21), (Turkey) | GDM (N = 76, age = 29 (24–28), BMI = 33.25 (22.8–52.2)); Controls (N = 82, age = 26 (18–35), BMI = 26.43 (19.1–47)) | Carpenter- Coustan | ELISA (Immundiagnostik, Immundiagnostik AG; Bensheim, Germany) | mg/mL | 24–28 | Serum RBP4 did not demonstrate significant differences between GDM and controls. |
| Hou W et al., 2018 (18), (China) | GDM (N = 131, age = 31.4 ± 3.8); Controls (N = 138, age = 30.4 ± 3.8) | IADPSG | N/A | mg/L | 12 | Multivariate models combining clinical markers and metabolites can potentially differentiate GDM subjects from healthy controls. Pre-pregnancy BMI was higher in GDM participants, as were ChE, RBP4, CysC and TG. |
| Jia X et al., 2022 (47), (China) | GDM (N = 62, age = 29.38 ± 4.65, BMI = 22.79 ± 2.93); Controls (N = 58, age = 28.93 ± 3.31, BMI = 25.8 ± 3.04) | People’s Republic of China Health Industry Standards | ELISA (American RD Company, San Francisco, CA, United States) | μg/mL | 24–28 | There were no statistically significant differences in RBP4 levels in GDM compared to healthy pregnancies. There were higher serum FGF-21 levels in GDM, which might be related to pre-pregnancy BMI, weight gain during pregnancy, leptin, RBP4, and adiponectin. |
| Jin C et al., 2020 (19), (China) | GDM (N = 135, age = 29 (28–33)); Controls (N = 135, age = 29 (28–33)) | IADPSG | ELISA (R&D Systems China, Shanghai) | μg/L | < 14, 24–28 | The GDM cases had significantly higher levels of RBP4 in the first trimester than controls. With adjustment for diet, physical activity, and other risk factors for GDM, the risk of GDM increased with every 1-log μg/L increment of RBP4 level. |
| Khovidhunkit W et al., 2012 (33), (Thailand) | GDM (N = 171, age = 33 (29–37)); Non-GDM (GIGT, NGT) (N = 361, age = 33 (28–36)); GCT− (N = 22, age = age = 32 (26–39)) | Carpenter-Coustan | ELISA (R&D Systems Minneapolis, MN) | μg/mL | 24–28 | The degree of IR was higher in the GDM group than the non-GDM group, but serum RBP4 levels between the 2 groups were not different. Serum RBP4 levels in pregnancy are not associated with IR. |
| Kim SH et al., 2007 (48), (South Korea) | GDM (N = 10, age = 32.6 ± 3); Controls (N = 9, age = 32.6 ± 3.3) | ADA | ELISA (Immundiagnostik, Bensheim, Germany) | μg/mL | 24–28 | Women with GDM had higher RBP4 concentrations than those seen in healthy women during pregnancy, but short-term rise in serum insulin did not modulate circulating RBP4 concentrations. |
| Klein K et al., 2010 (49), (Austria) | GDM (N = 63, age = 33.3 ± 4.8, BMI = 28.1 ± 6.2); Controls (N = 38, age = 32.7 ± 5.2, BMI = 27.7 ± 5.6) | German & Austrian Society for Diabetes (modified Carpenter Coustan) | ELISA (DRG Instruments, Marburg, Germany) | mg/L | 24–28, 33 | Serum RBP4 levels increased significantly between the two measurements in patients with GDM. In patients with GDM, RBP4 concentrations at 33 weeks of gestation correlated positively with mean blood glucose and HbA1c values. |
| Krzyzanowska K et al., 2008 (24), (Austria) | GDM (N = 41, age = 33 (29–35), BMI = 34 (29–38); Controls (N = 45, age = 28 (24–34), BMI = 29 (25–31)) | 4th Workshop Conference of GDM | ELISA (RBP4 EIA kit; Phoenix Pharmaceuticals, Belmont, CA, United States) | μg/mL | 29, 30, 8 weeks after delivery | Women with GDM had lower RBP4 levels than controls. The RBP4: retinol ratio and the RBP4:TTR ratio are more informative than RBP4 levels alone when assessing insulin–glucose homeostasis during pregnancy. |
| Kuzmicki M et al., 2011 (22), (Poland) | GDM (N = 88, age = 29.5 (27–33), BMI = 27.2 (25.2–30.1)); Controls (N = 86, age = 29.5 (27–31.5), BMI = 27.3 (23.1–29.4)) | WHO | ELISA (Phoenix Pharmaceuticals, Inc., United States) | mg/L | 24–30, 36–40 | Serum RBP4 concentration and its expression in SAT were higher in the women with GDM than in the controls. No association between serum or tissue RBP4 and the indices of IR was noted. |
| Lewandowski KC et al., 2008 (50), (Poland) | GDM (GCT+, OGTT+) (N = 15, age = 34 (29–36), BMI = 26.3 (29.4–30.1)); IGT (GCT+, OGTT−) (N = 15, age = 32 (32–36), BMI = 25.1 (23.7–28.4)); Controls (GCT−, OGTT−) (N = 20, age = 32 (29–35), BMI = 25.1 (23.5–28.2)) | WHO | Commercial RBP4 assay kit (Phoenix Pharmaceuticals Inc.: Burlingame, California, United States) | μg/mL | 28 | RBP4 levels were higher in women with GDM than in controls but did not correlate with IR. |
| Liu M et al., 2020 (51), (China) | GDM (N = 50, age = 33.88 ± 4.22, BMI = 27.69 ± 4.47); Controls (N = 47, age = 33.66 ± 3.97, BMI = 27.39 ± 2.32) | IADPSG | ELISA (Cusabio Biotech, Wuhan, Hubei, China) | μg/mL | 37–42 | GDM subjects had a lower RBP4/TTR ratio than the control subjects. |
| Maghbooli Z et al., 2010 (52), (Iran) | GDM (N = 92, age = 32.48 ± 5.23); Controls (N = 100, age = 27.88 ± 7.07) | O’Sullivan and Mahan criteria | ELISA (AdipoGen Kit, AdipoGen, Seoul, Korea) | μg/mL | 24–28 | RBP4 concentrations in GDM patients were significantly higher than in controls. |
| Mazaki-Tovi S et al., 2010 (25), (United States) | GDM (AGA: age = 34 (28–39), LGA: age = 32 (30–38)) (N = 97); Controls (AGA: age = 26 (22–29), LGA: age = 28 (22–32)) (N = 108) | WHO | Sensitive ELISA (Millipore Corporation, St. Charles, MO, United States) | ng/mL | >37 | Patients with GDM had a higher median plasma concentration of RBP4 than normal pregnant women. GDM is characterized by alterations in maternal circulating RBP4 concentrations. |
| Nanda S et al., 2013 (20), (United Kingdom) | GDM (N = 60, age = 32 (28.5–35.6), BMI = 28.6 (24.6–4.2)); Controls (N = 240, age = 33 (27.3–35.9), BMI = 23.8 (21.7–26.2)); Pre-eclampsia (N = 60); LGA (N = 60); SGA (N = 60) | WHO | ELISA (Immundiagnostik, Stubenwaldallee, Bensheim, Germany | ng/mL | 11–13 | The serum concentration of RBP4 in the first trimester was not significantly different between the groups. |
| Ortega-Senovilla H et al., 2011 (28), (Spain) | GDM (N = 98, age = 30.9 ± 0.5); Controls (N = 86, age = 28.7 ± 0.5) | Carpenter- Coustan | Sandwich ELISA (AdipoGen, Seoul, Korea) | μg/mL | 1 week before delivery | Maternal serum insulin, insulin-to-glucose ratio, HOMA-IR and RBP4 were higher, and adiponectin was lower in GDM than in control subjects. |
| Saucedo R et al., 2011 (40), (Mexico) | GDM (N = 60, age = 31.9 ± 5.6, BMI = 30.2 ± 4.9); Controls (N = 60, age = 24.8 ± 6.4, BMI = 28.4 ± 7.3) | ADA | RIA, using reagents from Phoenix Pharmaceuticals (Belmont, CA) | μg/mL | 30, 6 weeks postpartum, 6 months postpartum | Women with GDM showed higher IR than controls. There was no difference in adipokines between the two groups, but in women with a healthy pregnancy, RBP4 was associated with IR. |
| Skvarca A et al., 2012 (23), (Slovenia) | GDM (N = 30, age = 30.33 ± 4.86, BMI = 27.57 (24.88–29.76)); IGT (N = 19, age = 30.84 ± 4.51, BMI = 27.61 (23.78–31.18)); Controls (N = 25, age = 31.2 ± 3.34, BMI = 25.39 (23.18–27.43)) | 4th Workshop Conference of GDM | Commercially available ELISA | mg/L | 24–28 | Significant differences in HOMA–IR were found, but no significant differences in serum adipokine levels. Adiponectin, leptin, resistin, visfatin and RBP4 were not associated with the degree of glucose intolerance in pregnancy. |
| Su YX et al., 2010 (53), (China) | NP-NGT (N = 65, age = 28.1 ± 3.4); GDM (N = 63, age = 28.8 ± 1.8, BMI = 25.5 ± 2.6); Controls (N = 58, age = 28.4 ± 2.4, BMI = 24.9 ± 2.1) | ADA | Sandwich ELISA (a protocol developed in-house) using affinity chromatography-purified polyclonal and monoclonal antibodies generated against recombinant human RBP4 protein | mg/L | 24–28 | Serum RBP4 levels in the pregnant NGT and GDM groups were significantly higher than in the non-pregnant. RBP4 levels were much higher in the GDM vs. pregnant NGT group. Serum RBP4 levels significantly increase in pregnancy, independent of age and BMI. RBP4 levels appear to be a valuable marker of IR and dysfunctional lipid metabolism in pregnancy. |
| Tepper BJ et al., 2010 (35), (United States) | GDM (N = 12, age = 28.6 ± 4.9, BMI = 31.1 ± 0.6); Controls (N = 10, age = 28.8 ± 6.2, BMI = 31.1 ± 0.9) | Carpenter-Coustan | ELISA | μmol/L | 24–28 | RBP4, retinol and RBP4/retinol molar ratio were not different between the groups; GDM is not associated with RBP4 or retinol among borderline-obese pregnant women. |
| Wu P et al., 2021 (13), (China) | GDM (N = 332, age = 28 (25–30)); Controls (N = 664, age = 28 (25–30)) | IADPSG | ELISA (R&D Quantikine) | μg/mL | 9–12 | RBP4 was associated with a 1.39-fold higher risk of GDM. Serum RBP4 levels in early pregnancy, independent of metabolic risk factors, are positively associated with the risk of GDM. |
| Yuan X et al., 2017 (54), (China) | GDM (N = 86, age = 29 (27–33), BMI = 24.58 (21.72–26.98)); Controls (N = 273, age = 26 (24–28.25), BMI = 22.32 (20.66–28.25)) | IADPSG | Automatic biochemical analyzer (Hitachi 7,180; Hitachi, Ibaraki-ken, Japan) using commercial kits (Wako Pure Chemical Industries, Osaka, Japan) | μg/mL | 16–18 | The group that developed GDM had statistically significantly higher concentrations of ficolin-3, CRP, RBP4 and FFAs than the control group. The elevated ratios of RBP4/adiponectin were also observed in participants who developed GDM. |
| Zhang H et al., 2022 (55), (China) | GDM (N = 70, age = 25.68 ± 4.27); Controls (N = 70, age = 27.02 ± 3.54) | Obstetrics and Gynecology Section of the Chinese Medical Association | ELISA (R&D System, United States) | mg/L | 35–40 | Glucose metabolism and islet function in women with GDM are significantly correlated with serum RBP4. |
| Zhang Y et al., 2016 (56), (China) | GDM (N = 40, age = 32.24 ± 3.81, BMI = 27.55 ± 3.4); Controls (N = 240, age = 28.21 ± 4.12, BMI = 24.31 ± 2.92) | IADPSG | ELISA (R&D Systems, China, Shanghai) | mg/L | 24–28, >37 |
The GDM group showed greater levels of AFABP, leptin and RBP4 and a decreased adiponectin level. |
| Zhaoxia L et al., 2014 (57), (China) | GDM (N = 35, age = 29 ± 2.53); Controls (N = 35, age = 29.3 ± 3.06) | NDDG | Double antibody sandwich ELISA (Phoenix Pharmaceutical Company, Saint Joseph, MO) | μg/mL | 24–28 | Serum RBP4 levels in the GDM group were significantly higher than in the control group. Serum RBP4 levels in the GDM group were correlated with HOMA-IR, TG and blood glucose levels. |
| Zhu JP et al., 2014 (58), (China) | GDM (N = 177); Controls (N = 354) | N/A | N/A | mg/L | 24–28 | The plasma glucose, serum insulin, HOMA-IR, HbA1C and TG levels were significantly higher in the GDM group than in the controls. RBP4 levels of GDM women were significantly and positively correlated with the BMI. |
Units: age: years; BMI: kg/m2. ADA, American Diabetes Association; AFABP, adipocyte fatty acid-binding protein; AGA, appropriate for gestational age; BMI, body mass index; ChE, chemerin E; CRP, C-reactive protein; CysC, cystatin C; dGDM, diet treated gestational diabetes mellitus; ELISA, enzyme-linked immunosorbent assay; FABP4, fatty acid binding protein 4; FGF-21, fibroblast growth factor 21; FIGO, International Federation of Gynecology and Obstetrics; GCT−, normal glucose challenge test; GCT+: abnormal glucose challenge test; GDM, gestational diabetes mellitus; GIGT, gestational impaired glucose tolerance; HbA1c, glycated hemoglobin; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; IADPSG, International Association of Diabetes and Pregnancy Study Groups; iGDM, insulin treated gestational diabetes mellitus; IGT, impaired glucose tolerance; IR, insulin resistance; LGA, large for gestational age; mRNA, messenger ribonucleic acid; NDDG, National Diabetes Data Group; NGT, normal glucose tolerance; OGTT−, normal oral glucose tolerance test; OGTT+, abnormal oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; RBP4, retinol-binding protein 4; RIA, radioimmunoassay; SAT, subcutaneous adipose tissue; sOB-R, soluble leptin receptor; TG, triglycerides; TTR, transthyretin; WHO, World Health Organization.