Emerging biomarkers for gestational diabetes mellitus and related pediatric outcomes

Table 1 Summarized details of traditional biomarkers for gestational diabetes mellitus diagnosis and associated pediatric outcomes

Biomarker	Description	Diagnostic criteria	Sensitivity	Specificity	Notes	Ref.
Traditional biomarkers for GDM diagnosis
1-hour glucose challenge test	Measures glucose concentrations 1-hour post-glucose administration	≥ 140 mg/dL (7.8 mmol/L)	70%-90%	70%-80%	May require additional testing for diagnosis	Hosier et al[11], Ayesha et al[12], Zhao et al[13], Moon and Jang[14]
2-hour oral glucose tolerance test	Measures glucose concentrations 2-hour post-glucose administration	≥ 153 mg/dL (8.5 mmol/L)	80%-90%	90%-95%	Considered a gold standard for GDM diagnosis	Gautam et al[4], Jamieson et al[15], Prior et al[16], Madugalle et al[17]
Fasting plasma glucose	Measures glucose levels after an overnight fast	≥ 92 mg/dL (5.1 mmol/L)	70%-80%	80%-90%	May miss cases of GDM with normal fasting glucose	Ayesha et al[12], Beunen et al[18], Hasan et al[19]
Hemoglobin A1c	Evaluate mean glucose concentrations throughout the preceding 2-3 months	≥ 6.5% (48 mmol/moL)	40%-60%	80%-90%	May not be sensitive enough for GDM diagnosis	Valadan et al[20], Xiang et al[21], Tripathy et al[22]
Random plasma glucose	Monitors glucose levels at any time	≥ 200 mg/dL (11.1 mmol/L) with symptoms	Variable	Variable	Not recommended as a standalone diagnostic test	Jamieson et al[15], Huhn et al[23], Shaarbaf Eidgahi et al[24]

GDM: Gestational diabetes mellitus.

Table 2 Summarized details of traditional biomarkers for diagnosis of gestational diabetes mellitus associated pediatric outcomes

Biomarker	Pediatric outcome	Description	Diagnostic criteria	Sensitivity	Specificity	Notes	Ref.
Traditional biomarkers for pediatric outcomes in GDM
Birth weight	Macrosomia	Measures fetal growth	> 4000 g	70%-80%	80%-90%	Linked with an increased risk of obesity and metabolic diseases	Huhn et al[23], Zheng et al[27], Hu[28], Bernea et al[29]
Ponderal index	Fetal growth restriction	Measures fetal growth	< 2.2 or > 2.8	60%-70%	70%-80%	May indicate fetal growth restriction or macrosomia	Powel et al[30], Teshome et al[31], Mirabelli et al[32]
Cord blood glucose	Neonatal hypoglycemia	Measures glucose levels at birth	< 40 mg/dL (2.2 mmol/L)	80%-90%	90%-95%	Associated with increased risk of neonatal hypoglycemia	Wang et al[33], Shao et al[34]
Neonatal blood glucose	Neonatal hypoglycemia	Measures glucose levels after birth	< 40 mg/dL (2.2 mmol/L)	80%-90%	90%-95%	May require monitoring and treatment	Kariniemi et al[35], García-Moreno et al[36]
Anthropometric measures	Childhood obesity	Measures body mass index	> 95th percentile	70%-80%	80%-90%	Linked with an increased risk of obesity and metabolic diseases	Huang et al[37], Castaneda et al[38]

GDM: Gestational diabetes mellitus.

Table 3 Summarized details of traditional biomarkers for gestational diabetes mellitus prediction

Biomarker	Description	Predictive value	Sensitivity	Specificity	Notes	Ref.
Family history of diabetes	Diabetes prevalence among first-degree relatives	High risk	50%-70%	70%-80%	Important risk factor for GDM	Monod et al[40], Basil et al[41]
Body mass index ≥ 30	Obesity	Moderate risk	50%-70%	70%-80%	Increased risk of GDM with obesity	Teshome et al[31], Chen et al[42], Antoniou et al[43]
Age ≥ 35 years	Advanced maternal age	Moderate risk	40%-60%	60%-70%	Increased risk of GDM with advancing age	Deng et al[44], Guarga Montori et al[45], Machado-Gédéon et al[46]
Previous history of GDM	Previous diagnosis of GDM in a prior pregnancy	High risk	70%-90%	80%-90%	Strong predictor of GDM in subsequent pregnancies	Liang et al[47], Kouhkan et al[48]
Fasting plasma glucose in early pregnancy	Measures glucose levels in early pregnancy	High risk	70%-80%	80%-90%	May predict GDM development	Wang et al[49], Tong et al[50]
Triglycerides	Measures triglyceride levels	Moderate risk	50%-60%	70%-80%	May predict GDM development	Liang et al[47], Shi et al[51]
Adiponectin	Measures adiponectin levels, an adipokine involved in glucose regulation	Moderate risk	60%-70%	70%-80%	May predict GDM development	Mihai et al[52], Muntean et al[53], Moyce Gruber et al[54], Moyce Gruber et al[55]
Leptin	Measures leptin levels, an adipokine involved in energy balance	Moderate risk	50%-60%	70%-80%	May predict GDM development	Chico-Barba et al[56]
HCG	Measures elevated HCG levels	Moderate risk	50%-60%	70%-80%	May predict GDM development	Mandić-Marković et al[26], Kantomaa et al[57]
IGF-1	Measures IGF-1 levels, which may be associated with insulin resistance	Moderate risk	50%-60%	70%-80%	May predict GDM development	Tumminia et al[58], Alekseenkova et al[59]
Resistin	Measures resistin levels, which may be associated with insulin resistance	Moderate risk	50%-60%	70%-80%	May predict GDM development	Ferdousi et al[60], Saucedo et al[61]

GDM: Gestational diabetes mellitus; HCG: Human chorionic gonadotropin; IGF-1: Insulin growth factor-1.

Table 4 Summarized details of predictive biomarkers for pediatric outcomes of gestational diabetes mellitus

Predictive biomarkers for pediatric outcomes of GDM		Ref.
Fetal ultrasound	Valuable tool for monitoring the fetal development and pediatric outcomes. Detect growth restriction, growth patterns, congenital anomalies, and fetal macrosomia. Predict neurodevelopmental outcomes, such as cerebral palsy. Enables early detection of potential issues. Timely interventions and informing personalized care plans	Rathnayake et al[5], Parsaei et al[39], David et al[64], Sodje[65], Debbink et al[66]
Maternal glucose level	High level can lead to fetal macrosomia, increasing the risk of birth injuries and complications. Impact long-term pediatric outcomes, such as obesity and metabolic disorders. Regular monitoring is crucial for managing GDM and inform personalized care plans for pregnant women	Rathnayake et al[5], Bernea et al[29], Parsaei et al[39], Ornoy et al[67]

GDM: Gestational diabetes mellitus.

Table 5 Pediatric outcomes associated with gestational diabetes mellitus can have short-term and long-term effects on the child's health

Short-term outcomes		Ref.
Macrosomia	Excessive birth weight, which can increase the risk of complications during delivery	Gautam et al[4], Ornoy et al[67], Chen et al[71]
Neonatal hypoglycemia	Low blood sugar in newborns, which can be a complication of GDM	Gautam et al[4], Nakshine and Jogdand[69], Corcillo et al[72]
Respiratory distress syndrome	Difficulty breathing in newborns, which can be associated with GDM	Gautam et al[4], Chulkov et al[73], Cahen-Peretz et al[74]
Birth injuries	Elevated risk of birth injuries, including shoulder dystocia, linked to macrosomia	Gautam et al[4], Nakshine and Jogdand[69], Chen et al[71]
Long-term outcomes
Obesity	Children of mothers with GDM are at an increased risk of having obese in later life	Gautam et al[4], Ornoy et al[67], Nakshine and Jogdand[69], Semnani-Azad et al[70], Mantzorou et al[75]
T2DM	Children of mothers with GDM are at an elevated risk of getting T2DM in later life	Gautam et al[4], Nakshine and Jogdand[69], Semnani-Azad et al[70], Corcillo et al[72]
Metabolic syndrome	Children of mothers with GDM may have an elevated risk of developing metabolic syndrome, a group of disorders that enhance the risk of cardiovascular disease, cerebrovascular accidents, and T2DM	Gautam et al[4], Nakshine and Jogdand[69], Semnani-Azad et al[70], Corcillo et al[72], Pathirana et al[76]
Neurodevelopmental outcomes	Certain studies indicate that children delivered to mothers with GDM may have an elevated risk of neurodevelopmental delays or abnormalities	Ornoy et al[67], Hirata et al[77], Kim et al[78]

GDM: Gestational diabetes mellitus; T2DM: Type 2 diabetes mellitus.

Table 6 Summarized details of emerging epigenetic (microRNAs) biomarkers for diagnosis and early prediction of gestational diabetes mellitus and associated outcomes

MicroRNAs	Expression level	Potential role	Ref.
MiR-16	Upregulated	Involved in insulin resistance and glucose metabolism	Hocaoglu et al[83], Alimoradi et al[84], Sørensen et al[85]
MiR-29a	Upregulated	Involved in glucose metabolism and insulin signaling	Hocaoglu et al[83], Li et al[86], Dalgaard et al[87]
MiR-335	Upregulated	Regulating insulin resistance and pancreatic islet β-cell secretion	Gezginci-Oktayoglu et al[88], Li et al[89]
MiR-132	Upregulated	Associated with insulin resistance and GDM	Carr et al[90], Sałówka and Martinez-Sanchez[91]
MiR-222	Need for further research	Contributing to estrogen-induced insulin resistance	He et al[92], Valerio et al[93]
MiR-17	Upregulated	Involved in insulin signaling pathways	Ejaz et al[94], Jiang et al[95]
MiR-19a	Upregulated	Enhance β-cell function by targeting suppressor of cytokine signaling 3, contribute to pancreatic β-cell dysfunction and insulin resistance	Holvoet[96], Du et al[97]
MiR-19b	Upregulated	Involved in insulin signaling pathways	Chao et al[98], He et al[99]
MiR-20a	Upregulated	Involved in insulin signaling pathways	He et al[92], da Silva et al[100]
MiR-223	Downregulated	Associated with insulin sensitivity and GDM	He et al[92], da Silva et al[100], Masete et al[101]
MiR-330-3p	Upregulated	Potential biomarker for GDM diagnosis	He et al[92], da Silva et al[100]
MiR-144	Downregulated	Associated with insulin sensitivity and GDM	Juchnicka et al[102], Zhang et al[103]
MiR-195	Upregulated	Associated with insulin resistance and GDM	He et al[92], da Silva et al[100], Masete et al[101]
MiR-21	Upregulated	Potential biomarker for GDM prediction	Silva et al[100], Kunysz et al[104]

GDM: Gestational diabetes mellitus.

Table 7 Summarized details of emerging genetic biomarker (single nucleotide polymorphisms) for diagnosis and early prediction of gestational diabetes mellitus and associated outcomes

Gene	Variant/mutation	Potential role	Ref.
TCF7 L2	Rs7903146 (C/T)	Associated with GDM risk and insulin secretion	Shalabi et al[106], Fang et al[107]
KCNQ1	Rs2237892 (C/T)	Regulating insulin secretion and glucose metabolism	Ortega-Contreras et al[108], Alshammary et al[109]
CDKAL1	Rs7754840 (C/G)	Associated with GDM risk and insulin secretion	Mahdizade et al[110], Wang et al[111]
HHEX	Rs1111875 (C/T)	Associated with GDM risk and pancreatic function	Zeng et al[112], Xie et al[113]
SLC30A8	Rs13266634 (C/T)	Regulating zinc transport and insulin secretion	Xie et al[113], Zeng et al[114]
GCK	Rs1799884 (A/T)	Regulating glucose sensing and insulin secretion	Hu et al[115], Popova et al[116]
MTNR1B	Rs10830963 (G/C)	Associated with GDM risk and insulin secretion	Chen et al[117], Bai et al[118]
PPARγ	Rs1801282 (C/G)	Regulating glucose metabolism, insulin sensitivity, and adipogenesis	Chen et al[117], Wu et al[119]

GDM: Gestational diabetes mellitus.

Table 8 Summarized details of emerging inflammatory biomarker for diagnosis and early prediction of gestational diabetes mellitus and associated outcomes

Biomarker	Description	Expression level	Potential role	Ref.
IL-6	Pro-inflammatory cytokine	Upregulated	Associated with insulin resistance and GDM	Srivastava et al[122], Hosseini et al[123], Tutar et al[124]
IL-1β	Pro-inflammatory cytokine	Upregulated	Involved in inflammation and GDM	Zgutka et al[125], Yousif et al[126]
IL-8	Pro-inflammatory cytokine	Upregulated	Associated with inflammation and GDM	Vilotić et al[127]
CRP	Acute-phase protein	Upregulated	Exacerbating insulin resistance and glucose metabolism dysregulation	Quansah et al[128], Chakraborty et al[129]
Tumor necrosis factor-alpha	Pro-inflammatory cytokine	Upregulated	Involved in inflammation and GDM	Saucedo et al[61], Hosseini et al[123]
High-sensitivity CRP	Sensitive marker of inflammation	Upregulated	Potential biomarker for GDM prediction	Xiang et al[21], Tao et al[130]

CRP: C-reactive protein; GDM: Gestational diabetes mellitus; IL: Interleukin.

Table 9 Summarized details of emerging metabolic biomarkers for diagnosis and early prediction of gestational diabetes mellitus and associated outcomes

Biomarker	Amino acid/metabolic pathway	Potential role	Ref.
Metabolic biomarkers
Amino acid metabolites
Branched-chain amino acids	Leucine, isoleucine, valine	Associated with insulin resistance and GDM	Li et al[134], Ademolu[135]
Tryptophan	Tryptophan	Involved in various metabolic processes and altered tryptophan metabolism have been linked to insulin resistance and GDM	Zhou et al[136], Özdemir et al[137]
Phenylalanine	Phenylalanine	Elevated phenylalanine levels have been linked to insulin resistance and GDM	Yang et al[138]
Histidine	Histidine	Modified histidine concentrations have been associated with insulin resistance and GDM	Zhou et al[136], Yang et al[138]
Glutamic acid	Glutamic acid	Potential biomarker for GDM diagnosis	Yang et al[138], Kong et al[139]
N-Acetylproline	Proline	Altered N-Acetylproline levels have been linked to insulin resistance and GDM	Aleidi et al[140]
Alanine	Alanine	Potential biomarker for GDM diagnosis	Zhou et al[141], Spanou et al[142]
Tyrosine	Tyrosine	Potential biomarker for GDM prediction	Yang et al[138], Spanou et al[142]
Arginine	Arginine	Employed in glucose metabolism and GDM	Spanou et al[142], Zhan et al[143]
Glycine	Glycine	Associated with insulin sensitivity and GDM	Yang et al[138], Zhou et al[141], Spanou et al[142]
Lipid metabolites
Triacylglycerols	Insulin resistance-related lipid metabolites	Potential biomarkers for GDM prediction	Zhang et al[144], Balachandiran et al[145]
Inositol phosphate	Insulin resistance and glucose metabolism	Insulin resistance and glucose intolerance in GDM may be exacerbated by altered IP3 signaling	Pillai et al[146], Mazzera et al[147]
Glycerolipid	GDM and insulin resistance may exacerbate by elevated triacylglycerols	Predictive biomarker for GDM risk	Zhan et al[143], Zhang et al[144]
Omega-6-fatty acid	Changes in amino acid levels might be a factor in GDM and insulin resistance	Predictive biomarker for GDM risk	Egalini et al[132], Hosseinkhani et al[148]
Phosphatidylcholines	Phospholipids involved in glucose metabolism	Potential biomarkers for GDM diagnosis	Zhou et al[141], Wang et al[149]
Sphingomyelins	Sphingolipids associated with insulin resistance	Potential biomarkers for GDM prediction	Fakhr et al[150], Pinto et al[151]
Lysophosphatidylcholines	Phospholipid metabolites associated with GDM	Potential biomarkers for GDM diagnosis	Zhou et al[141], Zhan et al[143], Hung et al[152]
Ceramides	Sphingolipids associated with insulin resistance	Potential biomarkers for GDM prediction	Mustaniemi et al[153], Lantzanaki et al[154]
Free fatty acids	Lipid metabolites associated with insulin resistance	Potential biomarkers for GDM prediction	Kong et al[139], Hosseinkhani et al[148]
Acylcarnitines	Fatty acid metabolites associated with insulin resistance	Potential biomarkers for GDM prediction	Zhan et al[143], Pinto et al[151]
Glycolytic intermediates
1,5-Anhydroglucitol	Glycolysis	Marker of glycemic control and GDM diagnosis	Xu et al[155], Lin et al[156]
Pyruvate	Glycolysis	Potential biomarker for GDM diagnosis	Zhou et al[141], Bhushan et al[157]
Glyceraldehyde-3-phosphate	Glycolysis	Potential biomarker for GDM prediction	Saucedo et al[61]
Lactate	Glycolysis	Associated with insulin resistance and GDM	Zhou et al[141]
Fructose-1,6-bisphosphate	Glycolysis	Potential biomarker for GDM prediction	Wei et al[158], Wang et al[159]
Glucose-6-phosphate	Glycolysis	Potential biomarker for GDM diagnosis	Wei et al[158]
Phosphoenolpyruvate	Glycolysis	Potential biomarker for GDM prediction	Lai et al[160], Xu et al[161]

GDM: Gestational diabetes mellitus.

Table 10 Summarized details of emerging protein biomarkers for diagnosis and early prediction of gestational diabetes mellitus and associated outcomes

Biomarker	Protein function	Association with GDM	Potential role	Clinical utility	Advantages	Ref.
Fetuin-A	Insulin resistance	Elevated levels of fetuin-A have been associated with GDM	Fetuin-A may play a role in insulin resistance and glucose metabolism during pregnancy	Fetuin-A may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	Fetuin-A is a relatively stable protein that can be measured in maternal serum or plasma, making it a potentially useful biomarker for GDM	Bogdanet et al[6], Ruszała et al[7], Wu et al[170], Cai et al[171]
IGFBP-1	Glucose metabolism	Decreased levels of IGFBP-1 have been associated with GDM	IGFBP-1 may play a role in glucose metabolism and insulin sensitivity during pregnancy	IGFBP-1 may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	IGFBP-1 is a relatively stable protein that can be measured in maternal serum or plasma, making it a potentially useful biomarker for GDM	Alekseenkova et al[59], Hivert et al[172], Hong et al[173], Martín-Estal et al[174]
SHBG	Sex hormone transport	Low levels of SHBG have been associated with GDM	Associated with insulin resistance and GDM	SHBG may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	SHBG is a relatively stable protein that can be measured in maternal serum or plasma, making it a potentially useful biomarker for GDM	Bruno et al[175], Sharmin et al[176], Liu et al[177]
RBP4	Retinol transport	Elevated levels of RBP4 have been associated with GDM	RBP4 may play a role in insulin resistance and glucose metabolism during pregnancy	RBP4 may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	RBP4 is a relatively stable protein that can be measured in maternal serum or plasma, making it a potentially useful biomarker for GDM	Kučerová et al[178], Leca et al[179], Mousavi et al[180]
Afamin	Vitamin E transport	Elevated levels of Afamin have been associated with GDM	Afamin may play a role in glucose metabolism and insulin sensitivity during pregnancy	Afamin may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	Afamin is a relatively stable protein that can be measured in maternal serum or plasma, making it a potentially useful biomarker for GDM	Eroğlu et al[181], Atakul et al[182], Wang et al[183]
Fibronectin	Cell adhesion and migration	Altered levels of fibronectin have been associated with GDM	Fibronectin may play a role in placental development and function, and its dysregulation may contribute to GDM	Fibronectin may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	Fibronectin is a relatively stable protein that can be measured in maternal serum or plasma, making it a potentially useful biomarker for GDM	Ruszała et al[7], Karoutsos et al[184]
Betatrophin	Glucose and lipid metabolism	Altered levels of Betatropin have been associated with GDM	Betatropin may play a role in regulating glucose metabolism and insulin sensitivity during pregnancy	Betatropin may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	Betatropin is a relatively novel biomarker that may provide new insights into GDM pathophysiology	Xu et al[185], Guo et al[186], Kirlangic et al[187], Melekoglu and Celik[188]
PAPP-A	Regulating placental function and fetal growth	Altered levels of PAPP-A have been associated with GDM	PAPP-A may play a role in regulating insulin-like growth factor bioavailability and glucose metabolism during pregnancy	PAPP-A may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	PAPP-A is a well-established biomarker for placental function and may provide insights into GDM pathophysiology	Conover and Oxvig[189], Yanachkova et al[190]
SFlt-1	Regulating angiogenesis and vascular function	Altered levels of sFlt-1 have been associated with GDM	SFlt-1 may play a role in regulating angiogenesis and vascular function in GDM	SFlt-1 may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	SFlt-1 is a well-established biomarker for preeclampsia and may provide insights into GDM pathophysiology	Joshi et al[191], Liao et al[192], Gul Kara et al[193]
PlGF	Promoting angiogenesis, regulating placental development and enhancing vascular function	Altered levels of PlGF have been associated with GDM	PlGF may play a role in regulating angiogenesis and placental function in GDM	PlGF may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	PlGF is a well-established biomarker for placental function and may provide insights into GDM pathophysiology	Yanachkova et al[190], Bolatai et al[194]
Apo	Lipid metabolism	Altered levels of Apo (e.g., ApoA1, ApoB) have been associated with GDM	Apo may play a role in regulating lipid metabolism and insulin sensitivity in GDM	Apo may be used to identify women at high risk of developing GDM, allowing for early intervention and prevention strategies	Apo are well-established biomarkers for cardiovascular disease and may provide insights into GDM pathophysiology	Balachandiran et al[145], Bernea et al[169]

Apo: Apolipoproteins; GDM: Gestational diabetes mellitus; IGFBP-1: Insulin-like growth factor binding protein-1; PAPP-A: Pregnancy-associted plasma protein-A; PlGF: Placental growth factor; RBP4: Retinol-binding protein 4; SFlt-1: Soluble fms-like tyrosine kinase-1; SHBG: Sex hormone-binding globulin.