Maternal and neonatal outcomes according to the timing of diagnosis of gestational diabetes: A critical appraisal

Table 1 Commonly used gestational diabetes mellitus diagnostic criteria

Ref.1	Diagnostic approach	Standard screening period	GDM diagnosis: PG threshold values in mmol/L, at or above	GDM diagnosis: Criteria before 24 GW	Comments and controversies
O’Sullivan and Mahan[25], 1964	Two step screening, 50 g OCT, if positive, 100 g OGTT	Not specified by the authors	FPG 5, 1-hour PG 9.2, 2-hour PG 6.9, 3-hour PG 7, 2 abnormal values	Not specified by the authors	The first validated test for GDM diagnosis based mainly on future development of type 2 diabetes. No specific data of E-GDM. Controversy on sensitivity of OCT2. 100 g glucose produces gastric discomfort
NDDG, 1979	Two step screening; 50 g OCT, if positive, 100 g OGTT	Not specified by the NDDG	FPG 5.9, 1-hour PG 10.6, 2-hour PG 9.2, 3-hour PG 8.1, 2 abnormal values	Not specified by NDDG	14% change in glucose threshold values, considering the changes in laboratory standards from whole blood to plasma or serum glucose values. Controversy on sensitivity of OCT2. 100 g glucose produces gastric discomfort
Carpenter and Coustan[12], 1982	Two step screening, 50 g OCT, if positive, 100 g OGTT	Not specified by the authors	FPG 5.3, 1-hour 10, 2-hour 8.6, 3-hour 7.8, 2 abnormal values	Not specified by authors	Modification for plasma glucose estimation by glucose oxidase technique. Controversy on sensitivity of OCT2. 100 g glucose produces gastric discomfort. Many organizations recommend C & C criteria for E-GDM screening
IADPSG, 2010, modified 2016	One step, 75 g OGTT	24-28 GW	FPG 5.1, 1-hour PG 10, 2-hour 8.5, one abnormal value	Recommendation of FPG ≥ 5.1 mmol/L in 2010, withdrawn in 2016	Derived from the strong pregnancy outcome data of HAPO study. Concerns about marked increase in GDM prevalence and the cost effectiveness of these criteria. Many countries use these criteria for early pregnancy
WHO, 2013	One step, 75 g OGTT	24-28 GW	FPG 5.1, 1-hour PG 10, 2-hour 8.5, one abnormal value	Recommends same criteria as of 24-28 GW for high-risk women	In 2013, the WHO changed the 1999 criteria, accepting the IADPSG criteria
ADA, 2025	One step, IADPSG, or 2 step C & C criteria	24-28 GW	Either IADPSG or C & C criteria for diagnosis	For high-risk women: FPG 6.1-6.9 mmol/L, HbA1c 41-47 mmol/mol	Approves both IADPSG and C & C criteria, causing confusion among obstetricians/diabetologists. There are major differences in GDM prevalence by these criteria. Does not recommend IADPSG or C & C criteria for use in early pregnancy
ACOG, 2018	Two step screening, 50 g OCT, if positive, 100 g OGTT	24-28 GW	Either C & C criteria or alternative NDDG: FPG 5.8, 1-hour 10.6, 2-hour 9, 2 abnormal values	For high-risk women: Same criteria as for 24-28 GW	All concerns of C & C and NDDG criteria
NICE, 2020	One step screening, screening only for high-risk women, one step 75 g OGTT	24-28 GW	FPG 5.6, 2-hour PG 7.8, one abnormal value	Recommend 75 g OGTT at booking for women with GDM history: Same diagnostic criteria as for 24-28 GW	Mainly used in United Kingdom. Concerns about racial differences in GDM diagnosis by these criteria. Permitted for use in early pregnancy for women with history of GDM only (not for other risks)
CDA, 2018	Two step screening, 50 g OCT, if positive, 75 g OGTT. Alternatively, one step IADPSG criteria	24-48 GW	If 1-hour OCT 111 or 75 g OGTT: FPG 5.3, 1-hour PG 10.6, 2-hour PG 9, one abnormal value	High risk women: Same criteria as for 24-28 GW at any stage in pregnancy	Issues related with sensitivity of screening OCT as with ACOG criteria
Govt of India Guideline, 2018	One step, non-fasting 75 g OGTT	If negative for GDM at booking, rescreen at 24-28 GW	2-hour PG 7.8	Universal screening: 75 g OGTT at booking	Only diagnostic OGTT in non-fasting state. May be of relevance in rural setting. Concerns about the validity of this test
ADIPS, 2013	One step, 75 g OGTT	24-28 GW	FPG 5.1, 1-hour PG 10, 2-hour 8.5, one abnormal value	For high-risk women 75 g OGTT at first opportunity after conception. Same criteria as for 24-28 GW	Criteria same as in IADPSG, but permits its use in early pregnancy

¹The year of last update of the criteria by the author or professional association.

²Screening 50 g oral glucose challenge test can miss 20% gestational diabetes women, especially those with high fasting plasma glucose values.

GDM: Gestational diabetes mellitus; PG: Plasma glucose; GW: Gestational weeks; NDDG: National Diabetes Data Group; IADPSG: International Association of Diabetes in Pregnancy Study group; WHO: World Health Organization; ADA: American Diabetes Association; ACOG: American College of Obstetricians and Gynecologists; NICE: National Institute for Health and Clinical Excellence; CDA: Canadian Diabetes Association; ADIPS: Australasian Diabetes in Pregnancy Society; OCT: Oral glucose challenge test; OGTT: Oral glucose tolerance test; FPG: Fasting plasma glucose; E-GDM: Early-onset gestational diabetes; C & C criteria: Carpenter and Coustan criteria; HbA1c: Glycated hemoglobin A1c; HAPO: Hyperglycemia and Adverse Pregnancy Outcomes.

Table 2 Design of studies comparing of adverse pregnancy outcomes between women having early gestational diabetes and late-onset gestational diabetes

Ref.	Study time	Country	Study design	GDM diagnostic criteria	Adverse outcomes assessed in the study, statical methodology, confounding factors
Feghali et al[31]	January 2009 to October 2012	United States	Retrospective study; PGDM excluded; E-GDM < 24 GW, n = 167; L-GDM ≥ 24 GW, n = 1202; routine GDM care to all	Two step screening using; C & C criteria for both E-GDM and L-GDM; risk-based E-GDM screening	Macrosomia, preterm delivery, gestational hypertension, neonatal morbidity, conditional logistic regression analysis, reference L-GDM, confounding factors; maternal age, maternal race, education, private insurance, nulliparity, prepregnancy BMI, tobacco use, GDM history, 50 g glucose challenge test value, reference L-GDM
Shub et al[32]	January 2005 to January 2016	Australia	Retrospective study; PGDM exclusion: Not mentioned; E-GDM < 20 GW, n = 170; L-GDM ≥ 20 GW, n = 171; no GDM, n = 547; routine GDM care to all	One step screening; same criteria for E-GDM and L-GDM; till 2013: FPG ≥ 5.5 mmol/L, or 2-hour PG ≥ 8 mmol/L. From 2014: IADPSG criteria, risk-based E-GDM screening	Composite obstetric outcome (caesarian, macrosomia, LGA, perineal tear, shoulder dystocia), composite neonatal outcomes (Apgar < 7 at 5 minutes, NICU admission, neonatal hypoglycemia, major birth defect). Multivariate logistic regression, reference “no GDM”. Confounding factors; maternal age, BMI, parity and region of birth
Punnose et al[33]	January 2011 to September 2017	India	Retrospective study; PGDM excluded; E-GDM < 24 GW, n = 255 (< 14 GW, n = 125, 14-23 GW, n = 130); L-GDM ≥ 24 GW, n = 467; routine GDM care to all	One step screening by IADPG criteria for both E-GDM and L-GDM; risk-based E-GDM screening	Premature birth, caesarian delivery, LGA babies, NICU admission, gestational hypertension, induction of labor, macrosomia, Apgar < 7 at 1 or 5 minutes. Multivariate regression analysis, reference “no-GDM”. Confounding factors; age, gravida, gestational age at delivery (except for premature delivery and LGA babies), hemoglobin, socioeconomic level, education, hypertension in pregnancy (except for gestational hypertension), BMI
Yefet et al[34]	August 2005 to January 2018	Israel	Retrospective study; PGDM excluded; study groups, GDM < 14 GW (T1), n = 117, GDM 14-23 GW (T2), n = 116, GDM ≥ 24 GW (T3), n = 2334. Also grouped as E-GDM < 24 GW, n = 233, L-GDM ≥ 24 GW, n = 2334; routine GDM care to all	Two step screening; C & C criteria or NDDG criteria for E-GDM and L-GDM. Risk based E-GDM screening	Composite neonatal outcomes (LGA babies, neonatal hypoglycemia, neonatal hyperbilirubinaemia. Other outcomes: Preterm birth, shoulder dystocia, birth trauma, foetal malformations. Multivariable logistic regression analysis, reference L-GDM. Confounding factors: Type of GDM control (A1 with diet alone, A2 with medications, age, BMI, parity, delivery week
Tirado-Aguilar et al[35]	January 2022 to May 2023	Mexico	Prospective study; PGDM excluded; E-GDM < 24 GW, n = 173; L-GDM 24-28 GW, n = 196; routine GDM care	One step screening, IADPSG for both E-GDM and L-GDM groups. Universal OGTT at first prenatal visit, if negative repeat screening 24-28 GW	Gestational hypertension, neonatal hypoglycemia, respiratory distress syndrome, neonatal asphyxia, neonatal hyperbilirubinaemia, mechanical ventilation, neonatal death. Logistic regression model analysis, reference L-GDM. Confounding factors; maternal age, pregestational BMI
Regnault et al[28]	2018 French National Health Data	France	Retrospective study; PGDM excluded from GDM; 84705 women with hyperglycemia in pregnancy. GDM < 22 GW, n = 31134; GDM 22-30 GW, n = 44412; GDM > 30 GW, n = 8789; no GDM treatment details	Before 24 GW: FPG ≥ 5.1 mmol/L. > 24 GW: IADPSG criteria	Maternal outcomes: Caesarian, pre-eclampsia, ante and post-partum hemorrhage. Neonatal outcomes: Perinatal death, congenital malformations, LGA, Erb’s palsy and calvicular fracture, foetal distress, NICU admission, neonatal hypoglycemia preterm delivery. Multilevel Poisson regression analysis, reference l-GDM. Confounding factors; maternal age, socioeconomic status, and gestational age of delivery except for preterm delivery

PGDM: Pregestational diabetes mellitus; E-GDM: Early-onset gestational diabetes; L-GDM: Late-onset gestational diabetes; GDM: Gestational diabetes mellitus; GW: Gestational weeks; BMI: Body mass index; FPG: Fasting plasma glucose; PG: Plasma glucose; IADPSG: International Association of Diabetes in Pregnancy Study Group; LGA: Large for gestational age babies; NICU: Neonatal intensive care unit; BMI: Body mass index; C & C criteria: Carpenter and Coustan criteria; T1: First trimester; T2: Second trimester; T3: Third trimester; NDDG: National Diabetes Data Group; OGTT: Oral glucose tolerance test.

Table 3 Comparative assessment of gestational diabetes mellitus risk factors and maternal glycemia at diagnosis, among early gestational diabetes and late gestational diabetes women, mean ± SD/mean (interquartile range)/n (%)

Ref.	Number of GDM women (n)	Age, years	BMI, kg/m2	Nulliparity	History of GDM	Family history of diabetes	Race	FPG, mmol/L	1-hour PG, mmol/L	2-hour PG, mmol/L
Feghali et al[31]	E-GDM, 160; L-GDM, 1202	32.4 ± 5.2, 31.2 ± 5.5, P = 0.007	35.4 ± 8.5, 29.4 ± 7.5, P = 0.001	62 (37.1), 619 (51.5), P = 0.001	54 (32.9), 113 (9.5), P < 0.001		White 725%, White 76%, P = 0.1	5.51 ± 0.96, 5.06 ± 0.83, P < 0.0001	11.17 ± 1.71, 10.84 ± 1.46, P = 0.04	9.99 ± 2.23, 9.84 ± 1.47, P = 0.5
Shub et al[32]	E-GDM, 170, L-GDM, 171	33 (30-36), 32 (30-35), P < 0.001	29 (25-35), 27 (23-35), P = 0.15	39 (22.9), 43 (25.1), P = 0.01				5.01 ± 5.02, 4.63 ± 0.37, P < 0.001	9.82 ± 1.82, 8.18 ± 1.48, P < 0.001	8.41 ± 1.36, 6.41 ± 1.02, P < 0.001
Punnose et al[33]	E-GDM, 255 L-GDM, 467	29.42 ± 4.01, 28.35 ± 3.62, P < 0.001	26.4 ± 4.45, 25.37 ± 4.19, P = 0.021	111 (43.53), 234 (50.11), P = 0.273	107 (41.96), 178 (38.12), P = 0.111	103 (40.39), 110 (23.55), P < 0.001	255 (100), 461 (100), all Asian Indians	5.26 ± 0.46, 5.19 ± 0.43, P = 0.089	9.08 ± 1.72, 9.36 ± 1.60, P = 0.023	7.55 ± 1.43, 7.47 ± 1.37, P = 0.675
Yefet et al[34]	E-GDM, 243, L-GDM, 2334	33.3 ± 5.3, 32.1 ± 5.5, P = 0.002	30.5 ± 6.2, 27.5 ± 8.7, P < 0.001	30 (12), 642 (28), P = 0.001
Tirado-Aguilar et al[35]	E-GDM, 173, L-GDM, 196	32 (28-37), 32 (27-37), P = 0.657	8.5 (25.1-32.4), 27.6 (24.2-31.6), P = 0.067					5.17 (4.8-5.4), 4.97 (4.6-5.3), P = 0.010	8.94 (7.8-9.8), 9.27 (7.8-10), P = 0.173	7.06 (6-8.1), 7.39 (6.3-8.6), P = 0.016
Regnault et al[28]	E-GDM, 31134; L-GDM, 44412	32.3 ± 5.3, 32.3 ± 5.3

GDM: Gestational diabetes mellitus; BMI: Body mass index; FPG: Fasting plasma glucose; PG: Plasma glucose; E-GDM: Early-onset gestational diabetes; L-GDM: Late-onset gestational diabetes.

Table 4 Adverse pregnancy outcomes among treated early gestational diabetes women in comparison with late-onset gestational diabetes or non-gestational diabetes mellitus women

Outcome	Immanuel and Simmons[30], Ref: L-GDM, E-GDM, RR (95%CI)	Feghali et al[31], Ref: L-GDM, E-GDM, aOR (95%CI)	Tirado-Aguilar et al[35], Ref: L-GDM, E-GDM, aOR (95%CI)	Regnault et al[28], Ref: L-GDM, E-GDM, aPR (95%CI)	Yefet et al[34], Ref: L-GDM, E-GDM, aOR (95%CI)	Punnose et al[33]		Shub et al[32]
						Ref: No GDM, L-GDM, aOR (95%CI)	Ref: No GDM, E-GDM, aOR (95%CI)	Ref: No GDM, L-GDM, aOR (95%CI)	Ref: No GDM, E-GDM, aOR (95%CI)
LGA babies	1.07 (0.86-1.35)			1.101 (1.06-1.14)	NS	1.371 (1.08-1.75)	2.021 (1.51-2.71)	0.6 (0.40-1.02)	0.8 (0.49-1.23)
Perinatal mortality	3.581 (1.91-6.7)		0.29 (0.18-2.78)	1.511 (1.19-1.91)
Neonatal hypoglycemia	1.611 (1.02-2.55)		18.571 (2.69-21.2)	1.08 (0.96-1.22)	3.51 (2-6.1)			3.31 (1.5-7.06)	4.21 (2.01-9.00)
NICU admission	1.16 (0.9-1.49)			1.04 (0.98-1.12)		1.591 (1.22-2.07)	1.891 (1.37-2.62)	1.4 (0.85-2.29)	1.6 (0.95-2.63)
Small for gestational age	1.27 (0.92-1.75)
Macrosomia	1.05 (0.77-1.41)	21 (1-4.2)
Gestational hypertension or preeclampsia	1.34 (0.98-1.82)	1 (0.5-1.8)	0.71 (0.18-2.78)	0.96 (0.88-1.05)		0.74 (0.43-1.27)	0.82 (0.43-1.56)	0.52 (0.22-1.25)	0.48 (0.2-1.31)
Preterm	1.16 (0.84-1.61)	1.6 (0.9-2.9)		1.01 (0.95-1.07)	NS	2.041 (1.54-2.69)	3.141 (2.28-4.33)
Caesarian	1.09 (0.94-1.26)			1.03 (1-1.05)		1.02 (0.83-1.26)	1.381 (1.05-1.81)
Shoulder dystocia	1.76 (0.96-3.24)				10.31 (2.4-44.6)
Hyperbilirubinemia	1.16 (0.91-1.48)		1.14 (0.68-2.24)		1.3 (0.9-1.8)
Respiratory distress	1 (0.76-1.32)		4.761 (1.91-15.16)
Erb’s palsy and clavicular fracture				1.551 (1.22-1.99)
Apgar at 5-minute < 7/neonatal asphyxia			3.29 (0.61-17.9)			1.54 (0.59-2.51)	1.59 (0.86-1.08)	0.6 (0.17-2.30)	0.37 (0.08-1.80)
Induction of labor						1.451 (1.17-1.8)	1.25 (0.94-1.65)	2.481 (1.61-3.84)	2.461 (1.55-3.93)
Neonatal composite		1 (0.6-1.7)						1.4 (0.9-2.23	1.81 (1.15-2.92)
Obstetric composite								0.78 (0.53-1.12)	1.16 (0.79-1.71)
Others			NS. For still birth, enterocolitis, mechanical ventilation, ventricular hemorrhage	NS. For ante or post-partum hemorrhage, congenital malformations	NS. For birth trauma, fetal malformations			Comparable perineal tear, major birth defects	Comparable perineal tear, major birth defects

¹Statistically significant.

GDM: Gestational diabetes mellitus; E-GDM: Early-onset gestational diabetes; L-GDM: Late-onset gestational diabetes; RR: Risk ratio; aOR: Adjusted odds ratio; aPR: Adjusted prevalence ratio; CI: Confidence interval; LGA: Large for gestational age; NICU: Neonatal intensive care unit; NS: No difference in univariate analysis, no further multivariate analysis.

Table 5 The relative effect and anticipate absolute effects on adverse events: Comparison between treated early gestational diabetes and late-onset gestational diabetes women

Outcome	Immanuel and Simmons[30]			Feghali et al[31]			Tirado-Aguilar et al[35]			Regnault et al[28]			Yefet et al[34]
	Relative effect, relative risk (95%CI)	Anticipated absolute effect, risk with L-GDM treated per 1000 women	Anticipated absolute effect, risk difference with E-GDM treated per 1000 women	Relative effect, aOR (95%CI)	Anticipated absolute effect, risk with L-GDM treated per 1000	Anticipated absolute effect, risk difference with E-GDM treated per 1000	Relative effect, aOR (95%CI)	Anticipated absolute effect, risk with L-GDM treated per 1000	Anticipated absolute effect, risk difference with E-GDM treated per 1000	Relative effect; adjusted prevalence ratio (95%CI)	Anticipated absolute effect, risk with L-GDM treated per 1000	Anticipated absolute effect, risk difference with E-GDM treated per 1000	Relative effect, aOR (95%CI)	Anticipated absolute effect, risk with L-GDM treated per 1000	Anticipated absolute effect, risk difference with E-GDM treated per 1000
Large for gestational age babies	1.07 (0.86-1.35)	187	13 more (26 fewer to 66 more)							1.10 (1.06-1.14)	170	17 more (11 more to 24 more)
Perinatal mortality	3.58 (1.91-6.71)	2	6 more (2 more to 14 more)				0.29 (0.18-2.78)	10	8 fewer (9 fewer to 18 more)	1.51 (1.19-1.91)	2	1, 0 fewer to 2 more
Neonatal hypoglycemia	1.61 (1.02-2.55)	134	82 more (3 more to 207 more)				18.57 (2.69-21.2)	6	106 (11 more 122 more)	1.08 (0.96-1.22)	20	2 (2 fewer to 5 more)	3.5 (2-6.1)	27	68 more (27 more to 138 more)
Caesarian delivery	1.09 (0.94-1.26)	313	28 more (19 fewer to 81 more)							1.03 (1-1.05)	250	8 more (0 fewer 13 more)
Shoulder dystocia	1.76 (0.96-3.24)	16	12 more (19 fewer to 36 more)										10.3 (2.4-44.6)	3	28 more (5 more to 131 more)
Respiratory distress	1 (0.76-1.32)	38	0 fewer to 12 more				4.76 (1.91-15.16)	26	98 (24 more to 369 more)
Macrosomia	1.05 (0.77-1.41)	108	5 more (25 fewer to 55 more)	2 (1-4.2)	79	79 more, 0 fewer to 253 more
Erb’s plasy										1.55 (1.22-1.99	2	1 more, 0 fewer to 2 more

E-GDM: Early-onset gestational diabetes; L-GDM: Late-onset gestational diabetes; aOR: Adjusted odds ratio; CI: Confidence interval.

Table 6 Hyperglycemia in early pregnancy and fetal damage: Proposed mechanisms

Gestational period in weeks	Foetal physiology	Maternal hyperglycemia effects
0-14 GW	Implantation; early embryo organogenesis; decidual histotropic function; early placental development; spiral artery plugging. Low oxygen environment and anaerobic metabolism of glucose (glycolysis) and protection of embryo from oxygen-free radical-mediated damage	Mothers with pregestational prediabetes. Have several metabolic abnormalities: Mild dysglycemia and hyperinsulinemia, changes in HDL-C and triglycerides, C-reactive protein, tissue plasminogen activator antigen, adipokines, and insulin-like growth factor binding protein 2. Needs to explore the influence of these parameters on fetal physiology in the perinatal period and the benefits of preventive strategies
		GDM diagnosed in the first trimester. Probable hyperglycemia-induced organogenesis, implantation and decidual dysfunctions, and placentation defects. Greater pro-oxidant and pro-inflammatory intrauterine milieu induced by hyperglycemia disturb the anaerobic environment, leading to fetal changes and miscarriage
14 GW onwards	Extravillous cytotrophoblast cells invade and remodel decidual cells to enable the entry of fully oxygenated maternal blood to reach the intervillous space and fetoplacental unit. Hematotropic nutrition and fetal growth and development. Placental-derived signals like hormones and extracellular vesicles induce adaptive responses in maternal physiology to support the fetoplacental unit. The mother-placenta interplay persists throughout pregnancy	Hyperglycemia and hyperinsulinemia-induced changes in spiral artery remodeling can interfere with oxygen and nutrient supply to the fetus. This will alter fetal growth dynamics throughout gestation. Hyperglycemia can induce epigenetic alterations affecting the signaling pathway. Insulin is detected in fetal circulation by 12 weeks, and maternal hyperglycemia can trigger a “fetal glucose steal phenomenon” to produce LGA babies. Fetal hyperinsulinemia at 17 GW is associated with insulin resistance and high free fatty acids in the offspring at age 5. This observation suggests that maternal hyperglycemia prior to 24 GW may trigger fetal programming for metabolic outcomes in the offspring. This is presumed to be due to epigenetic factors like DNA methylation, histone post-translational modifications, and non-coding RNAs

GDM: Gestational diabetes mellitus; GW: Gestational weeks; LGA: Large for gestational age; HDL-C: High density lipoprotein cholesterol.