Abstract
Background
Gestational Diabetes Mellitus (GDM) presents a significant health concern during pregnancy, predisposing individuals to future diabetes. Despite established postpartum diabetes screening guidelines, adherence to follow-up remains inadequate.
Aims
This study aimed to assess the predictive value of the 50-gram glucose challenge test (GCT) for post-pregnancy diabetes development.
Materials and methods
A population-based retrospective cohort study was conducted on pregnant women aged 18–45 who underwent GCT screening between November 2007 and July 2017 in a large Israeli community medical organization. Baseline characteristics, GCT results, and diabetes development during follow-up were analyzed using univariate and multivariate Cox regression analyses.
Results
Among 8,675 women included, 2.4% developed diabetes over a median follow-up of 73.23 months. Elevated GCT results correlated with a higher risk of future diabetes, with a 4% rise in risk per 1 mg/dL increase in glucose above 140 mg/dL. Multivariate analysis revealed a 60-fold rise in the risk of future diabetes in women with GCT results ≥ 200 mg/dL compared to those with GCT < 140 mg/dL, adjusting for age, body mass index, pre-pregnancy glucose, cholesterol, and triglycerides. A GCT result between 140 and 199 mg/dL was a predictor of future diabetes, even when adjusted for GDM based on a subsequent GTT if performed.
Conclusions
GCT results during pregnancy strongly predict future diabetes development, with higher GCT values significantly increasing risk. Recognizing abnormal GCT results as indicative of a prediabetic state offers a practical approach for risk stratification, facilitating early diagnosis, and intervention in post-pregnancy care.
Keywords: GDM, GCT, Diabetes prediction, Diabetes risk
Introduction
Gestational diabetes mellitus (GDM) represents a prevalent medical complication occurring in 5–38% of pregnancies globally with its incidence steadily rising worldwide [1–3]. In 2019, the International Diabetes Federation (IDF) estimated that 1 in 6 live newborns worldwide experienced complications due to GDM during pregnancy [4]. Beyond its immediate impact on pregnancy, delivery, and infant well-being, GDM stands as a significant risk factor for the subsequent development of type 2 diabetes (T2DM) [5]. A meta-analysis of 20 studies involving 1.3 million individuals revealed a nearly tenfold increased relative risk for T2DM among women with a history of GDM compared to healthy controls, with cumulative incidence among these women ranging from 9.9 to 16.5% [6].
The diagnosis of GDM typically follows either a “two-step” approach or a “one-step” 75-gram oral glucose tolerance test (75-g OGTT) performed at 24 to 28 weeks of gestation. The two-step approach begins with a glucose challenge test (GCT), where blood glucose is measured one hour after consuming 50 g of oral glucose. If the GCT result exceeds the diagnostic threshold (130, 135, or 140 mg/dL depending on the guidelines, a confirmatory 3-hour, 100-gram oral glucose tolerance test (100-g OGTT) is then performed [7, 8]. The one-step method involves measuring blood glucose one and two hours after consuming 75-g of oral glucose. There is ongoing debate as to the best approach to GDM screening, with no clear consensus. Selective screening is considered appropriate for low-risk populations, but the rising prevalence of metabolic risk factors, even in young women, has led many countries to adopt universal screening. During the postpartum period however, international guidelines more consistently recommend screening for women with a history of GDM, using the 75-g OGTT within 4–12 weeks after delivery to identify cases of persistent diabetes [9]. Despite these recommendations, many women fail to adhere to the post-delivery screening protocol [10, 11].
Given this context, evaluating GDM screening tests as predictive tools for estimating future DM risk is important. The 50-g GCT, a simple and cost-effective method widely employed for GDM screening, remains underexplored in terms of its potential as an independent predictive tool for assessing future DM risk [12].We conducted a comprehensive analysis of medical records from a large community health maintenance organization (HMO) in Israel to determine the association between abnormal 50-g GCT screening results during pregnancy and the subsequent risk of developing diabetes.
Materials and methods
Study design
We conducted a population-based retrospective cohort study using data from the Jerusalem district of Clalit Health Services (CHS), the largest HMO in Israel covering approximately 40% of Jerusalem’s area population. Approval for this research was obtained from the Institutional Review Board and Ethics Committee of CHS for the purpose of accessing and analyzing the data. Individual patient informed consent was not required due to lack of intervention.
Study population
The study included pregnant women aged 18–45 who were members of the Jerusalem district of CHS and underwent a GCT between November 2007 and July 2017. The data consisted of two cohorts: one comprising women who underwent a 100-g GTT following a previously conducted GCT test, and the other consisting of women with a GCT result of ≥ 200 mg/dL who were diagnosed with GDM with no need to proceed to the subsequent step. Women were followed from their first GCT test date during the follow-up period until the development of diabetes or until end of the study in December 2017. Women who underwent testing after July 2017 were excluded to ensure a minimum six-month follow-up period. Women were excluded if they received steroid treatment for over three months during the year prior to the GCT, or if they had pre-existing diabetes before pregnancy, defined as a fasting glucose ≥ 126 mg/dL on two separate occasions or a single hemoglobin A1C ≥ 6.5%.
Definition of variables
Demographic data and laboratory test results, including glucose, total cholesterol, LDL cholesterol, and triglycerides, were obtained from the CHS computerized database as mean of lab results of the 2-year prior to pregnancy, at least 28 weeks before GCT date. Maternal age was recorded at the time of the GCT test and body mass index (BMI) was calculated from the last recorded height and weight prior to pregnancy. GCT values were categorized as < 140, 140–199, and ≥ 200 mg/dL, using GCT < 140 as reference. For women that had a subsequent OGTT, GDM was diagnosed based on 2 or more abnormal values based on the Carpenter and Coustan diagnostic thresholds [13].
Outcome definition
Diabetes was defined as a fasting glucose ≥ 126 mg/dL on two separate occasions or hemoglobin A1C ≥ 6.5%. Diagnostic codes for diabetes were not used due to their low accuracy. The outcome of interest was the proportion of women developing post-pregnancy diabetes during follow up period and time to development of diabetes, determined by blood tests conducted after pregnancy, with follow-up until the end of the study period in December 2017.
Statistical analysis
Variables were included in the model after assessing their optimal presentation based on model fit indices. Differences in characteristics between GCT groups were analyzed using chi-square test for categorical variables, t-test for normally distributed continuous variables, and the Mann–Whitney test for non-normally distributed continuous data. Collinearity between variables was assessed, and in cases of high collinearity, only the more significant variable was included. Univariate and multivariate Cox regression analyses were performed to identify the effect of GCT result group on time to diabetes development with adjustment for covariates, including age, pre-pregnancy body mass index (BMI), and biochemical variables. Confounders were tested and included in the multivariate model if found significant. Interactions were tested by adding a cross-product term between two-by-two factors at a time. The statistical significance level was set to P < 0.05. We conducted 3 multifactor-adjusted Cox’s proportional hazards regression analyses: In model 1, we adjusted for age, BMI, and glucose before pregnancy. In model 2, we additionally adjusted for cholesterol and TG. In Model 3, we adjusted for GDM diagnosis in women with GCT results below 200 mg/dL who proceeded to an OGTT, as only a small portion of those with GCT results above 200 had a subsequent OGTT. This model also incorporated the covariates from model 1. IBM SPSS Statistics version 20 was used for the analyses.
Results
A total of 9,010 women who underwent a GCT between November 2007 and July 2017 were identified, with follow-up continuing until December 2017. After applying the specified inclusion and exclusion criteria, 8675 women were included in the analysis (Fig. 1). The median time of follow-up was 73.23 months (interquartile range [IQR] 43.4,105.5).
Fig. 1.
Consort diagram. A description of the study population. Abbreviations: OGTT, oral 100 g glucose tolerance test; GCT, 50 g glucose tolerance test
Baseline characteristics categorized by GCT results are summarized in Table 1. Of the participants, 65.7% had a GCT result below 140 mg/dL, 31.9% had a result between 140 and 199 mg/dL, and 2.4% had a result of 200 mg/dL or above. Women in the GCT ≥ 200 group were notably older and had a higher BMI, low density lipoprotein (LDL), triglycerides (TG), cholesterol, and glucose before pregnancy.
Table 1.
Baseline characteristics according to GCT result group
| GCT group | ||||||
|---|---|---|---|---|---|---|
| < 140 mg/dL (N = 5698) |
140–199 mg/dL (N = 2767) |
≥ 200 mg/dL (N = 210) |
Total (N = 8675) |
P-value | ||
| Age, years | 27.3 ± 4.8 | 29.1 ± 5.5 | 31.1 ± 5.6 | 27.9 ± 5.2 | < 0.001 | |
|
Age, years categorical |
≤ 25 | 2022 (35.5%) | 690 (24.9%) | 31 (14.8%) | 2743 (31.6%) | < 0.001 |
| 25–35 | 3307 (58%) | 1638 (59.2%) | 119 (56.7%) | 5064 (58.4%) | ||
| ≥ 35 | 369 (6.5%) | 439 (15.9%) | 60 (28.6%) | 868 (10%) | ||
| BMI, kg/m2 | 24.8 ± 4.6 | 25.2 ± 5.0 | 28.2 ± 5.2 | 25.0 ± 4.7 | < 0.001 | |
|
BMI (kg/m2) dichotomous |
BMI < 30 | 4559 (87.0%) | 1998 (83.2%) | 85 (63.0%) | 6642 (85.4%) | < 0.001 |
| BMI ≤ 30 | 681 (13%) | 403 (16.8%) | 50 (37.0%) | 1134 (14.6%) | ||
|
BMI (kg/m2) categorical |
< 18.5 | 194 (3.7%) | 123 (5.2%) | 3 (2.2%) | 320 (4.2%) | < 0.001 |
| 18.5–24.9 | 2863 (55.3%) | 1192 (50.1%) | 38 (28.1) | 4093 (53.2%) | ||
| 25-29.9 | 1442 (27.8%) | 659 (27.7%) | 44 (32.6%) | 2145 (27.9%) | ||
| ≤ 30 | 681 (13.1%) | 403 (17.0%) | 50 (37.0%) | 1134 (14.7%) | ||
| Cholesterol (mg/dL) | 171.4 ± 36.6 | 175.5 ± 36.1 | 180.5 ± 35.6 | 173.0 ± 36.5 | < 0.001 | |
| Triglycerides (mg/dL) | 103.8 ± 59.1 | 115.9 ± 70.4 | 130.0 ± 75.5 | 108.2 ± 63.6 | < 0.001 | |
| LDL (mg/dL) | 98.5 ± 27.0 | 100.6 ± 27.2 | 107.3 ± 28.3 | 99.3 ± 27.1 | < 0.001 | |
| Glucose pre-pregnancy (mg/dL) | 83.9 ± 8.1 | 85.4 ± 8.7 | 96.9 ± 16.7 | 84.7 ± 8.8 | < 0.001 | |
| Women that have done a following oGTT | 902 (15.8%) | 2146 (77.6%) | 17 (8.1%) | 3065 (35.3%) | ||
| GDM based on diagnostic GTT ( = > 2 abnormal values)* | 67 (7.4%) | 449 (20.9%) | 13 (76.5%) | 529 (17.3%) | ||
| Diabetes post-pregnancy | 46 (0.8%) | 66 (2.4%) | 110 (52.4%) | 222 (2.6%) | < 0.001 | |
Variables are shown as n (%) for categorial variables and as mean ± SD for continuous variables
Abbreviations: BMI = body mass index; TG = triglycerides; LDL = low-density lipoprotein cholesterol, DM = diabetes mellitus
*Percentage out of the women that have done a following GTT test
In our study, 77.5% (2,146) of women with a GCT of 140–199 mg/dL underwent a following OGTT. Among these, 20.9% (449) were diagnosed with GDM based on the OGTT results. During study period, 222 (2.6%) women developed diabetes. The median time to diabetes onset was 32.6 months (IQR 20.4,61.6). Table 2 illustrates the univariate relationship between pre-pregnancy laboratory parameters, including GCT results and time to diabetes development after pregnancy.
Table 2.
Univariate Cox regression analysis for post-pregnancy diabetes
| HR | 95%CI | P-value | |
|---|---|---|---|
| GCT mg/dL (continuous) | 1.04 | 1.04–1.04 | < 0.001 |
| GCT result (categorical) | |||
| GCT < 140 (mg/dL), reference | |||
| GCT 140–199 (mg/dL) | 4.43 | 3.03–6.49 | < 0.001 |
| GCT ≥ 200 (mg/dL) | 118.39 | 83.62-167.61 | < 0.001 |
| GCT ≥ 200 vs. <200 (mg/dL) | 65.30 | 50.02–85.24 | < 0.001 |
| BMI kg/m 2 (continuous) | 1.10 | 1.07–1.13 | < 0.001 |
| BMI kg/m 2 (categorical) | |||
| BMI 18.5–25 kg/m2, reference | |||
| BMI < 18.5 kg/m2 | 1.88 | 0.74–4.77 | 0.18 |
| BMI 25–29.9 kg/m2 | 2.64 | 1.78–3.91 | < 0.001 |
| BMI ≤ 30 kg/m2 | 4.72 | 3.16–7.03 | < 0.001 |
| BMI categorical (≥ 30 vs. <30 kg/m 2 ) | 2.93 | 2.14–4.02 | < 0.001 |
| Age, years | 1.12 | 1.10–1.15 | < 0.001 |
| Cholesterol (mg/dL) | 1.01 | 1.00-1.01 | < 0.001 |
| Triglycerides (mg/dL) | 1.00 | 1.00-1.01 | < 0.001 |
| LDL (mg/dL) | 1.01 | 1.01–1.02 | < 0.001 |
| Glucose, pre-pregnancy (mg/dL) | 1.05 | 1.05–1.06 | < 0.001 |
Abbreviations: HR = hazard ratio; CI = confidence interval; GCT = glucose challenge test; BMI = body mass index; TG = triglycerides; LDL = low-density lipoprotein
A GCT result ≥ 140 mg/dL was associated with a 4-fold increase in the risk of future diabetes (hazard ratio [HR] 4.40; 95% confidence interval [CI] 3.03–6.49), compared to GCT < 140 mg/dL. Furthermore, a GCT ≥ 200 mg/dL was associated with a 118-fold risk of future diabetes compared to a normal GCT of < 140 mg/dL (HR 118.39; 95% CI 83.62-167.61). Elevated BMI, older age and higher cholesterol, TG, LDL, and glucose pre- pregnancy were also associated with an increased risk of future diabetes. Due to high collinearity (r = 0.88) between LDL and cholesterol, only total cholesterol was included in the multivariable model. Elevated GCT results correlated with a higher risk of future diabetes, with a 4% rise in risk per 1 mg/dL increase in glucose above 140 mg/dL.
In multivariate analysis (Tables 3 and 4) a GCT of ≥ 200 mg/dL remained significantly associated with a shorter time until future diabetes diagnosis, presenting a 60-fold increased risk compared to a GCT below 140 mg/dL after adjusting for age, BMI, pre-pregnancy glucose, cholesterol, and TG (aHR 60.45; 95% CI 39.03–93.60). Notably, cholesterol and TG were found to be insignificant in the multivariate model (Table 4). Figure 2 shows the adjusted association between GCT values and time to future diabetes development. In a multivariate model that included only women with a GCT result below 200 mg/dL, a GCT result above 140 mg/dL was still significantly associated with risk of future diabetes, even after adjusting for GDM diagnosis based on an abnormal OGTT result (Table 5).
Table 3.
Model 1 - Multivariate Cox regression model for diabetes post-pregnancy
| aHR | 95% CI | P-value | |
|---|---|---|---|
| GCT < 140 mg/dL, (reference) | |||
| GCT 140–199 mg/dL | 3.64 | 2.43–5.45 | < 0.001 |
| GCT group ≥ 200 mg/dL | 65.52 | 42.08–98.93 | < 0.001 |
| Age, years | 1.05 | 1.02–1.08 | 0.002 |
| BMI kg/m 2 (continuous) | 1.05 | 1.02–1.08 | 0.003 |
| Glucose pre-pregnancy | 1.03 | 1.02–1.04 | < 0.001 |
Abbreviations: HR = hazard ratio; CI = confidence interval; GCT = glucose challenge test; BMI = body mass index
Table 4.
Model 2 - Multivariate Cox regression model for diabetes post-pregnancy
| aHR | 95% CI | P-value | |
|---|---|---|---|
| GCT < 140 mg/dL, (reference) | |||
| GCT 140–199 mg/dL | 3.28 | 2.16–4.98 | < 0.001 |
| GCT ≥ 200 mg/dL | 60.45 | 39.03–93.60 | < 0.001 |
| Age, years | 1.04 | 1.01–1.07 | 0.01 |
| BMI kg/m 2 (continuous) | 1.04 | 1.01–1.07 | 0.02 |
| Glucose pre-pregnancy | 1.03 | 1.03–1.03 | < 0.001 |
| Cholesterol mg/dL | 1.01 | 1.00-1.01 | 0.05 |
| Triglycerides mg/dL | 1.00 | 1.00–1.00 | 0.47 |
Abbreviations: HR = hazard ratio; CI = confidence interval; GCT = glucose challenge test; BMI = body mass index
Fig. 2.
Risk of future diabetes over time according to GCT result. Abbreviations: DM: Diabetes mellitus; GCT: glucose challenge test. Model was adjusted for age, body mass index, cholesterol, triglycerides
Table 5.
Model 3 - Multivariate Cox regression model for diabetes post-pregnancy*
| aHR | 95% CI | P-value | |
|---|---|---|---|
| GCT 140–199 mg/dL Vs. <140 (mg/dL) | 3.08 | 2.03–4.68 | < 0.001 |
| Diagnostic GTT ( = > 2 abnormal values) | 3.19 | 2.1–4.82 | < 0.001 |
| BMI kg/m 2 (continuous) | 1.06 | 1.03–1.103 | 0.001 |
| Age, years | 1.03 | 0.99–1.07 | 0.15 |
| Glucose pre-pregnancy | 1.03 | 1.02–1.05 | < 0.001 |
* Model including only women with GCT < 200 and a following oGTT
Discussion
In the present study, we aimed to evaluate the predictive value of abnormal 50-g GCT results during pregnancy for the subsequent risk of developing diabetes in a large cohort of women. Over a median follow-up period of approximately six years, we found a strong association between GCT results and future diabetes risk, with a 4% increase in risk for each incremental rise in GCT value. Multivariate analysis revealed that women with GCT results between 140 and 199 mg/dL had a 3-fold increased risk of developing diabetes, while those with GCT results ≥ 200 mg/dL had a 60-fold increased risk compared to women with normal GCT results.
Our findings align with recent studies. Retnakaran et al. observed a 38% increased likelihood of developing diabetes (HR 1.38; 95% CI, 1.37–1.39) for each 1 mmol/L (18 mg/dL) increment in GCT in a Canadian cohort, following adjustments for confounders such as age, income, rurality, and hypertension [14]. A GCT threshold of 8.0 mmol/L (144 mg/dL) predicted a 5-year risk of 6.0% for future diabetes. Similarly, Bardugo et al. demonstrated that an abnormal GCT result predicts future diabetes, even in individuals with a normal 100-g OGTT result [15]. Our study findings support these results in an extended follow-up period (median > 6 years) and utilizing more accurate diagnostic criteria (both abnormal fasting glucose and HbA1c) rather than relying on HbA1c alone.
Among women with GCT results ≥ 200 mg/dL, 52.4% developed diabetes within a median follow-up of six years. This is comparable to the 51.5% 10-year diabetes risk observed in women with four abnormal values on the 100-g OGTT [16]. In addition to GCT results, we identified age, BMI, and pre-pregnancy fasting glucose as independent predictors of future diabetes. This association persisted after adjusting for key confounders such as BMI, pre-pregnancy glucose levels, cholesterol, and triglycerides, further highlighting the utility of GCT in assessing diabetes risk and guiding preventive strategies, particularly in women with a GCT result ≥ 200 mg/dL.
Interestingly, our study also demonstrated that a GCT result of 140–199 mg/dL poses an increased risk for future diabetes, similar to prediabetes. A recent Cochrane systematic review reported HRs of 4.32, 3.61, 6.9, and 5.55 for impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG plus IGT, and prediabetic-range HbA1c over a follow-up of 1–20 years [17]. Given that a GCT result of 140–199 mg/dL yielded an HR of 3.28 in our analysis, it seems reasonable to consider abnormal GCT results as a marker of prediabetes, warranting regular follow-up and lifestyle modification, similar to IFG and IGT management. Further analysis showed that GCT results between 140 and 199 mg/dL predicted future diabetes even after adjusting for the diagnosis of GDM based on subsequent OGTT results. This suggests that GCT and OGTT independently contribute to diabetes risk prediction, with GCT providing significant additional value.
Typically, healthy women aged 18–45 do not undergo screening tests for diabetes, despite the rising prevalence of DM in this demographic. Elevated GCT results, in addition to predicting future diabetes, is also recognized as a cardiovascular risk factor in this population [18]. Our findings highlight the main risk factors for future diabetes and enable clinicians to focus on high-risk women who may benefit from long-term periodic screening and lifestyle intervention after pregnancy.
The strengths of our study include its real-world applicability, large cohort size, and access to comprehensive clinical and laboratory data, allowing for accurate documentation of baseline characteristics, GCT results, and long-term outcomes. However, there are several limitations. The cohort is drawn from a single district, albeit with diverse ethnic and socioeconomic backgrounds, which may limit generalizability. Additionally, the predictive value of GCT is only applicable in regions where GCT is part of GDM screening protocols. Moreover, most women in our cohort underwent an OGTT following GCT, with fewer undergoing GCT alone, potentially inflating the percentage of women in the 140–199 mg/dL group (31% of the cohort), which could impact the diabetes risk estimates for this subgroup. Nevertheless, the significant association between GCT ≥ 200 mg/dL and future diabetes remains valid.
In conclusion, GCT screening during pregnancy is a strong, independent predictor of future diabetes with A GCT result of 140–199 mg/dL associated with a 4-fold increase in future diabetes risk, while a GCT ≥ 200 mg/dL was associated with a 118-fold increase compared to GCT < 140 mg/dL. Elevated BMI, older age, and higher cholesterol, TG, LDL, and glucose pre-pregnancy were also predictors of diabetes risk. Given these findings, considering abnormal GCT as indicative of a prediabetes state may be a useful approach for risk stratification and guiding follow-up care. This could help identify high-risk women who may benefit from lifestyle modifications and regular screening, potentially improving early diagnosis and diabetes prevention, akin to current recommendations for IFG or IGT.
Author contributions
The authors confirm contribution to the manuscript as follows: Study conception anddesign: M.F, A.T; Data collection: A.T, N.T, M.F; Analysis and interpretation of results: M.F, N.T, A.T; Draft manuscript preparation: M.F, N.T, R.P, A.T. All authors reviewed the results and approved the final version of the manuscript.
Funding
There was no funding for this study.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The study was approved by the Institutional Ethical Committee of Clalit Health Institute and informed consent was waived by the Institutional Review Board.
Consent for publication
Not Applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Meir Frankel and Noa Tsur equally contributed to this manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.