Metabolic Phenotypes of Women with Gestational Diabetes Mellitus Affect the Risk of Adverse Pregnancy Outcomes
Article information
Abstract
Background
Gestational diabetes mellitus (GDM) affects women with diverse pathological phenotypes, but little is known about the effects of this variation on perinatal outcomes. We explored the metabolic phenotypes of GDM and their impact on adverse pregnancy outcomes.
Methods
Women diagnosed with gestational glucose intolerance or GDM were categorized into subgroups according to their prepregnancy body mass index (BMI) and the median values of the gestational Matsuda and Stumvoll indices. Logistic regression analysis was employed to assess the odds of adverse pregnancy outcomes, such as large-for-gestational age (LGA), small-for-gestational age, preterm birth, low Apgar score, and cesarean section.
Results
A total of 309 women were included, with a median age of 31 years and a median BMI of 22.3 kg/m2. Women with a higher pre-pregnancy BMI had a higher risk of LGA newborns (adjusted odds ratio [aOR] for pre-pregnancy BMI ≥25 kg/m2 compared to 20–23 kg/m2, 4.26; 95% confidence interval [CI], 1.99 to 9.12; P<0.001; P for trend=0.001), but the risk of other adverse pregnancy outcomes did not differ according to pre-pregnancy BMI. Women with insulin resistance had a higher risk of LGA (aOR, 1.88; 95% CI, 1.02 to 3.47; P=0.043) and cesarean section (aOR, 2.12; 95% CI, 1.29 to 3.50; P=0.003) than women in the insulin-sensitive group. In contrast, defective β-cell function did not affect adverse pregnancy outcomes.
Conclusion
Different metabolic phenotypes of GDM were associated with heterogeneous pregnancy outcomes. Women with obesity and those with insulin resistance are at greater risk of adverse outcomes and might need strict glycemic management during pregnancy.
INTRODUCTION
Gestational diabetes mellitus (GDM) is defined as glucose intolerance that either begins or is first recognized during pregnancy [1]. It represents one of the most frequent complications associated with pregnancy. The condition arises from insulin resistance, which is induced by pregnancy-related hormones such as placental lactogen. Coupled with inadequate compensatory insulin secretion, insulin resistance leads to maternal hyperglycemia in women with GDM, subsequently causing fetal hyperinsulinemia [2]. This leads to an increased risk of adverse pregnancy outcomes in GDM deliveries, which include large-for-gestational age (LGA) and higher rates of cesarean section, preterm delivery, neonatal hypoglycemia, and low Apgar scores [2-5].
The diagnosis of type 2 diabetes and GDM is not based on etiology; rather, it involves ruling out other known causes, such as autoimmunity in type 1 diabetes and genetic alterations in maturity-onset diabetes of the young. Efforts to subtype individuals with diabetes according to pathophysiology have been made to better understand and characterize the heterogeneous population and to predict varying prognoses, including the risk of vascular complications associated with each subtype [6,7]. Ahlqvist et al. [6] categorized newly diagnosed diabetes into five subgroups based on six clinical variables: glutamate decarboxylase antibodies, age at diagnosis, body mass index (BMI), hemoglobin A1c (HbA1c), and homeostatic model assessment of beta cell function and insulin resistance. These subgroups were primarily defined by individual differences in insulin sensitivity and beta cell function. The study successfully highlighted variations in disease progression and the risk of diabetic complications among the subgroups. For example, individuals with the highest insulin resistance faced a greater risk of diabetic kidney disease compared to other subgroups [6]. Such research underscores the importance of sub-clustering diabetes to facilitate the implementation of precision medicine [7].
GDM affects women with a heterogeneous pathological background in terms of hyperglycemia; however, only a few studies have investigated the associations between subtypes of GDM and adverse outcomes and prognosis [8-12]. Notably, Asian populations exhibit unique metabolic characteristics compared to Western populations, including reduced pancreatic beta cell function and an increased risk of GDM at lower BMIs [13-15]. Hence, it remains unclear whether distinct phenotypes of GDM contribute to adverse pregnancy outcomes in Asian women with GDM. In this study, we aimed to investigate the risk of adverse pregnancy outcomes in women with different GDM phenotypes classified by (1) BMI and (2) physiological phenotypes based on insulin sensitivity and pancreatic beta cell function.
METHODS
Study design
This study was a multicenter prospective cohort study conducted at two tertiary hospitals, Cheil Hospital and Ajou University Hospital. Women diagnosed with GDM and gestational impaired glucose intolerance (GIGT) were recruited between 1995 and 1997. Out of a total of 475 women, 127 were excluded due to missing HbA1c or fasting glucose levels, and an additional 40 were excluded because of preexisting diabetes. Therefore, the study included 309 women, of whom 59 (19.1%) had GIGT and 250 (80.9%) had GDM. The study adhered to the principles of the Declaration of Helsinki, and the Institutional Review Board of Seoul National University Bundang Hospital approved the study (IRB No. B-1007-105-007). Informed consent was waived by the board.
Pregnant women were screened for GDM using a two-step approach, starting with an initial 50-g oral glucose load and followed by a 100-g, 3-hour oral glucose tolerance test (OGTT). This screening took place between 24 and 28 weeks of gestation. A positive screen was defined by a 1-hour glucose value of 130 mg/dL or higher. The participants included in this study were initially diagnosed with GDM based on the National Diabetes Data Group criteria, as recommended by the Third International Workshop-Conference on Gestational Diabetes Mellitus. These criteria were in use during the study’s enrollment phase [16]. In this study, we reclassified the patients as either GIGT or GDM using the Carpenter-Coustan criteria, currently recommended by the Korean Diabetes Association. This reclassification aimed to align with the contemporary management practices for GDM. Participants were classified as having GDM if they met two or more of the following criteria, and as GIGT if they met only one: fasting plasma glucose of 95 mg/dL or greater, 1-hour glucose of 180 mg/dL or greater, 2-hour glucose of 155 mg/dL or greater, or 3-hour glucose of 140 mg/dL or greater.
Phenotyping of GDM
Women were sub-clustered based on pre-pregnancy BMI, insulin sensitivity, or pancreatic beta cell function. They were categorized into four groups according to their pre-pregnancy BMI: underweight (pre-pregnancy BMI <20 kg/m2), normal weight (pre-pregnancy BMI ≥20 and <23 kg/m2), overweight (pre-pregnancy BMI ≥23 and <25 kg/m2), and obese (pre-pregnancy BMI ≥25 kg/m2).
Plasma glucose and insulin values were collected at 0, 60, 120, and 180 minutes during the diagnostic 100-g, 3-hour OGTT. From the 100-g OGTT data, we calculated the Matsuda index to assess insulin sensitivity and the Stumvoll index to evaluate pancreatic beta cell function [17,18]. The Stumvoll index calculation utilized insulin levels measured in micro-international units per milliliter at 0 minutes (Ins0) and 60 minutes (Ins60), and glucose levels measured in milligrams per decil2024-12-12iter at 60 minutes (Gluc60). The formula used was 1,194+4.724×6.945×Ins0–117.0×1/18×Gluc60+1.414×6.945×Ins60 [18]. Women with GDM who had Matsuda and Stumvoll indices below the median of all participants were categorized into insulin-resistant and lower pancreatic beta cell function subgroups, respectively.
Definition of adverse pregnancy outcomes
We assessed LGA, small-for-gestational age (SGA), preterm birth, low Apgar score, and whether a cesarean section was performed as adverse pregnancy outcomes. LGA and SGA were defined as birthweights greater than the 90th percentile and less than the 10th percentile for their gestational age based on Korean National Growth Charts, respectively [19]. Apgar scores were measured at 1 and 5 minutes after birth. A low Apgar score was defined as instances where at least one Apgar score was lower than 7 points. Babies born before 37 weeks of gestational age were regarded as preterm births.
Statistical methods
Continuous variables were presented as medians and interquartile ranges (IQRs), and categorical variables were presented as counts and percentages. Differences between GDM phenotypes were compared with the Kruskal-Wallis test, the chi-square test, the Fisher exact test for categorical variables, and the Wilcoxon rank sum test for continuous variables. The odds of adverse pregnancy outcomes were compared using logistic regression with adjustment for age, HbA1c, insulin treatment, preterm birth, and gravidity. Statistical analysis was performed with R version 4.32 (R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value of <0.05 was considered statistically significant.
RESULTS
Baseline characteristics according to maternal pre-pregnancy BMI
A total of 309 women were included in the analysis. Participants were stratified according to their pre-pregnancy BMI as underweight (BMI <20 kg/m2; n=70, 22.7%), normal weight (BMI ≥20 and <23 kg/m2; n=128, 61.2%), overweight (BMI ≥23 and <25 kg/m2; n=54, 17.5%), and obese (BMI ≥25 kg/m2; n=57, 18.4%), and their clinical characteristics are presented in Table 1. Women in the overweight and obese categories were older, while those in the underweight category were younger compared to the normal weight group (reference group). Fasting glucose, fasting insulin, and HbA1c levels at mid-gestation were elevated in the overweight and obese groups relative to the normal weight group. The Matsuda index, which measures insulin sensitivity, showed a decline as BMI increased, with the obesity group recording the lowest Matsuda index value of 3.1 (IQR, 2.1 to 4.8).
Baseline Characteristics of Women and Pregnancy Outcomes Based on Maternal Pre-Pregnancy Body Mass Index
Adverse pregnancy outcomes according to maternal pre-pregnancy BMI
Table 1 presents adverse pregnancy outcomes based on maternal pre-pregnancy BMI. Women with obesity experienced the highest incidence of LGA at 39.3%, followed by overweight women at 24.1%, and those with a normal weight at 15.8%. No significant differences were observed in the rates of preterm birth, low Apgar score, or cesarean section.
In a crude analysis, women with obesity had significantly higher odds of an LGA birth than women with a normal weight (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.69 to 7.10; P<0.001) (Table 2). Women with obesity had a higher risk of LGA after adjusting for covariates including age, HbA1c, insulin treatment, preterm birth, and gravidity (adjusted odds ratio [aOR], 4.26; 95% CI, 1.99 to 9.12; P<0.001; P for trend=0.001) (Fig. 1A). However, there were no significant differences in the risk of SGA, preterm birth, low Apgar score, or cesarean section according to pre-pregnancy BMI subgroups.
Risk of Adverse Pregnancy Outcomes by Pre-Pregnancy Body Mass Index
Outcomes for large-for-gestational age (LGA) based on (A) maternal pre-pregnancy body mass index (BMI) and (B, C) physiological subtypes. A forest plot displaying the risk of LGA based on maternal pre-pregnancy BMI and physiological subtypes reflecting insulin sensitivity and β-cell function. Dots represent odds ratio (OR) adjusted for age, hemoglobin A1c, insulin treatment, preterm birth, and parity, while lines represent 95% confidence intervals. GDM, gestational diabetes mellitus; UW, underweight; NW, normal weight; OW, overweight; OB, obese; IS, insulin-sensitive; IR, insulin-resistant; HB, higher beta cell function; LB, lower beta cell function.
Baseline characteristics according to physiologic phenotypes
Next, we investigated whether maternal insulin sensitivity and pancreatic beta cell function were associated with adverse pregnancy outcomes. The median of the Matsuda index was 4.58, and the median of the Stumvoll index was 775.24. Women were classified into the insulin-sensitive (GDM-IS) group (49.0%, n=136; Matsuda index ≥4.58) and the insulin-resistant (GDM-IR) group (51.0%, n=141; Matsuda index <4.58), according to their gestational Matsuda index, as well as into the higher beta cell function (GDM-HB) group (49.8%, n=138; Stumvoll index ≥775.24), and lower beta cell function (GDM-LB) group (50.1%, n=139; Stumvoll index <775.24) according to their gestational Stumvoll index (Table 3).
Basic Characteristics of Women and Pregnancy Outcomes Based on Insulin Sensitivity and Beta Cell Function
Compared to the GDM-IS group, the GDM-IR group had a higher pre-pregnancy BMI (GDM-IS: 20.9 kg/m2 [IQR, 19.1 to 22.7]; GDM-IR: 22.3 kg/m2 [IQR, 20.8 to 25.2]). The HbA1c level was also higher in the GDM-IR group (GDM-IS: 33 mmol/mol [5.2%] [IQR, 29 to 36 (4.8% to 5.4%)]; GDM-IR: 36 mmol/mol [5.4%] [IQR, 32 to 39 (5.1% to 5.7%)]). Glucose concentrations at 0, 60, and 120 minutes and insulin concentrations at 0, 60, 120, and 180 minutes in OGTT were higher in the GDM-IR group than in the GDM-IS group. The Stumvoll index was higher in the GDM-IR group (GDM-IR: 1,005.8 [IQR, 778.4 to 1,345.0]). There were no significant BMI differences between the GDM-HB and GDM-LB groups. As for 100-g OGTT, glucose concentrations at 60 and 120 minutes were higher in the GDM-LB group. Insulin concentrations were significantly lower in the GDM-LB group. The Matsuda index was higher in the GDM-LB group (GDM-LB: 5.8 [IQR, 4.5 to 8.0], GDM-HB: 3.2 [IQR, 2.4 to 4.3]).
Pregnancy outcomes according to physiological phenotypes
Compared to the GDM-IS group, the GDM-IR group had a significantly higher incidence of LGA (28.9% vs. 16.3%, P=0.021) and cesarean section (54.4% vs. 37.0%, P=0.007) (Table 3). In logistic regression models, women in the GDM-IR group had a higher risk of LGA than the GDM-IS group (OR, 1.98; 95% CI, 1.10 to 3.57; P=0.022) (Table 4). The risk for LGA in GDM-IR women remained elevated after adjusting for age, HbA1c, insulin treatment, preterm birth, and gravidity (aOR, 1.88; 95% CI, 1.02 to 3.47; P=0.043) (Fig. 1B). The risk of cesarean section was also significantly higher in the GDM-IR group in an unadjusted model (OR, 2.02; 95% CI, 1.25 to 3.28; P=0.004), and this risk remained elevated in the fully adjusted model (aOR, 2.12; 95% CI, 1.29 to 3.50; P=0.003). There were no significant differences in SGA, preterm birth, or low Apgar scores between the GDM-IS and GDM-IR groups. In contrast, women in the GDM-HB and GDM-LB groups had comparable risks of adverse pregnancy outcomes, including LGA, cesarean section, SGA, preterm birth, and a low Apgar score (Table 4, Fig. 1C).
Risk of Adverse Pregnancy Outcomes Based on Insulin Sensitivity and Beta Cell Function
DISCUSSION
In this prospective observational cohort study, we assessed the risk of adverse pregnancy outcomes in women with GDM depending on maternal pre-pregnancy BMI and the physiological phenotype based on insulin sensitivity and pancreatic beta cell function. We demonstrated heterogeneity in pregnancy outcomes in women with GDM depending on their pre-pregnancy BMI and physiological phenotypes. Specifically, pre-pregnancy obesity, which is defined as a BMI over 25 kg/m2 in Asian women, was significantly associated with a higher risk of LGA than in women with BMI of 20 to 23 kg/m2. Women in the insulin-resistant group, defined as those whose gestational Matsuda index was lower than 4.56, had a higher risk of LGA and cesarean section, whereas lower beta cell function was not associated with any adverse pregnancy outcomes.
Our findings are consistent with previous research that explored the risk of adverse pregnancy outcomes among different physiological subtypes of GDM. A study by Powe et al. [8], which included 809 North American women diagnosed with GDM, categorized these women into three physiological subtypes based on their insulin secretion and sensitivity: GDM predominantly characterized by an insulin secretion defect, GDM predominantly characterized by an insulin sensitivity defect, and GDM characterized by defects in both. This study found that women with a predominant insulin sensitivity defect were at a higher risk of having larger infants and experiencing GDM-associated adverse outcomes. A post hoc analysis of the Vitamin D and Lifestyle Intervention for GDM Prevention study indicated that women with GDM and insulin resistance were more likely to have LGA infants and undergo cesarean sections [11]. Additionally, women with GDM and lower beta-cell function exhibited adverse pregnancy outcomes similar to those of women with normal glucose tolerance [11]. Conversely, a study from Belgium found that women with GDM and insulin resistance were at an increased risk of preterm delivery and neonatal hypoglycemia, although not LGA [10].
Notably, we demonstrated that relative insulin resistance with a low BMI could also contribute to adverse pregnancy outcomes, including LGA and cesarean section. In our study, the median pre-pregnancy BMI in GDM women in the insulin-resistant group was 22.3 kg/m2, while in studies including Caucasians, the mean pre-pregnancy BMI in GDM women with insulin resistance was 36 kg/m2 [11] and the BMI in GDM women with insulin resistance in their first trimester was reported to range from 27.4 to 32.3 kg/m2 [8,10]. In addition, the median Matsuda index in women with GDM in the insulin-resistant group in this study was 3.04, while the median Matsuda index was 0.33 to 2.9 in Western studies [8,10,11], suggesting that compared to other studies, the women in this study were much leaner and more sensitive to insulin. Overall, our analysis focused on Asian women with GDM who had a distinct phenotype characterized by low BMI and insulin sensitivity; nonetheless, relative insulin resistance within this group still posed a risk for LGA and cesarean section.
Contrary to the global upward trend in obesity prevalence among young women [20], South Korea exhibits a stable or somewhat decreasing trend. According to the Korean National Health and Nutrition Examination Survey [21], the BMI of women aged 20 to 39 has remained steady from the late 1990s to the mid-2010s (22.2 kg/m2 in 1998 and 22.1 kg/m2 in 2013 to 2014; P for trend=0.32). The combined prevalence of overweight and obesity (defined as a BMI over 23 and 25 kg/m2, respectively) slightly decreased over these periods (33.6% in 1998 and 31.3% in 2013 to 2014; P for trend=0.02, β=–0.01). These tendencies can be attributed to young Korean women’s higher consciousness about weight compared to young women in other countries [22]. Our study’s findings are not only applicable to current young Korean women but also to the broader Asian population, which generally has a comparatively low BMI.
Over the past few decades in Korea, the average maternal age has been rising, a trend that significantly impacts adverse pregnancy outcomes. Although studies generally show that adverse pregnancy outcomes increase with maternal age [23,24], the association between maternal age and the risk of having an LGA infant remains a topic of debate. A study examining trends in low birth weight and advanced maternal age in South Korea found that from 1993 to 2016, as the average maternal age increased by approximately 4.85 years, the mean birth weight decreased, and the incidence of low-birth-weight infants rose [25]. While the precise mechanisms are not yet fully understood, research involving human and mouse models suggests that advanced maternal age might increase the risk of fetal growth issues due to placental dysfunction [26]. However, these findings contrast with those from a cohort study in China [27], which investigated the impact of maternal age on adverse pregnancy outcomes among women with GDM. This study reported an increased risk of outcomes such as LGA and cesarean delivery in older women. Therefore, further research is essential to clarify the effects of advanced maternal age on LGA and to deepen our understanding of the epidemiology and underlying mechanisms.
In accordance with previous studies, no association was found between lower beta cell function and adverse pregnancy outcomes [8,11]. In this study, the GDM-LB group had a tendency for a reduced risk of cesarean section (aOR, 0.66; 95% CI, 0.40 to 1.1; P=0.093) that did not reach statistical significance. In contrast, the OR for low Apgar score was higher than 1 (aOR, 2.06; 95% CI, 0.64 to 6.67; P=0.229). Generally, the risk directionality for adverse outcomes in the GDM-IR and GDM-LB groups was opposite. For example, adverse pregnancy outcomes with an aOR greater than 1 observed in the GDM-IR group were offset by aOR values less than 1 in the GDM-LB group. However, since this hypothesis is not supported by statistical significance, further investigation is necessary to explore the risk of adverse pregnancy outcomes associated with impaired beta cell function and to examine the interaction between insulin resistance and beta cell function on a larger scale.
Asian countries, including South Korea, use different cutoffs when defining overweight and obesity, considering a BMI ≥23 kg/m2 as overweight and ≥25 kg/m2 as obese [28], whereas in Western countries, BMI cutoffs of ≥25 and ≥30 kg/m2 are used to define overweight and obesity, respectively [29]. Previous studies, mainly conducted with Caucasians, have found that higher pre-pregnancy BMI in women with GDM is associated with an increased risk of adverse pregnancy outcomes, including a higher rate of LGA and cesarean section [30-32]. Our study extends these findings by including cases of GIGT, thus encompassing less severe forms of hyperglycemia during pregnancy. We also compared Asian women, who are generally leaner than their Western counterparts, using the Asia-Pacific BMI classifications to highlight racial and ethnic differences. The incidence of LGA in this study was consistent with previous findings. The risk of LGA was significantly higher in women with obesity (BMI ≥25 kg/m2) in both unadjusted and adjusted analyses. However, there was no significant difference in adverse pregnancy outcomes among women who were underweight (BMI <20 kg/m2), normal weight (BMI 20 to 23 kg/m2), or overweight (BMI 23 to 25 kg/m2).
In this study, we sub-clustered women with GDM according to their pre-pregnancy BMI and physiological phenotypes. We found that a higher BMI and relative insulin resistance were linked to adverse pregnancy outcomes, such as LGA and cesarean section, in Asian women. These women exhibit distinct metabolic phenotypes compared to Western women, including a lower BMI and greater insulin sensitivity. The limitations of our study include a small sample size and the absence of data on healthy controls without GDM. This lack of data restricted our ability to further assess whether the risk of adverse pregnancy outcomes in non-obese or insulin-sensitive women with GDM is comparable to those without GDM.
In conclusion, we have shown that different GDM phenotypes, classified according to pre-pregnancy BMI, insulin sensitivity, and pancreatic beta cell measures, contribute to adverse pregnancy outcomes. Our findings suggest that women with GDM who were obese prior to pregnancy and who exhibit insulin resistance may require enhanced monitoring and stringent glycemic control during pregnancy.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
ACKNOWLEDGMENTS
This research was supported by grants from the National Research Foundation (NRF) of Korea (grant numbers: 2021R1C 1C100987513 and RS-2023-00222910) and the Korea Health Industry Development Institute (HI22C0444 and RS-2024-00403679).
AUTHOR CONTRIBUTIONS
Conception or design: J.H.M., S.W., S.H.C., H.C.J. Acquisition, analysis, or interpretation of data: J.H.M, S.W., H.W., S.H.C., H.C.J. Drafting the work or revising: J.H.M., S.W., H.W. Final approval of the manuscript: all authors.