Glucose Intolerance in Pregnancy and Offspring Obesity in Late Adolescence

Gestational diabetes, diagnosed in the second or third trimester of pregnancy, is one of the most common complications of pregnancy and affects one in seven pregnancies worldwide (1,2). Gestational diabetes rates dramatically increased over the last decade, with a mean annual percent increase of 3.7% per year in the U.S. (3). The Carpenter-Coustan criteria, a two-step screening method, was initially developed to identify pregnant women at increased risk for later developing type 2 diabetes (4). Over the years, those criteria were found to be associated with multiple adverse outcomes relating to maternal and offspring health (1,5).

Exposure to hyperglycemia in utero predisposes offspring to an increased risk of newborn adiposity, which may persist in childhood and adolescence and contribute to metabolic abnormalities in young adulthood (6). Some studies (7,8), but not all (9–12), showed associations of gestational diabetes with long-term offspring overweight and obesity in childhood and adolescence (13). It remains unclear whether abnormal glucose levels that do not meet the criteria for gestational diabetes are also associated with a higher risk for overweight and obesity in childhood and adolescence (7,14). Notably, previous studies did not categorize obesity by classes of severity but treated it as a homogenous entity. Given its alarming increase in prevalence, severe obesity is likely to pose a major challenge for the future burden of cardiometabolic health (15,16).

In a nationally representative cohort of 33,482 mother-offspring pairs, we explored the association between various degrees of gestational glucose intolerance, as measured during pregnancy screening, with offspring adolescent overweight/obesity.

This mother-offspring historical cohort study was based on the linkage between the Israel Defense Forces military prerecruitment data and medical data of Maccabi Healthcare Services (MHS), the second largest health medical organization (HMO) in Israel (17). Israeli adolescents undergo medical assessment at age 17 years that determines their fitness for mandatory military service. The data of these assessments have been collected systematically since 1967 (18) and enable identification of family members across generations (19). This data set was linked to glucose challenge test (GCT) data performed during pregnancy for women insured by MHS using their civilian identification number (17). Since 2001, the MHS has consistently documented laboratory screening results for gestational diabetes. Thus, the merged file included mothers' sociodemographic and medical data during late adolescence (military prerecruitment) and glucose data at pregnancy, and their offspring's birth weight percentiles and medical data at late adolescence (military prerecruitment) (Fig. 1). The Israel Defense Forces Medical Corps and MHS Institutional Review Boards approved this study and waived the requirement for informed consent based on strict maintenance of anonymity of the individuals included. This study was performed in accordance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines.

A detailed description of the study sample build-up is provided in Supplementary Fig. 1. Included were Israeli women, members of MHS, who also 1) underwent a prerecruitment evaluation at adolescence (age 16–20 years); 2) had a singleton pregnancy (age at pregnancy 18–50 years) documented at MHS during 2001–2004, and underwent a two-step screening test for gestational diabetes: a 50-g glucose challenge test (GCT), and if abnormal, also a 100-g oral glucose tolerance test (OGTT); and 3) had a living 16- to 20-year-old offspring who was assessed at a military prerecruitment clinic with documented anthropometric measurements. Excluded from the cohort were 21,646 women for whom we did not identify an offspring who underwent prerecruitment evaluation by January 2021; the offspring were most probably too young to be called for prerecruitment assessment (Supplementary Fig. 1). Of note, during manuscript preparation (January to August 2021), 10,676 of the offspring (49.3%) completed the military prerecruitment evaluation (detailed analyses are available in Supplementary Tables 1 and 2). Additional exclusion criteria were the absence in the military database of weight or height data at age 16–20 years for either the mother or her offspring, the absence of an OGTT test if it was indicated, diabetes diagnosed before pregnancy, and multiple gestations. If more than one pregnancy with a suitable offspring was documented, the first pregnancy was chosen. Thus, a single offspring was considered for every mother included.

Military prerecruitment evaluations were consistently performed throughout the study period. Thus, all of the mothers, fathers (accounted for in a subanalysis), and their offspring underwent the same evaluation process within a similar age range. Medical assessments were performed by a military physician and included review of health summaries; measurements of weight, height, and blood pressure; a detailed medical interview; and a physical examination (18). Weight and height were measured (barefoot and in light clothing) using a beam balance and stadiometer to the nearest 0.1 kg and centimeter, respectively. BMI was calculated as the weight in kilograms divided by the square of the height in meters. BMI values were grouped according to sex and age using U.S. Centers for Disease Control and Prevention percentiles (20), which have been validated for Israeli adolescents (21).

Sociodemographic collected data included the number of years of formal schooling, as received from the Israeli Ministry of Education (<11 and ≥11 years) (22); socioeconomic position, which was based on the locality of residence and received from the Ministry of Interior (low, medium, and high) (23); and country of birth (Israeli born/other) (24). Conscripts also underwent a general intelligence test, performed by trained personnel; scores were classified as low, medium, and high (25). This measure was found to correlate highly with the intelligence quotient (IQ), and was suggested to have high external validity (26).

The two-step screening test for gestational diabetes, performed between 24 and 28 weeks of pregnancy, comprised the components of universal medical screening for gestational diabetes and was provided free of charge; overall compliance was 89% (27). Women with a serum glucose level between 140 and 200 mg/dL (7.8 mmol/L and 11.1 mmol/L) following 50-g GCT were referred to a 100-g OGTT. Women with GCT ≥200 mg/dL were usually not referred to an OGTT as they were already considered to have gestational diabetes. Abnormal OGTT values were defined according to the Carpenter-Coustan diagnostic thresholds (28) as follows: fasting serum glucose concentration >95 mg/dL (5.3 mmol/L); 1-h serum glucose concentration >180 mg/dL (10.0 mmol/L); 2-h serum glucose concentration >155 mg/dL (8.6 mmol/L); and 3-h serum glucose concentration >140 mg/dL (7.8 mmol/L). Of note, glycated hemoglobin (HbA_1c) was not systematically measured.

Glucose tolerance categories were defined as previously suggested (11): gestational diabetes: GCT ≥200 mg/dL (11.1 mmol/L) or two or more abnormal OGTT values; gestational impaired glucose tolerance (gestational IGT): one abnormal OGTT value; abnormal GCT with normal OGTT: GCT ≥140 mg/dL (7.8 mmol/L) and <200 mg/dL (11.1 mmol/L) with normal OGTT; gestational normoglycemia: normal GCT and normal OGTT values, if performed.

Insulin prescription during pregnancy, offspring birth weight, gestational age at delivery, and postpartum type 2 diabetes diagnosis status were retrieved from MHS. Of note, women with gestational IGT were not medically treated or systematically referred to a dietitian. Birth weight percentiles were calculated using sex-specific standards of the Israeli population per gestational age at delivery (29). Birth weight percentiles were classified as small (≤10th percentile), appropriate (10th–90th percentile), and large for gestational age (>90th percentile). Data regarding prepregnancy BMI were unavailable. Postpartum type 2 diabetes was defined as meeting one or more of the following criteria: 1) HbA_1c ≥7.2% (55.7 mmol/mol); 2) serum glucose concentrations of ≥200 mg/dL (11.1 mmol/L) in two tests performed at an interval of at least 1 month; 3) two purchases or more of glucose-lowering medications during 3 months; or 4) a diagnostic code given by a family physician with HbA_1c ≥6.5% (47.5 mmol/mol) or a serum glucose concentration of ≥126 mg/dL (7 mmol/L) in two tests 6 months before/after the diagnosis (30).

The primary outcome was offspring overweight/obesity in late adolescence, defined as BMI >85th percentile. In secondary outcome analyses, overweight (85th–94th percentile), mild obesity (95th to 120% of the 95th percentile), and severe obesity (≥120% of the 95th percentile) were considered as separate outcomes (31).

Means and SDs are reported for continuous variables, and numbers and percentages are reported for categorical variables. ANOVA for multiple comparison was applied to determine differences across the study groups. Logistic regression analyses were applied to determine the odds ratios (ORs) and the 95% CIs for offspring overweight/obesity in the three maternal groups of glucose intolerance, using gestational normoglycemia as the reference. Mother's age at adolescence and at GCT evaluation, adolescent BMI, and offspring birth weight percentiles were assessed as continuous variables, whereas all of the other variables were categorical. The association was tested in an unadjusted model and in prespecified multivariable models. Model 1 was adjusted for mothers' data at adolescence (age, intelligence score, years of education, residential socioeconomic position, birthplace, and BMI) and age at gestational diabetes screening. Model 2 was further adjusted for offspring's characteristics at birth (sex and birth weight percentile) and at adolescence (age, intelligence score, years of education, and residential socioeconomic position). Multinomial logistic regression was applied for multiple outcome analyses of the association by adolescent obesity severity. Model 1 was applied for these analyses. The E-value was calculated to assess unmeasured confounders (32,33). Analyses were performed using SPSS 25.0 statistical software.

Several subgroups and sensitivity analyses were performed:

1. To minimize an effect of offspring who may not have been old enough to attend the medical assessment, we limited the analysis to women who were screened for gestational diabetes in 2001, during which 88% of the women had offspring with complete prerecruitment evaluation.

2. To assess representativeness to the enlisted Israeli population, we compared adolescent characteristics between mothers who were insured with MHS and thus included in this study and between mothers in the other HMOs in Israel.

3. To better control for parental adiposity, 1) model 1 was additionally adjusted for adolescent paternal BMI; 2) the cohort was limited to mothers without adolescent overweight/obesity (BMI ≤85th percentile); and 3) the cohort was limited to mothers with low-normal adolescent BMI (5th–49th percentile).

4. To minimize confounding by coexisting illness, we limited the analysis to mothers with unimpaired health at adolescence by excluding those with any indication of chronic medical treatment or medical follow-up, or a history of major surgery or cancer.

5. We set a combined outcome that required both offspring adolescent overweight/obesity and abnormal blood pressure (systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥80 mmHg) at adolescence.

6. World Health Organization BMI for age charts were used for BMI status outcome definitions.

7. The analysis was limited to women with gestational diabetes who were not treated with insulin.

8. To mitigate bias related to undiagnosed pregestational diabetes, the analysis was limited to mothers who were not diagnosed with postpartum type 2 diabetes.

Table 1 presents the characteristics of the 33,482 mother-offspring pairs who were included in the cohort (Supplementary Fig. 1). The mean ages of mothers at adolescence and at gestational diabetes screening were 17.4 ± 0.4 years and 31.0 ± 4.1 years, respectively. At adolescence, mothers' residential socioeconomic position, years of education, and intelligence score were not materially different across categories of glucose intolerance. Compared with mothers with gestational normoglycemia, mothers who had abnormal GCT with normal OGTT, gestational IGT, and gestational diabetes, were more likely to have had adolescent overweight/obesity (9%, 10%, and 12%, respectively, vs. 8%, P < 0.0001). Of note, among women insured in MHS versus those insured by other HMOs, the prevalence of adolescent overweight/obesity was lower (8.3% vs. 11.2%, P < 0.0001), and the levels of all sociodemographic variables were slightly higher (Supplementary Table 3).

Birth weight data were available for 93% of offspring. Among offspring of mothers with glucose intolerance, birth weight percentiles were consistently higher, as was the proportion with large for gestation age (Table 1). Offspring sociodemographic data at adolescence were overall comparable across the mothers' glucose tolerance groups at pregnancy (Table 1).

In total, 6,516 offspring had overweight/obesity at late adolescence. Across increasing categories of pregnancy glycemia, the proportions of offspring with adolescent overweight/obesity increased: normoglycemia, 19%; abnormal GCT with normal OGTT, 22%; gestational IGT, 24%; and gestational diabetes, 25% (P < 0.0001) (Table 1). The unadjusted ORs for offspring overweight/obesity for the latter three groups compared with the normoglycemia group were 1.22 (95% CI 1.10–1.35), 1.36 (95% CI 1.20–1.54), and 1.47 (95% CI 1.32–1.65), respectively (Fig. 2). These point estimates remained nearly unchanged after adjustment for mothers' sociodemographic characteristics, BMI at adolescence, and age of delivery (model 1). Further adjustment for offspring characteristics, including sex, birth weight percentile, and sociodemographic variables at adolescence, yielded similar results, with ORs of 1.25 (95% CI 1.10–1.42), 1.26 (95% CI 1.07–1.47), and 1.41 (95% CI 1.22–1.64), respectively (model 2). Data on adolescent BMI were available for 94% of the fathers of the offspring: its addition to model 1 did not materially change the results (Supplementary Table 4). The estimated E-value for the association between gestational diabetes and offspring adolescent overweight/obesity was 1.7 (lower value of 95% CI 1.5).

The results persisted when the cohort was limited to mothers who were screened during 2001 (Supplementary Table 5), limited to mothers with lean adolescent BMI (Supplementary Table 6), and limited to mothers with unimpaired health at adolescence (Supplementary Table 7). The combined outcome of offspring adolescent overweight/obesity and abnormal blood pressure yielded accentuated ORs: 1.39 (95% CI 1.18–1.64), 1.25 (95% CI 1.02–1.54), and 1.66 (95% CI 1.39–1.98) for mothers with abnormal GCT with normal OGTT, gestational IGT, and gestational diabetes, respectively, compared with those with gestational normoglycemia (Supplementary Table 8).

Among mothers with gestational diabetes, adjusted ORs (model 1) were 1.21 (95% CI 1.04–1.40), 1.79 (95% CI 1.49–2.15), and 1.98 (95% CI 1.45–2.70) for offspring with overweight, mild obesity, and severe obesity, respectively (Fig. 3), compared with the gestational normoglycemia group. Prevalences of offspring severe obesity were 3% in gestational diabetes, 3% in gestational IGT, and 2% in abnormal GCT with OGTT compared with 1% in the gestational normoglycemia group. Higher ORs for offspring with severe obesity were demonstrated also for mothers with abnormal GCT and normal OGTT (OR 1.66, 95% CI 1.24–2.24) and for those with gestational IGT (OR 2.16, 95% CI 1.56–2.99) (Fig. 3). Of note, using World Health Organization definitions for adolescent overweight, obesity, and severe obesity resulted in similar point estimates (Supplementary Table 9).

Among mothers with gestational diabetes, 123 (∼7%) were treated with insulin during pregnancy. An analysis that excluded those women yielded similar point estimates (Supplementary Table 10). Postpartum type 2 diabetes incidences diagnosed at least 3 months after delivery were 0.7%, 2.3%, 6.2%, and 14.6% among mothers with gestational normoglycemia, abnormal GCT with normal OGTT, gestational IGT, and gestational diabetes, respectively. Exclusion of mothers diagnosed with type 2 diabetes after delivery did not substantially affect the point estimates for offspring overweight/obesity (Supplementary Table 11).

This study demonstrated that glucose intolerance, identified through universal screening during pregnancy, is associated with offspring overweight/obesity at late adolescence. This association was present across degrees of pregnancy glycemia and became stronger with increasing severity of obesity. Point estimates persisted following adjustment for maternal and paternal late adolescent BMI, health status, and sociodemographic characteristics of the mothers in late adolescence, maternal age, offspring birth weight percentiles, and offspring sociodemographic variables at late adolescence.

Several studies examined the association of gestational diabetes with offspring overweight/obesity at childhood or adolescence. A meta-analysis of this association reported an unadjusted pooled OR of 1.35 (95% CI 1.01–1.80), with an overall quality of evidence judged as “low” (13). The Hyperglycemia and Adverse Pregnancy Outcomes Follow-Up Study (HAPO-FUS) prospectively followed ∼4,700 mother-offspring pairs with active anthropometric measurements until age 11–14 years and reported adjusted point estimates of 1.4 (95% CI 1.2–1.7) for offspring overweight/obesity among offspring of mothers with gestational diabetes compared with offspring of mothers who did not have gestational diabetes (8). The results showed borderline significance after further adjustment for maternal BMI at pregnancy. Another study from that cohort estimated ORs for 1 SD difference in maternal glucose and showed that maternal glucose across a continuum is associated with childhood overweight/obesity (7). Our study underscores well-defined clinically applicable categories. We showed that offspring of mothers with abnormal 50-g GCT and normal 100-g OGTT, as well as those of mothers with gestational IGT, were at increased odds for overweight/obesity. Furthermore, our study sample was large enough to assess adolescent offspring obesity according to severity and to show that gestational IGT may more than double the odds for adolescent severe obesity.

The lack of data on BMI at pregnancy is a major limitation of the current study. Previous studies have demonstrated an attenuation of the relation between gestational diabetes and offspring childhood obesity, after adjustment for gestational BMI (8,10,12). Higher gestational BMI has been shown to be associated with higher offspring BMI through shared genetics, intrauterine environment, familial lifestyle, and other shared environmental factors (6). We adjusted all of the analyses to maternal adolescent BMI (mean age of 17 years), which has been shown to track well to young adulthood (34). Nevertheless, it is likely that some of the observed effect was mediated by a group-disproportionate weight gain prior to and during pregnancy. The calculated E-value suggests that an unknown confounder that is associated with both gestational diabetes and offspring overweight/obesity at adolescence would have to have an OR >1.7 (with a lower 95% CI value of at least 1.5) to fully account for the observed association. Given that previous studies estimated the effect of pregnancy BMI at an ∼OR of 1.2 (after other confounder adjustments) (8), we assume that pregnancy BMI does not solely account for the observed association.

This study has public health implications. The odds for offspring overweight/obesity at late adolescence was increased among the 11.5% of women in our cohort who had abnormal gestational glucose tolerance test results that do not currently meet the formal definition for gestational diabetes. Furthermore, the observed association was magnified with increasing severity of obesity, which was shown to be related to excess morbidity and mortality compared with its milder form (31). These findings corroborate the call to move from a perception of gestational glucose intolerance as a short-term medical disorder that confers increased risks for large infants to a potentially modifiable long-term disease that contributes to the growing burden of childhood obesity and cardiometabolic disorders in the subsequent generation (35).

This study has limitations. First, 38% of the women (21,646 of 57,561) did not have a living offspring who underwent prerecruitment evaluation until data extraction. This could potentially introduce selection bias. However, the distribution of glucose intolerance groups was similar, confirming a nondifferential gestational glucose tolerance pattern. Additionally, an analysis that included only mothers screened during 2001 (12% missing) yielded similar results. Moreover, examination of 10,676 offspring who were identified in the prerecruitment data set during the 8 months after data extraction confirmed that the lack of identification of offspring was due to their being too young to attend the medical assessment.

Second, we could not control for weight gain from adolescence until or during pregnancy, a possible mediator of the observed association.

Third, we could not account for maternal nutritional and lifestyle counseling or for the level of glycemic control. These interventions could potentially weaken the association by lowering gestational glucose levels.

Fourth, offspring body composition was not measured. Nevertheless, BMI is considered the preferable method for obesity screening according to the U.S. Preventive Services Task Force (36).

Fifth, we do not have data on key offspring environmental factors, including diet or physical activity levels.

Sixth, orthodox and ultraorthodox Jewish women, and also non-Jewish women are not obligated to serve in the army and were thus underrepresented in the cohort. Moreover, our study included only mothers who were insured in MHS; this represented a subpopulation that is slightly more educated, healthier, and with higher socioeconomic position than those insured in other HMOs. Notably, accounting for sociodemographic covariates had a negligible effect on the point estimates.

Seventh, our study population poorly represents some ethnicities, including native Americans, Pacific islanders, sub-Saharan Africans, and East Asians.

The strengths of this study include the linkage of two nationally representative databases with universal screening for gestational diabetes and recorded values of glucose levels, systematic data collection of sociodemographic variables, measured, rather than reported, weight and height values in both parents and offspring, comprehensive evaluation of adolescent health status (23,37), and heterogenous genetic ancestry (38).

In summary, our study provides new evidence for a relation between gestational glucose intolerance that does not meet the threshold for gestational diabetes and the risk for offspring overweight/obesity at late adolescence. These associations were more pronounced with increasing severity of obesity and independent of sociodemographic variables and parental adolescent BMI. Our findings should inform risk stratification, specifically targeted for prevention and early intervention at a lower degree of gestational glucose intolerance, with the intent of mitigating the epidemic of childhood and adolescent obesity.

Acknowledgments. The authors thank Erga Rivis (Kfar Truman, Israel) for creating the graphic illustration and Cindy Cohen (Tel Aviv, Israel) for her assistance in language editing.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributors. C.D.B. and A.B. wrote the original draft. C.D.B., A.B., E.D., and G.T. performed the formal analysis. C.D.B., A.B., G.C., and G.T. conceptualized the study, designed the methodology, and directly accessed and verified the underlying data reported in the manuscript. R.S.R., H.C.G., O.P.-H., A.T., T.C.-Y., Y.L., A.A., and G.C. reviewed and edited the manuscript. D.T. performed data curation. G.T. supervised the study. G.T. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented at the 82nd Scientific Sessions of the American Diabetes Association, New Orleans, LA, 3–7 June 2022.