Introduction

Women with gestational diabetes mellitus (GDM) and their infants have an increased risk of adverse pregnancy outcomes, including large for gestational age birthweight (LGA), neonatal intensive care unit (NICU) admission, pregnancy-related hypertension (HTN), and cesarean delivery. Moreover, women with gestational glucose intolerance (GGI), who have an abnormal initial screening glucose loading test (GLT), have an increased risk of the same adverse pregnancy outcomes, whether or not they meet the GDM diagnostic criteria. ^, Although the American College of Obstetricians and Gynecologists (ACOG) has suggested that some women with GGI who do not meet the GDM criteria may nevertheless be treated as if they have GDM, it is not yet known if every woman with GGI has an elevated risk of adverse pregnancy outcomes. Previously, we found that the risk of adverse pregnancy outcomes differs according to the underlying physiology leading to hyperglycemia in GDM ; similar heterogeneity may be present among women with GGI.

On average, women with GDM have diminished insulin sensitivity (insulin resistance) and diminished insulin secretion (insulin deficiency) compared with pregnant women with normal glucose tolerance (NGT). However, there is substantial heterogeneity in the underlying physiology leading to hyperglycemia in GDM. Our previous work defined GDM subtypes based on the presence or absence of insulin resistance and/or insulin deficiency, assessed using multiple timed glucose and insulin measurements from an oral glucose tolerance test (OGTT). In our previous study, we found that women with an insulin-resistant subtype of GDM had an increased risk of fetal overgrowth and GDM-associated pregnancy outcomes. In comparison, women with insulin-deficient or mixed pathophysiology subtypes of GDM did not have an increased risk of adverse pregnancy outcomes compared with women with NGT.

Here, we aimed to define the physiological subtypes of GGI (including all women who had an abnormal initial GDM screening test). Subtypes were delineated by insulin resistance, insulin deficiency, or mixed pathophysiology using homeostasis model assessment (HOMA), which uses fasting glucose and insulin measures. We aimed to determine if GGI subtypes are at differential risks of adverse pregnancy outcomes. We hypothesized that women with the insulin-resistant subtype of GGI would be at the highest risk of adverse pregnancy outcomes.

Materials and Methods

Participants were from the Massachusetts General Hospital (MGH) Obstetrical Maternal Study (MOMS) (n=9913), enrolled from 1998 to 2006. Institutional review board approval and informed consent were obtained before study procedures began. A subset of women in the cohort (n=1853) provided a fasting blood sample at 16 to 20 weeks’ gestation (serum frozen at −80°C). Here, we included women who had fasting glucose levels measured at the time of study who also had a 1-hour GLT (initial screening test for GDM) at >22 weeks’ gestation (median, 27.7 [interquartile range, 26.9–28.4] weeks). Of these women, those with GGI (1-hour GLT result of ≥140 mg/dL) were included if they had a stored fasting serum sample available for insulin measurement or had insulin previously measured. We included all women with NGT, regardless of sample availability. For pregnancy-related HTN analyses, we excluded women with chronic HTN, defined as an elevated blood pressure at the initial prenatal visit occurring at <20 weeks’ gestation. For cesarean delivery analyses, only nulliparous women were included.

The primary exposure was the physiological subtype of GGI, defined with HOMA using fasting glucose and insulin levels measured at 16 to 20 weeks’ gestation. Glucose levels were measured at the time of blood draw in the MGH Core Chemistry Laboratory (Boston, MA). We measured insulin levels on frozen serum using a chemiluminescent immunoassay (interassay variation of <5.6%) at the Brigham Research Assay Core (Boston, MA). For 25 participants with GGI in whom additional samples were not available, we used insulin levels previously measured using a radioimmunoassay from Linco Research (St. Louis, MO). Insulin resistance and/or deficiency was defined in pregnancies with GGI as HOMA-2S (a measure of insulin sensitivity using the HOMA2 model) or HOMA-2B (a measure of beta-cell function using the HOMA2 model) ^, of <50th percentile. The 50th percentile was determined in women with a GLT 1-hour glucose of <130 mg/dL who had insulin measured by the same assay as those with GGI. Women with GGI (including those with GDM) were classified into physiological subtypes based on the presence or absence of insulin resistance or deficiency: (1) insulin-resistant GGI, isolated insulin resistance; (2) insulin-deficient GGI, isolated insulin deficiency; (3) mixed pathophysiology GGI, both insulin resistance and insulin deficiency; and (4) uncategorized, neither insulin resistance nor deficiency. The referent group for examining outcomes was women with NGT (n=1472; GLT 1-hour glucose of <140 mg/dL).

The primary outcome was LGA birthweight, defined as a birthweight of >90th percentile for gestational age. Secondary outcomes included infant outcomes (birthweight percentile and NICU admission), and maternal outcomes (pregnancy-related HTN and cesarean delivery in nulliparous women). Hyperglycemia, including GDM, is known to contribute to pregnancy-related HTN, including preeclampsia. ^{, , , ,} We defined pregnancy-related HTN as gestational HTN or preeclampsia, ascertained using either prenatal outpatient blood pressures (systolic blood pressure [SBP] of ≥140 mm Hg or diastolic blood pressure [DBP] of ≥90 mm Hg after 20 weeks’ gestation) and/or by the notation of either of these diagnoses (as an indication for induction of labor or cesarean delivery or complication of labor) in the inpatient delivery record. Women with chronic HTN (defined as an SBP of ≥140 mm Hg or a DBP of ≥90 mm Hg at the initial prenatal visit) were excluded from the pregnancy-related HTN outcome analysis. We examined GDM diagnosis using the National Diabetes Data Group criteria, which were in clinical use at MGH at the time of data collection.

We compared participant characteristics according to the physiological subtype of GGI and NGT, using the Kruskal-Wallis tests for continuous variables or chi-square tests for categorical variables. If the global P value indicated a difference across subgroups ( P <.05), we performed post hoc pairwise testing using the Dunn test or chi-square tests, comparing each physiological subtype group with the NGT group (with the alpha level adjusted for 3 comparisons using the Bonferroni correction). We compared the odds of adverse outcomes in each subtype with the odds in women with NGT using logistic (odds ratios) or linear regression (beta coefficients) with adjustment for maternal age, race and ethnicity, marital status, and body mass index (BMI) measured at <20 weeks’ gestation, plus infant sex in LGA and birthweight models. We ran secondary analyses, excluding women with GDM, to determine whether findings were being driven by women in this treated subpopulation. To determine whether physiological subtypes provided information on the risk of outcomes beyond that provided by conventional BMI categories, we performed stratified analyses using linear and logistic regression models, grouping women by BMI into overweight or obesity (BMI≥25 kg/m ² ) and normal or underweight strata (BMI<25 kg/m ² ). We ran sensitivity analyses using the 25th percentile threshold ( Supplemental Table 2 ) for HOMA-2B and HOMA-2S to delineate GGI subtypes and using a cutoff of GLT of <130 mg/dL to define the NGT group ( Supplemental Table 3 ). Analyses were run using Stata statistical software (Release 16; StataCorp LLC, College Station, TX).

Results

Participant characteristics by GGI subtype are given in Table 1 and Supplemental Table 1 . Of 236 women with GGI (GLT≥140 mg/dL) ( Figure 1 ), 115 (49%) had insulin-resistant GGI, 70 (27%) had insulin-deficient GGI, 40 (17%) had mixed pathophysiology GGI, and 11 (5%) were uncategorized. GDM was diagnosed in 28 women with GGI (12%). Compared with the NGT referent group, women with the insulin-deficient and mixed pathophysiology subtypes were older ( Table 1 ). Women with insulin-resistant GGI were more likely to have a BMI of ≥30 kg/m ² than women with NGT; women with insulin-deficient GGI were more likely to have a BMI of <25 kg/m ² . There was no statistically significant difference in insurance status among the subtypes. Women with insulin-resistant GGI were less likely to be married than women with NGT. Furthermore, women with insulin-resistant GGI were more likely to identify as Latina. Women included in our analysis were similar to those who participated in the MOMS fasting parent study (data not shown).

Insulin sensitivity and secretion in physiological subtypes of GGI

Distribution of insulin sensitivity (HOMA-2S) and insulin secretion (HOMA-2B) in 236 subtyped women with GGI. Women with the insulin-resistant subtype of GGI ( red circle ) have preserved insulin secretion and decreased insulin sensitivity. Women with the insulin-deficient subtype of GGI ( blue square ) have preserved insulin sensitivity and decreased insulin secretion. Women with mixed pathophysiology GGI ( orange triangle ) have a combination of insulin resistance and deficiency.

GGI , gestational glucose intolerance; HOMA-2B, homeostasis model assessment derived indices of beta-cell function; HOMA-2S , homeostasis model assessment derived indices of insulin sensitivity.

Selen et al. Gestational glucose intolerance subtypes and adverse pregnancy outcomes. Am J Obstet Gynecol 2022.

The GLT results in each GGI subtype were similar and higher than the NGT group ( Table 1 ). As expected, given that HOMA-2 indices are calculated from these levels, there were differences in fasting glucose and insulin among subtypes ( Table 1 ). Fasting insulin was higher in women with an insulin-resistant subtype and lower in women with an insulin-deficient subtype than in women with NGT. Compared with women with NGT, fasting glucose was higher in women with insulin-resistant and mixed pathophysiology subtypes and similar in women with the insulin-deficient subtype.

Primary outcome: large for gestational age

For the primary outcome of LGA, women with insulin-resistant GGI had the greatest incidence of LGA (19%), whereas women with insulin-deficient and mixed pathophysiology subtypes had a similar risk of LGA to each other (14% and 13%, respectively); the lowest risk of LGA was in the women with NGT (9%) ( Figure 2 ). In unadjusted models, women with insulin-resistant GGI had significantly higher odds of an LGA birth than the NGT group ( Table 2 ). These odds remained higher after adjusting for age, race and ethnicity, marital status, BMI, and infant sex ( Table 2 ). Women with insulin-deficient GGI did not have significantly higher odds of an LGA infant than women with NGT before adjustment, but after adjustment (including BMI), the increased odds of LGA in this subtype became statistically significant ( Table 2 ).

Frequency of adverse pregnancy outcomes according to physiological subtype of GGI

Frequency was calculated as percentage of GGI for the insulin-resistant, insulin-deficient, and mixed pathophysiology subtypes or percentage of NGT for the referent group. Outcomes include LGA infant, NICU admission, pregnancy-related HTN, and rate of cesarean delivery among nulliparous women. Total number of women and percentages of each physiological subtype or the NGT referent group are listed. The asterisk represents P <.05 in adjusted regression models.

GGI , gestational glucose intolerance; HTN , hypertension; LGA , large for gestational age; NGT , normal glucose tolerance; NICU , neonatal intensive care unit.

Selen et al. Gestational glucose intolerance subtypes and adverse pregnancy outcomes. Am J Obstet Gynecol 2022.

Table 2

Risk of adverse pregnancy outcomes by physiological subtype of gestational glucose intolerance

Outcomes	Model	Insulin-resistant GGI:OR (95% CI) or β (95% CI)(n=115)	P value	Insulin-deficient GGI:OR (95% CI) or β (95% CI)(n=70)	P value	Mixed pathophysiology GGI:OR (95% CI) or β (95% CI)(n=40)	P value	Normal glucose tolerance(n=1472)
Primary outcome
LGA	Unadjusted	2.35 (1.43–3.88) a	.001 a	1.69 (0.84–3.38)	.14	1.42 (0.55–3.69)	.47	Ref
	Adjusted b	1.74 (1.02–3.48) a	.04 a	2.05 (1.01–4.19) a	.048 a	1.31 (0.49–3.48)	.60	Ref
Secondary infant outcomes
Birthweight percentile	Unadjusted	β=6.44 (1.05–11.83) a	.02 a	β=0.68 (−6.13 to 7.50)	.84	β=8.94 (0.03–17.85) a	.049 a	Ref
	Adjusted b	β=3.75 (−1.69 to 9.18)	.18	β=2.04 (−4.65 to 8.73)	.55	β=7.75 (−0.99 to 16.48)	.08	Ref
Neonatal intensive care unit admission	Unadjusted	2.09 (0.99–4.40)	.05	0.39 (0.05–2.93)	.37	1.50 (0.35–6.49)	.59	Ref
	Adjusted	1.74 (0.78–3.88)	.18	0.35 (0.05–2.60)	.30	1.08 (0.25–4.75)	.92	Ref
Secondary maternal outcomes
Pregnancy-related hypertension	Unadjusted	2.09 (1.31–3.33) a	.002 a	0.89 (0.43–1.83)	.74	1.19 (0.51–2.75)	.69	Ref
	Adjusted	1.77 (1.07–2.92) a	.03 a	0.99 (0.48–2.08)	.99	1.07 (0.45–2.51)	.88	Ref
Cesarean delivery rate among nulliparous women	Unadjusted	1.13 (0.65–1.97)	.65	1.01 (0.51–1.99)	.97	1.15 (0.42–3.14)	.79	Ref
	Adjusted	0.81 (0.45–1.46)	.48	1.03 (0.52–2.07)	.93	1.13 (0.41–3.15)	.81	Ref

 

ORs were taken from logistic regression models, and beta coefficients for birthweight percentiles were taken from linear regression models. Regression models were adjusted for the following covariates: age, race and ethnicity, marital status, and body mass index at <20 weeks’ gestation.

CI , confidence interval; GGI , gestational glucose intolerance; LGA , large for gestational age; OR , odds ratio; Ref , referent group.

Selen et al. Gestational glucose intolerance subtypes and adverse pregnancy outcomes. Am J Obstet Gynecol 2022.

a Statistically significant ORs, beta coefficients, and P values (with P <.05)

b For LGA and birthweight percentile models, infant sex was added as a covariate.

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