Abstract
Objective:
To evaluate whether values and the shape of the glucose curve during the oral glucose tolerance test (OGTT) in pregnancy identify women at risk of developing hypertension (HTN) later in life.
Methods:
Secondary analysis of a follow-up from a mild gestational diabetes mellitus (GDM) study that included a treatment trial for mild GDM (n=458) and an observational cohort of participants with abnormal 1-hour glucose loading test only (normal OGTT, n=430). Participants were assessed at a median 7 (IQR 6-8) years after their index pregnancy, and trained staff measured their blood pressure (systolic SBP; diastolic DBP). The association between values and the shape of the glucose curve during OGTT in the index pregnancy and the primary outcome defined as elevated BP (SBP≥120, DBP≥80 mmHg, or receiving anti-HTN medications), and secondary outcome defined as stage 1 or higher (SBP≥130, DBP≥80 mmHg, or receiving anti-HTN medications) at follow-up were evaluated using multivariable regression, adjusting for maternal age, body mass index, and pregnancy-associated hypertension during the index pregnancy.
Results:
There was no association between fasting, 1-hour OGTT and the outcomes. However, the 2-hour OGTT value was positively associated (aRR per 10-unit increase 1.04, 95%CI 1.01–1.08), and the 3-hour was inversely associated (aRR per 10-unit increase 0.96, 95%CI 0.93–0.99) with the primary outcome. When the shape of the OGTT curve was evaluated, a monophasic OGTT response (peak at 1 hour followed by a decline in glucose) was associated with increased risk of elevated BP (41.3% VS. 23.5%, aRR 1.66, 95% CI 1.17–2.35) and stage 1 HTN or higher (28.5% vs. 14.7%, aRR 1.83, 95% CI 1.15–2.92), compared with a biphasic OGTT response.
Conclusions:
Among persons with mild GDM or lesser degrees of glucose intolernace, the shape of the OGTT curve during pregnancy may help identify women who are at risk of HTN later in life, with biphasic shape to be associated with lower risk.
Keywords: gestational diabetes, glucose tolerance test, hypertension, elevated blood pressure
Introduction
Several observational studies and systematic reviews support the association between adverse pregnancy outcomes, including gestational diabetes mellitus (GDM), and future cardiovascular and metabolic disease in the mother.1-3 While previously recognized that women whose pregnancies were complicated by GDM are at higher risk of future metabolic disease, in particular type II diabetes,1,2,4-6 it is now apparent that they are also at increased risk of hypertension (HTN) and other associated cardiovascular morbidities.7-11
The American Heart Association includes history of GDM in their classification of cardiovascular risk factors in women.12 However, the data on which this guideline is based were derived largely from retrospective identification of pregnancy complications, linked birth and death registries, and administrative databases.5,12 The follow up study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network mild GDM trial revealed that almost 1/3 of women developed metabolic syndrome at median 7 years of follow up, and 20% had HTN.13 Additionally, recent data suggest that glucose screening tests in general population pregnant patients may identify those with an adverse postpartum cardiovascular risk factor profiles and at risk of future cardiovascular events, even among those without a diagnosis of GDM.14,15 In addition to values on the glucose screening tests, the shape of glucose values during the oral glucose tolerance test (OGTT) is thought to be a maker of cardiometabolic health and risk of diabetes, especially among patients with obesity10, with monophasic curves (peak in at 1 or 2 hours followed by decline in glucose values) conferring a higher risk compared with biphasic curves (peak at 1 hour, decline at 2 hours, and peak again in glucose at 3 hours).10,16,17
Recently, The American College of Cardiology/American Heart Association (ACC/AHA) revised their high blood pressure (BP) practice guidelines and definitions of HTN with elevated BP to be defined as either systolic (SBP) >=120 or diastolic (DBP) >=80 mmHg.18 However, there are no studies evaluating the impact of these changes on the association between GDM screening in pregnancy and later risk of HTN. Therefore, we sought to determine the association between OGTT features in pregnancy including glucose values and shape of the curve and risk of elevated BP and HTN later in life, as defined by the recent ACC/AHA guidelines.
Patients & Methods
Study Design
Women enrolled from October 2002 through mid-November 2007 in the NICHD MFMU Network mild GDM trial or concurrent non-GDM cohort were evaluated 5-10 years after their index pregnancy (February 2012 through September 2013). The original trial and the follow-up study were approved by the institutional review board of all participating centers. Details regarding the original GDM trial have been previously described.19 Briefly, women between 24 0/7 and 30 6/7 weeks of gestation, were screened for GDM using a two-step process (1-hour 50-gram glucose loading test (GLT) followed by 3-hour 100-gram oral glucose tolerance test (OGTT)). Women with mild GDM (defined as abnormal OGTT, but with normal fasting glucose value <95 mg/dl) were randomized to an intervention arm consisting of formal nutritional counseling and diet therapy, self-glucose monitoring and insulin pharmacotherapy if needed (treated mild GDM group) or usual prenatal care (untreated mild GDM group).
Women with an abnormal GLT (135-200 mg/dL) but normal OGTT and those diagnosed with mild GDM were contacted between 5 and 10 years after their index pregnancy. The follow-up study has been previously described.20 BP was measured by trained personnel after the participant was sitting quietly for at least 10 minutes, by auscultation using aneroid sphygmomanometer instrumentation or a hospital grade blood pressure/pulse machine. The average of two measurements was used in the analysis. To minimize bias, research staff involved in data collection were masked to the participant’s exposures during the original study.
This study is a secondary analysis of data from patients who were enrolled in the GDM follow-up study. This analysis was restricted to patients who were not pregnant at the time of follow-up and had BP measured. Additionally, patients did not have a history of pre-gestational diabetes mellitus, renal or cardiovascular disease, chronic hypertension, or preeclampsia in the index pregnancy at the time of enrollment in the original parent study. The exposures of interest for this analysis included the GLT glucose values, OGTT individual glucose values, and OGTT curve shape during the index pregnancy. The shape of the glucose response curve during OGTT, monophasic versus biphasic, identifies physiologically distinct groups of individuals with differences in insulin secretion and sensitivity, with monophasic curves thought to be associated with higher risk of cardiometabolic risk.16,17,21 In this study, curve shape was categorized into the following, as described elsewhere:10,16,17,21 1) monophasic with peak at 1 hour followed by a decline in glucose of ≥ 4.5 mg/dL; 2) monophasic with peak at 2 hour followed by a decline in glucose of ≥ 4.5 mg/dL; 3) biphasic with peak at 1 hour, decline at 2 hours, and peak again in glucose of ≥ 4.5 mg/dL at 3 hours, or 4) other, not fitting any of the aforementioned shapes (i.e., two consecutive values were approximately the same, within 4.5 mg/dl) (Supplementary Figure 1 for example shapes).
Study Outcomes
BP at follow-up was categorized per the American College of Cardiology / American Heart Association (ACC/AHA) high blood pressure practice guidelines18: normal, systolic blood pressure < 120 mmHg and diastolic blood pressure <80 mmHg; elevated, systolic blood pressure 120-129 mmHg and diastolic blood pressure <80 mmHg; stage 1 hypertension, systolic blood pressure 130-139 mmHg or diastolic blood pressure 80-89 mmHg; stage 2 hypertension, systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg. Women receiving hypertension medication were considered to have stage 2 hypertension. The primary outcome was elevated BP (or higher) defined as either SBP≥120 or DBP≥80 mmHg or receiving HTN medications, and secondary outcomes were stage I (or higher) HTN defined as SBP≥130 or DBP≥80 mmHg or receiving HTN medications.
Statistical Analysis
Descriptive analyses used the χ2 test or Kruskal-Wallis test to compare characteristics across study groups (GDM treated, GDM untreated, non-GDM). Modified Poisson multivariable regression was used to estimate the relative risk (RR) and 95% confidence interval (CI) adjusting for significant baseline co-variables using backwards elimination: age, body mass index, and pregnancy-associated hypertension during the index pregnancy. The OGTT model included all OGTT timed values, therefore for a particular timed value, it was adjusted for the other OGTT timed values. Study group, smoking during pregnancy, and duration of follow-up were not associated with the outcomes and thus not included in the parsimonious models. For the continuous glucose values, models included only linear terms as the quadratic terms were not significant. For the OGTT curve shape analysis, a biphasic curve was used as referent group. The area under the receiver operating characteristic curve (AUC) was estimated to characterize the classification ability of the models, with interpretation as follows: 0.5 was considered no better than chance; >0.5 to <0.7 poor; ≥0.7 to <0.8 acceptable; ≥0.8 to <0.9 excellent; ≥0.9 outstanding). SAS software version 9.2 was used for the analyses. All tests were two-tailed and p<.05 was used to define statistical significance. No imputation for missing data and no corrections for multiple comparisons were performed, being an exploratory analysis.
Results
Of the 1,889 women enrolled in the original trial, 950 (50%) participated in the follow up study. After excluding 62 patients who were pregnant at the time of follow-up, 888 were included in the present analysis (Figure 1). All 888 had blood pressure measured at follow-up. Table 1 shows baseline and follow-up characteristics of the patients included in this analysis, overall and stratified by study group. Follow-up occurred 5-10 years after the index pregnancy (median of 7 years and interquartile range, IQR 6-8), at a median age of 35 years (IQR 32-40) and body mass index of 28.5 kg/m2 (IQR 25.0-32.8). Approximately 56 percent of the patients self-identified as Hispanic and 82 percent did not smoke.
Figure 1:
Study flow chart of participants
Table 1:
Maternal characteristics according to study group.
| Characteristic | All n=888 | Mild GDM treated n=243 |
Mild GDM untreated n=215 |
Non-GDM (abnormal screen, normal OGTT) n=430 |
P- value* |
|---|---|---|---|---|---|
| Baseline | |||||
| Age at enrollment, years | 28 (24-32) | 29 (26-33) | 29 (25-33) | 28 (24-32) | <0.001 |
| Race/ethnicity | 0.64 | ||||
| Hispanic | 499 (56.2) | 128 (52.7) | 125 (58.1) | 246 (57.2) | |
| Non-Hispanic, White | 267 (30.1) | 82 (33.7) | 59 (27.4) | 126 (29.3) | |
| Non-Hispanic, Black | 96 (10.8) | 26 (10.7) | 22 (10.2) | 48 (11.2) | |
| Other | 26 (2.9) | 7 (2.9) | 9 (4.2) | 10 (2.3) | |
| Smoking during this pregnancy | 64 (7.2) | 20 (8.2) | 13 (6.1) | 31 (7.2) | 0.67 |
| BMI at enrollment, kg/m2 | 29.7 (26.9-33.0) | 29.7 (26.3-33.2) | 29.7 (27.0-33.0) | 29.7 (26.9-32.9) | 0.87 |
| Gestational age at delivery, weeks | 39.3 (38.4-40.1) | 39.1 (38.3-40.0) | 39.3 (38.1-40.0) | 39.3 (38.4-40.1) | 0.06 |
| Pregnancy-associated hypertension† | 86 (9.7) | 22 (9.1) | 23 (10.7) | 41 (9.6) | 0.83 |
| Follow-up | |||||
| Smoking at follow-up† | 0.88 | ||||
| Never | 729 (82.2) | 203 (83.5) | 177 (82.3) | 349 (81.4) | |
| Past | 82 (9.2) | 19 (7.8) | 19 (8.8) | 44 (10.3) | |
| Current | 76 (8.6) | 21 (8.6) | 19 (8.8) | 36 (8.4) | |
| Duration of follow-up, years | 7 (6-8) | 7 (6-8) | 7 (6-8) | 7 (6-8) | 0.08 |
| Age at follow-up, years | 35 (32-40) | 36 (33-40) | 36 (32-40) | 35 (30-39) | <0.001 |
| BMI at follow-up, kg/m2* | 28.5 (25.0-32.8) | 28.5 (24.9-33.4) | 28.4 (25.3-32.2) | 28.5 (25.0-32.8) | 0.93 |
BMI, body mass index
Data are n (%) or median (IQR), unless otherwise specified
Based on the χ2 test or Kruskal-Wallis test
Missing in 1
At follow-up, the majority of women (n=561, 63%) had normal blood pressure, (Supplementary Table 1) however, 327 (37%) developed the primary outcome of elevated blood pressure or higher and 230 (26%) the secondary outcome of stage 1 hypertension or higher. No differences were noted in these rates based on original trial group assignments (Supplementary Table 1).
GLT and OGTT values and their associations with study outcomes are reported in Table 2. On multivariable analyses, there were no associations between GLT and fasting and 1-hour values of the OGTT and the study outcomes. However, the 2-hour OGTT was positively associated (aRR per 10-unit increase 1.04, 95%CI 1.01–1.08), and the 3-hour OGTT was inversely associated (aRR per 10-unit increase 0.96, 95%CI 0.93–0.99), with elevated blood pressure or higher (Table 2). In addition, the 3-hour OGTT was also inversely associated (aRR per 10-unit increase 0.95, 95%CI 0.92–0.99) with stage 1 hypertension or higher. The AUC for the full model that included all OGTT values was 0.70 (95%CI 0.67-0.74) for the outcome of elevated blood pressure or higher and 0.70 (95%CI 0.66-0.74) for the outcome of stage 1 hypertension or higher.
Table 2.
Association between GLT and individual OGTT values during pregnancy and follow-up study outcomes
| Index pregnancy GLT and OGTT | |||||
|---|---|---|---|---|---|
| Outcomes at follow-up | GLT | OGTT fasting | OGTT 1 hour | OGTT 2 hour | OGTT 3 hour |
| Normal blood pressure | |||||
| Median (interquartile range), mg/dl | 152 (143–164) | 87 (82–90) | 176 (151–193) | 152 (128–170) | 126 (104–147) |
| Elevated blood pressure or higher or receiving hypertension medications | |||||
| Median (interquartile range), mg/dl | 154 (145–167) | 86 (83–90) | 181 (156–195) | 158 (136–174) | 121 (102–142) |
| Unadjusted RR (95%CI) per 10-unit increase in glucose value vs. normal blood pressure | 1.05 (0.99-1.11) | 1.09 (0.94-1.27) | 1.04 (1.01-1.07) | 1.04 (1.01-1.07) | 0.97 (0.95-1.00) |
| Adjusted RR* (95%CI) per 10-unit increase in glucose value vs. normal blood pressure | 1.04 (0.99-1.10) | 0.98 (0.84-1.13) | 1.00 (0.97-1.04) | 1.04 (1.01-1.08) | 0.96 (0.93-0.99) |
| Stage 1 hypertension or higher or receiving hypertension medications | |||||
| Median (interquartile range), mg/dl | 155 (146–166) | 87 (82–90) | 180 (156–194) | 157 (135–173) | 121 (98–143) |
| Unadjusted RR (95%CI) per 10-unit increase in glucose value vs. normal or elevated blood pressure | 1.04 (0.97-1.11) | 1.14 (0.95-1.38) | 1.03 (0.99-1.07) | 1.03 (1.00-1.07) | 0.96 (0.93-1.00) |
| Adjusted* RR (95%CI) per 10-unit increase in glucose value vs. normal or elevated blood pressure | 1.03 (0.96-1.10) | 1.03 (0.85-1.24) | 0.99 (0.94-1.04) | 1.04 (0.99-1.09) | 0.95 (0.92-0.99) |
GLT, glucose loading test; OGTT, oral glucose tolerance test; RR, relative risk; CI, confidence interval. Bold indicates RR p<0.05
Adjusted for baseline age, body mass index, and pregnancy-associated hypertension during the index pregnancy. In addition, the OGTT model included all OGTT timed values, therefore for a particular timed value, it was adjusted for the other OGTT timed values
When the shape of the OGTT curve was evaluated, a monophasic response with peak at 1 hour was associated with an increased risk of elevated BP (aRR 1.66, 95% CI 1.17–2.35) and of stage 1 HTN or higher (aRR 1.83, 95% CI 1.15–2.92), compared with a biphasic response (Table 3). OGTT curves not fitting a monophasic or biphasic response were associated with an increased risk of elevated BP (RR 1.49, 95% CI 1.02–2.19) and of stage 1 HTN or higher (RR 1.84, 95% CI 1.11–3.04), compared with a biphasic response. The AUC for the full model evaluating shape of the OGTT curve was 0.71 (95%CI 0.67-0.74) for the outcome of elevated blood pressure or higher and 0.70 (95%CI 0.66-0.74) for the outcome of stage 1 hypertension or higher.
Table 3.
Association between OGTT curve shape during pregnancy and follow-up study outcomes
| Index pregnancy OGTT curve shape | ||||
|---|---|---|---|---|
| Outcomes at follow-up | Monophasic, peak at OGTT1, n=516 |
Monophasic, peak at OGTT2, n=101 |
Biphasic, peak at OGTT1 & OGTT3, n=102 |
All other shapes, n=169 |
| Normal blood pressure | ||||
| N (%) | 303 (58.7) | 71 (70.3) | 78 (76.5) | 109 (64.5) |
| Elevated blood pressure or higher or receiving hypertension medications | ||||
| N (%) | 213 (41.3) | 30 (29.7) | 24 (23.5) | 60 (35.5) |
| Unadjusted RR (95%CI) vs. normal blood pressure | 1.75 (1.22-2.53) | 1.26 (0.80-2.00) | 1.00 (referent) | 1.51 (1.01-2.26) |
| Adjusted* RR (95%CI) vs. normal blood pressure | 1.66 (1.17-2.35) | 1.27 (0.81-1.99) | 1.00 (referent) | 1.49 (1.02-2.19) |
| Stage 1 hypertension or higher or receiving hypertension medications | ||||
| N (%) | 147 (28.5) | 22 (21.8) | 15 (14.7) | 46 (27.2) |
| Unadjusted RR (95%CI) vs. normal or elevated blood pressure | 1.94 (1.19-3.15) | 1.48 (0.82-2.69) | 1.00 (referent) | 1.85 (1.09-3.14) |
| Adjusted* RR (95%CI) vs. normal or elevated blood pressure | 1.83 (1.15-2.92) | 1.50 (0.85-2.66) | 1.00 (referent) | 1.84 (1.11-3.04) |
OGTT, oral glucose tolerance test; RR, relative risk; CI, confidence interval. Bold indicates RR p<0.05
Adjusted for baseline age, body mass index, and pregnancy-associated hypertension during the index pregnancy
Conclusions
In the present investigation, we found that the shape of the OGTT curve may help identify patients who are at risk of having elevated BP or HTN 5 to 10 years following pregnancy, with biphasic shape to be associated with lower risk. This supports the concept of pregnancy as a window to future health and represents a potential novel biomarker for maternal cardiovascular health screening. While this cohort consisted of women with mild GDM or lesser degrees of glucose intolerance and no known preexisting cardiovascular disease or hypertension, those with abnormal OGTT curves were more than 50% likely to have elevated BP or stage I HTN at 5-10 years follow-up. In addition, the 2- and the 3-hour OGTT values were positively and inversely associated with elevated BP, respectively.
While the predisposition to metabolic diseases, especially diabetes mellitus, has been previously recognized in former GDM women,1,2,4-6 it is now apparent that they are also at increased risk of HTN and other associated cardiovascular morbidities.7-11,22 A recent meta-analysis of more than 5 million women demonstrated that GDM was associated with a 2-fold higher risk of cardiovascular disease compared with those without GDM. In addition, this risk is usually apparent in the first decade after delivery, is independent of progression to diabetes mellitus, and is present irrespective of the GDM screening protocol or diagnostic criteria.22-29 In addition, previous studies have reported an association between glucose screening values (irrespective of diagnosis of GDM) and postpartum adverse cardiovascular risk profile and higher risk of cardiovascular morbidities.14,30 In a population based study of more than two hundred fifty thousand women, with a median follow-up of 3.9 years after delivery, each 1 mmol/L (18 mg/dL) increase in the 1-hour glucose value on the GLT was associated with a 13% increase in risk of cardiovascular disease morbidities including myocardial infarction, stroke, acute coronary syndrome, percutaneous coronary intervention, coronary artery bypass grafting, or carotid endarterectomy. This increase was observed irrespective of diagnosis of GDM in the index pregnancy or diabetes mellitus at time of follow-up.14 Moreover, glucose values on the GLT or OGTT, in a cohort of 503 patients, were found to be associated with increase in immediate (3 months) postpartum risk factors for cardiovascular disease including higher postpartum fasting glucose, total cholesterol, high-density lipoprotein cholesterol ratio, triglycerides, low-density lipoprotein cholesterol, apolipoprotein B, and apolipoprotein-B:apolipoprotein-A1, in addition to lower high-density lipoprotein cholesterol and adiponectin, even in women without GDM diagnosis.
This continuous relationship between degree of glycemia in pregnancy and risk of adverse morbidities has been demonstrated in pregnancy in which OGTT values are linearly associated with increased risk of adverse pregnancy outcomes.31 In addition, the shape of the OGTT curve in non-pregnant individuals has been demonstrated to be associated with risk of cardiometabolic and diabetes mellitus.21,32 In a cohort of 277 non-diabetic adolescents, a monophasic OGTT curve was associated with lower insulin sensitivity and poorer b-cell function, which are two major pathophysiological biomarkers of type 2 diabetes.10 In addition, individuals with a monophasic OGTT curve have a twofold risk of developing type 2 diabetes over 7-8 years follow-up, compared with those with biphasic curve.33 The American Heart Association includes history of GDM in their classification of cardiovascular risk factors in women.12 However, much of the data on which this guideline is based were derived from retrospective identification of pregnancy complications, linked birth and death registries, and administrative databases. The mechanisms by which pregnancy complications predispose women to future cardiovascular and metabolic diseases are unknown. It is plausible that dysglycemia may initiate or cause inflammation, oxidative stress and endothelial damage, leading arterial stiffening, plaque buildup and cardiovascular disease later in life.2,4,34 Women who develop GDM most often have underlying hyperinsulinemia and chronic insulin resistance, thus their susceptibility for GDM when faced by the metabolic challenges in pregnancy. This chronic insulin resistance is also related to elevated hypertension risk in pregnancy (gestational) as well as later in life, possibly secondary to a vascular insult and other common risk factors, which elevate the risk that hypertension develops years later.35,36 However, these mechanisms need to be studied in prospective studies evaluating biologic risk factors before, during, and after pregnancy, and the development of HTN later in life.35,36
Our study provided a unique opportunity to prospectively evaluate the association between pregnancy OGTT values as well as shape of the curve and subsequent HTN. A limitation of this study, however, was the relatively modest sample size which may have limited our power to detect statistically significant associations with HTN. Although women enrolled in the index trial did not have preexisting HTN, it is unknown whether some of them may have met criteria for HTN prior to pregnancy based on the current AHA guidelines. Furthermore, although our analysis controlled for several potentially confounding factors, we do not have detailed data about all the postpartum influences that may have occurred during the interval between delivery and follow-up. Last, failure to demonstrate differences between the GDM and non-GDM groups may be explained by the fact that the non-GDM may not have been truly euglycemic since they had an abnormal one-hour screen.
However, there are numerous strengths of this study. Participants were enrolled during pregnancy and therefore pregnancy outcomes and data at the follow-up visits were prospectively collected and defined using rigorous criteria and under a standardized research setting, rather than relying on vital statistics and administrative data sets, and trained research staff performed BP measurements. The evaluation of GLT and OGTT, irrespective of GDM diagnosis, limits the concerns regarding the generalizability of the study.
In conclusion, our results provide further support of the concept of pregnancy as a window to future health and reports on a novel biomarker which can be studied to determine if it identifies women who are good candidates for primary cardiovascular screening and prevention. The results also support the concept that gestational dysglycemia, irrespective of the diagnosis of GDM, are associated with long term maternal health.
Supplementary Material
Supplementary Figure 1: Examples of monophasic and biphasic OGTT response shapes
Acknowledgments:
The authors also thank Francee Johnson, R.N., B.S.N. and Lisa Moseley, R.N. for protocol development and coordination between clinical research centers; Lindsey Doherty, M.S. for protocol/data management; Vinay Bhandaru, MS for statistical programming; and Elizabeth Thom, Ph.D. Catherine Y. Spong, M.D. for protocol development and oversight.
Funding Sources:
The project described was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [HD27915, U10HD36801, HD34208, HD34116, HD40485, HD40500, HD27869, HD40560, HD40544, HD53097, HD40512, HD40545] and the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) [UL1TR001070, UL1TR000439]. Comments and views of the authors do not necessarily represent views of the NIH.
Appendix:
In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network are as follows:
University of Texas Medical Branch, Galveston, TX - A. Salazar, G. Saade, A. Acosta, S. Bouse, G. Hankins, S. Jain
The Ohio State University, Columbus, OH - F. Johnson, S. Wylie, D. Habash, S. Heintzman, E. Nini, J. Iams, C. Durnwald
University of Utah Health Sciences Center, Salt Lake City, UT - K. Hill, M. Thompson, A. Sowles, G. Anderson (Intermountain Healthcare)
University of Texas Southwestern Medical Center, Dallas, TX - L. Moseley, J. Price, A. Sias, K. Gonzales, Y. Delira
Columbia University, New York, New York - S. Bousleiman, M. Talucci, V. Carmona, I. Quezada, A. Ranzini (St. Peter's University Hospital), M. Lake (St. Peter's University Hospital), S. Davis (St. Peter's University Hospital), M. Hoffman (Christiana Care), S. Lynch (Christiana Care), J. Benson (Christiana Care), C. Kitto (Christiana Care), L. Plante (Drexel University), C. Tocci (Drexel University), Y. Williams (Drexel University)
Brown University, Providence, RI - D. Allard, B. Anderson, K. Pereda, E. Hipolito, J. McNamara
University of Alabama at Birmingham, Birmingham, AL - S. Harris, J. Biggio, A. McClain, J. Sheppard
University of North Carolina at Chapel Hill, Chapel Hill, NC - K. Clark, B. Eucker, S. Timlin, K. Pena, T. Varney
MetroHealth Medical Center-Case Western Reserve University, Cleveland, OH - W. Dalton, C. Milluzzi, P. Catalano, B. Mercer
Northwestern University, Chicago, IL - G. Mallet, M. Ramos-Brinson, C. Collins, L. Stein, M. Dinsmoor (NorthShore HealthSystems-Evanston Hospital)
University of Texas Health Science Center at Houston-Children’s Memorial Hermann Hospital, Houston, TX - F. Ortiz, B. Sibai, B. Rech, L. Garcia
The George Washington University Biostatistics Center, Washington, DC - E. Thom, L. Doherty, L. Mele
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD - C. Spong, S. Tolivaisa
MFMU Network Steering Committee Chair (Medical University of South Carolina, Charleston, SC) – J. P. VanDorsten, M.D.
Footnotes
Conflicts of Interest: None
Contributor Information
Maged M. Costantine, Departments of Obstetrics and Gynecology of University of Texas Medical Branch, Galveston, TX.
Madeline Murguia Rice, George Washington University Biostatistics Center, Washington, DC.
Mark B. Landon, The Ohio State University, Columbus, OH
Michael W. Varner, University of Utah Health Sciences Center, Salt Lake City, UT
Brian M. Casey, University of Texas Southwestern Medical Center, Dallas, TX
Uma M. Reddy, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Ronald J. Wapner, Columbia University, New York, New York
Dwight J. Rouse, Brown University, Providence, RI
Alan T. N. Tita, University of Alabama at Birmingham, Birmingham, AL
John M. Thorp, University of North Carolina at Chapel Hill, Chapel Hill, NC
Edward K. Chien, MetroHealth Medical Center -Case Western Reserve University, Cleveland, OH.
Alan M. Peaceman, Northwestern University, Chicago, IL
Sean C. Blackwell, University of Texas Health Science Center at Houston-Children’s Memorial Hermann Hospital, Houston, TX.
References:
- 1.Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes care. 2002;25(10):1862–1868. [DOI] [PubMed] [Google Scholar]
- 2.Kaaja RJ, Greer IA. Manifestations of chronic disease during pregnancy. JAMA. 2005;294(21):2751–2757. [DOI] [PubMed] [Google Scholar]
- 3.Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335(7627):974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ. 2002;325(7356):157–160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Committee on Practice B-O. ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus. Obstet Gynecol. 2018;131(2):e49–e64. [DOI] [PubMed] [Google Scholar]
- 6.Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49(12):2208–2211. [DOI] [PubMed] [Google Scholar]
- 7.Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035–2038. [DOI] [PubMed] [Google Scholar]
- 8.Kannel WB, McGee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes care. 1979;2(2):120–126. [DOI] [PubMed] [Google Scholar]
- 9.Fox CS, Coady S, Sorlie PD, et al. Trends in cardiovascular complications of diabetes. JAMA. 2004;292(20):2495–2499. [DOI] [PubMed] [Google Scholar]
- 10.Kim JY, Michaliszyn SF, Nasr A, et al. The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth. Diabetes care. 2016;39(8):1431–1439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Carr DB, Utzschneider KM, Hull RL, et al. Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes. Diabetes care. 2006;29(9):2078–2083. [DOI] [PubMed] [Google Scholar]
- 12.Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation. 2011;123(11):1243–1262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Casey BM, Rice MM, Landon MB, et al. Effect of Treatment of Mild Gestational Diabetes on Long-Term Maternal Outcomes. Am J Perinatol. 2020;37(5):475–482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Retnakaran R, Shah BR. Glucose screening in pregnancy and future risk of cardiovascular disease in women: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol. 2019;7(5):378–384. [DOI] [PubMed] [Google Scholar]
- 15.Retnakaran R, Ye C, Hanley AJ, Connelly PW, Sermer M, Zinman B. Screening Glucose Challenge Test in Pregnancy Can Identify Women With an Adverse Postpartum Cardiovascular Risk Factor Profile: Implications for Cardiovascular Risk Reduction. J Am Heart Assoc. 2019;8(21):e014231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Manco M, Nolfe G, Pataky Z, et al. Shape of the OGTT glucose curve and risk of impaired glucose metabolism in the EGIR-RISC cohort. Metabolism: clinical and experimental. 2017;70:42–50. [DOI] [PubMed] [Google Scholar]
- 17.Tura A, Morbiducci U, Sbrignadello S, Winhofer Y, Pacini G, Kautzky-Willer A. Shape of glucose, insulin, C-peptide curves during a 3-h oral glucose tolerance test: any relationship with the degree of glucose tolerance? Am J Physiol Regul Integr Comp Physiol. 2011;300(4):R941–948. [DOI] [PubMed] [Google Scholar]
- 18.Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127–e248. [DOI] [PubMed] [Google Scholar]
- 19.Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339–1348. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Landon MB, Rice MM, Varner MW, et al. Mild gestational diabetes mellitus and long-term child health. Diabetes care. 2015;38(3):445–452. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Tschritter O, Fritsche A, Shirkavand F, Machicao F, Haring H, Stumvoll M. Assessing the shape of the glucose curve during an oral glucose tolerance test. Diabetes care. 2003;26(4):1026–1033. [DOI] [PubMed] [Google Scholar]
- 22.Retnakaran R. Hyperglycemia in pregnancy and its implications for a woman's future risk of cardiovascular disease. Diabetes Res Clin Pract. 2018;145:193–199. [DOI] [PubMed] [Google Scholar]
- 23.Kramer CK, Campbell S, Retnakaran R. Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia. 2019;62(6):905–914. [DOI] [PubMed] [Google Scholar]
- 24.Daly B, Toulis KA, Thomas N, et al. Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: A population-based cohort study. PLoS Med. 2018;15(1):e1002488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Tobias DK, Stuart JJ, Li S, et al. Association of History of Gestational Diabetes With Long-term Cardiovascular Disease Risk in a Large Prospective Cohort of US Women. JAMA Intern Med. 2017;177(12):1735–1742. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kaul P, Savu A, Nerenberg KA, et al. Impact of gestational diabetes mellitus and high maternal weight on the development of diabetes, hypertension and cardiovascular disease: a population-level analysis. Diabet Med. 2015;32(2):164–173. [DOI] [PubMed] [Google Scholar]
- 27.Fadl H, Magnuson A, Ostlund I, Montgomery S, Hanson U, Schwarcz E. Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study. BJOG. 2014;121(12):1530–1536. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kessous R, Shoham-Vardi I, Pariente G, Sherf M, Sheiner E. An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. Heart. 2013;99(15):1118–1121. [DOI] [PubMed] [Google Scholar]
- 29.Shah BR, Retnakaran R, Booth GL. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes care. 2008;31(8):1668–1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Retnakaran R, Qi Y, Connelly PW, Sermer M, Zinman B, Hanley AJ. Glucose intolerance in pregnancy and postpartum risk of metabolic syndrome in young women. J Clin Endocrinol Metab. 2010;95(2):670–677. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Stuebe AM, Landon MB, Lai Y, et al. Is There a Threshold Oral Glucose Tolerance Test Value for Predicting Adverse Pregnancy Outcome? Am J Perinatol. 2015;32(9):833–838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Kanauchi M, Kimura K, Kanauchi K, Saito Y. Beta-cell function and insulin sensitivity contribute to the shape of plasma glucose curve during an oral glucose tolerance test in non-diabetic individuals. Int J Clin Pract. 2005;59(4):427–432. [DOI] [PubMed] [Google Scholar]
- 33.Abdul-Ghani MA, Lyssenko V, Tuomi T, Defronzo RA, Groop L. The shape of plasma glucose concentration curve during OGTT predicts future risk of type 2 diabetes. Diabetes Metab Res Rev. 2010;26(4):280–286. [DOI] [PubMed] [Google Scholar]
- 34.Williams D. Pregnancy: a stress test for life. Curr Opin Obstet Gynecol. 2003;15(6):465–471. [DOI] [PubMed] [Google Scholar]
- 35.Buchanan TA. Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab. 2001;86(3):989–993. [DOI] [PubMed] [Google Scholar]
- 36.Tobias DK, Hu FB, Forman JP, Chavarro J, Zhang C. Increased risk of hypertension after gestational diabetes mellitus: findings from a large prospective cohort study. Diabetes care. 2011;34(7):1582–1584. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplementary Figure 1: Examples of monophasic and biphasic OGTT response shapes