Objective
We sought to investigate whether maternal arterial stiffness is altered in pregnant women with gestational diabetes mellitus (GDM) and type 2 diabetes compared to normoglycemic women.
Study Design
We conducted a cross-sectional study involving 34 women with GDM and their controls (n = 34), and 34 women with type 2 diabetes and their controls (n = 34). Maternal arterial stiffness was assessed using applanation tonometry.
Results
In patients with GDM, compared to their controls, augmentation index (a measure of arterial wave reflection) was higher (13.1 ± 8.9% vs 0.7 ± 11.4%; P < .001) and pulse wave velocity (PWV) (arterial stiffness of the carotid-femoral) was marginally increased (6 ± 1.5 vs 5.4 ± 0.6 m/s; P = .07). In type 2 diabetics, compared to their controls, both augmentation index and PWV were increased (11.5 ± 11.4% vs 3.3 ± 12.5%; P = .006, and 6.8 ± 1.2 vs 5.6 ± 1 m/s; P < .001). When all groups were considered together, there was a significant trend of increasing augmentation index ( P = .001) and PWV ( P < .001) from controls to those with GDM to type 2 diabetes.
Conclusion
Pregnancies complicated by GDM and type 2 diabetes are associated with increased maternal arterial stiffness.
Impaired glucose tolerance and type 2 diabetes are known to be associated with increased cardiovascular morbidity and mortality, but the responsible mechanisms remain unclear. Several studies suggest that both conditions are associated with increased arterial stiffness, which in itself is an independent powerful predictor of cardiovascular mortality in these populations.
Pregnancy is a carbohydrate-intolerant state and as a result, gestational diabetes mellitus (GDM) develops in 3-5% of pregnant women. As in type 2 diabetes, GDM is associated with both insulin resistance and impaired insulin secretion. The 2 disorders share the same risk factors, have a similar prevalence within a given population, and have the same genetic susceptibility. Therefore, they are assumed to be etiologically indistinct with GDM preceding type 2 diabetes. In accordance to this, women with GDM have a 17-63% risk of developing type 2 diabetes within 5-16 years following the index pregnancy. Pregnancies complicated by GDM and pre-GDM are at increased risk of hypertensive disorders, which in turn are associated with increased maternal arterial stiffness and propensity to cardiovascular morbidity and mortality later on in life. Despite the above associations and the extensive number of studies assessing arterial stiffness in subjects with glucose intolerance outside the setting of pregnancy, the available information on maternal arterial stiffness and central hemodynamics in pregnancies complicated by GDM or type 2 diabetes is scarce.
Noninvasive assessment of arterial stiffness is possible by the simple, validated, and reproducible technique of applanation tonometry. Using this technique, pulse wave analysis of the radial artery waveform and pulse wave velocity (PWV) can be carried out. With pulse wave analysis of the radial artery waveform, it is possible to assess central pressures and augmentation index, a measure of arterial wave reflection, whereas with PWV it is possible to measure the stiffness in the carotid-radial (muscular) and carotid-femoral (elastic) parts of the arterial tree. In the current study, we used the above technique to investigate whether maternal arterial stiffness is altered in pregnant women with GDM and type 2 diabetes mellitus compared to women with uncomplicated pregnancies.
Materials and Methods
Study participants
This was a cross-sectional study involving the following groups of pregnant women. Group A consisted of 34 women with GDM, diagnosed with a 75-g, 2-hour oral glucose tolerance test using the World Health Organization criteria, and 34 normoglycemic women. Group B consisted of 34 women with pregestational type 2 diabetes and 34 normoglycemic women. The diagnosis of GDM was made in the third trimester of pregnancy and therefore the studies in women in group A were made at that time. Group B was examined at midpregnancy, because the peak of maternal cardiovascular adaptation to pregnancy, including maternal arterial stiffness, occurs during this time. No subject had a personal or family history of premature coronary artery disease. Maternal age, ethnic group, smoking status, parity, body mass index (BMI), and blood pressure (BP) were recorded. Thirty women in the GDM group were on insulin and 4 of them had their diabetes controlled with diet and exercise. All type 2 diabetic women were taking insulin including 4 who were taking insulin in combination with oral hypoglycemic agents. The insulin treatment regimen consisted of daily injections of a combination of long-/intermediate- and short-acting insulin. Glycosylated hemoglobin (HbA 1c ) was measured using an automated boronate affinity chromatography method (Primus Corp, Kansas City, MO). Birthweight percentiles were calculated based on the birthweight, gestation, sex of the neonate, and maternal characteristics. The study was approved by the institutional review committee and all women gave written informed consent.
Wave reflection and arterial stiffness measurements
Peripheral BP was measured in the right arm using an ambulatory BP monitor (3BTO-A2; Microlife Medical, Taipei, Taiwan), which has been validated in pregnancy. Systolic and diastolic BP were measured twice and averaged.
Each heartbeat generates a pulse wave that travels away from the heart and is reflected back at the areas of high resistance. The reflected wave travels back toward the heart and meets the advancing wave, augmenting its height. Generally, the reflected wave reaches the aorta during diastole, enhancing the cardiac perfusion. When arterial stiffness in increased, the arterial pulse wave travels faster, so the reflected wave reaches the advancing wave in the systole, resulting in significant augmentation of the systolic peak. This can be measured as increased augmentation index. Interrogation of the radial artery waveform (pulse wave analysis of the radial artery) can provide information on augmentation index and the central, aortic hemodynamics.
The radial artery was gently compressed at the wrist with the tip of a tonometer, which contains a high-fidelity micromanometer (SPC-301; Millar Instruments, Houston, TX) and provides an accurate recording of the pressure within the radial artery. A generalized transfer function was applied to the radial waveform to derive the aortic pressure waveform (Sphygmocor; AtCor Medical, Sydney, Australia) ( Figure 1 ). From this aortic pressure waveform, the augmentation index, a composite measure of systemic arterial stiffness and wave-reflection amplitude, and central systolic, diastolic, and pulse pressure were determined with the integrated software. Information on first, second (reflected) systolic peak, and aortic Tr (time between the start of the systolic curve and the inflection point) was also given. Mean arterial pressure was obtained by integration of the waveform.
Aortic (carotid-femoral) and brachial (carotid-radial) PWV and relevant transient times were measured as previously described. For each subject the distance in millimeters between each artery location (carotid, femoral, and radial) and the suprasternal notch was measured in a straight line using a pair of compasses to reduce the influence of altered body contour in pregnancy. All measurements were performed after a period of rest of at least 10 minutes in a left lateral position to avoid vena cava compression by the uterus. All measurements were made in duplicate and mean values used in the subsequent analyses. We have previously shown that the interobserver and intraobserver intraclass correlation coefficients were 0.95 and 0.97, respectively, for augmentation index and 0.9 and 0.9, respectively, for PWV.
Statistical analysis
Normality of the distribution of the data was examined with the Kolmogorov-Smirnov test. Data were expressed as mean ± SD or as median (interquartile range) for normally and nonnormally distributed data, respectively. Comparisons between groups were performed using unpaired Student t test, Mann-Whitney, or χ 2 for numerical and categorical data. Univariate analyses were performed when appropriate. Multiple regression analysis was performed when adjustment for potential confounders was thought to be necessary. To investigate whether there was a trend of alteration of maternal arterial stiffness with deterioration of insulin resistance from controls to GDM to type 2 diabetes, all women with uncomplicated pregnancies (controls from groups A and B) were considered together and consequently 3 groups were formed: controls (n = 68), GDM (n = 34), and type 2 diabetes (n = 34). A generalized linear model was used and maternal age, gestational age at examination, heart rate, mean arterial pressure, and aortic Tr were used as covariates. Post hoc analyses were performed, where appropriate. Power analysis indicated that a sample of 34 women with type 2 diabetes and the same number of controls would have >80% power with an alpha .05 (2-tail) for the detection of a mean difference of 1.67 m/s in the PWV between the groups. The effect size was estimated from previous publications. The statistical analyses were performed using the Statistical Package for Social Sciences (version 12.0; SPSS, Inc., Chicago, IL).
Results
Recordings were successfully obtained from all women and they all tolerated the studies well.
Study in GDM
The demographic and clinical characteristics of the study participants are given in Table 1 . The women with GDM were more likely to have higher BMI and deliver earlier, as expected. They were taking 40.5 ± 28 U of insulin daily in different preparations and HbA 1c levels indicated good glycemic control (5.7 ± 0.5%). From the diabetic women included in this study, 1 developed preeclampsia and 1 developed gestational hypertension, as defined by the International Society for the Study of Hypertension in Pregnancy.
| Group parameter | A | B | ||||
|---|---|---|---|---|---|---|
| Controls (n = 34) | Gestational diabetes (n = 34) | P | Controls (n = 34) | Type 2 diabetes (n = 34) | P | |
| Maternal age, y | 32 ± 5.4 | 33.9 ± 4.8 | .1 | 32.4 ± 5.1 | 34.1 ± 5.1 | .1 |
| Ethnic group | .6 | .4 | ||||
| White, n (%) | 15 (44.1) | 16 (47.1) | 19 (55.9) | 14 (41.2) | ||
| Black, n (%) | 15 (44.1) | 12 (35.3) | 11 (32.4) | 14 (41.2) | ||
| Others, n (%) | 4 (11.8) | 6 (17.6) | 4 (11.7) | 6 (17.6) | ||
| Smoking, n (%) | 7 (20.6) | 6 (17.6) | .7 | 6 (17.6) | 5 (14.7) | .7 |
| Nulliparity, n (%) | 22 (64.7) | 11 (33.3) | .01 | 11 (32.4) | 8 (23.5) | .4 |
| Maternal height, m | 1.6 ± 0.06 | 1.6 ± 0.07 | .8 | 1.6 ± 0.06 | 1.6 ± 0.07 | .2 |
| Maternal weight, kg | 76.1 ± 13.1 | 83.8 ± 14.4 | .02 | 71.4 ± 14.5 | 91.9 ± 18.3 | < .001 |
| Body mass index, kg/m 2 | 28.4 ± 4.2 | 31.5 ± 6.4 | .02 | 26.4 ± 4.3 | 34.9 ± 6.4 | < .001 |
| Gestational age at entry, d | 220.9 ± 20.4 | 224.2 ± 21.2 | .5 | 153.3 ± 13 | 150.6 ± 14.7 | .3 |
| Gestational age at delivery, d | 280.8 ± 8.6 | 269.9 ± 4.4 | < .001 | 284.5 ± 8.3 | 267.5 ± 10.3 | < .001 |
| Birthweight, g | 3568.6 ± 500.6 | 3271.6 ± 459.4 | .01 | 3519 ± 433.4 | 3308.4 ± 638.7 | .1 |
| Birthweight percentile | 56.5 ± 29.1 | 48.7 ± 32 | .3 | 48.1 ± 27.5 | 54.5 ± 32.3 | .3 |
The hemodynamic parameters are given in Table 2 . Peripheral and central, systolic, and mean BPs were higher in women with GDM. The augmentation index was higher in women with GDM compared to controls. Backward multiple linear regression analysis was performed with augmentation index as a dependent variable, to identify which factors are its significant predictors. Maternal age ( P < .0001), heart rate ( P < .0001), aortic Tr ( P < .0001), and presence of diabetes ( P = .003) were independently associated with augmentation index, whereas mean arterial pressure was not. This was the case even when women who developed hypertensive disorders were excluded. Within the group of diabetic women, the augmentation index was not associated with the control of diabetes, as assessed by the levels of HbA 1c ( P = .09).
