Abstract
The objective of this study was to examine whether aortic stiffness, as assessed by pulse wave analysis, could reliably discriminate between normal and hypertensive pregnancies. One hundred pregnant women were studied: five with severe pre-eclampsia, 27 with gestational hypertension, 14 with chronic hypertension and 54 with normal pregnancy. Central hemodynamic parameters were obtained by an applanation tonometry and included central aortic systolic blood pressure (CSBP), central aortic diastolic blood pressure (CDBP), augmentation pressure (AP), augmentation index (AIx), AIx corrected to a heart rate of 75 (AIx@75) and time to reflection (Tr). All measures of aortic stiffness, including AP, AIx and AIx@75 were significantly higher in women with gestational hypertension and pre-eclampsia compared with normal pregnancies and women with chronic hypertension (p < 0.05 for all comparisons). There were no significant differences between normal pregnancies and women with chronic hypertension (p > 0.05 for all comparisons). Tr was significantly shorter in women with pre-eclampsia and gestational hypertension compared with normal pregnancies (p < 0.05). Aortic stiffness, as assessed by pulse wave analysis, is significantly increased in women with pre-eclampsia and gestational hypertension but not in treated women with chronic hypertension. Pulse wave analysis has a potential as a screening tool in women at high risk for pre-eclampsia. The final role of this method should be determined in prospective studies.
Introduction
Pre-eclampsia is defined as new onset hypertension, proteinuria and edema after 20 weeks of gestation in a previously normotensive woman (Citation1).
It occurs in approximately 3–14% of all pregnancies worldwide and is a major cause of death in pregnant women, especially in developing countries (Citation2). Many risk factors have been described, but the exact pathogenesis remains unknown.
Maternal endothelial dysfunction has been observed in women with pre-eclampsia during (Citation3) and after pregnancy (Citation4). Moreover, endothelial dysfunction tends to precede the development of the clinical syndrome (Citation5,Citation6) and therefore has the potential to be used as an early predictor of this condition.
Currently, the most widely used non-invasive method for the assessment of endothelial function is flow-mediated dilation of the brachial artery as measured by ultrasound (Citation7). This method, however, is time consuming and operator dependent, precluding its use as a mass screening tool.
Recently, pulse wave analysis of peripheral arteries has been increasingly used as a tool for non-invasive detection of aortic stiffness and endothelial dysfunction (Citation8). It is fairly reproducible and easy to perform, enabling mass screening (Citation9,Citation10).
The aim of our study was to examine whether pulse wave analysis could reliably discriminate between normal and hypertensive pregnancies for possible future use in prediction of pre-eclampsia
Material and methods
Subject selection
The study was approved by the local ethics committee and all subjects gave informed consent.
Women were recruited from both the inpatient and outpatient services of the High-risk Pregnancy Department. All had singleton pregnancies and had no other risk factors for endothelial dysfunction including smoking, diabetes and hypercholesterolemia. Women with intrauterine growth retardation were also excluded. Four groups of pregnant women were studied:
Women presenting with severe pre-eclampsia as defined by one or more of the following criteria: hypertension (systolic higher than 160 or diastolic higher than 110 mmHg, on two occasions at least 2 h apart), proteinuria (5 g or higher on a 24-h urine specimen or 3+ or greater on two random urine samples at least 4 h apart), oliguria, cerebral or visual disturbances, pulmonary edema or cyanosis, epigastric or RUQ pain, impaired liver function, thrombocytopenia, fetal growth restriction (Citation11).
Women with gestational hypertension as defined by elevated blood pressure (systolic higher than 140 or diastolic higher than 90 mmHg), without proteinuria or other end-organ involvement, developing after 20 weeks of gestation (Citation11).
Women with chronic hypertension as defined by elevated blood pressure (systolic higher than 140 or diastolic higher than 90 mmHg), developing before 20 weeks gestation or predating the index pregnancy (Citation12).
Women with normal pregnancy and no cardiovascular or metabolic complications or use of any medications except for iron supplementation.
Clinical and pulse wave measurements
All measurements were taken by one observer (BA).
After 20 min of rest in a semi recumbent position and in a temperature controlled room (25°C), brachial artery blood pressure was measured by a semi-automated sphygmomanometer (Accutorr plus, Datascope Corp. Mahwah, NJ 07430, USA).
Radial artery pulse wave recordings were obtained by an applanation tonometer (Millar Instruments, Houston, Texas, USA) applied to the radial artery. Aortic pressure waveforms were derived from the peripheral recordings by the apparatus software (SphygmoCor PVX, AtCor Medical, Sydney Australia) using a validated transfer function (Citation8,Citation9). Central hemodynamic parameters obtained included central systolic blood pressure (CSBP), central aortic diastolic blood pressure (CDBP), augmentation pressure (AP = P2-P1), augmentation index (AIx = AP/aortic pulse pressure, expressed in percentages), AIx corrected to a heart rate of 75 (AIx@75) and time to reflection (Tr) (). Only recordings with a quality index (an index calculated by the software) of 85% or above were included in the analysis.
Figure 1. Aortic pulse wave. P1, wave formed by left ventricle ejection; P2, reflected wave; AP, augmentation pressure (P2-P1); PP, pulse pressure; Tr, time to reflection.
Statistical analysis
Group data are presented as mean±SD. Differences between means were compared using one-way analysis of variance (ANOVA) with Scheffe's method for a post-hoc multiple comparisons or by the non-parametric Kruskal-Wallis test when appropriate. The confounding effect of SBP and DBP was also taken into consideration when the ANOVA models were used. A p-value less than 0.05 was considered to be statistically significant. The statistical software SPSS (version 14.0.1 SPSS Inc., Chicago, IL) was used for all analyses.
Results
One hundred pregnant women were studied: 54 were pregnant and normotensive, 27 had gestational hypertension, 14 had chronic hypertension, and five had severe pre-eclampsia. Ten women with chronic hypertension were on antihypertensive treatment (nine on methyldopa and one on metoprolol). All the women with pre-eclampsia were treated with magnesium sulfate and one was treated with magnesium sulfate and labetalol.
Demographic characteristics of the four groups are shown in (the results in and are for the simultaneous comparison, using ANOVA, of the four study's groups). We also used Scheffe's method to compare subsets of groups. Women with gestational hypertension were in an advanced gestational age compared with women with chronic hypertension (p = 0.007), while other comparisons between groups were not significant. Women with chronic hypertension had a significantly higher body mass index (BMI) compared with women with normal pregnancies, gestational hypertension and severe pre-eclampsia (p < 0.001, 0.022 and 0.02, respectively).
Table I. Subjects demographic characteristics.
Table II. Subjects peripheral and central hemodynamic measurements.
Peripheral and central hemodynamic measurements of the four groups are presented in . Both peripheral and central systolic and diastolic blood pressures were significantly higher in all three hypertensive groups compared with normal pregnancies (p < 0.001 for all comparisons). Women with severe pre-eclampsia had significantly higher peripheral and CSBPs compared with women with gesta-tional and chronic hypertension (p < 0.001 for both groups). There were no significant differences in blood pressure measurements between women with gestational hypertension and chronic hypertension. No significant difference was found in heart rate between the groups.
AP, AIx and AIx@75 were significantly higher in women with gestational hypertension and pre-eclampsia compared with normal pregnancies and women with chronic hypertension (p < 0.02, p < 0.02, p < 0.001 respectively). There were no significant differences between normal pregnancies and women with chronic hypertension.
Time to reflection (Tr), which is a surrogate for pulse wave velocity, was significantly shorter in women with gestational hypertension and pre-eclampsia compared with normal pregnancy (p = 0.005 and p = 0.027, respectively). Women with pre-eclampsia had the shortest values compared with women with gestational hypertension and chronic hypertension. Tr values did not differ significantly between women with chronic and gestational hypertension.
After adjusting for peripheral systolic and dia-stolic blood pressures, AP and AIX were still significantly different (p < 0.001 and p = 0.017, respectively) between all four groups.
Discussion
Endothelial dysfunction has been well documented in pre-eclampsia and gestational hypertension, and plays an important role in both the etiology and the sequels of hypertensive pregnancy (Citation13,Citation14). A major component of endothelial dysfunction is a blunted response to nitric oxide-mediated vasodilation either related to reduced production or decreased bioavail-ability (Citation15). Ex vivo studies of small subcutaneous arteries from women with pre-eclampsia have shown blunted nitric oxide-mediated vasodilation (Citation16).
Flow-mediated dilation of the brachial artery (as measured by ultrasound) is a widely used, non-invasive measure of endothelial function (Citation7). Using this method, several studies have demonstrated decreased flow-mediated dilation in pre-eclamptic women, which preceded the development of the clinical syndrome (Citation3,Citation5,Citation6). This method, however, involves the use of relatively expensive equipment and trained technicians, and is therefore not suitable for mass screening.
Pulse wave analysis has been increasingly used for the non-invasive assessment of endothelial function (Citation17). It is easy to perform and needs minimal training, making it an attractive tool for screening.
Normal pregnancy is associated with a decrease in central blood pressure and aortic stiffness, reaching a nadir by mid-pregnancy and increasing toward pre-pregnancy levels at term (Citation18). This effect is probably mediated by increased NO production during normal pregnancy (Citation19,Citation20). The normal values of aortic stiffness at various gestational ages throughout normal pregnancy have been recently defined by Smith et al. (Citation21), and our results in normal pregnancy are in agreement with their findings.
In our study, we have shown that women with gestational hypertension and pre-eclampsia have significantly higher indexes of aortic stiffness as indicated by higher AIx and shorter Tr. This observation was still significant even after adjusting to peripheral blood pressures.
Interestingly, aortic stiffness in women with chronic hypertension was not different from women with normal pregnancies despite significantly increased blood pressure values. This observation may be related to the effect of antihypertensive treatment on aortic stiffness. Indeed, Khalil et al. have recently demonstrated that antihypertensive treatment of women with pre-eclampsia and gestational hypertension resulted in a significant reduction in central blood pressure and decreased aortic stiffness (Citation22). This effect, however, was limited only to women with pre-eclampsia and was not observed in women with gestational hypertension. Alternatively, our findings may be an indication of the different pathophys-iology between chronic hypertension and gestational hypertension or pre-eclampsia, where endothelial dysfunction may have a more prominent role. Thus, increased indexes of aortic stiffness persist in women with pre-eclampsia in the postpartum period, even after normalization of blood pressure (Citation23).
Pharmacologic treatment for women with chronic hypertension is still controversial (Citation12). Our findings, if replicated in larger and prospective studies may help identify women that can benefit most from anti-hypertensive therapy.
Aortic stiffness indexes in hypertensive pregnancy have been reported by several investigators: Ronnback et al. (Citation24) and Spasojevic et al. (Citation25) have shown significantly increased AIx values in women with pre-eclampsia but less so in women with gesta-tional hypertension. Elvan-Taspinar et al. (Citation26) studied women with pre-eclampsia, pregnancy-induced hypertension and chronic hypertension. In their study too, women with pre-eclampsia and hypertensive pregnancies had a significantly higher AIx compared with normal pregnancy. As with our study, AIx in women with pregnancy-induced hypertension was similar to that of women with chronic hypertension and there was no difference in AIx between women with or without antihypertensive treatment.
The role of pulse wave analysis as a tool to predict the development of pre-eclampsia has been recently assessed in a prospective study (Citation27). Increased values of AIx during the first trimester had a 79% detection rate of pre-eclampsia. If these results are confirmed by larger-scale studies and other investigators, pulse wave analysis may prove to be a valuable screening method for pre-eclampsia.
Liro et al. examined the correlation between aortic stiffness in hypertensive pregnancies, (as assessed indirectly by measurements of peripheral pulse pressure readings), and pregnancy outcomes (Citation28). In their retrospective study, pulse pressure was a significant factor in predicting an adverse outcome in hypertensive pregnancies.
Our study has its limitations, being an observational study assessing aortic stiffness at one time point during pregnancy. In addition, as our patient population was recruited mainly from a day clinic, (and most women with pre-eclampsia are treated as in patients in our institution), we examined only a small number of women with pre-eclampsia.
In conclusion, women with gestational hypertension and pre-eclampsia have significantly higher indexes of aortic stiffness. Women with chronic hyper tension, however, had aortic stiffness similar to that of women with normal pregnancies, despite significantly increased blood pressure values (). Pulse wave analysis is a promising non-invasive method for prediction, follow-up and assessment of endothelial function in hypertensive pregnancies.
Table III. Summary.
Acknowledgment
We thank Roni Braunstein, Ph.D., for performing the statistical analysis.
Potential conflict of interest
Dr. Dishy is currently an employee of Daiichi Sankyo Inc.
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