Antihypertensive Therapy and Central Hemodynamics in Women With Hypertensive Disorders in Pregnancy

Asma Khalil,
MRCOG,

Eric Jauniaux,

PhD,

and Kevin Harrington,

MD

OBJECTIVE: To estimate the changes in central hemodynamics features of pregnant women presenting with hypertensive disorders and to analyze the effects of standard antihypertensive treatment on maternal central hemodynamics. METHODS: Applanation tonometry was used to record the radial artery pulse waveform in 80 women presenting with preeclampsia or gestational hypertension and 80 normotensive controls matched for gestational age. In each case, an averaged aortic waveform was derived and analyzed to calculate augmentation pressure and augmentation index at heart rate 75 beats per minute (bpm). RESULTS: In women with preeclampsia and gestational hypertension, both augmentation pressure (P<.001 and P<.05, respectively) and augmentation index at heart rate 75 bpm (P<.001 and P<.001, respectively) were significantly higher than in controls. Augmentation pressure and augmentation index at heart rate 75 bpm were significantly higher in early- compared with late-onset preeclampsia (P<.001) and in severe compared with mild preeclampsia (P<.001). Antihypertensive therapy with alpha methyldopa resulted in a significant fall in both augmentation pressure and augmentation index at heart rate 75 bpm in preeclampsia (P<.001) but not in gestational hypertension. CONCLUSION: Arterial stiffness is increased in women with hypertensive disorders of pregnancy compared with normotensive controls. In preeclampsia, vascular stiffness was significantly improved by antihypertensive treatment
From the The Homerton University Hospital NHS Trust, Queen Mary and Westfield College, University of London; and Academic Department of Obstetrics and Gynaecology, UCL Institute for Womens Health, University College London, London, United Kingdom. Corresponding author: Dr. Asma Khalil, UCL Institute for Womens Health, 86-96 Chenies Mews, London WC1E 6HX, United Kingdom; asmakhalil79@ googlemail.com. Financial Disclosure The authors did not report any potential conflicts of interest. 2009 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/09

with alpha methyldopa, but remained higher than in normotensive controls.

(Obstet Gynecol 2009;113:64654)

LEVEL OF EVIDENCE: II

ypertensive disorders of pregnancy, and preeclampsia in particular, are a leading cause of maternal and neonatal morbidity and mortality.13 Preeclampsia is associated with4 7 the release of antiangiogenic factors; plasma volume is contracted and widespread effects on vascular endothelium lead to the maternal syndrome of preeclampsia. Outside pregnancy, arterial stiffness has been shown to be increased in hypertensive patients, using a variety of methods such as Doppler color echocardiography and pulse wave velocity.8,9,10 13 Another technique, pulse wave analysis, the noninvasive analysis of the aortic pressure waveform and aortic stiffness, is possible by the simple, validated, and reproducible technique of applanation tonometry.14 20 Pulse wave analysis has been widely studied in the general population14 20 and can quantify alterations in vascular compliance associated with conditions that cause endothelial dysfunction, such as diabetes, renal disease, and arteriosclerosis. Central pressures may be more relevant than brachial artery blood pressure to cardiovascular pathophysiology; for example, central pulse pressure is a better predictor of cardiovascular events than is brachial blood pressure.21,22 Studies in nonpregnant women have found differential effects of antihypertensive drugs on central hemodynamics, despite similar effects on peripheral blood pressure measurements.2325 These findings have contributed to a major change in the guidelines on the management of hypertension outside pregnancy. Normal values for pulse wave analysis in uncomplicated pregnancies have recently been established.26 Three studies using pulse wave analysis2729

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showed that arterial stiffness is increased in women with hypertensive disorders of pregnancy compared with normotensive pregnant women. However, these study groups were small and none had data comparing before and after treatment. No study has investigated central hemodynamics before and after antihypertensive therapy in pregnancy. The aim of our study was to estimate the changes in central hemodynamics in women presenting with hypertensive disorders in pregnancy and to investigate the effect of antihypertensive treatment on these measures.

MATERIALS AND METHODS

Women in the second half of pregnancy were randomly recruited at The Homerton University Hospital between January 2006 and September 2007. Maternal demographics and clinical data, including age, body mass index (BMI), blood pressure (BP), parity, and gestational age were recorded. Gestational age was established on the basis of the last menstrual period and confirmed by ultrasonographic examination before 20 weeks of gestation. Exclusion criteria included multiple pregnancy, a history of chronic hypertension, diabetes, renal disorder, immune disorders, or significant anemia (hemoglobin 9 g/dL or less). Ethics approval was received from the Camden & Islington Community Local Research Ethics Committee, and all participants gave written informed consent. Women were allocated to either hypertensive or normotensive groups. Eighty women with hypertensive disorders of pregnancy were further subdivided into preeclampsia and gestational hypertension groups. The preeclampsia group comprised 51 women. Preeclampsia was defined according to the guidelines of the International Society for the Study of Hypertension in Pregnancy. This definition requires two recordings of diastolic BP of 90 mm Hg or more at least 4 hours apart in a previously normotensive woman; and proteinuria of 300 mg or more in 24 hours, or two readings of at least on dipstick analysis of a midstream or catheter specimen of urine (if no 24hour urine collection was available).30 Severe preeclampsia was defined as severe hypertension (diastolic BP of 110 mm Hg or more) and mild proteinuria, or mild hypertension and severe proteinuria (24-hour urinary protein 3.5g or more or a urine specimen 3 protein or more by dipstick measurement). If proteinuria was present, urinary tract infection was excluded by urine culture. Patients with abnormal liver function (aspartate aminotransferase more than 70 international units/L) and thrombocytopenia (platelet

count less than 100,000/cm3) were also classified as having severe preeclampsia. The gestational hypertension group comprised 29 women. The definition of gestational hypertension was a diastolic BP of 90 mm Hg or more on at least two consecutive occasions in the second half of pregnancy without proteinuria, in a previously normotensive woman.3 Women with gestational hypertension were followed up until 2 weeks after pregnancy to ensure they did not develop preeclampsia. Fetal growth restriction was defined as birth weight less than the 5th centile for gestational age. The normotensive group comprised 80 pregnant women attending the antenatal clinic, who were matched on a one-to-one basis for maternal age, gestational age, and parity with the hypertensive group and had uncomplicated pregnancies. None of these women had a history of cardiovascular disease, chronic hypertension, hypertensive disorder of pregnancy, or fetal growth restriction. None used medication that might affect BP. Pulse wave analysis was measured in the hypertensive group before and after (24 48 hours) antihypertensive therapy was commenced. The antihypertensive therapy used was oral alpha methyldopa, with a loading dose of 1 g, followed by a maintenance dose of 750 1,500 mg/d, continued until after delivery in accordance with local clinical protocols. Women in the normotensive group had a single pulse wave analysis measurement only, on the basis that no significant change would be expected in the course of 48 hours.23 All BP measurements were performed in the same room at room temperature, after a period of rest of at least 10 minutes. The women were asked to refrain from caffeine intake on the day of the study. During measurements, participants were asked not to move or speak. Brachial artery BP was measured in the nondominant upper arm using a calibrated standard mercury sphygmomanometer. Brachial artery systolic BP was defined by the first Korotkoff sound and diastolic BP by the fifth Korotkoff sound.31 For each woman, the average of two readings was used. Pulse pressure was defined as systolic BP minus diastolic BP. The radial artery waveform was recorded using applanation tonometry, and the Sphygmocor system (Atcor Medical, West Ryde, Australia) was used to analyze the radial artery wave contour.32,33 Augmentation index, augmentation pressure (measures of arterial stiffness), mean arterial BP (MAP), central systolic and diastolic BP, and pulse pressure were determined with the integrated software. All hypertensive women had measurements

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taken at the time of recruitment, shortly before antihypertensive treatment was commenced, and 24 48 hours after starting antihypertensive treatment. All measurements were made in duplicate, and mean values were used in the subsequent analysis. The tip of the tonometer was pressed gently against the radial artery at the site of maximum pulsation at the wrist. This micromanometer precisely records pressure within the artery (Millar Instruments, Houston, TX).10 A generalized transfer function (described elsewhere)34 36 was applied to the radial artery waveform to derive the aortic waveform. The augmentation pressure is defined as the height of the late systolic peak above the inflection point (Fig. 1A). Augmentation index is expressed as a percentage of the aortic pulse pressure. Augmentation index is a measure of the stiffness of the arterial walls. Because there is a linear relationship between augmentation index and heart rate, augmentation index was standardized to a heart rate of 75 bpm (augmentation index-75).37 All measurements were performed by the same observer (A.K.). After an initial learning

period (duplicate measurements in approximately 20 women), satisfactory reproducibility was achieved (less than 5% variability between duplicate measurements in the same woman). Additionally, the Sphygmocor software incorporates a quality control feature that is displayed on the screen and was respected for each measurement. We calculated that we would need 27 women in each hypertensive group to have 90% power to detect a difference of 2.5 percentage points in augmentation index-75 at the 5% level. DAgostino-Pearson Omnibus test38 was used to assess normality of continuous data. For those parameters that were not normally distributed, logarithmic transformation was performed. The logged values were checked using a histogram and Q-Q plot. Baseline characteristics, eg, age, body mass index, parity, and ethnicity were compared using 2 test (Fisher exact test when appropriate) for categorical variables and independent t test for continuous variables. Although cases were matched to controls for maternal age, gestational age, and parity, when comparing any two of the three groups (preeclampsia, gestational hypertension, and controls), we chose to use unpaired t test because of concerns that other differences between the groups in BMI, smoking status, and ethnicity (which were not matched) could potentially bias the results. For comparison of all three groups, one-way analysis of variance (ANOVA) with Dunnetts post-hoc test was used. Data were analyzed in two gestational age intervals: less than 34 weeks, representing early-onset disease, and 34 weeks or more, representing lateonset disease. Measurements before and after starting antihypertensive therapy were compared using paired t test. Data were analyzed using SPSS 14.0, 2005 (SPSS Inc., Chicago, IL). GraphPad Prism 5.0 for Windows (InStata, GraphPad Software Inc., San Diego, CA) was used to test the normality of data. Results were considered statistically significant at P.05.

RESULTS
Fig. 1. A.Typical ascending aortic pulse waveform, showing two systolic peaks (P1 and P2). Augmentation index is calculated as the difference between P2 and P1 (P), expressed as percentage of pulse pressure. The designation P1 is the first inflection point; P2 is the second inflection point. B. In hypertensive disorders, arterial wall stiffness is increased; the arterial pulse wave travels faster, so the reflected wave reaches the advancing wave in systole, resulting in greater augmentation of the systolic peak. Time tr is the time to reach the reflected wave.
Khalil. Antihypertensives and Pulse Wave Analysis. Obstet Gynecol 2009.

Of the 32 women recruited with gestational hypertension (16 at less than 34 weeks and 16 at 34 or more weeks of gestation), three subsequently developed preeclampsia (three in the gestational hypertension group recruited less than 34 weeks and none in the gestational hypertension group recruited 34 or more weeks of gestation) and were excluded. The baseline characteristics of the study groups and the time interval between the two measurements in the hypertensive women are shown in Table 1. There were no significant differences in baseline characteristics, but

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Table 1. Baseline Characteristics of the Study Groups According to Gestational Age

Less Than 340 wk Characteristic
n Age (y) BMI Nulliparity Current smoker Caucasian GA at recruitment (wk) GA at delivery (wk) Birth weight (g) Interval between samples (h)

340 wk or More P
.6 .07 .6 1 .7 .5 .001 .001

Controls
41 314 274 25 (61) 1 (2) 20 (48) 301.3 39.72.3 3,398529

PE
28 305 304 20 (71) 0 (0) 13 (46) 300.4 331.7 1,685204 32 (4)

GH
13 324 274 7 (54) 0 (0) 7 (54) 30.40.8 36.72.9 2,725198 34 (3)

Controls
39 314 283 21 (53) 2 (5) 23 (59) 36.62.4 39.81.6 3,405526

PE
23 304 27) 16 (70) 1 (4) 13 (57) 362.3 37.32 2,896689 38 (6)

GH
16 325 295 9 (56) 0 (0) 9 (56) 36.42 38.62.3 3,174591 39 (7)

P
.2 .2 .3 1 .4 .4 .001 .001

PE, preeclampsia; GH, gestational hypertension; BMI, body mass index; GA, gestational age. Data are n (%) or meanstandard deviation and analyzed by one-way analysis of variance with Bonferroni post hoc analysis.

as expected, birth weight and gestation at delivery were lower in women with hypertensive disorders compared with controls. None of the women with gestational hypertension had associated fetal growth restriction. Among the 51 women with preeclampsia, 16 (31%) had associated fetal growth restriction: 13 early onset and three late onset. Before treatment, both mean augmentation index-75 and mean augmentation pressure were significantly higher in women with preeclampsia who also had fetal growth restriction compared with those with preeclampsia without fetal growth restriction (38.1 compared with 27.3, P.001; and 19 compared with 10.6, P.001, respectively). Eight (16%) of the 51 women with preeclampsia had severe preeclampsia. All the severe preeclampsia cases were in the early-onset group. The hemodynamic characteristics for each study group before treatment are presented and compared in Table 2. Mean arterial pressure and brachial and central systolic, diastolic, and pulse pressures were all significantly (P.05) higher in both preeclampsia and

gestational hypertension compared with the control group. There were no significant differences in brachial systolic, diastolic, pulse, or mean arterial pressure between the two hypertensive groups. Within each group (controls, preeclampsia, gestational hypertension) before treatment, there were no significant differences in augmentation pressure or augmentation index (augmentation index-75) between primigravid and multigravid women. Both augmentation pressure and augmentation index-75 were significantly higher in early-onset compared with late-onset preeclampsia (P.001) and in severe compared with mild preeclampsia (P.001) (Figure 2). Hemodynamic measures before and after antihypertensive treatment are compared in Table 3. Peripheral and central pressures were all significantly (P.05) lower after treatment with alpha methyldopa. Figure 3 shows augmentation pressure and augmentation index-75 before and after antihypertensive therapy, stratified according to early-onset (less than

Table 2. Heart Rate and Brachial and Central Hemodynamic Measurements Before Antihypertensive Therapy
Hemodynamic Variable
n Heart rate Brachial systolic pressure Brachial diastolic pressure Brachial pulse pressure Mean arterial pressure Central systolic pressure Central diastolic pressure Central pulse pressure

Controls
80 82.09.4 108.111.6 67.38.0 40.88.7 80.68.8 94.410.0 68.58.2 25.95.6

PE
51 81.08.6 156.110.6* 101.67* 54.411.6* 116.39.4* 143.611.5* 103.46.8* 40.211.3*

GH
29 82.79.0 151.917.8* 99.37.7* 52.712.6* 118.618.9* 13815.9* 1018* 3710.9*

P
.4 .2 .2 .5 .5 .07 .2 .2

PE, preeclampsia; GH, gestational hypertension. Data are meanstandard deviation unless otherwise specified. Heart rate scores are in beats per minute; blood pressure scores are in mm Hg. The measurements in preeclampsia and gestational hypertension are compared using the unpaired t test (P value in the last column). * P.05 for either preeclampsia or gestational hypertension compared with the control group.

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Fig. 2. Augmentation pressure (A) and augmentation index at heart rate 75/min (augmentation index75) (B) measurements in women with early onset (n28) and late onset preeclampsia (n23) and in women with mild (n43) and severe preeclampsia (n8). Error bars represent standard error of the mean. The early-onset preeclampsia group was compared with the late onset preeclampsia group, and the mild preeclampsia group was compared with the severe preeclampsia group using unpaired t tests.
Khalil. Antihypertensives and Pulse Wave Analysis. Obstet Gynecol 2009.

34 weeks) or late-onset (34 weeks or more) hypertension. Before treatment, both augmentation pressure and augmentation index-75 were significantly higher in preeclampsia compared with normotensive controls (P.001 for both). Similarly, both augmentation pressure and augmentation index-75 were significantly higher in gestational hypertension compared with normotensive controls (P.05 and P.001). However, augmentation pressure and augmentation index-75 were significantly higher in preeclampsia compared with gestational hypertension (P.001 and P.001, respectively), suggesting that preeclampsia is

associated with a greater reduction in vascular compliance than gestational hypertension. In preeclampsia, in both gestational age intervals, both augmentation pressure and augmentation index-75 were significantly (P.001) lower after treatment. In gestational hypertension, however, there was no significant change after treatment in either augmentation pressure (less than 34 weeks, P.2; 34 weeks or more, P.7) or augmentation index-75 (less than 34 weeks, P.7; 34 weeks or more, P.07). When we compared pulse wave analysis indices between women with preeclampsia after antihypertensive therapy and the

Table 3. Brachial and Central Hemodynamic Measurements Before and After Alpha Methyldopa Therapy
Hemodynamic Variable
Brachial systolic pressure Brachial diastolic pressure Brachial pulse pressure Mean pressure Central systolic pressure Central diastolic pressure Central pulse pressure

PE Before
156.110.6 101.67.0 54.411.6 116.39.4 143.611.5 103.46.8 40.211.3

PE After
129.415.2 84.87.1 44.610.6 105.013.9 116.913.7 86.37.4 30.68.7

Mean Difference
26.720.6 16.910.7 9.916.5 11.315 26.719.7 17.110.7 9.614.4

P
.001 .001 .001 .06 .001 .001 .001

GH Before
151.917.8 99.37.7 52.712.6 118.618.9 138.015.9 101.08.0 37.010.9

GH After
138.219.6 87.08.1 51.215.2 110.012.5 124.118.6 88.88.3 35.313.4

Mean Difference
13.724.9 12.312.2 1.518.2 8.625.3 13.921.9 12.212.5 1.714.7

P
.023 .001 .72 .14 .01 .001 .6

PE, preeclampsia; GH, gestational hypertension. Data are meanstandard deviation. Measurements before and after alpha methyldopa therapy were compared using paired t test.

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Fig. 3. Augmentation pressure (A and B) and augmentation index at heart rate 75 beats per minute (augmentation index-75) (C and D) measurements in normotensives (controls), women with preeclampsia, and women with gestational hypertension according to gestational age interval. Early onset is less than 34 weeks of gestation (A and C; 41 controls, 28 women with preeclampsia, 13 women with gestational hypertension), and late onset is at or beyond 34 weeks (B and D; 39 controls, 23 women with preeclampsia, 16 women with gestational hypertension). Error bars represent standard error of the mean. Measurements before and after alpha methyldopa therapy are shown for women with preeclampsia and women with gestational hypertension. The measurements in the three groups were compared using analysis of variance with Bonferroni Dunns post-hoc tests. The levels before and after antihypertensive therapy are compared using the paired t test. The P value for comparisons between the following groups was less than .001: Preeclampsia before methyldopa therapy and controls (AD); preeclampsia before therapy and gestational hypertension before therapy (AD); preeclampsia before therapy and preeclampsia after therapy (A); preeclampsia after therapy and controls (AD) preeclampsia before therapy and preeclampsia after therapy (C); hypertension before therapy and controls (C and D); gestational hypertension after therapy and controls (C). P values are shown only for differences that are statistically significant. *P.05; **P.01; ***P.001.
Khalil. Antihypertensives and Pulse Wave Analysis. Obstet Gynecol 2009.

normotensive controls, a significant difference persisted for both augmentation pressure and augmentation index-75 (P.001 for both). In women with both preeclampsia and fetal growth restriction (n16), treatment with antihypertensive medication was associated with a significant fall in both augmentation index-75 (38.1 compared with 26.6, P.001) and augmentation pressure (19 compared with 9.7, P.001).

DISCUSSION
Using pulse wave analysis, we have confirmed that vascular compliance is decreased in women with hypertensive disorders of pregnancy, but in preeclampsia is improved by treatment with alpha methyldopa. Each heartbeat generates a pulse wave that travels away from the heart. This waveform is reflected from bifurcations within the arterial tree and from the junctions of the preresistance and resistance vessels.13,17,18 The reflected wave travels back toward the

heart and meets the advancing wave, augmenting its height (Fig. 1A). Generally, the reflected wave reaches the aorta during diastole, boosting the height of the diastolic portion of the wave. When arterial wall stiffness is increased (as in hypertensive disorders of pregnancy) the arterial pulse wave travels faster, so the reflected wave reaches the advancing wave in systole, resulting in significant augmentation of the systolic peak (Fig. 1B). This can be measured as raised augmentation pressure and augmentation index. Previous studies have demonstrated that, in normal pregnancy, aortic compliance increases in response to increased levels of estrogen, mediated by increased circulating nitric oxide levels: resistance remains low until delivery.39 However, vascular compliance remains poor in women with hypertensive disorders. In a small observational study of 16 women with hypertensive disorders in pregnancy,26 no difference in arterial stiffness was found between those receiving antihypertensive treatment and those who

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did not. However, hemodynamic measures were compared between women who received treatment and those who did not; there are no data comparing before and after treatment. It is estimated that 1525% of women who present with gestational hypertension progress to preeclampsia.40 We found that arterial stiffness is increased in gestational hypertension compared with normotensive pregnant women, but increased significantly more in women with preeclampsia. These findings support the concept that gestational hypertension may represent a mild form of preeclampsia. However, it is more likely that women who have poor vascular adaptability are prone to hypertension and that the strain of pregnancy reveals this underlying weakness; increased endothelial dysfunction in preeclampsia exacerbates this problem. The differences in vascular compliance may also be partly explained by changes in maternal blood volume; in preeclampsia, plasma volume is contracted, whereas in gestational hypertension it may be unchanged or increased. The fact that augmentation pressure and augmentation index-75 are higher in early-onset compared with late-onset, and severe compared with mild, preeclampsia is consistent with the view that early and severe preeclampsia are part of the spectrum of the disease, and not a different pathophysiologic entity. In preeclampsia, the improvement in arterial stiffness with methyldopa is probably due in part to normalization of BP (BP increases arterial stiffness).41,42 Even after antihypertensive therapy, however, arterial stiffness remained higher when compared with normotensive pregnant women. This finding suggests that other factors are involved, such as poor vessel wall compliance and endothelial dysfunction. Alpha methyldopa acts on 2-adrenergic receptors, primarily in the central nervous system, leading to reduced central sympathetic outflow and a reduction in BP.4351 We have recently shown that antihypertensive therapy with alpha methyldopa in women with preeclampsia but not in gestational hypertension is associated with significantly reduced placental and serum levels of the antiangiogenic factors soluble FMS-like tyrosine kinase-1 and soluble endoglin.52 The beneficial effect of this drug on arterial stiffness may be due to a direct effect on the arterial wall or may be mediated through reduced circulating antiangiogenic factors. These findings support the concept of a fundamental difference in pathophysiology between gestational hypertension and the pathologic endothelial toxic effect of preeclampsia.

Pulse wave analysis has previously been used to assess vasoactive medications, particularly antihypertensive drugs, in the nonpregnant population. For example, a randomized controlled study comparing atenolol and ramipril found that both cause a similar reduction in peripheral BP.53 However, the fall in central systolic pressure is significantly greater with ramipril. Pulse wave analysis showed that this difference is due to the greater reduction in arterial stiffness caused by ramipril, and probably explains its greater long-term benefits. Studies such as these have led to a significant change in guidelines for managing hypertension in the nonpregnant population.33 Our findings suggest that pulse wave analysis may also have an important role to play in the assessment of new and existing antihypertensive medications used in pregnancy, so that centralas well as peripheral effects can be determined.18,54,55 Pulse wave analysis is simple, noninvasive, easy to learn, and inexpensive. It therefore offers a realistic option for assessing all women with preeclampsia and gestational hypertension. Ideally, we would have included in our study a group of women with a similar degree of preeclampsia who did not receive antihypertensive therapy and another group of normotensive women who did. However, because of ethical concerns about the potential effects of such management, this was not possible. In this study, our objective was to investigate whether antihypertensive treatment has any effect on arterial stiffness in women with hypertensive disorders in pregnancy, so pulse wave analysis examinations were repeated only after a short time interval (48 hours). It would be interesting to investigate the effect of antihypertensive therapy at longer intervals; this will form the basis of our future work. Further research is needed to evaluate the effect of prolonged antihypertensive therapy, and whether different antihypertensive drugs have differential beneficial effects on maternal central hemodynamics. Women who develop preeclampsia are at significantly increased risk later in life of cardiovascular disease, such as ischemic heart disease and stroke. In this context, it would be interesting to investigate whether arterial stiffness as measured by pulse wave analysis returns to normal after delivery in these women and if so, how long this takes. REFERENCES
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