Preeclampsia, a syndrome of pregnancy characterized by new-onset hypertension and proteinuria, affects about 5–8% of all first pregnancies.1 Preeclampsia accounts for considerable maternal and associated fetal morbidity and mortality. Recent epidemiological data have shown an association between preeclampsia and cardiovascular and renal disease in later life.2–4 Within 10 to 20 years after complicated pregnancy, these women have a threefold to fourfold higher risk of developing chronic hypertension and a twofold higher risk of stroke, venous thromboembolism, and ischemic heart disease compared with healthy parous controls.2 Later kidney disease, diagnosed by biopsy or the presence of end-stage renal disease, is more prevalent among formerly preeclamptic women compared with controls.5,6 Additionally, life expectancy is reduced by 3 to 9 years, with excess mortality mainly as a consequence of cardiovascular disease.7
The etiology of preeclampsia is only partly resolved. Impaired early-pregnancy placentation and endothelial dysfunction seem to play a central role. A large body of evidence favors the hypothesis of pregnancy-related hypertensive disease being superimposed on a preexisting disorder.8–10 Underlying pathophysiological phenotypes may be hypertensive (latent or present), metabolic, autoimmunologic, thrombophilic, or any combination of these.10 These disorders share the capacity to jeopardize both endothelial and placental function. It has been proposed that preeclampsia relates to later cardiovascular disease because of shared risk factors.11,12 However, the exact mechanism underlying the increased cardiovascular disease risk in preeclamptic women has not been unraveled yet. It is well known that aging negatively influences the vascular system. Aging increases vascular stiffness and affects renal function; however, women seem to be protected in the premenopausal phase.13–16 Hemodynamic and renal functions have not been studied previously in middle-aged, formerly preeclamptic women. In this study, we tested the hypothesis that preeclampsia predisposes to remote central hemodynamic and renal impairments.
MATERIALS AND METHODS
We performed this cross-sectional study in 22 formerly preeclamptic women and 29 parous controls in the period of 2001 until 2008. Participants were all white and matched for age, body mass index (BMI), and date of birth. Figure 1 illustrates the selection procedure. We retrieved clinical information for all women who delivered after a preeclamptic pregnancy in the period between 1979 and 1987 at the Department of Obstetrics of the Academic Hospital of Maastricht in the Netherlands. Preeclampsia was defined according to the criteria of the Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.1 An uncomplicated pregnancy was defined as a term singleton pregnancy without complications such as fetal growth restriction, pregnancy-induced hypertension, or gestational diabetes. For every primiparous preeclamptic woman, we selected chronologically from the birth register the next two matching primiparous women with uncomplicated pregnancies and deliveries. From the women identified, four women had died in the period elapsed since their pregnancies—three from cancer, and one formerly preeclamptic woman had had a fatal cardiac event. Eight formerly preeclamptic women were excluded for medical reasons, namely non–insulin-dependent diabetes mellitus (n=2), cancer therapy (n=3), chronic corticosteroid use (n=1), and chronic renal failure (n=2) due to nephrosclerosis and chronic pyelonephritis. Eventually, 44 formerly preeclamptic women and 72 parous controls were invited to participate in this study. From these women, 22 formerly preeclamptic women (50%) and 29 controls (40%) gave informed consent to participate. Main reasons for refusal were lack of time (45%), psychological burden (25%), and invasiveness of measurements (10%). The study protocol was approved by the hospital medical ethical committee board.
Hypertension was defined as blood pressure above 140/90 mm Hg during the measurement session, using antihypertensive drugs, or both. Women were considered postmenopausal if they had had 1 year without menstrual bleeding. Early-onset preeclampsia was defined as preeclampsia resulting in birth before a gestational age of 34 weeks.
All experiments were preceded by 1 week of standardized sodium intake (100 mmol sodium/d), representing the mean sodium intake in our population. Antihypertensive drugs were discontinued 2 weeks before the measurements. Participants did not drink caffeine- or alcohol-containing beverages and refrained from smoking and eating for at least 10 hours before the experiment. Measurements were performed in standardized conditions in a temperature-controlled room (25–26°C), with as little external disturbance as possible, in the mid-follicular phase (day 5±2) of the menstrual period or randomly when postmenopausal. The measurement session started at 8:00 am with the insertion of a 20-gauge catheter into a vein of the right forearm to enable estimation of renal function as detailed below. A second catheter was inserted into a vein of the contralateral forearm to collect blood samples. Throughout the measurement session, patients were lying on their backs on a comfortable bed. After an acclimatization period of 30 minutes, we recorded arterial blood pressure and heart rate in supine position at 3-minute intervals using a semi-automatic oscillometric device (Dinamap Vital Signs Monitor 1846, Critikon, Tampa, FL).
Effective renal plasma flow was measured by continuous infusion of para-aminohippurate sodium (MSD, West Point, PA). We used creatinine clearance as an estimate for glomerular filtration rate because inulin was not available owing to manufacturing problems. Both variables were corrected for body surface area and expressed in mL/min/1.73 m2. Effective renal blood flow was obtained by dividing the effective renal plasma flow by (1-hematocrit). Renal vascular resistance (dyne · s/cm5/1.73 m2) was obtained by dividing mean arterial pressure by effective renal blood flow. At least 2 hours after the initiation of the para-aminohippurate sodium infusion, we collected blood samples for the later measurement of the circulating levels of para-aminohippurate sodium and creatinine. Creatinine (micromol/L) was measured by standard chemical techniques. An extra blood sample was obtained to measure hematocrit (volume %). Creatinine clearance was calculated from the 24-hour creatinine output during the day before measurement. In this collection, we also measured albumin excretion. Microalbuminuria was defined as a urinary albumin excretion rate higher than 3.5 g/mol creatinine (BN ProSpec nephelometer; Siemens Healthcare Diagnostics, Deerfield, IL).
Echocardiography to assess cardiac function was performed in semi-left lateral position after 5 minutes of rest, using a cross-sectional, phased-array echocardiographic Doppler system.17 Cardiac output (CO, L/min) was calculated by multiplying stroke volume (mL) by heart rate. In this formula, heart rate was obtained by taking the reciprocal of the mean of five consecutive R-R intervals on the electrocardiogram. Stroke volume was calculated by multiplying the aortic velocity integral and the aortic area. Aortic flow was measured across the aortic valves from an apical approach. The average area under the aortic velocity curve (aortic velocity integral) of five consecutive ejections was used to calculate stroke volume. Aortic valve diameter, necessary for the calculation of the aortic area, was measured off-line at the orifice during systole using M-mode. Cardiac index (L/min/m2) was used to correct for body surface area. Total peripheral vascular resistance was calculated by 80 times mean arterial pressure divided by CO. The value used for mean arterial pressure was obtained by blood pressure measurement during the CO measurement and was calculated as the mean of three consecutive recordings. An estimate for arterial compliance (mL/mm Hg) was obtained by dividing pulse pressure (mm Hg) by stroke volume.
Data distribution was evaluated using histograms and quantile–quantile plots. Homogeneity of variance was tested by Levene's test. Differences between groups were tested by Student t-test or Mann-Whitney U-test. Binary outcomes were tested by χ2 test. Using both multiple logistic and linear regression analysis, we adjusted for postmenopausal state. We further analyzed our data after stratification for hypertension by one-way analysis of variance followed by Dunnet's test or the Kruskal-Wallis test followed by Dunn's test. P<.05 was considered statistically significant. Data are presented as mean with standard deviation or median with interquartile range.
Table 1 lists the characteristics of our study population. Both groups were comparable with respect to age, BMI at measurement, and follow-up time. Mean age was 49.8 (range 42.2–59.0) years for women in the control group and 49.0 (range 42.7–58.1) years for formerly preeclamptic women. Eight formerly preeclamptic women (36%) and five women in the control group (17%) were postmenopausal. None of the women used hormone replacement therapy. Twelve formerly preeclamptic women (55%) and two women in the control group (7%) had hypertension at the time of measurement (relative risk 7.9, 95% confidence interval 2.0–31.8), with nine formerly preeclamptic women using antihypertensive medication at the time of recruitment. We diagnosed hypertension at the time of the measurement session in two women in the control group. Two formerly preeclamptic women and one woman in the control group had a history of stroke. Three formerly preeclamptic women and one woman in the control group had a history of thrombosis. Nine formerly preeclamptic women (41%) had a history of early-onset preeclampsia, and five (23%) had recurrent preeclampsia in their subsequent pregnancy. None of the women in the control group had hypertensive complications during subsequent pregnancies.
Table 2 lists the cardiovascular and renal variables comparing both study groups. Similar results were found after adjustment for postmenopausal state (not presented). Formerly preeclamptic women had higher systolic, diastolic, and mean arterial blood pressure compared with women in the control group. Cardiac function did not differ between the study groups. Formerly preeclamptic women differed from women in the control group by a 20% higher total peripheral vascular resistance and a lower arterial compliance. Renal vascular resistance was more than 30% higher and effective renal plasma flow about 15% lower in formerly preeclamptic women compared with women in the control group. Creatinine clearance was lowered in formerly preeclamptic women relative to women in the control group. The incidence of microalbuminuria was similar in both groups.
Table 3 illustrates the comparison of hemodynamic and renal variables between formerly preeclamptic women, with or without hypertension, and women in the control group. Blood pressure variables and creatinine clearance in normotensive formerly preeclamptic women were intermediate between the values observed in hypertensive formerly preeclamptic women and women in the control group. Like hypertensive formerly preeclamptic women, the normotensive formerly preeclamptic women also differed from women in the control group by higher total peripheral and renal vascular resistance and a lower arterial compliance. Left ventricular mass-index tended to be higher only in hypertensive formerly preeclamptic women.
In this study, we observed differences in central hemodynamics and renal function between formerly preeclamptic women and parous controls 23 years after pregnancy. The hemodynamic pattern we observed in formerly preeclamptic women (high blood pressure, increased peripheral vascular resistance, and a normal CO) is consistent with the changes observed in so-called volume-dependent essential hypertension.18,19 The kidneys play a central role in this theory because they adjust the setpoint for blood pressure by their effect on sodium homeostasis. The exact pathophysiology of essential hypertension is complex and only partly unraveled. The development of hypertension is the ultimate outcome of activated pathways involving systemic and renal vasoconstriction. These include hyperactivity of the sympathetic nervous system, hyperactivity of the renin-angiotensin system, and endothelial dysfunction.20 Our data suggest that renal vasoconstriction plays a central role in the pathogenesis of hypertension in formerly preeclamptic women. This concept is supported by the raised renal vascular resistance and reduced creatinine clearance in the formerly preeclamptic women compared with the women in the control group, a difference already detected in normotensive formerly preeclamptic women. The renal impairment observed could be due to lower nephron number and glomerulosclerosis.21,22 We observed a low incidence of microalbuminuria in both groups; however, other studies report an increased incidence of microalbuminuria several years after preeclamptic pregnancy.23,24
The intermediate position of the group of the normotensive formerly preeclamptic women between, on the one hand, hypertensive formerly preeclamptic women and, on the other hand, the women in the control group, can be interpreted as prehypertension. The latter is characterized by loss of arterial compliance accompanied by raised systemic and renal vascular resistance and precedes manifest hypertension in high-risk groups such as adolescents of hypertensive parents.25–27 Our data suggest that impaired hemodynamic function precedes the onset of chronic hypertension in formerly preeclamptic women. However, these data do not exclude the possibility that these impairments reflect an end-stage in the subgroup of normotensive formerly preeclamptic women.
Whether or not the observed changes were present before the preeclamptic pregnancy is obscure. There is increasing evidence for the concept that these women may have an altered vascular function already in their first years of life. During growth and development, genetic factors act in concert with environmental factors to determine the final functional capacity of the vascular system.28,29 Low-birth weight, preeclampsia, and essential hypertension seem to share a reduced vascular functional reserve capacity; for example, density of the capillary bed seems to be reduced in those conditions.30–32 In this view, preeclamptic women can be considered to represent a subgroup of women predestined to develop hypertension irrespective of pregnancy.
This study has certain limitations. Firstly, the recruitment of the women for the control group may have been hampered by some selection bias because women with certain health problems may have been more eager to participate in this study than their counterparts without any health problems. As the latter could have an attenuating effect on potential differences with formerly preeclamptic women, this effect may have only reduced the already marked differences observed in this study. Secondly, more than 20 years elapsed since either the preeclamptic or uneventful pregnancies. Since then, health in both groups has been influenced by a wide range of demographic and lifestyle factors, which could have had an unknown effect on the variables measured. By matching the controls for age and BMI, we intended to minimize the effect of obesity and its associated metabolic abnormalities, such as insulin resistance and dyslipidemia. A strategy to deal with most shortcomings would be to follow women longitudinally with respect to age-related hemodynamic changes. Preeclampsia may identify a subgroup of women at risk of accelerated aging, enabling exploration of the mechanism of accelerated cardiovascular aging.
In summary, in this cross-sectional study, we found evidence for impaired hemodynamic and renal function in both normotensive and hypertensive middle-aged, formerly preeclamptic women. These data support the view that formerly preeclamptic women would benefit from surveillance of blood pressure.
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