Heart disease continues to be the leading cause of death in women, both in the United States and throughout the rest of the world.1 A history of preeclampsia appears to be associated with an increased risk of cardiovascular diseases in later life.2–7 Moreover, it was found that preeclampsia was an independent risk factor for subsequent coronary artery disease.4 Irgens et al8 published a study of 626,272 live births in Norway between 1967 and 1992. The increased risk of death from cardiovascular causes among women with preeclampsia and a preterm delivery was 8.12-fold higher than in the reference group (women who died from cardiovascular causes and who had term deliveries without preeclampsia).
Preeclampsia and cardiovascular disease share several risk factors, including preexistent hypertension, thrombophilia (factor II or factor V Leiden mutations), dyslipidemia, obesity, insulin resistance, diabetes mellitus, inflammation, and family history of heart disease or stroke.9–12 These findings tend to support the theory that a preexisting tendency to cardiovascular disease increases a women’s susceptibility to develop hypertension in pregnancy. Furthermore, the exaggerated metabolic changes in preeclampsia, such as dyslipidemia13 and increased insulin resistance,14 are well known to be atherogenic and may therefore accelerate the progression of atherosclerosis in this group of women, and/or preeclampsia itself may result in a susceptibility to cardiovascular disease in later life.
Intima-media thickness (IMT) of the carotid and femoral arteries measured by high resolution B-mode ultrasonography is a generally accepted marker of preclinical atherosclerosis.15 An increased IMT is an independent cardiovascular risk predictor, but is also associated with risk factors for existing cardiovascular disease.15–17 The aim of our study was to investigate whether women who recently had a pregnancy complicated by early-onset preeclampsia have an increased IMT of the carotid and femoral arteries compared with women with normal pregnancies and to nulliparous nonpregnant women.
MATERIALS AND METHODS
Between January 2003 and August 2004, 22 primiparous women who had previously been hospitalized in the University Medical Center Groningen for early-onset preeclampsia (diagnosis before 34 weeks of gestation) were recruited for our study. During the same period, we recruited two control groups: a group of 22 primiparous women who recently experienced a normal pregnancy, and a group of 22 nulliparous nonpregnant women. The control groups were frequency-matched to the preeclampsia group with respect to age, body mass index and smoking habits.
Recruitment of controls took place by inviting women with uneventfully carried pregnancies and who delivered with no complications in our hospital, and by placing advertisements in newspapers. All controls delivered between January 2003 and April 2004. Fifteen controls did not deliver at our hospital but at home or at other hospitals. From these 15 women, the relevant data regarding the course of pregnancy (eg, pregnancy outcome) were available. The study was designed to detect a difference of 25% in IMT of the common carotid artery between the preeclampsia group and the normal-pregnancy control group with power of 85% at significance level of 5%. For this and regarding a drop out, we planned to study 50 women in each group. Preeclampsia was defined according to the criteria of the International Society for the Study of Hypertension in Pregnancy18: the appearance of a diastolic blood pressure 90 mm Hg or higher measured at 2 occasions at least 4 hours apart in combination with proteinuria (≥ 300 mg/24 hours or 2+ dipstick) developing after a gestational age of 20 weeks in a previously normotensive woman. Hemolysis, Elevated liver enzymes and low platelet count (HELLP syndrome) was defined as serum lactate dehydrogenase more than 600 Units/L, serum aspartate aminotransferase and serum alanine aminotransferase more than 50 Units/L, and a platelet count less than 100 × 109/L. Severe preeclampsia was defined as previously described.19 Women with preexisting hypertension (blood pressure before 20 weeks of gestation ≥ 140/90 mm Hg or using antihypertensive medication), diabetes mellitus, renal disease, multiple pregnancy, or postpartum thyroiditis were excluded. The interval between delivery and investigation was similar for both patients and control subjects, between 3 and 13 months postpartum and at least 6 weeks after ending lactation. The study was approved by the medical ethics committee of the University Medical Center Groningen, and all women gave written informed consent.
We obtained information on personal and family history (first and second degree) relating to premature cardiovascular disease (in men < 55 years, in women < 65 years) and on smoking status by means of a questionnaire. Smoking was defined as having smoked in the past 5 years or current smoking of at least 1 cigarette per day.20
Postpartum blood pressures were measured in the office three times in the nondominant arm with an automated oscillometric blood pressure monitor. Additionally, using an ambulatory blood pressure monitor (Spacelabs 90207, Redmond, WA) in the preeclampsia group, postpartum hypertension was defined to be present when the mean 24-hour blood pressure was equal to or above 125/80 mm Hg.21
Blood samples were taken after an overnight fast to measure blood glucose and serum lipid levels (total cholesterol, high-density lipoprotein cholesterol, and triglycerides) using standard laboratory methods. Low-density lipoprotein cholesterol was calculated by the Friedewald formula. Prothrombin 20210 G-A mutation and factor V Leiden mutation were demonstrated by routine polymerase chain reactions. Levels of lipoprotein (a) were determined by nephelometry (BN ProSpec; Dade Behring Holding GmbH, Liederbach, Germany). Plasma homocysteine was analyzed by a fluorescence polarization immunoassay (IMx; Abbott Laboratories, Abbott Park, IL). Urinary albumin-creatinin ratio was measured by radioimmunoassay (Diagnostic Products Corporation, Los Angeles, CA). Microalbuminuria was defined as an albumin-creatinin ratio higher than 3.4 g/mol in at least 2 of 3 specimens.22
Noninvasive vascular parameters were obtained in a standardized fashion using high resolution B-mode ultrasonography (Acuson 128XP10; Acuson Corporation, Mountainview, CA) as reported previously.23 In short, with the subject in supine position, the common carotid, the internal carotid, the carotid bulb, the common femoral and the superficial femoral arterial far wall segments were scanned bilaterally from a lateral transducer position and recorded on s-VHS tape. The arterial segments were defined as following: the common carotid arterial wall segment as 1 cm proximal to the carotid dilatation, the carotid bulb as the segment between the carotid dilation and the carotid flow divider, the internal carotid segment as a 1-cm long arterial segment distal to the flow divider, the common femoral arterial segment as a 1-cm arterial segment proximal to the femoral dilatation, and the superficial femoral artery as a 1-cm arterial segment distal to the flow divider. Off-line video analysis was performed by one reader unaware of the clinical characteristics. Intima-media thickness was defined as the mean distance between the intima and media double-line pattern, as average of left- and right-sided values and expressed in millimeters. An atherosclerotic plaque was defined by an IMT more than 1.2 mm.24,25
From previous studies performed in our vascular laboratory, intersonographer variability amounted to be 0.05 mm at a mean IMT of 0.80 mm, corresponding to 6.3%.26
To compare the three groups with respect to the five vascular variables, we used linear regression analysis methods. For an overall comparison, either corrected or uncorrected for possible confounders, we fitted a multivariable multiple regression model and used the Wilks’ λ test. This analysis was accompanied by univariate (in terms of the outcome variable) multiple regression analyses, carried out separately for each of the five vascular outcome variables. The advantage of the multivariable analysis is that it accounts for multiple testing. The results of univariate analyses help to clarify the role of individual variables, and we present them without any correction for multiple testing. We interpreted multivariable analysis P values of 5% or less as statistically significant.
Apart from this main analysis, we also compared the groups with respect to several relevant clinical and biochemical characteristics by means of analysis of variance or χ2 tests. For statistical analysis of lipoprotein (a) levels, we used logarithmic transformations to normalize distributions. Presented P values are not corrected for multiple comparisons. To apply the Bonferroni correction for pairwise comparisons of the three groups, the presented P values should be multiplied by 2 or 3, depending on the preferred number of comparisons. Boxplots show the median, interquartile range and outliers.
Data are given as mean (standard deviation) unless stated otherwise. At the time of the index pregnancy, 11 women in the preeclampsia group developed the HELLP syndrome, and 2 women had one or more eclamptic seizures. For the preeclampsia group, the time interval between admission and delivery was 8 (8) days with a maximum recorded systolic blood pressure of 170 (21) mm Hg and a maximum recorded diastolic blood pressure of 110 (14) mm Hg. The high number of birth weights below the 10th percentile together with the low gestational age at delivery in the group of recently preeclamptic women underlines the severity of their previous preeclamptic condition. All 22 women (100%) in the preeclampsia group met the criteria for the diagnosis of a severe, early-onset preeclampsia. Clinical characteristics of the 3 groups, at the time of the investigation post partum, are summarized in Table 1.
Four women (18%) in the preeclampsia group appeared to be hypertensive on ambulatory blood pressure monitoring. None of the controls had a mean office blood pressure equal to or above 140/90 mm Hg. The biochemical results are presented in Table 2.
An overall comparison of the preeclampsia group to the nulliparous control group by means of the Wilks’ λ test revealed a significant difference, both uncorrected (P < .001) and corrected (P = .004). The difference between the preeclampsia group and the normal-pregnancy control group was significant uncorrected (P = .046), but did not remain significant after correction (P = .080). Neither the difference between nulliparous control group and the normal-pregnancy control group, uncorrected (P = .22) nor corrected (P = .28) was significant. Of the eight considered confounding variables, only the effect of triglyceride was significant (P = .022).
The subsequent inspection of separate multiple regression analyses revealed that overall differences between the groups were primarily caused by differences with respect to the common femoral artery IMT (Fig. 1) and to the common carotid artery IMT (Fig. 2). Table 3 presents the uncorrected means of all the five vascular variables. As the size of differences between groups was not much affected by correcting for possible confounding factors, we do not present the full details of the regression analyses, only for the common carotid artery and common femoral artery IMT in Table 4.
This study shows increased IMT of the common femoral artery in a group of women who recently had a pregnancy complicated by early-onset preeclampsia. As IMT of the femoral artery, besides the IMT of the common carotid artery, is generally accepted as early marker of atherosclerosis,15–17 our findings might indicate accelerated atherosclerosis in these formerly preeclamptic women. Therefore, they are in line with literature confirming that women with a history of preeclampsia have higher risk of developing cardiovascular diseases in later life.
One of the first steps in the development of atherosclerosis is endothelial activation followed by endothelial dysfunction. In preeclampsia, vascular endothelial activation or dysfunction is also considered to play a key role in the development of many of the clinical manifestations in the mother.27 Plasma and serum markers of endothelial activation are elevated in preeclampsia.28,29 We recently demonstrated that endothelium-dependent (acetylcholine-mediated) vasodilatation is abnormal in the skin microcirculation in women within 3 to 11 months after a pregnancy complicated by early onset preeclampsia.30
Of further interest is our finding that pregnancy, both normal as well as complicated by preeclampsia, was associated with a significant increase in IMT of the common carotid artery when compared with that of nulliparous women. There are several explanations for this phenomenon. Pregnancy is accompanied by extensive physiological adaptations, which include metabolic, cardiovascular, and immunological responses.31 Of these metabolic changes, hyperlipidemia and increased insulin resistance are well known to accelerate the development of atherosclerosis in nonpregnant women. In preeclampsia, these metabolic and changes are even much more exaggerated,32 and the same holds true for the inflammatory response evoked by pregnancy.33 If such physiological, metabolic, and inflammatory responses of pregnancy have increased IMT irreversibly, this raises questions about possible long-term consequences. In this respect, it is noteworthy that epidemiological studies found positive associations between parity and risk of carotid artery plaques in elderly women34 and multigravidity and rates of coronary artery diseases.35
Whether our observed increased IMT in the preeclampsia group is secondary to a relative increase in IMT as a consequence of a decrease in vessel diameter during (functional) vasoconstriction, rather than structural changes remains unclear. Vascular constriction, with a decrease in vessel diameter, might have occurred at the time of the preeclampsia, but seems unlikely to still exist at a time span of 6–7 months postpartum. Spaanderman et al36 reported that there was no difference in femoral artery diameter between women who had preeclampsia and control women, measured in a time period of, at minimum, 5 months after delivery.
An alternative possibility is that the pregnancy-associated and/or preeclampsia-associated IMT changes are reversible but need more time to disappear fully. Although sufficient power is lacking due to the relatively small sample sizes, we could not find a strong association between IMT and the time elapsed since the end of pregnancy.
Ultrasound imaging cannot discriminate between the intimal layer and the medial layer of the vessel wall to distinguish true atherosclerosis viewed as a disorder restricted to the intimal layer and the medial layer versus the adaptive response of the medial layer to changes in tensile stress such as during hypertension. However, the time period of exposure to the high blood pressures during admission was no longer than 27 days. Moreover, blood pressure values declined after delivery to normal in the large majority, as documented by the ambulatory blood pressure monitor measurements. Besides, IMT of the carotid artery is considered especially influenced by arterial wall hypertrophy ascribed to increased pulsed pressure, whereas atherosclerotic changes have been reported to be more advanced in the femoral artery.24,36 Taking this into consideration, the higher increase in femoral artery IMT in the preeclampsia group suggests accelerated atherosclerosis rather than a blood pressure effect.
A weakness of this study would be the small sample sizes. The study was assumed to enroll 50 women per group within a period of 1 1/2 years. Unfortunately, the planning turned out to be too optimistic. By the closing date, only 22 women per group entered the study. Consequently, the study is underpowered. Despite this, we feel that it provides valuable information.
A large part of our preeclampsia patients also had intrauterine growth restriction. The high rate of intrauterine growth restriction in our severe early-onset preeclampsia group is comparable with the recently published findings of Shear et al37 who report a rate of 60% in a similar cohort. In this respect, we emphasize that we recruited our patient group only on criteria mentioned in the methods section and not on base of the severity of the preeclampsia itself. We found no (significant) differences either in IMT thicknesses or in lipid profiles between the two groups.
One of the most intriguing questions along this study is which comes first: Do women with elevated IMT and other factors associated with atherosclerosis have an increased risk of preeclampsia (are they predisposed), or does the preeclamptic pregnancy initiate the cascade toward atherosclerotic heart disease?
Our cross-sectional study cannot explain whether the increase in IMT can be attributed to, was already present before, and/or was accelerated during the (preeclamptic) pregnancy. In this respect, the concept of pregnancy as a stress test for life38 is applicable here. It might well be possible that the development of preeclampsia is the result of an already-affected vascular system that is unable to meet the increased physiological demands of pregnancy. Prospective follow-up studies will be needed and have meanwhile been started to determine whether preexisting atherosclerosis or the (preeclamptic) pregnancy itself is responsible for the increase in IMT.
Preeclampsia is proven to be an independent risk factor for subsequent coronary artery disease.4 Even with these small sample sizes, we were able to find an increased IMT after preeclampsia, which might be used as indicator of a potential increased vascular risk. Furthermore, IMT measurements after preeclampsia could offer an opportunity to identify a high-risk group of women who might benefit from early screening and preventive measures. These measures could include lifestyle interventions such as improving diet and physical activity, and increased surveillance of blood pressure, blood glucose and serum lipids.
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© 2006 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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