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Endothelial dysfunction after pregnancy-induced hypertension
International Journal of Gynecology and Obstetrics 124 (2014) 230–234
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Endothelial dysfunction after pregnancy-induced hypertension Ana C.P.T. Henriques a,⁎, Francisco H.C. Carvalho a, Helvécio N. Feitosa b, Raimunda H.M. Macena c, Rosa M.S. Mota a, Júlio C.G. Alencar c a b c
Department of Public Health, Federal University of Ceara, Fortaleza, Brazil Department of Maternal and Child Health, Federal University of Ceara, Fortaleza, Brazil Medical School, Federal University of Ceara, Fortaleza, Brazil
a r t i c l e
i n f o
Article history: Received 9 April 2013 Received in revised form 14 August 2013 Accepted 13 November 2013 Keywords: Hypertension Pre-eclampsia Pregnancy-induced Vascular endothelium
a b s t r a c t Objective: To carry out long-term analysis of the presence of endothelial dysfunction after the development of pregnancy-induced hypertension (PIH). Methods: In a retrospective cohort study, data were analyzed from 60 women who delivered at a tertiary maternity hospital in Fortaleza, Ceara, Brazil, between 1992 and 2002. Thirty women had a history of PIH and 30 had no history of complications. Anthropometric and laboratory data were collected, and endothelial function was evaluated by flow-mediated dilatation of the brachial artery. Continuous variables were analyzed via Student t test, and Mann–Whitney test was used to compare means. Clinical and metabolic measures were categorized according to cardiovascular risk by cutoff points determined by national consensus; χ2 and Fisher exact tests were used to compare the groups. Relative risk was calculated for variables that were statistically significant (P b 0.05). Results: Women with a history of PIH had higher body mass index (P = 0.03), systolic blood pressure (P = 0.03), low-density lipoprotein cholesterol (P = 0.02), and fasting glucose (P = 0.02) compared with women with no pregnancy complications. The frequency of endothelial dysfunction was 60% among all women, with a significant difference between the 2 groups (P = 0.01). Conclusion: Women with a history of PIH were found to have a higher frequency of long-term endothelial dysfunction. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Among the morbid conditions that can compromise the normal course of pregnancy, pregnancy-induced hypertension (PIH) has great clinical significance and is considered a major cause of maternal and perinatal mortality [1,2]. Occurrence of PIH has been associated with an abnormal placentation process, which results in the release of anti-angiogenic factors into the mother’s circulation leading to endothelial injury and maternal and fetal damage—situations currently included in category of “placental syndromes” [3,4]. The changes related to PIH do not seem to be resolved during pregnancy, resulting in clinical outcomes with long-term cardiometabolic effects that can change the female epidemiologic profile [5]. Endothelial dysfunction has been identified to be responsible for many of the clinical features of maternal pre-eclampsia syndrome and has been recognized as the main factor related to adverse cardiovascular risk among women with a history of this condition [6,7]. On the one hand, several theories present endothelial dysfunction as a predisposing factor for obstetric complications such as PIH and gestational loss, because impaired endothelial function can damage the ⁎ Corresponding author at: Department of Public Health, St Prof. Costa Mendes, 1608 – 5th floor, Rodolfo Teófilo, Fortaleza, Ceará, Brazil Zip code: 60.430-140. Tel.: +55 85 9944 9523; fax: +55 85 3366 8045. E-mail address: [email protected] (A.C.P.T. Henriques).
physiologic process of placentation. On the other hand, other studies view endothelial dysfunction as a change caused by long-term preeclampsia, making women susceptible to chronic hypertension and cardiovascular disease (CVD) [8–11]. Because many studies have shown that an assessment of endothelial function is an important subclinical measure of future changes in cardiovascular events, the aim of the present study was to analyze the presence of endothelial dysfunction among women with a history of PIH after a long follow-up period [8,10,12]. 2. Materials and methods In a retrospective cohort study conducted at the Assis Chateaubriand Maternity Teaching Hospital (MEAC), Federal University of Ceara, Fortaleza, Ceara, Brazil, data were reviewed from women who gave birth between January 1, 1992, and December 31, 2002. The study was approved by the MEAC Ethics Committee under Norm No. 83/11; informed consent was obtained from all participants. Women diagnosed with PIH documented in their medical records on discharge were included in the cohort group. The participants in the comparison group were women without a history of PIH who gave birth during the same period as the women in the cohort group, with equal numbers in each group. The study sample was calculated on the basis of a 1:1 ratio in a 2-tailed analysis, a power of 80%, a significance level of 5%, and an
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A.C.P.T. Henriques et al. / International Journal of Gynecology and Obstetrics 124 (2014) 230–234
expected reduction of 25% in dilation of brachial artery lumen during reactive hyperemia, in accordance with previous studies that have evaluated endothelial dysfunction among women with a history of preeclampsia [10]. In total, 44 patients (22 in each group) were required. Potential participants were contacted by home visits and telephone using information in their medical records. For those who were contacted successfully, the purpose of the study was explained and an invitation was given to participate in the evaluation. If the women were not present for the visit and telephone contact was not possible, an invitation letter was left at the residence together with survey information and the contact number of the researchers. Interviews were used to collect medical data on current obstetric history, demographic data, history of current morbidities, lifestyle, and family history of CVD. Clinical evaluation was carried out via the collection of anthropometric and laboratory variables by trained investigators using a verification protocol defined in accordance with national consensus [13,14]. Endothelial function was verified by measuring flow-mediated dilatation (FMD) in the right brachial artery with the patient lying comfortably with abduction of the right arm and supination of the hand in order to expose the anteromedial side of the arm to the examiner. The test was conducted in a softly lit, silent room, after a rest of at least 20 minutes. A 10-MHz linear probe of a GE Healthcare Logiq P6 (General Electric Company, Hatfield, UK) ultrasound instrument was placed on the medial side of the arm, longitudinally and perpendicular to the skin, 5 cm above the antecubital crease, sounding the brachial artery and directly adjacent to the biceps muscle. Seven zones were identified corresponding to the 2 middle-adventitia interfaces, the 2 intimal regions, the 2 medium regions, and the luminal of the artery, confirming that the transducer was at the center of and perpendicular to the vessel [15]. The luminal diameter was measured in the center of the vessel at the time corresponding to end diastole; this was considered the basal diameter (D1) [16]. After verification of the basal diameter, the skin was marked with a pen at the position of the transducer when making the measurement. The sphygmomanometer’s cuff was positioned on the ipsilateral forearm, the pressure was adjusted to 250 mm Hg, and this occlusion was maintained for 5 minutes. The post-occlusion diameter (D2) was measured, using the same standards described above, 60 seconds after removal of the cuff because this was considered to be the moment of maximum hyperemia. The FMD value was obtained from the following calculation: FMD (%) = [(D2 – D1)/D1] × 100. The FMD was considered normal when greater than or equal to 10% and abnormal when less than 10%, in accordance with the criteria of Celermarjer et al. [17]. In an attempt to decrease interobserver variations, all of the tests were performed by the same examiner who was blind to the patient's pregnancy history during the test; only 1 test was performed for each patient. The data collected were tabulated and analyzed via Stata version 18.0 (StataCorp, College Station, Texas, USA). For the analysis, only patients with complete clinical evaluation at the end of the protocol (anthropometry, laboratory, and FMD analysis) were included. The mean ± SD of clinical and metabolic variables was calculated, and the Kolmogorov–Smirnov test was used to test the normality of the variables. Student t test was used to analyze the differences between the 2 groups for variables with normal distributions, and the Mann–Whitney test was used for data with non-normal distributions. Pearson χ2 test or Fisher exact test was used for categorical data. A P value of less than 0.05 was considered significant. The crude relative risk (RR) was calculated for variables that showed significance in the primary analysis (P b 0.05). Variables for which the 95% confidence interval (CI) did not include unity were included in a multiple logistic regression and presented as the adjusted RR and 95% CI. A logistic regression model was used to assess the dependent variable (FMD) as a function of the variables that were significant in
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the initial evaluation via a backward stepwise approach and the Wald statistic at a 5% significance level. 3. Results The study included 60 women: 30 in the group with a history of PIH and 30 in the group without a history of PIH. Fig. 1 shows the identification and recruitment of women for the study. Among the 30 patients in the PIH group, 13 (43.3%) had severe pre-eclampsia, 9 (30.0%) had mild pre-eclampsia, 3 (10.0%) had chronic arterial hypertension (CAH), 2 (6.7%) had gestational hypertension, 2 (6.7%) had preeclampsia superimposed on CAH, and 1 (3.3%) had eclampsia in their index pregnancy. Patient records were used to gather data on clinical and maternal obstetric characteristics in a follow-up period ranging between 10 and 20 years with a mean of 15.2 ± 3.5 years (Table 1). There was no significant difference in the follow-up period between the 2 groups (P = 0.94). The mean age of women at the index delivery was 26.2 ± 7.7 years. Overall, 76.7% of the study women were nonwhite. There was no significant difference in ethnicity between the 2 groups (P = 0.76). The follow-up clinical and obstetric patient characteristics, and the anthropometric and metabolic variables obtained through physical assessment and laboratory tests are given in Table 2. The women’s current age ranged from 28 to 61 years (mean 41.3 ± 8.8 years); there was no difference in age between the 2 groups. In terms of the diagnosis of current conditions and/or treatments in progress, 40% of women reported at least 1 diagnosed disease (26.7% in the PIH group versus 53.3% in the no-PIH group, P = 0.06). CAH was the most frequent disease, being reported by 15 (25.0%) patients either in association with other pathologies or not. Diabetes mellitus type 2 (DM2) was the second most reported disease (8 cases; 13.3%). Statistical analysis showed that there was a significant difference in the diagnosis of CAH (P = 0.001) and type 2 diabetes (P = 0.002) between the 2 groups. There were 3 cardiovascular events among women with a history of PIH and 0 among women with no history of PIH, but the difference was not significant. However, statistical differences were found in the risk factors for these events. There was a significant difference in the use of antihypertensive drugs: 10% in the no-PIH group were using antihypertensive drugs, compared with 36.7% in the PIH group (P = 0.03). Overall, the use of hypoglycemic agents was reported by 13.3% of the women. Body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) ranged from 19.7 to 46.9 (mean 29.9 ± 4.9). There was a significant difference between the 2 groups (P = 0.03). Women in the PIH group had a higher mean systolic blood pressure (SBP) (P = 0.03). Similarly, LDL cholesterol and fasting glucose were higher in the group of women with a history of PIH (both P = 0.02). The percentage dilation of the brachial artery after reactive hyperemia ranged between 0% and 40% (mean 12.4% ± 7.9%). Dilation values were significantly lower in the group of women with a history of PIH than in the group without PIH (10.0% ± 6.8% versus 14.8% ± 8.3%, P = 0.01). When categorized by the presence of endothelial dysfunction (FMD b 10%), the PIH group showed a significantly higher frequency of dysfunction (RR, 4.12; 95% CI, 1.4–12.2). After smokers and users of anticoagulants (factors known to alter endothelial function) were excluded, the difference remained significant (RR, 4.74; 95% CI, 1.5–15.1; P = 0.01). To verify the influence of the factors that differed significantly between the groups and might be associated with endothelial dysfunction (BMI, SBP, LDL cholesterol, and glucose), multiple logistic regression was carried out via a backward stepwise approach and the Wald statistic. None of BMI, SBP, LDL, and glucose contributed significantly to variations in the prevalence of alterations of FMD; in other words,
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Medical records analyzed (n=934)
Medical records of women with PIH (n=533)
Medical records of women with no PIH (n=401)
Prior exclusion (n=302): MRF and hinterland (n=302)
Prior exclusion (n=229): MRF and hinterland (n=201); associated pathologies (n=28)
Women with contact details (n=231)
Patients interviewed and invited (n=72)
Women with contact details (n=172)
Patients not contacted (n=159) Patients interviewed and invited (n=102)
Refusal (n=28) Incomplete evaluations (n=13) Pregnant (n=1)
Patients not contacted (n=70)
Refusals (n=46) Incomplete evaluations (n=24) Pregnant (n=2)
Analysis group of women with PIH (n=30)
Analysis group of women with PIH (n=30)
Fig. 1. Flow chart showing the selection and recruitment of women for the study.
there was no dependency between the probability of an FMD of less than 10% and the variables BMI (coefficient, –0097; P = 0.184), SBP (coefficient, 0.019; P = 0.367), LDL cholesterol (coefficient, 0.014; P = 0.177) and glucose (coefficient, 0.017; P = 0.130). After adjustment for FMD (coefficient, 1.253; P = 0.014) and removal of the factors Table 1 Demographic and maternal obstetric characteristics at delivery among women with and without a history of pregnancy-induced hypertension. Characteristic
Study groupa
P value
No history of PIH History of PIH Age, y Race White Non-white Number of pregnancies Number of deliveries Number of spontaneous abortions Complications in pregnancies prior to the index gestatione a b c d e
24.8 ± 7.2
27.5 ± 8.1
8 (26.7) 22 (73.3) 2.2 ± 2.3 1.0 ± 1.9 0.2 ± 0.4 5 (38.5)
6 (20.0) 24 (80.0) 3.0 ± 4.1 1.2 ± 2.7 0.8 ± 1.9 10 (66.7)
Values are given as mean ± SD or number (percentage). By Student t test. By Pearson χ2 test. By Mann–Whitney test. Excluding primiparous women.
0.17b 0.76c
0.78d 0.26d 0.25d 0.25c
not significant at the 5% level, the frequency of endothelial dysfunction remained higher in the PIH group (RR, 3.5; 95% CI, 1.35–9.04). 4. Discussion The present findings showed the presence of endothelial dysfunction, as measured by FMD, among women with a history of PIH after a long follow-up period, which, when combined with other identified risk factors, might confer a significant cardiovascular risk on this group of patients. Factors known to significantly affect endothelial function, such as smoking and use of anticoagulants, were considered in the original analysis; however, the statistical significance between the 2 study groups persisted after women affected by these factors were excluded from the analysis. Flow-mediated dilatation is one of the most popular evaluation measures of endothelial function, and the abnormalities that it detects are associated with most of the traditional and non-traditional risk factors for CVD. Endothelial dysfunction is considered the key to the beginning, progression, and complications of atherosclerosis [12]. Wikström et al. [18] state that the main mechanism for the association between pre-eclampsia and the development of ischemic heart disease is endothelial dysfunction, which is therefore an important subclinical marker to be considered in the evaluation of patients with differentiated risk for CVD. It has been shown that endothelial
A.C.P.T. Henriques et al. / International Journal of Gynecology and Obstetrics 124 (2014) 230–234 Table 2 Current clinical and obstetric history and anthropometric and metabolic characterization of women with and without a history of pregnancy-induced hypertension. Characteristic
Current age, y Classification of diseasesd SAH Diabetes mellitus Dyslipidemias Use of medications Antihypertensive Hypoglycemic Anthropometric variables Weight, kg BMI SBP, mm Hg DPB, mm Hg Waist circumference, cm Hip circumference, cm Waist/hip ratio Metabolic variables Total cholesterol, mg/dL Triglycerides, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL VLDL cholesterol, mg/dL Fasting glycemia, mg/dL FMD, %
Study groupa
P value
No history of PIH
History of PIH
40.1 ± 8.7
42.5 ± 8.9
0.28b
2 (6.7) 1 (3.3) 2 (6.7)
13 (43.3) 7 (23.3) 6 (20.0)
0.001c 0.02c 0.12c
3 (10.0) 1 (3.3)
11 (36.7) 7 (23.3)
0.03c 0.05c
68.6 ± 9.5 28.5 ± 3.2 119.4 ± 14.3 78.9 ± 11.3 86.5 ± 8.6 102.7 ± 8.3 0.8 ± 0.1
72.3 ± 14.8 31.2 ± 5.9 129.9 ± 22.1 83.5 ± 15.0 89.1 ± 11.8 106.9 ± 11.1 0.8 ± 0.1
0.25b 0.03b 0.03b 0.19b 0.32b 0.10b 0.63b
177.6 ± 40.1 143.4 ± 97.5 104.7 ± 31.4 42.2 ± 11.1 28.2 ± 20.1 96.5 ± 9.9 14.8 ± 8.3
191.6 ± 30.8 155.1 ± 73.3 124.0 ± 28.4 39.9 ± 10 30.2 ± 12.9 121.1 ± 59.3 10 ± 6.8
0.13b 0.60b 0.02b 0.40b 0.66b 0.02c 0.01b
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); DPB, diastolic blood pressure; FMD, flow-mediated dilatation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SAH, systemic arterial hypertension; SPB, systolic blood pressure; VLDL, very low density lipoprotein. a Values are given as mean ± SD or number (percentage). b By Student t test. c By Fisher exact test. d Some women cited 1 or more morbid conditions.
dysfunction is common during pregnant women with PIH; changes in flow-mediated vasodilatation, pulse pressure, and pulse wave velocity in the femoral carotid have been observed in the emergence of symptoms of pre-eclampsia [19]. Pàez et al. [20] analyzed the pulse wave velocity and FMD among 55 non-pregnant women: 15 nulliparous, 20 with a history of normotensive pregnancies, and 20 with a history of pre-eclamptic pregnancies. They found a decrease in distensibility and endothelium-dependent vasodilatation among those women with a history of pre-eclampsia. The follow-up time was only 2 years [20]. Analyzing endothelial function among 22 patients with uneventful pregnancy histories, 25 with severe pre-eclampsia and 29 with recurrent fetal loss, Germain et al. [10] found a low percentage of endotheliumdependent dilation of 6.4% ± 1.3% among patients with a history of severe pre-eclampsia and even more pronounced endothelial dysfunction among patients with a history of recurring losses. The follow-up time in their study was also short, ranging from 11 to 27 months. Chambers et al. [9] evaluated endothelium-dependent and endothelium-independent vasodilatation among pre-eclamptic women and a comparison group of women with uncomplicated pregnancies, on average 3 years after delivery, and found impaired endothelial function among the women with previous pre-eclampsia (0.9% ± 4.1%) [9]. In addition, Blaauw et al. [21] found signs of early atherosclerosis and changes in microvascular reactivity among women with a history of pre-eclampsia in a study with a short follow-up time of 3–13 months. In another study aiming to assess arterial elasticity 5 years after childbirth among 30 women, including 14 women with a history of pre-eclampsia, Souwer [22] found a decrease in the elasticity of large and small arteries, in addition to higher BMI, blood pressure, and serum triglycerides in the women who had had pre-eclampsia. These findings may indicate persistent endothelial dysfunction even years after the occurrence of a pre-eclamptic pregnancy.
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In the present study, the endothelial function of women with a history of different forms of PIH was assessed at a mean follow-up of 15.2 ± 3.5 years. Significant differences in the presence endothelial dysfunction were found between the group of women with a history of PIH and the control group. The concomitance of other abnormalities associated with endothelial dysfunction among patients draws attention to their cardiovascular risk profile and should be considered in the context of an increased risk for cardiovascular events. In the present study, BMI, SBP, LDL cholesterol, and fasting glucose—important parameters when characterizing an adverse cardiometabolic risk—were higher among patients with a history of PIH, consistent with the results of other studies on a similar group of patients [23]. Because these factors, by themselves, can confer changes in endothelial function, logistic regression analysis considering FMD as the outcome was performed; however, the difference in FMD remained between the 2 groups, indicating that these factors do not account for endothelial dysfunction found in the PIH group. The retrospective approach, the long-term follow-up, and changes of address for a large proportion of the women with PIH might have contributed to the small sample number in the present study. However, several previous studies had a design and number of patients similar to the present study, but an even shorter follow-up period, and reported results similar to the present findings. To our knowledge, no study has performed this type of analysis after such a long postpartum period and fully addressed the parameters making up the cardiovascular risk profile with emphasis on endothelial dysfunction. Whether endothelial dysfunction exists and is a risk factor for the development of pre-eclampsia, or whether it is a consequence of the pathologic changes presented during pre-eclampsia are issues that have been raised in some studies. It was not the objective of the present investigation to resolve these issues. Conclusions in this regard might be achieved only with prospective cohort studies that assess endothelial function and identify the cardiovascular risk profile both before conception and after a long-term postnatal follow-up [9,10,20]. The prognostic impact of endothelial dysfunction suggests that peripheral endothelial function might represent a significant additional stratification factor of patients at possible risk for cardiovascular events, emphasizing the importance of this evaluation among different at-risk population groups [24]. Conflict of interest The authors have no conflicts of interest. References [1] Kullima AA, Kawuwa MB, Audu BM, Usman H, Geidam AD. A 5-year review of maternal mortality associated with eclampsia in a tertiary institution in northern Nigeria. Ann Afr Med 2009;8(2):81–4. [2] Novo JLVG, Gianini RJ. Eclampsia as a cause of maternal mortality. Rev Bras Saúde Matern Infant 2010;10(2):209–17. [3] Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003;69(1):1–7. [4] Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366(9499):1797–803. [5] Chesley LC. Recognition of the long-term sequelae of eclampsia. Am J Obstet Gynecol 2000;182(1 Pt 1):249–50. [6] Davison JM, Homuth V, Jeyabalan A, Conrad KP, Karumanchi SA, Quaggin S, et al. New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol 2004;15(9):2440–8. [7] Teixeira PG, Cabral ACV, Andrade SP, Reis ZSN, Rezende CAL, Victória MML, et al. Clinical relevance of angiogenese factor in preeclampsia. Femina 2008;36(2):231–5. [8] Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK. Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol Heart Circ Physiol 2004;286(4):H1389–93. [9] Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285(12):1607–12. [10] Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, et al. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 2007;49(1):90–5.
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[11] Lampinen KH, Rönnback M, Kaaja RJ, Groop PH. Impaired vascular dilatation in women with a history of pre-eclampsia. J Hypertens 2006;24(4):751–6. [12] Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003;23(2):168–75. [13] Brazilian Association for the Study of Obesity and Metabolic Syndrome. Brazilian Guidelines on Obesity 2009/2010. http://www.abeso.org.br/pdf/diretrizes_brasileiras_ obesidade_2009_2010_1.pdf. Published 2009. Accessed October 12, 2012. [14] Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão, Sociedade Brasileira de Nefrologia. VI Brazilian Guidelines on Hypertension. Arq Bras Cardiol 2010;95(1 Suppl.):1–51. [15] Regattieri NAT, Leite SP, Koch HA, Montenegro CAB. Flow-mediated dilation of the brachial artery: development of technical study in patients at risk for atherosclerosis and in a control group. Rev Bras Ultrason 2006;9(1):9–13. [16] Filho EV, Mohr C, Filho BJ, Gadonski G, Paula LG, Antonello IC, et al. Flow-mediated dilatation in the differential diagnosis of preeclampsia syndrome. Arq Bras Cardiol 2010;94(2):182–6 195–200,185–9. [17] Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340(8828):1111–5.
[18] Wikström AK, Haglund B, Olovsson M, Lindeberg SN. The risk of maternal ischaemic heart disease after gestational hypertensive disease. BJOG 2005;112(11): 1486–91. [19] Rönnback M, Lampinen K, Groop PH, Kaaja R. Pulse wave reflection in currently and previously preeclamptic women. Hypertens Pregnancy 2005;24(2):171–80. [20] Pàez O, Alfie J, Gorosito M, Puleio P, de Maria M, Prieto N, et al. Parallel decrease in arterial distensibility and in endothelium-dependent dilatation in young women with a history of pre-eclampsia. Clin Exp Hypertens 2009;31(7):544–52. [21] Blaauw J, Graaff R, van Pampus MG, van Doormaal JJ, Smit AJ, Rakhorst G, et al. Abnormal endothelium-dependent microvascular reactivity in recently preeclamptic women. Obstet Gynecol 2005;105(3):626–32. [22] Souwer ET, Blaauw J, Coffeng SM, Smit AJ, Van Doormaal JJ, Faas MM, et al. Decreased arterial elasticity in formerly early-onset preeclamptic women. Acta Obstet Gynecol Scand 2011;90(7):797–801. [23] Forest JC, Girouard J, Massé J, Moutquin JM, Kharfi A, Ness RB, et al. Early occurrence of metabolic syndrome after hypertension in pregnancy. Obstet Gynecol 2005;105(6): 1373–80. [24] Reriani MK, Lerman LO, Lerman A. Endothelial function as a functional expression of cardiovascular risk factors. Biomark Med 2010;4(3):351–60.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Endothelial dysfunction after pregnancy-induced hypertension Ana C.P.T. Henriques a,⁎, Francisco H.C. Carvalho a, Helvécio N. Feitosa b, Raimunda H.M. Macena c, Rosa M.S. Mota a, Júlio C.G. Alencar c a b c
Department of Public Health, Federal University of Ceara, Fortaleza, Brazil Department of Maternal and Child Health, Federal University of Ceara, Fortaleza, Brazil Medical School, Federal University of Ceara, Fortaleza, Brazil
a r t i c l e
i n f o
Article history: Received 9 April 2013 Received in revised form 14 August 2013 Accepted 13 November 2013 Keywords: Hypertension Pre-eclampsia Pregnancy-induced Vascular endothelium
a b s t r a c t Objective: To carry out long-term analysis of the presence of endothelial dysfunction after the development of pregnancy-induced hypertension (PIH). Methods: In a retrospective cohort study, data were analyzed from 60 women who delivered at a tertiary maternity hospital in Fortaleza, Ceara, Brazil, between 1992 and 2002. Thirty women had a history of PIH and 30 had no history of complications. Anthropometric and laboratory data were collected, and endothelial function was evaluated by flow-mediated dilatation of the brachial artery. Continuous variables were analyzed via Student t test, and Mann–Whitney test was used to compare means. Clinical and metabolic measures were categorized according to cardiovascular risk by cutoff points determined by national consensus; χ2 and Fisher exact tests were used to compare the groups. Relative risk was calculated for variables that were statistically significant (P b 0.05). Results: Women with a history of PIH had higher body mass index (P = 0.03), systolic blood pressure (P = 0.03), low-density lipoprotein cholesterol (P = 0.02), and fasting glucose (P = 0.02) compared with women with no pregnancy complications. The frequency of endothelial dysfunction was 60% among all women, with a significant difference between the 2 groups (P = 0.01). Conclusion: Women with a history of PIH were found to have a higher frequency of long-term endothelial dysfunction. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Among the morbid conditions that can compromise the normal course of pregnancy, pregnancy-induced hypertension (PIH) has great clinical significance and is considered a major cause of maternal and perinatal mortality [1,2]. Occurrence of PIH has been associated with an abnormal placentation process, which results in the release of anti-angiogenic factors into the mother’s circulation leading to endothelial injury and maternal and fetal damage—situations currently included in category of “placental syndromes” [3,4]. The changes related to PIH do not seem to be resolved during pregnancy, resulting in clinical outcomes with long-term cardiometabolic effects that can change the female epidemiologic profile [5]. Endothelial dysfunction has been identified to be responsible for many of the clinical features of maternal pre-eclampsia syndrome and has been recognized as the main factor related to adverse cardiovascular risk among women with a history of this condition [6,7]. On the one hand, several theories present endothelial dysfunction as a predisposing factor for obstetric complications such as PIH and gestational loss, because impaired endothelial function can damage the ⁎ Corresponding author at: Department of Public Health, St Prof. Costa Mendes, 1608 – 5th floor, Rodolfo Teófilo, Fortaleza, Ceará, Brazil Zip code: 60.430-140. Tel.: +55 85 9944 9523; fax: +55 85 3366 8045. E-mail address: [email protected] (A.C.P.T. Henriques).
physiologic process of placentation. On the other hand, other studies view endothelial dysfunction as a change caused by long-term preeclampsia, making women susceptible to chronic hypertension and cardiovascular disease (CVD) [8–11]. Because many studies have shown that an assessment of endothelial function is an important subclinical measure of future changes in cardiovascular events, the aim of the present study was to analyze the presence of endothelial dysfunction among women with a history of PIH after a long follow-up period [8,10,12]. 2. Materials and methods In a retrospective cohort study conducted at the Assis Chateaubriand Maternity Teaching Hospital (MEAC), Federal University of Ceara, Fortaleza, Ceara, Brazil, data were reviewed from women who gave birth between January 1, 1992, and December 31, 2002. The study was approved by the MEAC Ethics Committee under Norm No. 83/11; informed consent was obtained from all participants. Women diagnosed with PIH documented in their medical records on discharge were included in the cohort group. The participants in the comparison group were women without a history of PIH who gave birth during the same period as the women in the cohort group, with equal numbers in each group. The study sample was calculated on the basis of a 1:1 ratio in a 2-tailed analysis, a power of 80%, a significance level of 5%, and an
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expected reduction of 25% in dilation of brachial artery lumen during reactive hyperemia, in accordance with previous studies that have evaluated endothelial dysfunction among women with a history of preeclampsia [10]. In total, 44 patients (22 in each group) were required. Potential participants were contacted by home visits and telephone using information in their medical records. For those who were contacted successfully, the purpose of the study was explained and an invitation was given to participate in the evaluation. If the women were not present for the visit and telephone contact was not possible, an invitation letter was left at the residence together with survey information and the contact number of the researchers. Interviews were used to collect medical data on current obstetric history, demographic data, history of current morbidities, lifestyle, and family history of CVD. Clinical evaluation was carried out via the collection of anthropometric and laboratory variables by trained investigators using a verification protocol defined in accordance with national consensus [13,14]. Endothelial function was verified by measuring flow-mediated dilatation (FMD) in the right brachial artery with the patient lying comfortably with abduction of the right arm and supination of the hand in order to expose the anteromedial side of the arm to the examiner. The test was conducted in a softly lit, silent room, after a rest of at least 20 minutes. A 10-MHz linear probe of a GE Healthcare Logiq P6 (General Electric Company, Hatfield, UK) ultrasound instrument was placed on the medial side of the arm, longitudinally and perpendicular to the skin, 5 cm above the antecubital crease, sounding the brachial artery and directly adjacent to the biceps muscle. Seven zones were identified corresponding to the 2 middle-adventitia interfaces, the 2 intimal regions, the 2 medium regions, and the luminal of the artery, confirming that the transducer was at the center of and perpendicular to the vessel [15]. The luminal diameter was measured in the center of the vessel at the time corresponding to end diastole; this was considered the basal diameter (D1) [16]. After verification of the basal diameter, the skin was marked with a pen at the position of the transducer when making the measurement. The sphygmomanometer’s cuff was positioned on the ipsilateral forearm, the pressure was adjusted to 250 mm Hg, and this occlusion was maintained for 5 minutes. The post-occlusion diameter (D2) was measured, using the same standards described above, 60 seconds after removal of the cuff because this was considered to be the moment of maximum hyperemia. The FMD value was obtained from the following calculation: FMD (%) = [(D2 – D1)/D1] × 100. The FMD was considered normal when greater than or equal to 10% and abnormal when less than 10%, in accordance with the criteria of Celermarjer et al. [17]. In an attempt to decrease interobserver variations, all of the tests were performed by the same examiner who was blind to the patient's pregnancy history during the test; only 1 test was performed for each patient. The data collected were tabulated and analyzed via Stata version 18.0 (StataCorp, College Station, Texas, USA). For the analysis, only patients with complete clinical evaluation at the end of the protocol (anthropometry, laboratory, and FMD analysis) were included. The mean ± SD of clinical and metabolic variables was calculated, and the Kolmogorov–Smirnov test was used to test the normality of the variables. Student t test was used to analyze the differences between the 2 groups for variables with normal distributions, and the Mann–Whitney test was used for data with non-normal distributions. Pearson χ2 test or Fisher exact test was used for categorical data. A P value of less than 0.05 was considered significant. The crude relative risk (RR) was calculated for variables that showed significance in the primary analysis (P b 0.05). Variables for which the 95% confidence interval (CI) did not include unity were included in a multiple logistic regression and presented as the adjusted RR and 95% CI. A logistic regression model was used to assess the dependent variable (FMD) as a function of the variables that were significant in
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the initial evaluation via a backward stepwise approach and the Wald statistic at a 5% significance level. 3. Results The study included 60 women: 30 in the group with a history of PIH and 30 in the group without a history of PIH. Fig. 1 shows the identification and recruitment of women for the study. Among the 30 patients in the PIH group, 13 (43.3%) had severe pre-eclampsia, 9 (30.0%) had mild pre-eclampsia, 3 (10.0%) had chronic arterial hypertension (CAH), 2 (6.7%) had gestational hypertension, 2 (6.7%) had preeclampsia superimposed on CAH, and 1 (3.3%) had eclampsia in their index pregnancy. Patient records were used to gather data on clinical and maternal obstetric characteristics in a follow-up period ranging between 10 and 20 years with a mean of 15.2 ± 3.5 years (Table 1). There was no significant difference in the follow-up period between the 2 groups (P = 0.94). The mean age of women at the index delivery was 26.2 ± 7.7 years. Overall, 76.7% of the study women were nonwhite. There was no significant difference in ethnicity between the 2 groups (P = 0.76). The follow-up clinical and obstetric patient characteristics, and the anthropometric and metabolic variables obtained through physical assessment and laboratory tests are given in Table 2. The women’s current age ranged from 28 to 61 years (mean 41.3 ± 8.8 years); there was no difference in age between the 2 groups. In terms of the diagnosis of current conditions and/or treatments in progress, 40% of women reported at least 1 diagnosed disease (26.7% in the PIH group versus 53.3% in the no-PIH group, P = 0.06). CAH was the most frequent disease, being reported by 15 (25.0%) patients either in association with other pathologies or not. Diabetes mellitus type 2 (DM2) was the second most reported disease (8 cases; 13.3%). Statistical analysis showed that there was a significant difference in the diagnosis of CAH (P = 0.001) and type 2 diabetes (P = 0.002) between the 2 groups. There were 3 cardiovascular events among women with a history of PIH and 0 among women with no history of PIH, but the difference was not significant. However, statistical differences were found in the risk factors for these events. There was a significant difference in the use of antihypertensive drugs: 10% in the no-PIH group were using antihypertensive drugs, compared with 36.7% in the PIH group (P = 0.03). Overall, the use of hypoglycemic agents was reported by 13.3% of the women. Body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) ranged from 19.7 to 46.9 (mean 29.9 ± 4.9). There was a significant difference between the 2 groups (P = 0.03). Women in the PIH group had a higher mean systolic blood pressure (SBP) (P = 0.03). Similarly, LDL cholesterol and fasting glucose were higher in the group of women with a history of PIH (both P = 0.02). The percentage dilation of the brachial artery after reactive hyperemia ranged between 0% and 40% (mean 12.4% ± 7.9%). Dilation values were significantly lower in the group of women with a history of PIH than in the group without PIH (10.0% ± 6.8% versus 14.8% ± 8.3%, P = 0.01). When categorized by the presence of endothelial dysfunction (FMD b 10%), the PIH group showed a significantly higher frequency of dysfunction (RR, 4.12; 95% CI, 1.4–12.2). After smokers and users of anticoagulants (factors known to alter endothelial function) were excluded, the difference remained significant (RR, 4.74; 95% CI, 1.5–15.1; P = 0.01). To verify the influence of the factors that differed significantly between the groups and might be associated with endothelial dysfunction (BMI, SBP, LDL cholesterol, and glucose), multiple logistic regression was carried out via a backward stepwise approach and the Wald statistic. None of BMI, SBP, LDL, and glucose contributed significantly to variations in the prevalence of alterations of FMD; in other words,
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Medical records analyzed (n=934)
Medical records of women with PIH (n=533)
Medical records of women with no PIH (n=401)
Prior exclusion (n=302): MRF and hinterland (n=302)
Prior exclusion (n=229): MRF and hinterland (n=201); associated pathologies (n=28)
Women with contact details (n=231)
Patients interviewed and invited (n=72)
Women with contact details (n=172)
Patients not contacted (n=159) Patients interviewed and invited (n=102)
Refusal (n=28) Incomplete evaluations (n=13) Pregnant (n=1)
Patients not contacted (n=70)
Refusals (n=46) Incomplete evaluations (n=24) Pregnant (n=2)
Analysis group of women with PIH (n=30)
Analysis group of women with PIH (n=30)
Fig. 1. Flow chart showing the selection and recruitment of women for the study.
there was no dependency between the probability of an FMD of less than 10% and the variables BMI (coefficient, –0097; P = 0.184), SBP (coefficient, 0.019; P = 0.367), LDL cholesterol (coefficient, 0.014; P = 0.177) and glucose (coefficient, 0.017; P = 0.130). After adjustment for FMD (coefficient, 1.253; P = 0.014) and removal of the factors Table 1 Demographic and maternal obstetric characteristics at delivery among women with and without a history of pregnancy-induced hypertension. Characteristic
Study groupa
P value
No history of PIH History of PIH Age, y Race White Non-white Number of pregnancies Number of deliveries Number of spontaneous abortions Complications in pregnancies prior to the index gestatione a b c d e
24.8 ± 7.2
27.5 ± 8.1
8 (26.7) 22 (73.3) 2.2 ± 2.3 1.0 ± 1.9 0.2 ± 0.4 5 (38.5)
6 (20.0) 24 (80.0) 3.0 ± 4.1 1.2 ± 2.7 0.8 ± 1.9 10 (66.7)
Values are given as mean ± SD or number (percentage). By Student t test. By Pearson χ2 test. By Mann–Whitney test. Excluding primiparous women.
0.17b 0.76c
0.78d 0.26d 0.25d 0.25c
not significant at the 5% level, the frequency of endothelial dysfunction remained higher in the PIH group (RR, 3.5; 95% CI, 1.35–9.04). 4. Discussion The present findings showed the presence of endothelial dysfunction, as measured by FMD, among women with a history of PIH after a long follow-up period, which, when combined with other identified risk factors, might confer a significant cardiovascular risk on this group of patients. Factors known to significantly affect endothelial function, such as smoking and use of anticoagulants, were considered in the original analysis; however, the statistical significance between the 2 study groups persisted after women affected by these factors were excluded from the analysis. Flow-mediated dilatation is one of the most popular evaluation measures of endothelial function, and the abnormalities that it detects are associated with most of the traditional and non-traditional risk factors for CVD. Endothelial dysfunction is considered the key to the beginning, progression, and complications of atherosclerosis [12]. Wikström et al. [18] state that the main mechanism for the association between pre-eclampsia and the development of ischemic heart disease is endothelial dysfunction, which is therefore an important subclinical marker to be considered in the evaluation of patients with differentiated risk for CVD. It has been shown that endothelial
A.C.P.T. Henriques et al. / International Journal of Gynecology and Obstetrics 124 (2014) 230–234 Table 2 Current clinical and obstetric history and anthropometric and metabolic characterization of women with and without a history of pregnancy-induced hypertension. Characteristic
Current age, y Classification of diseasesd SAH Diabetes mellitus Dyslipidemias Use of medications Antihypertensive Hypoglycemic Anthropometric variables Weight, kg BMI SBP, mm Hg DPB, mm Hg Waist circumference, cm Hip circumference, cm Waist/hip ratio Metabolic variables Total cholesterol, mg/dL Triglycerides, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL VLDL cholesterol, mg/dL Fasting glycemia, mg/dL FMD, %
Study groupa
P value
No history of PIH
History of PIH
40.1 ± 8.7
42.5 ± 8.9
0.28b
2 (6.7) 1 (3.3) 2 (6.7)
13 (43.3) 7 (23.3) 6 (20.0)
0.001c 0.02c 0.12c
3 (10.0) 1 (3.3)
11 (36.7) 7 (23.3)
0.03c 0.05c
68.6 ± 9.5 28.5 ± 3.2 119.4 ± 14.3 78.9 ± 11.3 86.5 ± 8.6 102.7 ± 8.3 0.8 ± 0.1
72.3 ± 14.8 31.2 ± 5.9 129.9 ± 22.1 83.5 ± 15.0 89.1 ± 11.8 106.9 ± 11.1 0.8 ± 0.1
0.25b 0.03b 0.03b 0.19b 0.32b 0.10b 0.63b
177.6 ± 40.1 143.4 ± 97.5 104.7 ± 31.4 42.2 ± 11.1 28.2 ± 20.1 96.5 ± 9.9 14.8 ± 8.3
191.6 ± 30.8 155.1 ± 73.3 124.0 ± 28.4 39.9 ± 10 30.2 ± 12.9 121.1 ± 59.3 10 ± 6.8
0.13b 0.60b 0.02b 0.40b 0.66b 0.02c 0.01b
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); DPB, diastolic blood pressure; FMD, flow-mediated dilatation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SAH, systemic arterial hypertension; SPB, systolic blood pressure; VLDL, very low density lipoprotein. a Values are given as mean ± SD or number (percentage). b By Student t test. c By Fisher exact test. d Some women cited 1 or more morbid conditions.
dysfunction is common during pregnant women with PIH; changes in flow-mediated vasodilatation, pulse pressure, and pulse wave velocity in the femoral carotid have been observed in the emergence of symptoms of pre-eclampsia [19]. Pàez et al. [20] analyzed the pulse wave velocity and FMD among 55 non-pregnant women: 15 nulliparous, 20 with a history of normotensive pregnancies, and 20 with a history of pre-eclamptic pregnancies. They found a decrease in distensibility and endothelium-dependent vasodilatation among those women with a history of pre-eclampsia. The follow-up time was only 2 years [20]. Analyzing endothelial function among 22 patients with uneventful pregnancy histories, 25 with severe pre-eclampsia and 29 with recurrent fetal loss, Germain et al. [10] found a low percentage of endotheliumdependent dilation of 6.4% ± 1.3% among patients with a history of severe pre-eclampsia and even more pronounced endothelial dysfunction among patients with a history of recurring losses. The follow-up time in their study was also short, ranging from 11 to 27 months. Chambers et al. [9] evaluated endothelium-dependent and endothelium-independent vasodilatation among pre-eclamptic women and a comparison group of women with uncomplicated pregnancies, on average 3 years after delivery, and found impaired endothelial function among the women with previous pre-eclampsia (0.9% ± 4.1%) [9]. In addition, Blaauw et al. [21] found signs of early atherosclerosis and changes in microvascular reactivity among women with a history of pre-eclampsia in a study with a short follow-up time of 3–13 months. In another study aiming to assess arterial elasticity 5 years after childbirth among 30 women, including 14 women with a history of pre-eclampsia, Souwer [22] found a decrease in the elasticity of large and small arteries, in addition to higher BMI, blood pressure, and serum triglycerides in the women who had had pre-eclampsia. These findings may indicate persistent endothelial dysfunction even years after the occurrence of a pre-eclamptic pregnancy.
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In the present study, the endothelial function of women with a history of different forms of PIH was assessed at a mean follow-up of 15.2 ± 3.5 years. Significant differences in the presence endothelial dysfunction were found between the group of women with a history of PIH and the control group. The concomitance of other abnormalities associated with endothelial dysfunction among patients draws attention to their cardiovascular risk profile and should be considered in the context of an increased risk for cardiovascular events. In the present study, BMI, SBP, LDL cholesterol, and fasting glucose—important parameters when characterizing an adverse cardiometabolic risk—were higher among patients with a history of PIH, consistent with the results of other studies on a similar group of patients [23]. Because these factors, by themselves, can confer changes in endothelial function, logistic regression analysis considering FMD as the outcome was performed; however, the difference in FMD remained between the 2 groups, indicating that these factors do not account for endothelial dysfunction found in the PIH group. The retrospective approach, the long-term follow-up, and changes of address for a large proportion of the women with PIH might have contributed to the small sample number in the present study. However, several previous studies had a design and number of patients similar to the present study, but an even shorter follow-up period, and reported results similar to the present findings. To our knowledge, no study has performed this type of analysis after such a long postpartum period and fully addressed the parameters making up the cardiovascular risk profile with emphasis on endothelial dysfunction. Whether endothelial dysfunction exists and is a risk factor for the development of pre-eclampsia, or whether it is a consequence of the pathologic changes presented during pre-eclampsia are issues that have been raised in some studies. It was not the objective of the present investigation to resolve these issues. Conclusions in this regard might be achieved only with prospective cohort studies that assess endothelial function and identify the cardiovascular risk profile both before conception and after a long-term postnatal follow-up [9,10,20]. The prognostic impact of endothelial dysfunction suggests that peripheral endothelial function might represent a significant additional stratification factor of patients at possible risk for cardiovascular events, emphasizing the importance of this evaluation among different at-risk population groups [24]. Conflict of interest The authors have no conflicts of interest. References [1] Kullima AA, Kawuwa MB, Audu BM, Usman H, Geidam AD. A 5-year review of maternal mortality associated with eclampsia in a tertiary institution in northern Nigeria. Ann Afr Med 2009;8(2):81–4. [2] Novo JLVG, Gianini RJ. Eclampsia as a cause of maternal mortality. Rev Bras Saúde Matern Infant 2010;10(2):209–17. [3] Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003;69(1):1–7. [4] Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366(9499):1797–803. [5] Chesley LC. Recognition of the long-term sequelae of eclampsia. Am J Obstet Gynecol 2000;182(1 Pt 1):249–50. [6] Davison JM, Homuth V, Jeyabalan A, Conrad KP, Karumanchi SA, Quaggin S, et al. New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol 2004;15(9):2440–8. [7] Teixeira PG, Cabral ACV, Andrade SP, Reis ZSN, Rezende CAL, Victória MML, et al. Clinical relevance of angiogenese factor in preeclampsia. Femina 2008;36(2):231–5. [8] Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK. Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol Heart Circ Physiol 2004;286(4):H1389–93. [9] Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285(12):1607–12. [10] Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, et al. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 2007;49(1):90–5.
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