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Association of Remote Hypertension in Pregnancy With Coronary Artery Disease

A Case-Control Study
Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.108.127068Hypertension. 2009;53:733–738

Abstract

Because hypertensive pregnancies have been associated with increased cardiovascular disease, we aimed to identify whether angiographically characterized coronary artery disease differed in women with previous normotensive pregnancies or hypertensive pregnancies (HPs). The study group included 217 parous women, aged 60.9±9.2 (SD) years, who required coronary angiography between January 2006 and December 2007, 36.8±9.9 and 28.8±10.5 years after their first and last pregnancy, respectively; 146 had normotensive pregnancies and 71 had ≥1 HP, according to a questionnaire including reproductive history and cardiovascular risks. Body mass index, smoking, and frequency of diabetes were similar in both groups. Chronic hypertension (93% versus 78%; P=0.007), hyperlipidemia (82% versus 69%; P=0.049), and premature familial cardiovascular disease (42% versus 20%; P=0.001) prevailed in HPs. Participants with HPs were younger (58.9±8.3 versus 61.9±9.6 years; P=0.025) than participants with normotensive pregnancies. Although 49% of all participants had hemodynamically significant coronary artery disease (≥70% stenosis), no differences were observed between groups in the number of stenotic arteries; however, their number increased by 28% and 22% over a 10-year period in HPs and normotensive pregnancies, respectively (P=0.034). Multivariate analysis showed that HPs had a nonsignificant risk of having coronary artery disease (odds ratio: 1.21; 95% CI: 0.64 to 2.28), and being a current smoker (odds ratio: 4.13; 95% CI: 1.85 to 9.25), a diabetic (odds ratio: 2.29; 95% CI: 1.85 to 9.25), or having a family history of premature cardiovascular disease (odds ratio: 2.34; 95% CI: 1.17 to 2.39) significantly increased the risk of coronary artery disease. This study demonstrates that women with HPs have earlier coronary disease, probably related to intermediate cardiovascular risks that have a gestational expression.

Indirect evidence has linked preeclampsia, other forms of hypertension in pregnancy, and placentation-related defects to cardiovascular (CV) disease later in life.1–12 Although most studies have used registry bases, one includes clinical follow-up,10 one compares women with angiographically characterized coronary lesions with patients who only underwent clinical screening for coronary disease,8 and another evaluates coronary calcification, a predictor of coronary artery disease.11 A prospective study performed in a cohort of women with a precise classification of obstetric outcomes would be necessary to evaluate the tentative association between reproductive and CV complications, but because this is a relatively new finding, any ongoing or new study will need at least a couple of decades to be completed. Furthermore, included subjects would have to be left to the natural evolution of CV disease, and it is ethically inadmissible to abstain from CV preventive management.

We decided to take an intermediate stance, by testing whether those subjects who had hypertensive pregnancies (HPs) developed earlier or more extensive coronary lesions than controls who had normotensive pregnancies (NPs). For this purpose, we evaluated the remote obstetric histories in women who underwent coronary angiography, the gold standard for defining coronary disease.

Methods

This investigation was a case-control observational retrospective study, with the results of coronary angiography as the dependent variable. Women undergoing coronary angiographies because of suspected coronary disease at Hospital Sótero del Río, in the southeast zone of Santiago, Chile, from January 1, 2006, to December 31, 2007, completed a questionnaire (please see the online data supplement at http://hyper.ahajournals.org) to determine their CV risk factors, including the following: family history; age of onset and end of menstrual cycles; hormonal replacement therapy; number of pregnancies; spontaneous isolated, recurrent, or elective abortions; and presence of hypertension, diabetes, preterm birth, and hospitalizations during pregnancies. Furthermore, a detailed history of each pregnancy was obtained, including its duration, presence of hypertension, other pregnancy-related disorders, and newborn weight. The participants lived in an urban area of Santiago and represented the predominant socioeconomic strata and the European-Amerindian mixture of the Chilean population.13 The study protocol was approved by the institutional review board, and all of the patients gave their informed consent before answering the questionnaire; this was completed after angiography, either during hospitalization or by telephone after discharge. It was administered by 2 of the authors (F.Q. and G.V.), who were blinded to the degree of coronary disease. At the time of interview, the patients were aware of the interventions derived from the procedure but were not informed of the number of stenotic arteries.

Body mass index was calculated for all of the participants. A personal history of hypertension, diabetes mellitus, and hyperlipidemia was defined by previous medical diagnosis or by current specific treatment. According to tobacco use, subjects were defined as nonsmokers, former smokers (ie, those who had stopped smoking for a year or more), and current smokers (ie, those who smoked any tobacco in the year before angiography).14 Premature familial CV disease was defined by myocardial infarction, coronary bypass, or stroke in first-degree relatives, occurring before 60 and 65 years of age in men and women, respectively.

HPs were defined by high blood pressure during any time during pregnancy, with no distinction made between the different types of hypertension in pregnancy. Low birth weight was defined as ≤2500 g and preterm births as those occurring at <36 weeks (ie, ≤8 months) in singleton pregnancies; recurrent abortions as ≥2 consecutive miscarriages; and impeccable gestational history by uncomplicated gestations in women who carried all pregnancies to term. The reports of these complications were obtained by recall, as the obstetric records could not be accessed.

Selective coronary angiograms, performed using the Judkins technique, were assessed by observers blinded to the obstetric history. Hemodynamically significant coronary stenosis was defined by a ≥70% narrowing of arterial lumen. Recent myocardial infarctions were diagnosed by regional alteration of left ventricular contractility and, when remote, by the presence of ≥2 of the following: electrocardiographic and enzymatic abnormalities at the time of the event, and alterations in left ventricular contractility.

Of the 486 women who underwent angiography during the 2-year study period, 9 died during the acute event; of the 477 remaining women, 268 (56.2%) could be contacted. The study group was composed of 217 women, aged 61.2±9.2 (SD) years, who underwent coronary angiography 36.8±9.9 and 28.8±10.5 years after the first and last pregnancies, respectively. These data describe the group after 51 women were excluded (27 women who had not received qualified professional attention in ≥1 pregnancy, 11 nulliparas, 9 women who declined or were unable to participate in the interview, and 4 women who provided discordant data). For the women who were deceased, not contacted, or excluded (n=269), data on CV risks and severity of coronary disease were obtained from the admission charts at the time of angiography.

Data Analysis

Results are expressed as means±SDs. Multiple-birth pregnancies were excluded from the analysis of pregnancy complications. The numeric analysis was performed using SPSS software. Normality was evaluated by the Shapiro-Wilks test. An unpaired t test was used for variables with a normal distribution, whereas the nonparametric Mann-Whitney test was used for variables with a nonnormal distribution. In addition, univariate and multivariate analysis, logistic regression, and Poisson regression were performed. Statistical significance was considered for P values ≤0.05.

The reproducibility of maternal recall regarding several of the parameters included in the study was tested by repeated interviews in a subgroup of 15 randomly selected participants, which, posthoc, presented a representative distribution of obstetric complications. Complete agreement was achieved when women were asked whether they had previous NPs or HPs and term or preterm births; for the number of reproductive complications (per woman), the intraclass correlation coefficient was 0.92 for HPs, 0.87 for preterm births, and 0.85 for weights ≤2500 g; for age of menarche and menopause, the coefficients were 0.83 and 0.76, respectively, all with a P<0.000. The agreement for newborn weights was analyzed by mixed methods for 2 factors15 in the same 15 women, who had given birth to 52 children; this yielded an intraclass correlation coefficient of 0.90, with a 95% CI of 0.83 to 0.94 for data obtained in a single interview.

Results

The demographic characteristics of the study group are summarized in the Table. Of the 217 parous women who had received professional attention during their pregnancies, 146 (66.4%) had NPs, and 71 (33.7%) had ≥1 HP.

Table. Demographic, CV, and Obstetric Profiles of the Study Population

VariableTotal (N=217)NP (N=146; 66.4%)HP (N=71; 33.7%)P
NS indicates nonsignificant; BMI, body mass index; OB/GYN, obstetric/gynecologic.
Demographics
    Age, mean±SD, y60.9±9.261.9±9.658.9±8.30.025
    Education, mean±SD, y7.6±4.07.5±4.17.6±3.9NS
    BMI, mean±SD, kg/m228.1±4.727.7±4.429.1±5.30.098
CV risks
    Current smoking, n (%)67 (31)42 (29)25 (36)NS
    Former smokers, n (%)63 (29)40 (28)23 (32)NS
    Nonsmokers, n (%)85 (39)62 (43)23 (32)NS
    Hyperlipidemia, n (%)156 (73)98 (69)68 (82)0.049
    Hypertension, n (%)179 (86)113 (78)66 (93)0.007
    Diabetes mellitus, n (%)84 (39)56 (39)28 (40)NS
    Premature familial CV disease, n (%)71 (33)30 (20)30 (42)0.001
Coronary disease
    Coronary lesion, n (%)104 (49)67 (46)37 (52)NS
    Vessels with ≥stenosis, mean±SD0.8±1.00.7±0.90.9±1.1NS
    Myocardial infarction, n (%)61 (28)41 (28)20 (28)NS
    Age myocardial infarction, mean±SD, y58.5±10.359.2±1156.9±8.7NS
OB/GYN history
    Menarche, mean±SD, y12.8±1.912.8±1.912.7±1.8NS
    Menopause, mean±SD, y46.7±6.845.8±6.948.3±6.30.046
    Hormonal supplementation, n (%)54 (25)37 (25)17 (24)NS
    Duration hormonal supplementation, mean±SD, y4.2±4.65.1±5.42.4±2.0NS
    No. of pregnancies, mean±SD4.6±2.44.4±2.54.8±2.0NS
    Spontaneous abortions, n (%)77 (36)46 (31)31 (44)0.078
    Preterm births, n (%)67 (31)35 (24)32 (46)0.001
    Birth weight <2500 g, n (%)44 (21)21 (15)23 (33)0.0007
    Stillbirths, n (%)18 (8)9 (6)9 (13)NS
    Gestational diabetes, n (%)17 (8)11 (8)6 (9)NS
    Recurrent abortions, n (%)14 (7)9 (6)5 (7)NS

As shown in the Table, the frequency of the smoking habit and of diabetes mellitus did not differ in women with NPs and HPs, whereas hypertension, hyperlipidemia, and a family history of premature CV disease were more frequent in participants with HPs; in addition, body mass index tended to be higher in women with HPs. In concordance with their high CV risk profile, almost half of all of the participants had hemodynamically significant coronary lesions, and approximately half of them had myocardial infarctions; 67% of the infarctions occurred before 65 years of age, thus qualifying as premature CV disease. Neither the frequency nor the duration of hormonal replacement therapy differed between study groups; this was used for >5 years in 6% of the women; of them, 2 were on supplementation at the time of angiography, and 1 had received it for a year at the time of infarction.

Women who had HPs were younger and had later menopause than women who had NPs; those with HPs also had a marked family history of premature atheromatous disease. Women with HPs who presented with myocardial infarction at the time of angiography, or previously, were younger than those with NPs, but the difference did not attain statistical significance.

Regarding the number of stenotic coronary arteries, no significant differences were observed among the NP and HP groups. According to a Poisson regression analysis of the correlation between age and the number of diseased coronary vessels, the mean number of stenotic arteries increased in both groups with age (P=0.006); however, the logarithm of the 10-year progression of the number of stenosed arteries was 28% per 10 years in HPs and 22% in NPs (P=0.034; Figure 1).

Figure 1. Correlation between age and log number of stenotic coronary arteries in women with NPs (gray line and diamonds) and HPs (black line and diamonds), according to Poisson’s regression analysis. a=−1.93; b=0.02 (NP) and 0.025 (HP); P=0.05 and 0.034 for age and for the interaction of age with HP, respectively.

With respect to obstetric outcomes (Table), apart from the 33.7% of the participants with HPs, a high percentage of women had spontaneous abortions, preterm births, and infants with low birth weight. Women with preterm births and infants with low birth weights prevailed in the HPs, whereas women with spontaneous abortions tended to increase in HPs. Other pregnancy complications, such as gestational diabetes, recurrent abortions, intrahepatic cholestasis, placenta previa, ectopic pregnancy, and placenta abruptio, were observed in 1% to 8% of women; only 1 woman presented eclampsia. No significant differences were observed between HPs and NPs in the rates of these complications. Only 39 women in the entire study group had impeccable reproductive histories.

In the multivariate analysis, coronary artery disease was nonsignificantly associated with HPs but showed a significant association with diabetes mellitus, a family history of premature CV disease, and current smoking (Figure 2). HPs were associated in the univariate analysis with a higher likelihood of a familial premature CV disease (odds ratio [OR]: 2.8; CI: 1.5 to 5.2) and in the multivariate analysis with future hypertension (OR: 4.4, CI: 1.5 to 12.5) and a border line significance with hyperlipidemia (OR: 1.9, CI: 0.96 to 4.1).

Figure 2. ORs relating coronary artery disease to smoking, familial premature CV disease, diabetes mellitus, and HP adjusted by age, smoking, diabetes mellitus, body mass index, and familial premature CV disease. *OR for HP according to univariate analysis.

Despite using an unbiased selection for contacting and excluding study participants, we wished to characterize women who underwent angiography but were not included in the analysis. These women did not differ from the study group in body mass index (27.4±4.6) and in the frequency of hypertension (82%), diabetes mellitus (33%), presence of coronary lesions (53%), and myocardial infarctions (32%). Although age and the number of stenotic coronary arteries were higher among these women (62.7±11.3 years and 0.9±1.1 arteries per woman; P=0.059) than among the participants, this difference did not attain statistical significance (P=0.058 and P=0.059, respectively).

Discussion

To our knowledge, this is the first case-control study to use selective angiography in all of the participants to test the influence of remote hypertension in pregnancy on hemodynamically significant coronary artery disease. The analysis shows that coronary artery disease presented earlier, and had a greater increase in coronary lesions with age, in women with previous HPs than in women with previous NPs. The study also underscores the importance of the relationship between premature familial vascular disease and increases of the risk of HPs, and later of coronary disease, a finding probably related to the genetic and environmental clustering of related (cognate and yet unidentified) CV risks.

The main strength of this study was the use of selective angiography, the gold standard to define coronary disease; these angiographies permitted testing of the association of remote HPs with a wide range of coronary conditions, from intact arterial beds to multiple vessel disease, as well as with the sequelae of myocardial infarctions. Another advantage derived from a relative lack of interventions, as apart from the previous management of hypertension and diabetes mellitus, hyperlipidemia was diagnosed and smoking eliminated once the angiographies had been performed. Lastly, the participants presented a high frequency of CV risk factors, exceeding the prevalences observed in similar age groups in the Chilean population,16 which explains the magnitude and early onset of coronary disease; it is likely that this contributed several decades in advance to a high incidence of obstetric complications, similar to that reported recently by Catov et al17 for a group with marked CV risks.

The most important limitation of the study is that the obstetric complications, the mainstay for categorizing the participants, were obtained by maternal recall. In spite of this, we believe that the reliability of the obstetric data was high based on the complete agreement obtained in a subgroup of randomly selected participants when asked in 2 separate interviews whether they had HPs, preterm births, and low birth weight infants. In addition, the numbers of these same complications per women were similar in both interviews. Moreover, a concordance of 0.90 was obtained for recalled birth weight of all of the infants, within the range observed by Catov et al.18 We attribute the good reproducibility to double checking within the interview, a precaution that increases sensitivity and specificity,11,19 to the time spent in the interview, and to the fact that women were asked about HPs, a term that has yielded a higher agreement than preeclampsia, an unfamiliar medical term.19–21 However, because the concordance for the age of menopause was intermediate, this parameter was excluded from the multivariate analysis. A bias to report false-positive HPs among women with chronic hypertension would have diluted the association between HPs and coronary artery disease.

Another limitation of this study is the lack of characterization of the different presentations of hypertension in pregnancy. Because the need for a precise definition of HPs in the clinical setting to be used for research purposes has been reinforced rather recently,22 it is highly likely that medical charts lacked an accurate diagnosis in a significant number of patients. Similarly, the presence of CV risk factors during the reproductive years may not have been evaluated in most of these patients, because the impact of such factors on gestation has been evident only recently.23–31 Some reports do not differentiate between types of HPs,7,11 and others show a greater association between preeclampsia and CV disease.1,4,5,8,9 Based on these latter studies, our failure to characterize the different forms of HPs could have blunted their impact on coronary disease.

It might be argued that the 3-year difference with which women with previous HPs were submitted to coronary angiograms and the 6% increase in stenotic vessels over a 10-year period observed in them as compared with women with previous NPs (28% versus 22%) are smaller than the relative risks attributed previously to HPs. However, greater incidence of CV disease after HPs has been reported with shorter follow-up32 and in younger women.1 A weaker association than that estimated by previous reports could also be accounted for by the possibility of earlier CV deaths associated with HPs. Finally, we must be aware that this study was focused on identifying atheromatous plaques in the major coronary arteries and has missed coronary microvascular and/or endothelial dysfunction, which should be especially considered in the women with myocardial ischemia and nonobstructive or absent coronary lesions33; thus, endothelial dysfunction could represent the persistence of a condition found after a preeclamptic pregnancy,34,35 in addition to being the initial stage of the atheromatous lesions. Even so, with the current difficulties in the evaluation, diagnosis, and management of coronary disease in women,36 the clinical impact of even the small temporal differences found by us may be amplified, making the remote prognosis of HPs an important public health issue.

The lack of a significant relative risk between coronary disease and HPs could be influenced by the power of the present study. However, the risk posed by familial premature disease in both conditions supports the role of common intermediate mediators. Because CV risk factors increase along a continuum, it is likely that our study group had accrued, during their reproductive years, incipient circulating and functional CV risks and even vascular morphological changes.37–43 This hypothesis is supported by a significant association of hypertension in pregnancy with chronic hypertension and by a borderline association with hyperlipidemia late in life. It is highly likely that conventional, arbitrary blood pressure cutoffs may not be valid in the face of the metabolic, hemodynamic, and immunologic challenges posed to the pregnant mother, as demonstrated by the association of preeclampsia with high-normal blood pressures.27 Based on the hypothesis that hypertension in pregnancy expresses underlying maternal conditions, we propose that proteinuric versus nonproteinuric HPs relate to CV complications through 2 different pathophysiologic pathways. In proteinuric HP (ie, preeclampsia), there may be an underlying endothelial dysfunction because of CV risk factors,23–32,34,35,37–43 which is exacerbated and clinically expressed by increased syncytiotrophoblast debris shedded into the maternal circulation.44–50 In nonproteinuric HP (ie, transient hypertension or exacerbation of an underlying hypertension), there is a restricted capacity to stimulate vasodilatory and antiaggregating factors (eg, prostacyclin,51 tissue kallikrein,52 and angiotensin-[1-7]53); this limitation hampers the adaptation to the systemic hemodynamic changes of pregnancy54–57 and may favor CV disease later in life.

We believe that the finding of earlier angiographic coronary lesions in women who reported HPs adds a piece to the puzzle initiated by the registry-based cohort follow-up. Further studies are needed in women undergoing coronary angiography, which should ideally be matched to their remote obstetric records, to test whether the present findings may be extended to populations of different ages and ethnicities. In addition, diagnostic tests for coronary microvascular and/or endothelial dysfunction should be incorporated in future studies.

Perspectives

This study confirms the link between HPs and CV disease and emphasizes the need to detect clinical and biochemical markers of CV risks before gestation. Such early detection would allow primary prevention of CV disease, and possibly prediction and early management of gestational complications. The awareness that pregnancy represents a CV “stress test” should reinforce early management of CV risks in women presenting an abnormal response, leading to effective prevention or a delay of CV disease.

We are indebted to the cardiologists Alejandro Fajuri, Eduardo Guarda, and Lucio León for performing the coronary angiograms; to Claudia Mena, Rebeca Figueroa, and Paola Zuanic, RN, for their collaboration in contacting the study participants; and to Arnaldo Foradori, MD, for his constructive help in the review of the article.

Sources of Funding

This study was partly supported by grant 1080228 from Fondo Nacional de Ciencia y Tecnología (Fondecyt), Chile. F.Q. and A.v.S. received a grant for medical students participating in elective research programs of the Pontificia Universidad Católica School of Medicine.

Disclosures

None.

Footnotes

Correspondence to Gloria Valdés, Departamento de Nefrología y Centro Investigaciones Médicas, Escuela Medicina Pontificia Universidad Católica, Marcoleta 391, PO Box 114-D, Santiago, Chile. E-mail

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