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Cardiovascular and thromboembolic events following hypertensive pregnancy
Cardiovascular and Thromboembolic Events Following Hypertensive Pregnancy Bryan Kestenbaum, MD, Stephen L. Seliger, MD, Thomas R. Easterling, MD, Daniel L. Gillen, MS, Cathy W. Critchlow, PhD, Catherine O. Stehman-Breen, MD, and Stephen M. Schwartz, PhD ● Background: Hypertension is a common complication of pregnancy. Previous evidence has linked pregnancyrelated hypertension to maternal cardiovascular disease. We conducted a population-based cohort study to estimate the risks for cardiovascular and thromboembolic events in women with pregnancy-related hypertension. Methods: We analyzed data from all singleton births recorded in Washington State from 1987 to 1998. Mothers were classified as having gestational hypertension, preeclampsia, or chronic hypertension based on hospital discharge and birth record information. Birth records were linked to subsequent hospitalizations within Washington State. Proportional hazards models were used to estimate the relationship between each form of pregnancy-related hypertension and subsequent risk for cardiovascular and thromboembolic events. Results: We identified 31,239 eligible hypertensive pregnancies from 807,010 births. During follow-up, there were 118 hospitalizations for a first acute cardiovascular event and 172 hospitalizations for a first thromboembolic event. Gestational hypertension, mild preeclampsia, and severe preeclampsia were associated with 2.8-fold (95% confidence interval [CI], 1.6 to 4.8), 2.2-fold (95% CI, 1.3 to 3.6), and 3.3-fold (95% CI, 1.7 to 6.5) greater risks for cardiovascular events, respectively. Severe preeclampsia was associated with a 2.3-fold (95% CI, 1.3 to 4.2) greater risk for thromboembolic events. Conclusion: Preeclampsia and gestational hypertension are associated with increased risk for cardiovascular events. Pregnancy-induced hypertension appears to be an important risk factor for the development of future cardiovascular disease in young women. Am J Kidney Dis 42:982-989. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Preeclampsia; pregnancy; hypertension; myocardial infarction; stroke.
H
YPERTENSION complicates approximately 7% of all pregnancies.1,2 Gestational hypertension, broadly defined as hypertension occurring after the 20th week of pregnancy, may be complicated further by proteinuria and systemic disturbances that characterize the syndrome of preeclampsia.3 Preeclampsia imparts excess perinatal risk to both mother and fetus.4-7 Pregnancies complicated by preeclampsia often are delivered prematurely to protect the mother and fetus from a deteriorating intrauterine environment. A number of pathophysiological findings have been associated with preeclampsia, including en-
dothelial dysfunction, insulin resistance, and thrombophilia.8-13 Women who have experienced a hypertensive pregnancy are at increased risk for chronic hypertension later in life.14-17 In addition, population-based registry studies have linked preeclampsia with maternal cardiovascular and thromboembolic disease.18,19 We used birth certificate and hospitalization data to examine risks for cardiovascular and thromboembolic events in a large cohort of women giving birth in Washington State between 1987 and 1998. METHODS
Study Population From the Department of Medicine, Division of Nephrology; Departments of Obstetrics and Gynecology; and Biostatistics; Department of Epidemiology, HPV Research Group; Division of Nephrology, Puget Sound Health Care System; and Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington; and the Fred Hutchinson Cancer Research Center, Program in Epidemiology, Seattle, WA. Received May 9, 2003; accepted in revised form July 22, 2003. Address reprint requests to Bryan Kestenbaum, MD, Division of Nephrology, Box 3565221 BB 1265 Health Sciences Bldg, 1959 NE Pacific, Seattle, WA 98195. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4205-0008$30.00/0 doi:10.1053/S0272-6386(03)01012-6 982
Data were obtained from all live singleton births recorded in the Washington State Birth Events Record Database (BERD), which links birth hospitalization records with state birth certificate data. For purposes of this analysis, birth record data from 1987 to 1998 were used. Sociodemographic, medical, and obstetrical histories and complications of the index pregnancy were recorded on birth certificates by hospital staff from interviews with the mother and/or from patients’ charts, then submitted electronically to the state department of health. Potential cases of pregnancyrelated hypertension were screened on the basis of having an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for hypertension during pregnancy (ICD-9-CM codes 642.x) or a positive response on the birth certificate to the items “pregnancy induced hypertension,” “chronic hypertension,” or “eclampsia.” Mothers with preexisting cardiac or renal disease,
American Journal of Kidney Diseases, Vol 42, No 5 (November), 2003: pp 982-989
HYPERTENSIVE PREGNANCY AND CLINICAL OUTCOMES Table 1.
Classification System to Define Forms of Pregnancy-Related Hypertension
Hospital Discharge Data ICD-9 Code
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ICD-9 Code Description
Birth Certificate Data Eclampsia
Chronic HTN
Included patients 642.3 Gestational HTN No No 642.3 Gestational HTN Yes No 642.4 Mild preeclampsia No No 642.4 Mild preeclampsia Yes No 642.5 Severe preeclampsia Any No 642.6 Eclampsia Any No Total included Excluded patients 642.3-6 Gestational HTN/preeclampsia Any Yes 642.0 Essential HTN Any Any 642.1 Renal HTN Any Any 642.2 Preexisting HTN Any Any 642.7 Preeclampsia with chronic HTN Any Any Unclassified HTN Any Any Because of nonlinkage with maternal hospitalization data Because of lack of ICD-9 code for pregnancy-related HTN 642.9 Because of ICD-9 code 642.9, unspecified HTN Total excluded
No. of Patients (%)
Classification of HTN
10,687 (24.5) 112 (0.3) 15,508 (35.6) 931 (2.1) 3,591 (8.2) 410 (0.9) 31,239
Gestational HTN Severe preeclampsia Mild preeclampsia Severe preeclampsia Severe preeclampsia Severe preeclampsia
681 (1.6) 572 (1.3) 41 (0.1) 122 (0.3) 1,116 (2.7) 9,830 (22.5) 3,436 (7.9) 5,009 (11.5) 1,385 (3.2) 12,362
Chronic HTN Chronic HTN Chronic HTN Chronic HTN Chronic HTN Unclassified HTN
Abbreviation: HTN, hypertension.
established diabetes, or age older than 45 or younger than 15 years were excluded from this analysis.
Classification of Pregnancy-Related Hypertension Cases in which ICD-9-CM hospital discharge codes did not link to the delivery, were missing, or coded for “unspecified hypertension” were excluded (Table 1). Remaining cases were classified into gestational hypertension, mild preeclampsia, and severe preeclampsia based on a combination of birth certificate data and ICD-9-CM codes linked to the index pregnancy (Table 1). Mothers were classified as having chronic hypertension if they had a positive response to the item “chronic hypertension” on their birth record or had any of the following ICD-9-CM codes linked to their delivery: 642.0, benign hypertension; 642.1, renal related hypertension; 642.2, preexisting hypertension; or 642.7, preeclampsia superimposed on preexisting hypertension. Our conservative strategy attempted to remove all suspected instances of chronic hypertension from the gestational hypertension and preeclampsia groups.
Ascertainment and Definition of Outcomes Maternal birth hospitalizations were linked to subsequent hospitalizations recorded in the Comprehensive Hospital Abstract Reporting System (CHARS) database, which collects discharge diagnoses from all nonfederal hospitals in the State of Washington. CHARS was complete through December 31, 2000. For each hospitalization, up to 9 ICD-9-CM diagnoses codes and 6 ICD-9 procedure codes were analyzed. Cardiovascular events are defined as hospitalizations for acute myocardial infarction (ICD-9-CM code 410.x),
acute stroke (ICD-9-CM codes 430.x, 431.x, 434.x, 436.x), or coronary artery revascularization procedure, including coronary artery bypass grafting (ICD-9 procedure codes 36.x).20-22 Because of their low sensitivity and specificity for predicting stroke, ICD-9-CM codes 432, 433, and 435 were not used.21 Thromboembolic events are defined as hospitalizations for deep venous thrombosis (ICD-9-CM code 451.1 or 453.x) or pulmonary embolism (ICD-9-CM code 415.1). For mothers with multiple outcomes, the first outcome was retained for analysis.
Matching A sample of control mothers without hypertension during pregnancy was randomly selected from live singleton births in BERD. Nonhypertensive controls are defined as having no indication of pregnancy-related hypertension during any recorded pregnancy based on birth record data and ICD-9 codes linked to the deliveries. Approximately 4 control mothers were matched to each hypertensive mother by age, parity, and calendar year of delivery. Because of logistic constraints, control mothers were randomly sampled from BERD without respect to their subsequent outcomes before matching. Matching on exposure status was performed to reduce potential confounding caused by age, parity, and delivery year. We adjusted further for these variables in the final multivariate models to reduce residual confounding and increase precision of the multivariate models.
Statistical Analysis Cox’s proportional hazards model23 was used to estimate the relationship, in the form of hazard ratios, between each
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KESTENBAUM ET AL Table 2.
Age at delivery* (y) Primipara* Race White African American Hispanic Other Gestational diabetes Smoking Cesarean section Uninsured/Medicaid Prepregnancy weight (lbs)† Years of education† Family income (annual $) Month of prenatal visit 1 Alcohol use Gestational age (wk) Birth weight (g) Five-minute Apgar score
Baseline Characteristics of the Study Population
Control Births (n ⫽ 92,902)
Gestational Hypertension (n ⫽ 10,687)
Mild Preeclampsia (n ⫽ 15,508)
Severe Preeclampsia (n ⫽ 5044)
26.2 ⫾ 6.1 73.2 (67,997)
26.5 ⫾ 6.1 69.0 (7,378)
26.1 ⫾ 6.1 75.3 (11,682)
26.0 ⫾ 6.4 75.6 (3,815)
79.0 (71,797) 3.2 (2,894) 9.1 (8,312) 8.7 (7,927) 2.2 (2,011) 18.3 (16,473) 18.7 (17,331) 36.1 (33,568) 141.3 ⫾ 31.0 12.9 ⫾ 2.8 30,767 ⫾ 10,045 2.6 ⫾ 1.5 3.0 (2,189) 39.3 ⫾ 1.9 3,429 ⫾ 543 8.9 ⫾ 0.7
84.1 (8,804) 3.6 (379) 5.7 (597) 6.6 (689) 4.9 (519) 13.5 (1,403) 23.2 (2,478) 32.2 (3,437) 159.6 ⫾ 38.8 13.1 ⫾ 2.4 31,571 ⫾ 9,356 2.5 ⫾ 1.4 2.5 (246) 39.0 ⫾ 1.6 3,376 ⫾ 576 8.8 ⫾ 0.7
81.3 (12,329) 3.7 (567) 7.8 (1,179) 7.1 (1,082) 11.4 (1,772) 15.4 (2,177) 26.7 (4,127) 36.0 (5,575) 155.2 ⫾ 37.5 12.9 ⫾ 2.6 30,847 ⫾ 10,018 2.5 ⫾ 1.5 2.5 (260) 38.8 ⫾ 1.9 3,333 ⫾ 615 8.8 ⫾ 0.8
74.7 (3,682) 5.7 (280) 11.9 (588) 7.8 (382) 7.8 (394) 13.2 (621) 44.7 (2,251) 40.5 (2,041) 150.7 ⫾ 37.6 12.6 ⫾ 2.9 29,994 ⫾ 10,034 2.6 ⫾ 1.6 2.4 (94) 36.8 ⫾ 3.4 2,763 ⫾ 895 8.4 ⫾ 1.2
NOTE. Values expressed as mean ⫾ SD or percent (number of patients). *Variable matched by design. †Variable added to birth record after 1991.
form of pregnancy-related hypertension and subsequent risk for a first cardiovascular or first thromboembolic event. Wald-type confidence intervals (CIs) were calculated by using model-based variance estimates after accounting for clustering by matching group, defined by age, parity, and calendar year of delivery. Variables included in multivariate models were selected a priori on the basis of their known relationship with cardiovascular and thromboembolic disease and completeness of the birth certificate data. Multivariate models included age (in continuous years), parity (prima versus multi), race/ethnicity (white, African American, Hispanic, other), gestational diabetes (yes versus no), smoking (yes versus no), cesarean section (yes versus no), and type of insurance used for the index pregnancy (Medicaid or uninsured versus insured). We examined whether hazard ratio estimates were appreciably different across subgroups of mothers by evaluating the goodness-of-fit of interaction terms using the likelihood ratio test. Prepregnancy weight and years of education were added to the birth record after 1991 and thus were unsuitable for inclusion in the models because of the resulting high proportion (⬎50%) of missing data. We included these variables for visual inspection of baseline characteristics in Table 2. Median family income was derived by linkage of address data to census bureau data for the census tract. When available, body mass index (BMI) was determined by obtaining maternal height through linkage to the Washington State drivers’ license registry. Each mother was considered at risk throughout her follow-up period (until the study closed December 31, 2001) unless it was determined that she had died, at which time she
was censored. Deaths were determined by linking BERD to Washington State death records. Analysis of residuals and graphic methods were used verify the existence of proportional hazards for each covariate in the multivariate model. Approval for this study was obtained from the University of Washington Human Subjects Division (Seattle, WA).
RESULTS
We identified 44,550 potential hypertensive pregnancies (5.5%) from 807,010 singleton births in Washington State between 1987 and 1998. We excluded 144 mothers (0.3%) with preexisting cardiac disease, 194 mothers (0.4%) with preexisting renal disease, 426 mothers (1.0%) with established nongestational diabetes, and 185 mothers (0.4%) with age younger than 15 or older than 45 years, leaving 43,601 women with a potential hypertensive pregnancy. We further excluded 2,532 mothers (5.8%) with suspected chronic hypertension and 9,830 mothers (22.5%) for whom hypertension during pregnancy could not be classified because ICD-9-CM discharge codes did not link to the index pregnancy, were missing, or indicated “unspecified hypertension” (Table 1). After these exclusions, 31,239 hypertensive pregnancies were classified into gestational hypertension, mild preeclampsia, and severe preeclampsia, as listed in Table 1. A sample
HYPERTENSIVE PREGNANCY AND CLINICAL OUTCOMES Table 3.
Normotensive pregnancy Gestational hypertension Mild preeclampsia Severe preeclampsia Race White African American Hispanic Other Smoking Gestational diabetes Cesarean section Uninsured
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Risk for Cardiovascular Events After a Hypertensive Pregnancy
Events (n ⫽ 118)
Events/100,000 Patient-Years
Crude Hazard Ratio (95% CI)
P
Adjusted Hazard Ratio (95% CI)
64 19 24 11
8.9 25.3 18.4 29.4
2.9 (1.8-4.9) 2.0 (1.3-3.2) 3.3 (1.8-6.3)
⬍0.001 0.003 ⬍0.001
Reference 2.8 (1.6-4.8) 2.2 (1.3-3.6) 3.3 (1.7-6.5)
⬍0.001 0.002 0.001
83 10 10 12 32 8 33 41
10.8 32.0 14.2 16.3 18.7 20.5 15.8 11.9
3.0 (1.6-5.8) 1.4 (0.7-2.6) 1.5 (0.8-2.8) 1.7 (1.1-2.6) 1.7 (0.8-3.5) 1.4 (0.9-2.1) 1.0 (0.7-1.4)
0.001 0.337 0.170 0.009 0.149 0.106 0.838
Reference 3.8 (2.0-7.2) 2.1 (1.0-4.3) 1.5 (0.8-2.9) 2.3 (1.5-3.6) 1.2 (0.6-2.5) 1.0 (0.7-1.5) 1.2 (0.7-1.8)
⬍0.001 0.054 0.184 ⬍0.001 0.661 0.954 0.509
P
NOTE. Subjects with pregnancy-related hypertension were matched to normotensive subjects by age, parity, and delivery year.
of 92,902 control mothers without pregnancyrelated hypertension was matched to the sample of hypertensive mothers by age, parity, and calendar year of delivery to achieve a total cohort size of 124,141. At the index pregnancy, mothers with a hypertensive pregnancy generally were more likely to have gestational diabetes, have a greater prepregnancy weight, and have undergone delivery by cesarean section and were less likely to smoke (Table 2). Socioeconomic factors, such as median family income, years of education, and type of medical insurance, did not differ appreciably between births with or without pregnancyrelated hypertension. Birth weights were appreciably lower among births complicated by severe preeclampsia, but not gestational hypertension or mild preeclampsia. There were no notable differences in baseline characteristics between mothers excluded because of unclassified hypertension versus those included with pregnancyrelated hypertension. Mean length of follow-up was 7.8 years (intraquartile range, 4.8, 7.6, and 10.6 years), providing 964,140 person-years of follow-up. During follow-up, there were 118 first hospitalizations for acute cardiovascular events among all mothers in the study cohort. Mean maternal age at the time of a first cardiovascular event was 36.1 years (intraquartile range, 30.7, 36.8, and 42.0 years). Among women who developed cardiovascular events, mean time between the index preg-
nancy and first cardiovascular event was 5.1 years (intraquartile range, 2.0, 4.7, and 7.9 years). Among women without hypertension during pregnancy, the incidence density of hospitalization for a first cardiovascular event was 8.9 events/100,000 patient-years compared with 25.3, 18.4, and 29.4 first events/100,000 person-years among women with gestational hypertension, mild preeclampsia, and severe preeclampsia, respectively. After adjustment for confounding factors, all forms of pregnancy-associated hypertension were associated with a significantly increased risk for cardiovascular events (Table 3). AfricanAmerican race and smoking also were associated with a significantly increased risk for cardiovascular outcomes. The magnitude of excess risk associated with preeclampsia was similar to that for smoking. The relationship between pregnancy-related hypertension and cardiovascular events was not found to differ significantly according to age, race, parity, and smoking status. In the entire study cohort, there were 172 hospitalizations for a first acute thromboembolic event. Mean maternal age at the time of first thromboembolic event was 31.1 years. In control mothers, the incidence density of first thromboembolic events was 15.4/100,000 patient-years compared with 21.3, 23.0, and 40.1 events/ 100,000 person-years in mothers with gestational hypertension, mild preeclampsia, and severe preeclampsia, respectively. After adjustment, women with severe preeclampsia had a signifi-
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KESTENBAUM ET AL Table 4.
Normotensive pregnancy Gestational hypertension Mild preeclampsia Severe preeclampsia Race White African American Hispanic Other Smoking Gestational diabetes Cesarean section Uninsured
Risk for Thromboembolic Events After a Hypertensive Pregnancy
Events (n ⫽ 172)
Events/100,000 Patient-Years
Crude Hazard Ratio (95% CI)
P
Adjusted Hazard Ratio (95% CI)
111 16 30 15
15.4 21.3 23.0 40.1
1.4 (0.8-2.4) 1.5 (1.0-2.2) 2.6 (1.5-4.5)
0.208 0.055 ⬍0.001
Reference 1.5 (0.9-2.5) 1.4 (0.9-2.2) 2.3 (1.3-4.2)
0.142 0.099 0.006
141 9 5 11 45 11 44 70
18.3 28.8 7.1 14.9 26.3 28.2 21.1 20.3
1.6 (0.8-3.1) 0.4 (0.2-1.0) 0.8 (0.4-1.5) 1.7 (1.2-2.3) 1.6 (0.9-2.9) 1.2 (0.9-1.7) 1.2 (0.9-1.7)
0.182 0.043 0.529 0.004 0.132 0.220 0.178
Reference 1.5 (0.7-3.0) 0.4 (0.2-1.1) 0.8 (0.4-1.6) 1.5 (1.1-2.2) 1.3 (0.6-2.7) 1.2 (0.8-1.7) 1.2 (0.8-1.9)
0.313 0.065 0.556 0.025 0.481 0.306 0.276
P
NOTE. Subjects with pregnancy-related hypertension were matched to normotensive subjects by age, parity, and delivery year.
cantly greater risk for a first thromboembolic event compared with control women without hypertension during pregnancy (Table 4). Smoking also was associated with a significantly greater risk for a first thromboembolic event. We found no significant interaction between age, race, parity, smoking status, and relationship between pregnancy-related hypertension and thromboembolic events. To examine whether excluded women with unclassified hypertension during pregnancy may have differed from those included in the study, we examined the risk for cardiovascular and thromboembolic events in women with unclassified hypertension. The hazard ratio for acute cardiovascular events in women with unclassified hypertension was 2.1 (95% CI, 1.1 to 4.1). The hazard ratio for acute thromboembolic events among women with unclassified hypertension was 1.6 (95% CI, 0.9 to 2.9). DISCUSSION
We found gestational hypertension and preeclampsia to be associated with a significantly increased risk for cardiovascular events. Gestational hypertension, mild preeclampsia, and severe preeclampsia were associated with 2.8-, 2.2-, and 3.3-fold greater risks for cardiovascular events, respectively. Severe preeclampsia was associated with an increased long-term risk for deep venous thrombosis and pulmonary embolism.
Our results are consistent with those of 2 population-based studies from the United Kingdom.18,19 Smith et al18 reported a 2-fold greater risk for death or hospitalization for ischemic heart disease in preeclamptic women identified from the Scottish Morbidity Record. Hannaford et al19 found an increased risk for myocardial infarction, stroke, and thromboembolic disease in preeclamptic women enrolled in the Royal College of General Practitioners’ Oral Contraceptive Study. The current study aims to build on previous work by adding ICD-9-CM hospital discharge data from the index pregnancy to birth record data in an attempt to remove suspected instances of chronic hypertension and further subclassify women to individual forms of pregnancy-related hypertension. Ours also is the first study to associate gestational hypertension and preeclampsia with increased risk for cardiovascular events in a large sample of women from the United States. Previous case series have suggested an association between preeclampsia and risk for chronic hypertension, renal disease, and death.14-16,18,24,25 Chesley et al24 reported a 2- to 5-fold increase in risk for mortality in subgroups of women with eclampsia after 30 years of follow-up. In 2 case series, Sibai et al15,25 reported a substantially greater incidence of chronic hypertension in women with clinically confirmed preeclampsia/ eclampsia compared with women with a normotensive pregnancy. However, previous case se-
HYPERTENSIVE PREGNANCY AND CLINICAL OUTCOMES
ries have lacked the statistical power to evaluate relative risks for cardiovascular or thromboembolic outcomes associated with a hypertensive pregnancy. A number of mechanisms may explain the observed association between pregnancy-related hypertension and cardiovascular disease. Adverse physiological changes reported during preeclampsia include endothelial cell dysfunction, hemodynamic abnormalities, and insulin resistance.12,13,26-30 Evidence of endothelial cell injury can be observed in the characteristic pathological lesions of preeclampsia found in the glomerulus and uterine boundary vessels.27,31 The endothelialderived vasodilatory factors nitric oxide and prostacyclin are deficient in preeclampsia,30,32,33 possibly explaining the late increase in vasomotor tone observed in some preeclamptic patients.8 In addition, preeclampsia shares important features with insulin resistance. Although baseline glucose levels often are normal during preeclamptic pregnancies, abnormally high insulin levels have been reported after glucose tolerance testing.34 In addition, preeclampsia is characterized by an early increase in cardiac output beyond that expected during normal pregnancy, resembling the early stages of insulin resistance.12,13 If insulin resistance and endothelial dysfunction were to remain active after a hypertensive pregnancy, they could explain the increased risk for cardiovascular disease. Alternatively, hypertension during pregnancy may be the early expression of an adverse genotype associated with premature cardiovascular disease. Previous studies have yielded conflicting results about whether women with preeclampsia possess a specific defect of the coagulation system.11,35 Our results are consistent with those of Hannaford et al19 documenting an increased risk for thromboembolic disease in a large cohort of women with preeclampsia. The specific abnormalities of the coagulation system responsible for the increased risk for clotting await identification. Based on our results, a history of a hypertensive pregnancy is an important risk factor for the development of premature cardiovascular disease. We found the magnitude of excess risk for serious premature cardiovascular events associated with a hypertensive pregnancy to be similar to that of smoking. Women with a history of a
987
hypertensive pregnancy may require more aggressive attention to comorbid cardiovascular risk factors and may demand a lower clinical threshold to initiate diagnostic testing when cardiovascular symptoms arise. The use of birth certificate data and ICD-9 codes to define pregnancy-related hypertension may have resulted in misclassification of the exposure. It seems plausible that errors in classifying subjects with or without pregnancy-related hypertension would be unrelated to whether they subsequently develop cardiovascular or thromboembolic outcomes. If this assumption is correct, the true association between pregnancy-related hypertension, in aggregate, and maternal outcomes is likely to be even stronger than what we report. However, if women with chronic hypertension were preferentially miscoded as having gestational hypertension or preeclampsia, bias may have occurred. Also, the use of ICD-9 codes to classify individual forms of pregnancy-related hypertension may be particularly prone to classification error. Thus, although our results provide evidence of an association between all forms of pregnancy-related hypertension and subsequent maternal outcomes, they provide only a tentative indication regarding possible differences in associations among specific types of pregnancyrelated hypertension. The resultant loss of greater than 20% of the cohort because of unspecified or missing ICD9-CM codes may limit the generalizability of our results. However, we found that baseline characteristics in hypertensive mothers excluded because of improper coding did not differ from those included in the study, suggesting that excluded mothers were similar to those included in the study. In addition, we found hazard ratios for cardiovascular and thromboembolic events to be similar between women included in the study and those excluded because of unspecified or missing ICD-9-CM codes. The use of ICD-9-CM codes to define cardiovascular and thromboembolic events may lead to some misclassification of these outcomes. However, the ICD-9-CM codes used in this study to define acute myocardial infarction and acute stroke have been found to have a positive predictive value of 79% to 96% and 70% to 90%, respectively.20-22,36 No large studies have validated ICD-9-CM codes for deep venous thrombo-
988
sis or pulmonary embolism. We would not expect misclassification of thromboembolic events to be differential with respect to exposure and outcome; therefore, it should not lead to biased results. Similarly, migration into and out of Washington State may result in some loss of power because of noncaptured outcomes, but migration would not be expected to be strongly related to the development of preeclampsia and thus should not cause bias. It is possible that women with a hypertensive pregnancy have other attributes that result in their increased risk for cardiovascular events. We attempted to account for known and measured potential confounding factors by including them in multivariate models. Given the magnitude of the association found between hypertensive pregnancy and subsequent outcomes, an unmeasured factor would have to be very strongly associated with both the development of pregnancy-related hypertension and long-term risk for cardiovascular or thromboembolic events to appreciably change our estimates. Maternal weight was a concern as a potential confounder and could not be directly included in multivariate models because of the high proportion of missing data and resultant loss of power. However, using available data from 35 cardiovascular events in 60,113 women who gave birth after 1991, we found little change in hazard ratios for any form of pregnancy-related hypertension after including weight in the multivariate models. Similarly, we did not find significant changes in hazard ratio estimates when including BMI in the multivariate models. These analyses suggest that weight (or BMI) does not significantly confound the relationships we observed. We did not have direct information regarding oral contraceptive use, which can increase the risk for thromboembolic events in young women.37,38 We attempted to address this issue by analyzing the number of future pregnancies within exposure groups as a surrogate marker for contraceptive use. We found no difference in number of future pregnancies comparing women with and without pregnancyrelated hypertension. In summary, gestational hypertension and preeclampsia were associated with a significantly increased risk for subsequent cardiovascular events. Severe preeclampsia was associated with a significantly increased risk for thromboem-
KESTENBAUM ET AL
bolic events distant from pregnancy. The increase in cardiovascular disease risk associated with forms of pregnancy-induced hypertension was similar to that of smoking. Women with a history of gestational hypertension and preeclampsia may require more careful medical follow-up, with particular attention to their risk for premature cardiovascular disease. ACKNOWLEDGMENT The authors thank Bill O’Brien for technical assistance in preparing data for this analysis.
REFERENCES 1. Lindmark G, Lindberg B, Hogstedt S: The incidence of hypertensive disease in pregnancy. Acta Obstet Gynecol Scand Suppl 118:29-32, 1984 2. Sibai BM: Hypertension in pregnancy, in Gabbe SG, Nieby JR, Simpson JL (eds): Obstetrics: Normal and Problem Pregnancies (ed 3). New York, NY, Churchill Livingstone, 1996, pp 935-996 3. Cunningham FMP, Gant N: Hypertensive disorders in pregnancy, in Cunningham FG, MacDonald PC, Gant NF (eds): Williams Obstetrics (ed 18). Norwalk, CT, Appleton & Lange, 1989, pp 654-694 4. Ananth CV, Peedicayil A, Savitz DA: Effect of hypertensive diseases in pregnancy on birthweight, gestational duration, and small-for-gestational-age births. Epidemiology 6:391-395, 1995 5. McCowan LM, Buist RG, North RA, Gamble G: Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 103:123-129, 1996 6. Rey E, Couturier A: The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol 171:410-416, 1994 7. Sibai BM, Taslimi MM, el-Nazer A, Amon E, Mabie BC, Ryan GM: Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 155:501-509, 1986 8. VanWijk MJ, Boer K, van der Meulen ET, Bleker OP, Spaan JA, VanBavel E: Resistance artery smooth muscle function in pregnancy and preeclampsia. Am J Obstet Gynecol 186:148-154, 2002 9. Ashworth JR, Warren AY, Baker PN, Johnson IR: Loss of endothelium-dependent relaxation in myometrial resistance arteries in pre-eclampsia. Br J Obstet Gynaecol 104: 1152-1158, 1997 10. Lyall F, Hayman RG, Ashworth JR, Duffie E, Baker PN: Relationship of cell adhesion molecule expression to endothelium-dependent relaxation in normal pregnancy and pregnancies complicated with preeclampsia or fetal growth restriction. J Soc Gynecol Invest 6:196-201, 1999 11. Kupferminc MJ, Eldor A, Steinman N, et al: Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340:9-13, 1999 12. Easterling TR, Benedetti TJ, Schmucker BC, Millard SP: Maternal hemodynamics in normal and preeclamptic
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pregnancies: A longitudinal study. Obstet Gynecol 76:10611069, 1990 13. Bosio PM, McKenna PJ, Conroy R, O’Herlihy C: Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol 94:978-984, 1999 14. Marin R, Gorostidi M, Portal CG, Sanchez M, Sanchez E, Alvarez J: Long-term prognosis of hypertension in pregnancy. Hypertens Pregnancy 19:199-209, 2000 15. Sibai BM, el-Nazer A, Gonzalez-Ruiz A: Severe preeclampsia-eclampsia in young primigravid women: Subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 155:1011-1016, 1986 16. Sibai BM, Sarinoglu C, Mercer BM: Eclampsia. VII. Pregnancy outcome after eclampsia and long-term prognosis. Am J Obstet Gynecol 166:1757-1761, discussion 17611763, 1992 17. North RA, Simmons D, Barnfather D, Upjohn M: What happens to women with preeclampsia? Microalbuminuria and hypertension following preeclampsia. Aust N Z J Obstet Gynaecol 36:233-238, 1996 18. Smith GC, Pell JP, Walsh D: Pregnancy complications and maternal risk of ischaemic heart disease: A retrospective cohort study of 129,290 births. Lancet 357:20022006, 2001 19. Hannaford P, Ferry S, Hirsch S: Cardiovascular sequelae of toxaemia of pregnancy. Heart 77:154-158, 1997 20. Tirschwell DL, Longstreth WT Jr: Validating administrative data in stroke research. Stroke 33:2465-2470, 2002 21. Rosamond WD, Folsom AR, Chambless LE, et al: Stroke incidence and survival among middle-aged adults: 9-Year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke 30:736-743, 1999 22. Petersen LA, Wright S, Normand SL, Daley J: Positive predictive value of the diagnosis of acute myocardial infarction in an administrative database. J Gen Intern Med 14:555-558, 1999 23. Cox D: Regression models and life tables. J R Stat Soc 34:187-220, 1972 24. Chesley SC, Annitto JE, Cosgrove RA: The remote prognosis of eclamptic women. Sixth periodic report. Am J Obstet Gynecol 124:446-459, 1976 25. Sibai BM, Mercer B, Sarinoglu C: Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis. Am J Obstet Gynecol 165:1408-1412, 1991 26. Roberts RN, Henriksen JE, Hadden DR: Insulin sensitivity in pre-eclampsia. Br J Obstet Gynaecol 105:10951100, 1998 27. Shanklin DR, Sibai BM: Ultrastructural aspects of
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preeclampsia. I. Placental bed and uterine boundary vessels. Am J Obstet Gynecol 161:735-741, 1989 28. Morris NH, Eaton BM, Dekker G: Nitric oxide, the endothelium, pregnancy and pre-eclampsia. Br J Obstet Gynaecol 103:4-15, 1996 29. Klockenbusch W, Goecke TW, Krussel JS, Tutschek BA, Crombach G, Schror K: Prostacyclin deficiency and reduced fetoplacental blood flow in pregnancy-induced hypertension and preeclampsia. Gynecol Obstet Invest 50:103107, 2000 30. Seligman SP, Buyon JP, Clancy RM, Young BK, Abramson SB: The role of nitric oxide in the pathogenesis of preeclampsia. Am J Obstet Gynecol 171:944-948, 1994 31. Roberts JM, Taylor RN, Goldfien A: Clinical and biochemical evidence of endothelial cell dysfunction in the pregnancy syndrome preeclampsia. Am J Hypertens 4:700708, 1991 32. Davidge ST, Stranko CP, Roberts JM: Urine but not plasma nitric oxide metabolites are decreased in women with preeclampsia. Am J Obstet Gynecol 174:1008-1013, 1996 33. Mills JL, DerSimonian R, Raymond E, et al: Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: A multicenter prospective study. JAMA 282: 356-362, 1999 34. Jacober SJ, Morris DA, Sowers JR: Postpartum blood pressure and insulin sensitivity in African-American women with recent preeclampsia. Am J Hypertens 7:933-936, 1994 35. Kim YJ, Williamson RA, Murray JC, et al: Genetic susceptibility to preeclampsia: Roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation. Am J Obstet Gynecol 184:1211-1217, 2001 36. van Walraven C, Wang B, Ugnat AM, Naylor CD: False-positive coding for acute myocardial infarction on hospital discharge records: Chart audit results from a tertiary centre. Can J Cardiol 6:383-386, 1990 37. Lidegaard O, Edstrom B, Kreiner S: Oral contraceptives and venous thromboembolism: A five-year national case-control study. Contraception 65:187-196, 2002 38. Lewis MA, Heinemann LA, Spitzer WO, MacRae KD, Bruppacher R: The use of oral contraceptives and the occurrence of acute myocardial infarction in young women: Results from the Transnational Study on Oral Contraceptives and the Health of Young Women. Contraception 56:129140, 1997
H
YPERTENSION complicates approximately 7% of all pregnancies.1,2 Gestational hypertension, broadly defined as hypertension occurring after the 20th week of pregnancy, may be complicated further by proteinuria and systemic disturbances that characterize the syndrome of preeclampsia.3 Preeclampsia imparts excess perinatal risk to both mother and fetus.4-7 Pregnancies complicated by preeclampsia often are delivered prematurely to protect the mother and fetus from a deteriorating intrauterine environment. A number of pathophysiological findings have been associated with preeclampsia, including en-
dothelial dysfunction, insulin resistance, and thrombophilia.8-13 Women who have experienced a hypertensive pregnancy are at increased risk for chronic hypertension later in life.14-17 In addition, population-based registry studies have linked preeclampsia with maternal cardiovascular and thromboembolic disease.18,19 We used birth certificate and hospitalization data to examine risks for cardiovascular and thromboembolic events in a large cohort of women giving birth in Washington State between 1987 and 1998. METHODS
Study Population From the Department of Medicine, Division of Nephrology; Departments of Obstetrics and Gynecology; and Biostatistics; Department of Epidemiology, HPV Research Group; Division of Nephrology, Puget Sound Health Care System; and Department of Epidemiology, Cardiovascular Health Research Unit, University of Washington; and the Fred Hutchinson Cancer Research Center, Program in Epidemiology, Seattle, WA. Received May 9, 2003; accepted in revised form July 22, 2003. Address reprint requests to Bryan Kestenbaum, MD, Division of Nephrology, Box 3565221 BB 1265 Health Sciences Bldg, 1959 NE Pacific, Seattle, WA 98195. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4205-0008$30.00/0 doi:10.1053/S0272-6386(03)01012-6 982
Data were obtained from all live singleton births recorded in the Washington State Birth Events Record Database (BERD), which links birth hospitalization records with state birth certificate data. For purposes of this analysis, birth record data from 1987 to 1998 were used. Sociodemographic, medical, and obstetrical histories and complications of the index pregnancy were recorded on birth certificates by hospital staff from interviews with the mother and/or from patients’ charts, then submitted electronically to the state department of health. Potential cases of pregnancyrelated hypertension were screened on the basis of having an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for hypertension during pregnancy (ICD-9-CM codes 642.x) or a positive response on the birth certificate to the items “pregnancy induced hypertension,” “chronic hypertension,” or “eclampsia.” Mothers with preexisting cardiac or renal disease,
American Journal of Kidney Diseases, Vol 42, No 5 (November), 2003: pp 982-989
HYPERTENSIVE PREGNANCY AND CLINICAL OUTCOMES Table 1.
Classification System to Define Forms of Pregnancy-Related Hypertension
Hospital Discharge Data ICD-9 Code
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ICD-9 Code Description
Birth Certificate Data Eclampsia
Chronic HTN
Included patients 642.3 Gestational HTN No No 642.3 Gestational HTN Yes No 642.4 Mild preeclampsia No No 642.4 Mild preeclampsia Yes No 642.5 Severe preeclampsia Any No 642.6 Eclampsia Any No Total included Excluded patients 642.3-6 Gestational HTN/preeclampsia Any Yes 642.0 Essential HTN Any Any 642.1 Renal HTN Any Any 642.2 Preexisting HTN Any Any 642.7 Preeclampsia with chronic HTN Any Any Unclassified HTN Any Any Because of nonlinkage with maternal hospitalization data Because of lack of ICD-9 code for pregnancy-related HTN 642.9 Because of ICD-9 code 642.9, unspecified HTN Total excluded
No. of Patients (%)
Classification of HTN
10,687 (24.5) 112 (0.3) 15,508 (35.6) 931 (2.1) 3,591 (8.2) 410 (0.9) 31,239
Gestational HTN Severe preeclampsia Mild preeclampsia Severe preeclampsia Severe preeclampsia Severe preeclampsia
681 (1.6) 572 (1.3) 41 (0.1) 122 (0.3) 1,116 (2.7) 9,830 (22.5) 3,436 (7.9) 5,009 (11.5) 1,385 (3.2) 12,362
Chronic HTN Chronic HTN Chronic HTN Chronic HTN Chronic HTN Unclassified HTN
Abbreviation: HTN, hypertension.
established diabetes, or age older than 45 or younger than 15 years were excluded from this analysis.
Classification of Pregnancy-Related Hypertension Cases in which ICD-9-CM hospital discharge codes did not link to the delivery, were missing, or coded for “unspecified hypertension” were excluded (Table 1). Remaining cases were classified into gestational hypertension, mild preeclampsia, and severe preeclampsia based on a combination of birth certificate data and ICD-9-CM codes linked to the index pregnancy (Table 1). Mothers were classified as having chronic hypertension if they had a positive response to the item “chronic hypertension” on their birth record or had any of the following ICD-9-CM codes linked to their delivery: 642.0, benign hypertension; 642.1, renal related hypertension; 642.2, preexisting hypertension; or 642.7, preeclampsia superimposed on preexisting hypertension. Our conservative strategy attempted to remove all suspected instances of chronic hypertension from the gestational hypertension and preeclampsia groups.
Ascertainment and Definition of Outcomes Maternal birth hospitalizations were linked to subsequent hospitalizations recorded in the Comprehensive Hospital Abstract Reporting System (CHARS) database, which collects discharge diagnoses from all nonfederal hospitals in the State of Washington. CHARS was complete through December 31, 2000. For each hospitalization, up to 9 ICD-9-CM diagnoses codes and 6 ICD-9 procedure codes were analyzed. Cardiovascular events are defined as hospitalizations for acute myocardial infarction (ICD-9-CM code 410.x),
acute stroke (ICD-9-CM codes 430.x, 431.x, 434.x, 436.x), or coronary artery revascularization procedure, including coronary artery bypass grafting (ICD-9 procedure codes 36.x).20-22 Because of their low sensitivity and specificity for predicting stroke, ICD-9-CM codes 432, 433, and 435 were not used.21 Thromboembolic events are defined as hospitalizations for deep venous thrombosis (ICD-9-CM code 451.1 or 453.x) or pulmonary embolism (ICD-9-CM code 415.1). For mothers with multiple outcomes, the first outcome was retained for analysis.
Matching A sample of control mothers without hypertension during pregnancy was randomly selected from live singleton births in BERD. Nonhypertensive controls are defined as having no indication of pregnancy-related hypertension during any recorded pregnancy based on birth record data and ICD-9 codes linked to the deliveries. Approximately 4 control mothers were matched to each hypertensive mother by age, parity, and calendar year of delivery. Because of logistic constraints, control mothers were randomly sampled from BERD without respect to their subsequent outcomes before matching. Matching on exposure status was performed to reduce potential confounding caused by age, parity, and delivery year. We adjusted further for these variables in the final multivariate models to reduce residual confounding and increase precision of the multivariate models.
Statistical Analysis Cox’s proportional hazards model23 was used to estimate the relationship, in the form of hazard ratios, between each
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KESTENBAUM ET AL Table 2.
Age at delivery* (y) Primipara* Race White African American Hispanic Other Gestational diabetes Smoking Cesarean section Uninsured/Medicaid Prepregnancy weight (lbs)† Years of education† Family income (annual $) Month of prenatal visit 1 Alcohol use Gestational age (wk) Birth weight (g) Five-minute Apgar score
Baseline Characteristics of the Study Population
Control Births (n ⫽ 92,902)
Gestational Hypertension (n ⫽ 10,687)
Mild Preeclampsia (n ⫽ 15,508)
Severe Preeclampsia (n ⫽ 5044)
26.2 ⫾ 6.1 73.2 (67,997)
26.5 ⫾ 6.1 69.0 (7,378)
26.1 ⫾ 6.1 75.3 (11,682)
26.0 ⫾ 6.4 75.6 (3,815)
79.0 (71,797) 3.2 (2,894) 9.1 (8,312) 8.7 (7,927) 2.2 (2,011) 18.3 (16,473) 18.7 (17,331) 36.1 (33,568) 141.3 ⫾ 31.0 12.9 ⫾ 2.8 30,767 ⫾ 10,045 2.6 ⫾ 1.5 3.0 (2,189) 39.3 ⫾ 1.9 3,429 ⫾ 543 8.9 ⫾ 0.7
84.1 (8,804) 3.6 (379) 5.7 (597) 6.6 (689) 4.9 (519) 13.5 (1,403) 23.2 (2,478) 32.2 (3,437) 159.6 ⫾ 38.8 13.1 ⫾ 2.4 31,571 ⫾ 9,356 2.5 ⫾ 1.4 2.5 (246) 39.0 ⫾ 1.6 3,376 ⫾ 576 8.8 ⫾ 0.7
81.3 (12,329) 3.7 (567) 7.8 (1,179) 7.1 (1,082) 11.4 (1,772) 15.4 (2,177) 26.7 (4,127) 36.0 (5,575) 155.2 ⫾ 37.5 12.9 ⫾ 2.6 30,847 ⫾ 10,018 2.5 ⫾ 1.5 2.5 (260) 38.8 ⫾ 1.9 3,333 ⫾ 615 8.8 ⫾ 0.8
74.7 (3,682) 5.7 (280) 11.9 (588) 7.8 (382) 7.8 (394) 13.2 (621) 44.7 (2,251) 40.5 (2,041) 150.7 ⫾ 37.6 12.6 ⫾ 2.9 29,994 ⫾ 10,034 2.6 ⫾ 1.6 2.4 (94) 36.8 ⫾ 3.4 2,763 ⫾ 895 8.4 ⫾ 1.2
NOTE. Values expressed as mean ⫾ SD or percent (number of patients). *Variable matched by design. †Variable added to birth record after 1991.
form of pregnancy-related hypertension and subsequent risk for a first cardiovascular or first thromboembolic event. Wald-type confidence intervals (CIs) were calculated by using model-based variance estimates after accounting for clustering by matching group, defined by age, parity, and calendar year of delivery. Variables included in multivariate models were selected a priori on the basis of their known relationship with cardiovascular and thromboembolic disease and completeness of the birth certificate data. Multivariate models included age (in continuous years), parity (prima versus multi), race/ethnicity (white, African American, Hispanic, other), gestational diabetes (yes versus no), smoking (yes versus no), cesarean section (yes versus no), and type of insurance used for the index pregnancy (Medicaid or uninsured versus insured). We examined whether hazard ratio estimates were appreciably different across subgroups of mothers by evaluating the goodness-of-fit of interaction terms using the likelihood ratio test. Prepregnancy weight and years of education were added to the birth record after 1991 and thus were unsuitable for inclusion in the models because of the resulting high proportion (⬎50%) of missing data. We included these variables for visual inspection of baseline characteristics in Table 2. Median family income was derived by linkage of address data to census bureau data for the census tract. When available, body mass index (BMI) was determined by obtaining maternal height through linkage to the Washington State drivers’ license registry. Each mother was considered at risk throughout her follow-up period (until the study closed December 31, 2001) unless it was determined that she had died, at which time she
was censored. Deaths were determined by linking BERD to Washington State death records. Analysis of residuals and graphic methods were used verify the existence of proportional hazards for each covariate in the multivariate model. Approval for this study was obtained from the University of Washington Human Subjects Division (Seattle, WA).
RESULTS
We identified 44,550 potential hypertensive pregnancies (5.5%) from 807,010 singleton births in Washington State between 1987 and 1998. We excluded 144 mothers (0.3%) with preexisting cardiac disease, 194 mothers (0.4%) with preexisting renal disease, 426 mothers (1.0%) with established nongestational diabetes, and 185 mothers (0.4%) with age younger than 15 or older than 45 years, leaving 43,601 women with a potential hypertensive pregnancy. We further excluded 2,532 mothers (5.8%) with suspected chronic hypertension and 9,830 mothers (22.5%) for whom hypertension during pregnancy could not be classified because ICD-9-CM discharge codes did not link to the index pregnancy, were missing, or indicated “unspecified hypertension” (Table 1). After these exclusions, 31,239 hypertensive pregnancies were classified into gestational hypertension, mild preeclampsia, and severe preeclampsia, as listed in Table 1. A sample
HYPERTENSIVE PREGNANCY AND CLINICAL OUTCOMES Table 3.
Normotensive pregnancy Gestational hypertension Mild preeclampsia Severe preeclampsia Race White African American Hispanic Other Smoking Gestational diabetes Cesarean section Uninsured
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Risk for Cardiovascular Events After a Hypertensive Pregnancy
Events (n ⫽ 118)
Events/100,000 Patient-Years
Crude Hazard Ratio (95% CI)
P
Adjusted Hazard Ratio (95% CI)
64 19 24 11
8.9 25.3 18.4 29.4
2.9 (1.8-4.9) 2.0 (1.3-3.2) 3.3 (1.8-6.3)
⬍0.001 0.003 ⬍0.001
Reference 2.8 (1.6-4.8) 2.2 (1.3-3.6) 3.3 (1.7-6.5)
⬍0.001 0.002 0.001
83 10 10 12 32 8 33 41
10.8 32.0 14.2 16.3 18.7 20.5 15.8 11.9
3.0 (1.6-5.8) 1.4 (0.7-2.6) 1.5 (0.8-2.8) 1.7 (1.1-2.6) 1.7 (0.8-3.5) 1.4 (0.9-2.1) 1.0 (0.7-1.4)
0.001 0.337 0.170 0.009 0.149 0.106 0.838
Reference 3.8 (2.0-7.2) 2.1 (1.0-4.3) 1.5 (0.8-2.9) 2.3 (1.5-3.6) 1.2 (0.6-2.5) 1.0 (0.7-1.5) 1.2 (0.7-1.8)
⬍0.001 0.054 0.184 ⬍0.001 0.661 0.954 0.509
P
NOTE. Subjects with pregnancy-related hypertension were matched to normotensive subjects by age, parity, and delivery year.
of 92,902 control mothers without pregnancyrelated hypertension was matched to the sample of hypertensive mothers by age, parity, and calendar year of delivery to achieve a total cohort size of 124,141. At the index pregnancy, mothers with a hypertensive pregnancy generally were more likely to have gestational diabetes, have a greater prepregnancy weight, and have undergone delivery by cesarean section and were less likely to smoke (Table 2). Socioeconomic factors, such as median family income, years of education, and type of medical insurance, did not differ appreciably between births with or without pregnancyrelated hypertension. Birth weights were appreciably lower among births complicated by severe preeclampsia, but not gestational hypertension or mild preeclampsia. There were no notable differences in baseline characteristics between mothers excluded because of unclassified hypertension versus those included with pregnancyrelated hypertension. Mean length of follow-up was 7.8 years (intraquartile range, 4.8, 7.6, and 10.6 years), providing 964,140 person-years of follow-up. During follow-up, there were 118 first hospitalizations for acute cardiovascular events among all mothers in the study cohort. Mean maternal age at the time of a first cardiovascular event was 36.1 years (intraquartile range, 30.7, 36.8, and 42.0 years). Among women who developed cardiovascular events, mean time between the index preg-
nancy and first cardiovascular event was 5.1 years (intraquartile range, 2.0, 4.7, and 7.9 years). Among women without hypertension during pregnancy, the incidence density of hospitalization for a first cardiovascular event was 8.9 events/100,000 patient-years compared with 25.3, 18.4, and 29.4 first events/100,000 person-years among women with gestational hypertension, mild preeclampsia, and severe preeclampsia, respectively. After adjustment for confounding factors, all forms of pregnancy-associated hypertension were associated with a significantly increased risk for cardiovascular events (Table 3). AfricanAmerican race and smoking also were associated with a significantly increased risk for cardiovascular outcomes. The magnitude of excess risk associated with preeclampsia was similar to that for smoking. The relationship between pregnancy-related hypertension and cardiovascular events was not found to differ significantly according to age, race, parity, and smoking status. In the entire study cohort, there were 172 hospitalizations for a first acute thromboembolic event. Mean maternal age at the time of first thromboembolic event was 31.1 years. In control mothers, the incidence density of first thromboembolic events was 15.4/100,000 patient-years compared with 21.3, 23.0, and 40.1 events/ 100,000 person-years in mothers with gestational hypertension, mild preeclampsia, and severe preeclampsia, respectively. After adjustment, women with severe preeclampsia had a signifi-
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KESTENBAUM ET AL Table 4.
Normotensive pregnancy Gestational hypertension Mild preeclampsia Severe preeclampsia Race White African American Hispanic Other Smoking Gestational diabetes Cesarean section Uninsured
Risk for Thromboembolic Events After a Hypertensive Pregnancy
Events (n ⫽ 172)
Events/100,000 Patient-Years
Crude Hazard Ratio (95% CI)
P
Adjusted Hazard Ratio (95% CI)
111 16 30 15
15.4 21.3 23.0 40.1
1.4 (0.8-2.4) 1.5 (1.0-2.2) 2.6 (1.5-4.5)
0.208 0.055 ⬍0.001
Reference 1.5 (0.9-2.5) 1.4 (0.9-2.2) 2.3 (1.3-4.2)
0.142 0.099 0.006
141 9 5 11 45 11 44 70
18.3 28.8 7.1 14.9 26.3 28.2 21.1 20.3
1.6 (0.8-3.1) 0.4 (0.2-1.0) 0.8 (0.4-1.5) 1.7 (1.2-2.3) 1.6 (0.9-2.9) 1.2 (0.9-1.7) 1.2 (0.9-1.7)
0.182 0.043 0.529 0.004 0.132 0.220 0.178
Reference 1.5 (0.7-3.0) 0.4 (0.2-1.1) 0.8 (0.4-1.6) 1.5 (1.1-2.2) 1.3 (0.6-2.7) 1.2 (0.8-1.7) 1.2 (0.8-1.9)
0.313 0.065 0.556 0.025 0.481 0.306 0.276
P
NOTE. Subjects with pregnancy-related hypertension were matched to normotensive subjects by age, parity, and delivery year.
cantly greater risk for a first thromboembolic event compared with control women without hypertension during pregnancy (Table 4). Smoking also was associated with a significantly greater risk for a first thromboembolic event. We found no significant interaction between age, race, parity, smoking status, and relationship between pregnancy-related hypertension and thromboembolic events. To examine whether excluded women with unclassified hypertension during pregnancy may have differed from those included in the study, we examined the risk for cardiovascular and thromboembolic events in women with unclassified hypertension. The hazard ratio for acute cardiovascular events in women with unclassified hypertension was 2.1 (95% CI, 1.1 to 4.1). The hazard ratio for acute thromboembolic events among women with unclassified hypertension was 1.6 (95% CI, 0.9 to 2.9). DISCUSSION
We found gestational hypertension and preeclampsia to be associated with a significantly increased risk for cardiovascular events. Gestational hypertension, mild preeclampsia, and severe preeclampsia were associated with 2.8-, 2.2-, and 3.3-fold greater risks for cardiovascular events, respectively. Severe preeclampsia was associated with an increased long-term risk for deep venous thrombosis and pulmonary embolism.
Our results are consistent with those of 2 population-based studies from the United Kingdom.18,19 Smith et al18 reported a 2-fold greater risk for death or hospitalization for ischemic heart disease in preeclamptic women identified from the Scottish Morbidity Record. Hannaford et al19 found an increased risk for myocardial infarction, stroke, and thromboembolic disease in preeclamptic women enrolled in the Royal College of General Practitioners’ Oral Contraceptive Study. The current study aims to build on previous work by adding ICD-9-CM hospital discharge data from the index pregnancy to birth record data in an attempt to remove suspected instances of chronic hypertension and further subclassify women to individual forms of pregnancy-related hypertension. Ours also is the first study to associate gestational hypertension and preeclampsia with increased risk for cardiovascular events in a large sample of women from the United States. Previous case series have suggested an association between preeclampsia and risk for chronic hypertension, renal disease, and death.14-16,18,24,25 Chesley et al24 reported a 2- to 5-fold increase in risk for mortality in subgroups of women with eclampsia after 30 years of follow-up. In 2 case series, Sibai et al15,25 reported a substantially greater incidence of chronic hypertension in women with clinically confirmed preeclampsia/ eclampsia compared with women with a normotensive pregnancy. However, previous case se-
HYPERTENSIVE PREGNANCY AND CLINICAL OUTCOMES
ries have lacked the statistical power to evaluate relative risks for cardiovascular or thromboembolic outcomes associated with a hypertensive pregnancy. A number of mechanisms may explain the observed association between pregnancy-related hypertension and cardiovascular disease. Adverse physiological changes reported during preeclampsia include endothelial cell dysfunction, hemodynamic abnormalities, and insulin resistance.12,13,26-30 Evidence of endothelial cell injury can be observed in the characteristic pathological lesions of preeclampsia found in the glomerulus and uterine boundary vessels.27,31 The endothelialderived vasodilatory factors nitric oxide and prostacyclin are deficient in preeclampsia,30,32,33 possibly explaining the late increase in vasomotor tone observed in some preeclamptic patients.8 In addition, preeclampsia shares important features with insulin resistance. Although baseline glucose levels often are normal during preeclamptic pregnancies, abnormally high insulin levels have been reported after glucose tolerance testing.34 In addition, preeclampsia is characterized by an early increase in cardiac output beyond that expected during normal pregnancy, resembling the early stages of insulin resistance.12,13 If insulin resistance and endothelial dysfunction were to remain active after a hypertensive pregnancy, they could explain the increased risk for cardiovascular disease. Alternatively, hypertension during pregnancy may be the early expression of an adverse genotype associated with premature cardiovascular disease. Previous studies have yielded conflicting results about whether women with preeclampsia possess a specific defect of the coagulation system.11,35 Our results are consistent with those of Hannaford et al19 documenting an increased risk for thromboembolic disease in a large cohort of women with preeclampsia. The specific abnormalities of the coagulation system responsible for the increased risk for clotting await identification. Based on our results, a history of a hypertensive pregnancy is an important risk factor for the development of premature cardiovascular disease. We found the magnitude of excess risk for serious premature cardiovascular events associated with a hypertensive pregnancy to be similar to that of smoking. Women with a history of a
987
hypertensive pregnancy may require more aggressive attention to comorbid cardiovascular risk factors and may demand a lower clinical threshold to initiate diagnostic testing when cardiovascular symptoms arise. The use of birth certificate data and ICD-9 codes to define pregnancy-related hypertension may have resulted in misclassification of the exposure. It seems plausible that errors in classifying subjects with or without pregnancy-related hypertension would be unrelated to whether they subsequently develop cardiovascular or thromboembolic outcomes. If this assumption is correct, the true association between pregnancy-related hypertension, in aggregate, and maternal outcomes is likely to be even stronger than what we report. However, if women with chronic hypertension were preferentially miscoded as having gestational hypertension or preeclampsia, bias may have occurred. Also, the use of ICD-9 codes to classify individual forms of pregnancy-related hypertension may be particularly prone to classification error. Thus, although our results provide evidence of an association between all forms of pregnancy-related hypertension and subsequent maternal outcomes, they provide only a tentative indication regarding possible differences in associations among specific types of pregnancyrelated hypertension. The resultant loss of greater than 20% of the cohort because of unspecified or missing ICD9-CM codes may limit the generalizability of our results. However, we found that baseline characteristics in hypertensive mothers excluded because of improper coding did not differ from those included in the study, suggesting that excluded mothers were similar to those included in the study. In addition, we found hazard ratios for cardiovascular and thromboembolic events to be similar between women included in the study and those excluded because of unspecified or missing ICD-9-CM codes. The use of ICD-9-CM codes to define cardiovascular and thromboembolic events may lead to some misclassification of these outcomes. However, the ICD-9-CM codes used in this study to define acute myocardial infarction and acute stroke have been found to have a positive predictive value of 79% to 96% and 70% to 90%, respectively.20-22,36 No large studies have validated ICD-9-CM codes for deep venous thrombo-
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sis or pulmonary embolism. We would not expect misclassification of thromboembolic events to be differential with respect to exposure and outcome; therefore, it should not lead to biased results. Similarly, migration into and out of Washington State may result in some loss of power because of noncaptured outcomes, but migration would not be expected to be strongly related to the development of preeclampsia and thus should not cause bias. It is possible that women with a hypertensive pregnancy have other attributes that result in their increased risk for cardiovascular events. We attempted to account for known and measured potential confounding factors by including them in multivariate models. Given the magnitude of the association found between hypertensive pregnancy and subsequent outcomes, an unmeasured factor would have to be very strongly associated with both the development of pregnancy-related hypertension and long-term risk for cardiovascular or thromboembolic events to appreciably change our estimates. Maternal weight was a concern as a potential confounder and could not be directly included in multivariate models because of the high proportion of missing data and resultant loss of power. However, using available data from 35 cardiovascular events in 60,113 women who gave birth after 1991, we found little change in hazard ratios for any form of pregnancy-related hypertension after including weight in the multivariate models. Similarly, we did not find significant changes in hazard ratio estimates when including BMI in the multivariate models. These analyses suggest that weight (or BMI) does not significantly confound the relationships we observed. We did not have direct information regarding oral contraceptive use, which can increase the risk for thromboembolic events in young women.37,38 We attempted to address this issue by analyzing the number of future pregnancies within exposure groups as a surrogate marker for contraceptive use. We found no difference in number of future pregnancies comparing women with and without pregnancyrelated hypertension. In summary, gestational hypertension and preeclampsia were associated with a significantly increased risk for subsequent cardiovascular events. Severe preeclampsia was associated with a significantly increased risk for thromboem-
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bolic events distant from pregnancy. The increase in cardiovascular disease risk associated with forms of pregnancy-induced hypertension was similar to that of smoking. Women with a history of gestational hypertension and preeclampsia may require more careful medical follow-up, with particular attention to their risk for premature cardiovascular disease. ACKNOWLEDGMENT The authors thank Bill O’Brien for technical assistance in preparing data for this analysis.
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