ABSTRACT
Background and Objectives: Pre-eclampsia (PE) shares a number of proposed pathophysiologic mechanisms related to those implicated in cardiovascular disease (CVD), such as endothelial dysfunction, inflammation, insulin resistance, and impaired renal regulation. PE has also been associated with subsequent hypertension, CVD, and related mortality in later life. Methods: At follow-up, the four most recent blood pressures, body mass index (BMI), and use of hypertensive medications were recorded from clinic visits of 130 PE cases and 289 normal pregnancies. Student’s t test, Chi-square testing, multivariate linear, and logistic regression were used in analysis. Results: Follow-up measurements occurred a mean of 13.11 years post PE pregnancy. Multivariate linear regression showed a significant and independent association between current systolic blood pressure and previous history of PE (β = 4.47, p = 0.04), while adjusting for age, BMI, and blood pressure from 1 year prior to and up to the 20th week of gestation. A similarly adjusted multivariate logistic regression model found an odds ratio of 3.43, 95% CI 1.83–6.43, p = 0.001 for subsequent hypertension. Logistic regression analysis of the quartile with follow-up of less than 7.19 years also shows independent association of prior PE with subsequent hypertension. Discussion and Conclusions: PE appears to confer risk of subsequent hypertension on this cohort of American Indian women within as little as 8 years. This risk is independent of additional risk factors such as increased age, BMI, and blood pressure prior to 20 weeks of gestation. There is evidence of increased risk among those with more severe PE.
Introduction
Pre-eclampsia (PE) and the more severe “eclampsia” together affect approximately 2%–8% of pregnancies and result in more than 50,000 maternal deaths globally (Citation1). The incidence of hypertensive disorders of pregnancy in the US appears to have increased 25% in the last two decades (Citation2), and is a leading contributor to maternal and infant morbidity and mortality (Citation3). Diagnostic criteria have recently been revised to de-emphasize the previously required documentation of proteinuria and to allow greater emphasis on clinical findings (Citation4). None the less, PE has been classically based on the new onset of hypertension and proteinuria after 20 weeks of gestation (Citation5). With severe PE, multiple organ systems can be affected, potentially resulting in complications such as renal failure, stroke, congestive heart failure, disseminated intravascular coagulopathy, and liver failure. Obstetric risk factors for development of PE have previously been identified, such as primiparity, multifetal pregnancy, and prior pregnancy with PE. In addition, traditional cardiovascular disease (CVD) risk factors, such as increased age, obesity, altered glucose metabolism, and pre-existing hypertension, also play a role (Citation4). Specific details of the underlying etiology of PE are unknown; but the condition seems to develop initially from reduced placental perfusion, which leads to systemic inflammatory, metabolic, and thrombotic changes that impair maternal vascular function and lead to multiorgan damage (Citation6).
Although the blood pressure (BP) and albuminuria of patients with PE typically return to normal values within months of delivery, evidence is accumulating that acute episodes of PE are linked to future CVD. From a few reports beginning in 1976 (Citation7) to increasingly strong analyses in the past two decades, evidence is showing that women who experience PE have an increased risk of hypertension and other cardiovascular conditions in later life (Citation8–Citation10). In addition to a four-fold increased risk of hypertension (Citation5), PE is also associated with increased risk of other serious morbidity, including myocardial infarction (Citation11), renal disease (Citation12), diabetes (Citation13), and stroke (Citation14). There also appears to be a “dose effect” (Citation15,Citation16) with those experiencing more severe or earlier manifestations of PE being at increased risk of adverse outcomes, compared with those having had less severe PE.
One interpretation of these findings is that PE and CVD share risk factors that may be subtle or currently unrecognized in young, pregnant women; and that the additional physiologic stress of pregnancy unmasks this predisposition years ahead of its eventual manifestation. Thus, PE is viewed as a positive “stress test,” predictive of future CVD (Citation17).
Regardless of whether PE is an independent factor in the causal chain of future CVD or simply shares other primary risk factors with CVD, PE was identified by the American Heart Association and the American College of Cardiology as a useful, clinical risk factor for heart disease and stroke. Indeed, the additional risk of future CVD attributed to a history of PE is comparable to that of smoking (Citation9).
The purpose of this study was to determine if there is an association between a history PE and future development of hypertension in an American Indian population.
Methods
This investigation utilized data of American Indian women from a previously described case–control study of genetic influences on risk of PE (Citation18). Case status is equivalent to exposure status in this analysis. A retrospective review of medical records was conducted of women with and without PE that gave birth from January 1, 1995, to December 31, 2012. Institutional Review Board (IRB) permission for this study was obtained from the Indian Health Service facility in the northern plains, the American Indian community, and the University of North Dakota. Cases comprised of women with PE (N = 130), of which 96 met criteria as severe PE as defined by the American College of Obstetrics and Gynecology (Citation19). Controls are women (N = 288) that did not meet criteria for PE.
Hospital diagnostic codes were searched from 1995 forward to ascertain potential cases. Criteria for the case and control definitions of PE in this study are fully described in previous publications (Citation18). In brief, cases were defined as those meeting criteria for PE if at least two of the following were identified:
At least two BP values above either 140 mmHg systolic or 90 mmHg diastolic on separate occasions at least 4 hours apart; and absence of a diagnosis of, or treatment for hypertension (during the year prior to conception and the first 20 weeks of gestation).
Proteinuria as indicated by a 24-h excretion of >300 mg, or at least two +1 dipstick measurements in the absence of prior proteinuria.
A diagnosis of PE, eclampsia, or the hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome by an attending physician after 20 weeks of gestation.
Potential controls were chosen by contacting the two women delivering just prior and after the case; and repeating the process until two control women consented to participate. Both cases and controls were excluded if they had a clinical diagnosis of hypertension prior to the identified pregnancy. The two highest BP readings recorded within the period from 1 year prior to the pregnancy up to 20 weeks of gestation were collected. When available, the mean of both the systolic and diastolic pressures was calculated and used as covariates to adjust models.
The electronic medical records were searched for the four most recent BP readings that were measured on separate office visits during the 2 years prior to follow-up and if a hypertensive medication were prescribed in the past two years. Antihypertensive medications (AHMs) included angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, and/or thiazide diuretics. The mean systolic and diastolic BPs were calculated from at least two of the four possible measurements. Defining criteria for “subsequent” hypertension of both cases and controls were a mean systolic BP ≥140 … AND a mean diastolic ≥90 …OR a prescription for AHM. The most recent body mass index (BMI) during the prior 3 years was also recorded. The BMI calculated at the time of pregnancy used the recorded weight and height at the first prenatal visit.
The statistical software, SPSS 13.0.1 for Windows, was used to analyze demographic and clinical characteristics of patients. Frequencies and relative percentages were computed for each categorical variable. Chi-square tests and Fisher’s exact tests were performed to determine which categories were significantly different from one another, and Student’s t-test was used to compare continuous variables. Cytel Studio software, version 11.0.0, was used to calculate logistic regression results. All p-values were two-sided, and a p-value < 0.05 was considered significant. Missing data were excluded from analysis.
Results
The relevant baseline characteristics of the cases and controls are shown in . Women with a history of PE were more likely to be primiparous, have a higher BMI, have higher recorded BPs prior to 20 weeks of gestation, and have exhibited gestational diabetes during their pregnancy. The mean gestational age at the time of first prenatal visit (when BMI was calculated) was 13.02, and only 4.7% of cases and controls attended their first prenatal visit at 30 weeks of gestation or later. Smoking prevalence was similar between cases and controls.
Table 1. Characteristics of cases and controls at the time of pregnancy.
Characteristics of women at follow-up are found in . Follow-up occurred at a mean (standard deviation, minimum, maximum) of 13.5 years (7.1, 3.6, 36.7) for cases and 12.9 years (6.7, 3.6, 36.6) for controls. There was no significant difference in length of follow-up between cases and controls (p = 0.421). At follow-up, cases had higher mean BMI, systolic and diastolic BP, prevalence of AHM, and study-defined hypertension, but otherwise were of similar age.
Table 2. Characteristics of cases and controls at follow-up.
The results of linear regression models are shown in . This analysis shows increased subsequent systolic BP of approximately 3 mm of mercury among those with a history of prior PE, even when simultaneously adjusted for age, BMI, and average systolic pressure prior to 20 weeks of gestation. The association is also seen when the analysis is limited to those participants in the lowest quartile of follow-up time (between 3.59 and 7.19 years) as detailed in , along with summary results from the remaining quartiles. If baseline (rather than current) measures of age and BMI were used as adjusting covariates in these linear models, the covariate association with follow-up BPs lost independent significance. Models including gestational diabetes failed to show significant, independent association in either the linear or logistic regression analyses. Analysis of controls only indicates significant and independent association between BPs prior to 20 weeks of gestation, age, and BMI.
Table 3. Multivariate linear regression model analyses.
indicates the results of multivariate logistic regression analysis with subsequent, study-defined hypertension as the outcome and adjusting covariates as noted for the linear analyses. This also shows the association between prior PE and future hypertension (OR 3.43, 95% CI 1.83–6.43, p = 0.001), even when limited to those within the lowest quartile of follow-up. When the analysis is limited to the controls and those with severe PE (mild cases omitted), the point estimate of the odds ratio is greater (OR 4.18, 95% CI 2.19–8.00, p = 0.001). If the history of PE is entered as an ordinal variable, with control status, mild PE, and severe PE entered as 0, 1, and 2, respectively, the odds ratio is 2.19 (95% CI 1.54–3.10, p = 0.001) for each increasing step of severity. In logistic analyses, substituting baseline age or BMI for current measures did not materially affect the association with PE, but did result in a loss of independent association for age at delivery.
Table 4. Multivariate logistic regression model analyses.
The inclusion of pre-natal tobacco use showed only marginally significant association with systolic BP (p = 0.055) and no association in other fully adjusted linear or logistic models for diastolic pressure and subsequent hypertension, respectively. Results of logistic regression analysis of the controls alone indicated significant, independent association with prior systolic BP and age, but not BMI.
A number of analyses were conducted in an attempt to separate the effects of PE per se from the effects of increasing obesity during the follow-up period, As seen in , the prevalence of hypertension among cases was nominally lower (17/65 = 26.2%) among those with the greatest increase in BMI, compared with (22/60 = 36.7%) among those with the least, but this was not statistically significant (p = 0.463). The participants were stratified into those with a change in BMI below or above the median increase of 3.7 BMI units; and these results are presented in . Among those with the lesser change (mean and median change of −0.53, and +0.37 BMI units, respectively), both the linear and logistic regression relationship to history of PE remained significant and strong. Among those with the greater change in BMI (mean and median change of +8.08 and +7.08 units, respectively), the linear models now showed no association with systolic or diastolic pressure, whereas the logistic models continued to show statistically significant association with future hypertension as defined (OR 2.67, 95% CI 1.06–6.70, p = 0.036). Last, an additive model, attempting to scale the effects of PE and increasing BMI over time, showed a strong relationship to subsequent hypertension, as seen in .
Table 5. Analyses contrasting those above and those below the median change in BMI from pregnancy to follow-up.
Women with a history of PE were also more likely to be prescribed AHM (OR 3.07, 95% CI 1.60–5.91, p = 0.001) compared to women experiencing normal pregnancies.
Discussion
Our findings clearly demonstrate that this cohort of American Indian women with a history of PE have an increased risk of future hypertension both over relatively short and longer periods of follow-up. This is in agreement with several investigations, primarily conducted among European populations (Citation8,Citation13,Citation20,Citation21). Bellamy et al. (Citation15) conducted a meta-analysis of 13 studies with a mean follow-up of 14.1 years, finding a composite relative risk (RR 3.70, 95% CI 2.70–5.05) for subsequent hypertension, albeit with significant heterogeneity between studies (smaller studies showing increased RR). This result is nearly identical to our present study. Of note, case–control studies were excluded in this meta-analysis of cohorts, of which all but three (Citation8,Citation14,Citation22) evaluated fewer cases and controls than the present study. Only one of the larger cohorts (Citation14) adjusted for BMI and obtained an odds ratio of 3.98 for a physician’s diagnosis of hypertension.
Although not our primary objective and well-established in the literature (Citation23), we provide additional evidence of the association between obesity and hypertension, both as an independent factor in the relationship between PE and subsequent hypertension and among those with previously normal pregnancies. The lack of a difference in hypertension prevalence between those with greater or lesser increases in BMI supports the independent influence of PE on the risk of subsequent hypertension. The stratified analysis showing a strong association with PE and subsequent hypertension among those with less than the median increase in BMI during follow-up gives further weight to the hypothesis that risk of future hypertension is not due merely to a tendency of those with PE toward obesity. Interestingly, those with the greatest increase in BMI continued to show a relationship between hypertension and PE in logistic analysis, but not in linear analysis of BP. This may be due to the increased effect of obesity overwhelming the influence of prior PE. There are relatively few studies of PE associated with an outcome of hypertension that are adjusted for BMI, but one moderate-sized investigation (Citation14) found an odds ratio of 2.62 (95% CI 1.77–3.86, p = 0.001).
We have been able to identify only three reports relating PE to hypertension among non-European populations. These include studies among Samoan (Citation24), Jordanian (Citation25), and primarily African American (Citation22). There is no prior information available regarding subsequent hypertension among American Indian women.
An interesting question is whether the pathophysiologic changes of PE alter the cardiovascular system of women in a lasting way that increases the risk of future hypertension and CVD events, or whether the stress of pregnancy merely unmasks the underlying pathophysiology that is common to both PE and CVD. This debate is well described in a review by Garovic et al. (Citation26); but remains unresolved. The current study offers additional support for PE as an independent, intrinsic risk factor, in that those with a lesser increase in BMI during follow-up continued to show a strong association with PE, discounting the theory that obesity is perhaps one of multiple primary risk factors for future hypertension. While the addition of BP prior to pregnancy and up to 20 weeks of gestation attenuates the association of PE with subsequent BPs in both linear and logistic analyses, a couple of caveats need to be considered. First, the BP at follow-up will be lessened in those under treatment for hypertension, thus decreasing the power of these linear analyses. The logistic models take into account hypertensive treatment and thus capture this potential effect of PE exposure. Second, a large portion of the “prior” BP measures were obtained during the first 20 weeks of gestation and could well have captured mild elevations from PE that preceded the formal definition of PE (i.e., “after 20 weeks of gestation”). Thus, the use of these prior BPs as a covariate may result in “overadjustment.” The results of logistic models showing subsequent hypertension significantly and independently associated with a history of PE, even among those with the shortest follow-up, are especially impressive in the light of these caveats.
Other studies provide clear evidence of persisting abnormalities in cardiovascular function (Citation27) and even anatomy (Citation28) post PE, but no comparable measures from these women prior to pregnancy. To know whether PE directly affects these changes, detailed longitudinal studies of a cohort of women from pre-pregnancy to a couple years post pregnancy would be ideal, but would be difficult due to the large population needed, continuing difficulty discriminating between possibly distinct forms of PE (e.g., early versus late pregnancy, young versus older women), and the need to control or adjust for pre-existing risk factors. This question is not without practical implications. If PE is the cause of a persistent increase in CVD risk, then management of women with PE may require more aggressive interventions to prevent adverse outcomes (Citation26).
Strengths of this study include PE as a well-defined exposure, confirmed by clinical measures and a conservative definition, and similarly reliable clinical measures of outcome (BP and prescribed medications). Important covariates were also well-documented, in some cases both during pregnancy and at the end of follow-up; and there was adequate power to analyze both long- and short-term outcome. These results from a non-European population support the view that there is a generalizable physiology underlying this association.
Limitations to this investigation include the possibility that some BMIs from the time of pregnancy were obtained during a late prenatal visit, and thus biased upward, although the proportion of women over 30 weeks gestation at first prenatal was less than 5%. It is possible that some women were seen and actively treated for hypertension at a facility other than the Indian Health Service in this community. If there was a systematic bias in loss to follow-up, this could have affected the results. Reassuringly, although abstraction was limited to about 200 per abstractor due to time constraints, of the 418 abstracted (out of a potential 542), all but one had at least three BPs measured within the prior 3 years (resulting in a minimum follow-up of 77%). Loss to follow-up did occur due to death for two control women from the original study; and the cause is unknown. We also caution that these findings from a single community may not generalize to other American Indian populations; and further studies in other areas would be useful.
CVD is the leading cause of death for women ≥65 years of age in the United States (Citation29), and the American Heart Association has recognized the importance of PE as a CVD risk factor (Citation30), which is comparable to the effects of smoking (Citation9). These insights and the development of clinical recommendations for the prevention and treatment of PE have made vital contributions to women’s health (Citation31).
Declaration of interest
The authors report no conflicts of interest.
Acknowledgments
We thank the study participants, Indian Health Service facilities, and participating tribal communities for their extraordinary cooperation and involvement, which has been critical to the success of this investigation. The views expressed in this article are those of the authors and do not necessarily reflect those of the Indian Health Service.
Funding
Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103442.
Additional information
Funding
References
- Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;33(3):130–7. [PubMed:19464502]
- Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004. Am J Hypertens 2008;21(5):521–6. [PubMed:18437143]
- Lindheimer MD, Taler SJ, Cunningham FG. Hypertension in pregnancy. J Am Soc Hypertens 2010;4(2):68–78. [PubMed:20400051]
- American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122(5):1122–31. [PubMed:24150027]
- U.S. Department of Health and Human Services, National Institute of Health, National Heart, Lung and Blood Institute (2000) Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 183:S1–S22.
- Jeyabalan A. Epidemiology of preeclampsia: impact of obesity. Nutr Rev 2013;71 Suppl 1: S18–S25. [PubMed: 24147919]
- Mann JI, Doll R, Thorogood M, et al. Risk factors for myocardial infarction in young women. Br J Prev Soc Med 1976;30(2):94–100. [PubMed:953382]
- Hannaford P, Ferry S, Hirsch S. Cardiovascular sequelae of toxaemia of pregnancy. Heart 1997;77(2):154–8. [PubMed:9068399]
- Chen CW, Jaffe IZ, Karumanchi SA. Pre-eclampsia and cardiovascular disease. Cardiovasc Res 2014;101(4):579–86. [PubMed:24532051]
- Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal mortality. Curr Opin Obstet Gynecol 2013;25(2):124–32. [PubMed PMID:23403779]
- 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. [PubMed:16225567]
- Vikse BE, Irgens LM, Leivestad T, et al. Preeclampsia and the risk of end-stage renal disease. N Engl J Med 2008;359(8):800–9. [PubMed: 18716297]
- Lykke JA, Langhoff-Roos J, Sibai BM, et al. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53(6):944–51. [PubMed:19433776]
- Wilson BJ, Watson MS, Prescott GJ, et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 2003;326(7394):845. [PubMed:12702615]
- Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335(7627):974. [PubMed:17975258]
- McDonald SD, Malinowski A, Zhou Q, et al. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156(5):918–30. [PubMed:19061708]
- Myatt L, Webster RP. Vascular biology of preeclampsia. J Thromb Haemost 2009;7(3):375–84. [PubMed: 19087223]
- Best LG, Saxena R, Anderson CM, et al. Two variants of the C-reactive protein gene are associated with risk of pre-eclampsia in an American Indian population. PLoS One 2013;8(8):e71231. [PubMed:23940726]
- ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002;77(1):67–75. [PubMed:12094777]
- Magnussen EB, Vatten LJ, Smith GD, Romundstad PR. Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol 2009;114(5):961–70. [PubMed:20168095]
- McDonald SD, Ray J, Teo K, et al. Measures of cardiovascular risk and subclinical atherosclerosis in a cohort of women with a remote history of preeclampsia. Atherosclerosis 2013;229(1):234–9. [PubMed:23664201]
- 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 1986;155(5):1011–6. [PubMed:3777042]
- Abramson BL, Melvin RG. Cardiovascular risk in women: focus on hypertension. Can J Cardiol 2014;30(5):553–9. [PubMed:24786446]
- 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 1996;36(3):233–8. [PubMed:8883742]
- Shammas AG, Maayah JF. Hypertension and its relation to renal function 10 years after pregnancy complicated by pre-eclampsia and pregnancy induced hypertension. Saudi Med J 2000;21(2):190–2. [PubMed:11533780]
- Garovic VD, August P. Preeclampsia and the future risk of hypertension: the pregnant evidence. Curr Hypertens Rep 2013;15(2):114–21. [PubMed:23397213]
- Chambers JC, Fusi L, Malik IS, et al. Association of maternal endothelial dysfunction with preeclampsia. JAMA 2001;285(12):1607–12. [PubMed:11268269]
- Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is associated with persistent postpartum cardiovascular impairment. Hypertension 2011;58(4):709–15. [PubMed: 21844489]
- Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2011 update: a report from the Ame-rican Heart Association. Circulation 2011;123(4):e18–e209. [PubMed:21160056]
- Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association. Circulation. 2011;123(11):1243–62. [PubMed:21325087]
- Bushnell C, McCullough LD, Awad IA, et al. American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council for High Blood Pressure Research. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45(5):1545–88. [PubMed:24503673]