Curr Hypertens Rep (2014) 16:484 DOI 10.1007/s11906-014-0484-2
PREECLAMPSIA (VD GAROVIC, SECTION EDITOR)
Hypertensive Pregnancy Disorders and Future Renal Disease Steven Wagner & Iasmina Craici
Published online: 30 August 2014 # Springer Science+Business Media New York 2014
Abstract Hypertensive pregnancy disorders affect approximately 6 to 8 % of otherwise normal pregnancies. A growing body of evidence links these disorders with the future development of hypertension, coronary disease, cerebrovascular disease, and peripheral arterial disease. Larger studies associating hypertensive pregnancy to future development of renal disease have been lacking until recently, with publication of several compelling studies in the last 5 years. In this review, we will focus on the recent evidence associating hypertensive pregnancy disorders with the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD), as well as the development of microalbuminuria. We will also attempt to answer whether these renal risks are due to direct effects of hypertension during pregnancy, or whether they are due to shared environmental and genetic risk factors. Keywords Preeclampsia . Pregnancy-induced hypertension . CKD . ESRD
Introduction Hypertensive disorders of pregnancy cover a spectrum of disease from gestational hypertension, through preeclampsia (PE), and includes severe manifestations such as eclamptic seizures and HELLP (Hemolysis, elevated liver enzymes, low platelets) syndrome. Especially, in their more severe forms, these disorders are associated with and appear to increase the risk of future cardiac disease, hypertension, strokes, and peripheral vascular disease [1, 2]. Preeclampsia, HELLP, and eclampsia are generally diagnosed in the setting of proteinuria and are therefore indicative of significant renal aberrations. Given the obvious renal involvement in preeclamptic This article is part of the Topical Collection on Preeclampsia S. Wagner (*) : I. Craici University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA e-mail: [email protected]
disorders, proteinuria during pregnancy might be expected to herald future renal disease. Various studies indicate that there may be an association between hypertensive pregnancy and development of future microalbuminuria, chronic kidney disease (CKD), and even end-stage renal disease (ESRD). See Table 1 for a summary of the studies that will be reviewed. The data are sometimes conflicting, and all of the adequately powered studies must, by necessity, be retrospective chart reviews. In this article, we will review recent evidence and attempt to answer the question: Do the hypertensive disorders of pregnancy independently increase a woman’s risk for future renal disease? Approximately 6 to 8 % of pregnancies in the USA are affected by hypertension [3]. In a world with over 132 million births per year, 8 to 10 million women experience these disorders every year [4]. If hypertension during pregnancy increases the risk of future renal impairment by even a small margin, the overall burden of renal disease in the population might be considerable due to the volume of patients “exposed” every year. This is happening in a time when other risk factors for renal disease, such as diabetes and obesity, are increasing. The relationship between hypertensive pregnancy disorders and future risk of CKD and ESRD is therefore highly relevant, as increased monitoring and early intervention in those at risk might help prevent future morbidity and mortality.
Review of the Evidence Hypertensive Pregnancies and the Future Risk for Microalbuminuria Microalbuminuria is recognized as a risk factor for incipient CKD in a variety of disorders, most notably diabetic nephropathy [5]. The detection of small amounts of albumin in diabetic patients with otherwise normal renal function should prompt assessment and adjustment of risk factors, as well as
2014 Insurance claim review (Taiwan)
Wu et al. [14•]
Findings
ESRD
CKD ESRD
ESRD
Questionnaire-based small odds ratio, wide confidence interval No data on smoking or obesity
Underpowered, small control group
Meta-analysis of seven heterogenous studies
Limitations
GHTN HR=5.82 Chronic HTN HR=15.99 PE HR=9.46 PE superimposed on HTN HR=44.72
Risk of incomplete data using billing records Risk of PE superimposed on chronic HTN is not different than the hazard from chronic HTN without PE
>1 pregnancy: RR 4.7 with PE in 1st pregnancy > 2 pregnancies: RR 3.2 with PE in 1st pregnancy RR 6.7 with PE in 2nd pregnancy RR 6.4 with PE in 1st and 2nd pregnancy CKD HR=9.38 Risk of incomplete data using billing records ESRD HR=12.4 Findings become much less impressive ESRD HR=14 (history of PE) after adjusting for hypertension and ESRD HR=9.03 (history of GHTN) diabetes
Microalbuminuria 7.1 years 4-fold risk for PE postpartum 8-fold risk for severe PE Microalbuminuria 9– No association 11 years postpartum Microalbuminuria OR 1.37 (1.02–1.85)
Outcome(s)
NT normotensive, HPD hypertensive pregnancy disorder, PE preeclampsia, HR hazard ratio, OR odds ratio, HTN hypertension, GHTN gestational hypertension
HPD (13,633) NT (930,841)
HPD (26,651) NT (213,397)
2013 Insurance claim review (Taiwan)
Wang et al. [13•]
Vikse et al. [12•]
HPD (475) NT (2,199) ESRD (477) No ESRD (569,956)
2013 Pregnancy-history questionnaire 2008 Medical birth registry review (Norway)
Kattah et al. [11•]
Comparison groups (n) PE (273) NT (333) PE (89) NT (69)
Year Study type
McDonald et al. 2010 Meta-analysis of 7 studies [9•] [28, 7, 29, 30, 8, 31, 32] Sandvik et al. [10•] 2013 Medical birth registry review (Norway)
Authors
Table 1 Studies of hypertensive pregnancy disorders and future renal disease (in order of appearance)
484, Page 2 of 6 Curr Hypertens Rep (2014) 16:484
Curr Hypertens Rep (2014) 16:484
enhanced monitoring and consideration of ACE inhibition or angiotensin receptor blockade, both of which have been shown to slow the progression of diabetic renal disease [6]. Identification of a link between hypertensive pregnancy disorders and future microalbuminuria might provide a therapeutic window to apply targeted therapy aimed at slowing or preventing the development and progression of CKD. Several studies have shown an association between previous hypertensive pregnancies and later development of microalbuminuria. In a group of 48 women with preeclamptic pregnancies, albumin excretion was higher compared to 44 controls at 2–4 months after delivery as well as 3–5 years later [7]. The risk is not confined to women with a history of preeclampsia, as evidenced by a study of 49 women with gestational hypertension, 45 with preeclampsia, and 44 normotensive controls. In this 7-year follow-up study, the risk of microalbuminuria was markedly increased for those with a history of preeclampsia and gestational hypertension compared to controls, and was associated with systemic hypertension at follow-up [8]. Seven small studies were recently examined in a meta-analysis involving 273 preeclamptic and 333 normotensive pregnancies after 7 years of follow-up. Findings included a fourfold increased risk of microalbuminuria in women with a history of preeclampsia and an impressive eightfold risk in those with a history of severe preeclampsia [9•]. Considering the inherent limitations of meta-analytical methods, including publication bias and the small sample size even after combining several studies, larger studies were needed. Using data from the Medical Birth Registry in Norway, Sandvik et al. examined 89 women with preeclampsia and 69 normal controls 9 to 11 years after the index pregnancy [10•]. The authors found no association between microalbuminuria and prior preeclamptic pregnancy (p=0.54). Though larger than previous studies, this study remains relatively underpowered; it is interesting that the authors chose to limit their statistical power further by having a control group smaller than the preeclamptic group. In contrast, through the use of a pregnancy-history questionnaire, an analysis of the Family Blood Pressure Program Study between 2000 and 2004 (n= 3,015) defined 475 women with at least one prior hypertensive pregnancy [11•]. Compared to 2,199 women with normotensive pregnancies, the risk of microalbuminuria >25 mg/g was increased (OR 1.37) but with a relatively wide confidence interval (1.02–1.85, p=0.04). Large sample sizes are required to find small differences between heterogeneous groups. While it remains somewhat unclear, the majority of the studies seem to support an association between hypertensive pregnancy disorders and future microalbuminuria. Whether the microalbuminuria after hypertensive pregnancy is associated with future risk of CKD and ESRD is an entirely different question that has not been adequately investigated. It might be extrapolated from evidence linking microalbuminuria with
Page 3 of 6, 484
future CKD in other renal disorders such as diabetic nephropathy, which of course is a progressive systemic disease and not a fixed renal defect. With smaller studies such as that by Bar et al. showing microalbuminuria almost immediately after a hypertensive pregnancy, as well as many years later, it is possible that hypertensive pregnancy causes a fixed renal defect that may or may not progress to CKD or ESRD given that baseline data are often unavailable or incomplete, it is also possible that microalbuminuria might have been present before pregnancy and increased the risk of hypertensive pregnancy. In either case, identification of microalbuminuria increases a patient’s risk for future cardiovascular disease and therefore should be identified and managed appropriately. Regardless of whether hypertensive pregnancy is microalbuminuria’s chicken or egg, in order to understand whether hypertension during pregnancy increases the risk of CKD, we must progress past searching for risk factors such as microalbuminuria and examine CKD and ESRD risk directly. Hypertensive Pregnancies and Future Risk of CKD and ESRD Even if hypertensive pregnancy disorders impart a risk of future CKD and ESRD, the outcome will only be seen years after the insult. By the time CKD and ESRD develop, a history of preeclamptic pregnancy may have been either forgotten or lost in a sea of other CKD risk factors such as smoking, diabetes, chronic hypertension, obesity, and peripheral vascular disease. Linking CKD with a hypertensive pregnancy 10 or 20 years in the past is difficult at best. That said, there have been several recent studies showing an association between hypertensive pregnancy and future CKD and ESRD. The largest of these involved 570,433 women registered in the Medical Birth Registry of Norway who had a first singleton birth between 1967 and 1991 [12•]. These records were cross-referenced with the Norwegian Renal Registry, which tabulates all patients with ESRD since 1980. ESRD developed in 477 of these women. Of those with one or more pregnancies, the relative risk of ESRD was 4.7 in those with preeclampsia during the first pregnancy. Those with two or more pregnancies had a relative risk of 3.2 when preeclampsia occurred in the first pregnancy, 6.7 when during the second pregnancy, and 6.4 when both of the first two pregnancies were affected by preeclampsia. The overall rate of ESRD was low at just 3.7 per 100,000 women per year. However, when one considers the sheer number of women diagnosed with hypertensive pregnancy disorders every year, the contribution to ESRD might be substantial. Two studies from Taiwan’s National Health Insurance Research Database support an increased risk of ESRD after hypertensive pregnancy. The first of these examined 26,651 women with a history of at least one hypertensive pregnancy and found an unadjusted 10-fold risk of future ESRD; this was
484, Page 4 of 6
essentially unchanged after adjusting for urban status, CAD, congestive heart failure (CHF), hyperlipidemia, and placental abruption [13•]. However, the risk all but disappears after adjusting for hypertension and diabetes, falling to 2.72 (CI 1.76–4.22). One cannot help but conclude that the risk of ESRD after a hypertensive pregnancy might be due to shared risk factors rather than as a direct result of the hypertensive pregnancy itself. Women with preeclampsia had a 14-fold risk, while those with gestational hypertension had only a 9fold risk, indicating that the severity of the hypertensive condition might impact future renal risk. A very similar study of 13,633 women with a history of hypertensive pregnancy found a 10-fold risk of ESRD compared to women with only normotensive pregnancies [14•]. Interestingly, women with preeclampsia superimposed on chronic hypertension had the highest risk, with a hazard ratio of 44.72. This was higher than the risk of preeclampsia alone (p
PREECLAMPSIA (VD GAROVIC, SECTION EDITOR)
Hypertensive Pregnancy Disorders and Future Renal Disease Steven Wagner & Iasmina Craici
Published online: 30 August 2014 # Springer Science+Business Media New York 2014
Abstract Hypertensive pregnancy disorders affect approximately 6 to 8 % of otherwise normal pregnancies. A growing body of evidence links these disorders with the future development of hypertension, coronary disease, cerebrovascular disease, and peripheral arterial disease. Larger studies associating hypertensive pregnancy to future development of renal disease have been lacking until recently, with publication of several compelling studies in the last 5 years. In this review, we will focus on the recent evidence associating hypertensive pregnancy disorders with the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD), as well as the development of microalbuminuria. We will also attempt to answer whether these renal risks are due to direct effects of hypertension during pregnancy, or whether they are due to shared environmental and genetic risk factors. Keywords Preeclampsia . Pregnancy-induced hypertension . CKD . ESRD
Introduction Hypertensive disorders of pregnancy cover a spectrum of disease from gestational hypertension, through preeclampsia (PE), and includes severe manifestations such as eclamptic seizures and HELLP (Hemolysis, elevated liver enzymes, low platelets) syndrome. Especially, in their more severe forms, these disorders are associated with and appear to increase the risk of future cardiac disease, hypertension, strokes, and peripheral vascular disease [1, 2]. Preeclampsia, HELLP, and eclampsia are generally diagnosed in the setting of proteinuria and are therefore indicative of significant renal aberrations. Given the obvious renal involvement in preeclamptic This article is part of the Topical Collection on Preeclampsia S. Wagner (*) : I. Craici University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA e-mail: [email protected]
disorders, proteinuria during pregnancy might be expected to herald future renal disease. Various studies indicate that there may be an association between hypertensive pregnancy and development of future microalbuminuria, chronic kidney disease (CKD), and even end-stage renal disease (ESRD). See Table 1 for a summary of the studies that will be reviewed. The data are sometimes conflicting, and all of the adequately powered studies must, by necessity, be retrospective chart reviews. In this article, we will review recent evidence and attempt to answer the question: Do the hypertensive disorders of pregnancy independently increase a woman’s risk for future renal disease? Approximately 6 to 8 % of pregnancies in the USA are affected by hypertension [3]. In a world with over 132 million births per year, 8 to 10 million women experience these disorders every year [4]. If hypertension during pregnancy increases the risk of future renal impairment by even a small margin, the overall burden of renal disease in the population might be considerable due to the volume of patients “exposed” every year. This is happening in a time when other risk factors for renal disease, such as diabetes and obesity, are increasing. The relationship between hypertensive pregnancy disorders and future risk of CKD and ESRD is therefore highly relevant, as increased monitoring and early intervention in those at risk might help prevent future morbidity and mortality.
Review of the Evidence Hypertensive Pregnancies and the Future Risk for Microalbuminuria Microalbuminuria is recognized as a risk factor for incipient CKD in a variety of disorders, most notably diabetic nephropathy [5]. The detection of small amounts of albumin in diabetic patients with otherwise normal renal function should prompt assessment and adjustment of risk factors, as well as
2014 Insurance claim review (Taiwan)
Wu et al. [14•]
Findings
ESRD
CKD ESRD
ESRD
Questionnaire-based small odds ratio, wide confidence interval No data on smoking or obesity
Underpowered, small control group
Meta-analysis of seven heterogenous studies
Limitations
GHTN HR=5.82 Chronic HTN HR=15.99 PE HR=9.46 PE superimposed on HTN HR=44.72
Risk of incomplete data using billing records Risk of PE superimposed on chronic HTN is not different than the hazard from chronic HTN without PE
>1 pregnancy: RR 4.7 with PE in 1st pregnancy > 2 pregnancies: RR 3.2 with PE in 1st pregnancy RR 6.7 with PE in 2nd pregnancy RR 6.4 with PE in 1st and 2nd pregnancy CKD HR=9.38 Risk of incomplete data using billing records ESRD HR=12.4 Findings become much less impressive ESRD HR=14 (history of PE) after adjusting for hypertension and ESRD HR=9.03 (history of GHTN) diabetes
Microalbuminuria 7.1 years 4-fold risk for PE postpartum 8-fold risk for severe PE Microalbuminuria 9– No association 11 years postpartum Microalbuminuria OR 1.37 (1.02–1.85)
Outcome(s)
NT normotensive, HPD hypertensive pregnancy disorder, PE preeclampsia, HR hazard ratio, OR odds ratio, HTN hypertension, GHTN gestational hypertension
HPD (13,633) NT (930,841)
HPD (26,651) NT (213,397)
2013 Insurance claim review (Taiwan)
Wang et al. [13•]
Vikse et al. [12•]
HPD (475) NT (2,199) ESRD (477) No ESRD (569,956)
2013 Pregnancy-history questionnaire 2008 Medical birth registry review (Norway)
Kattah et al. [11•]
Comparison groups (n) PE (273) NT (333) PE (89) NT (69)
Year Study type
McDonald et al. 2010 Meta-analysis of 7 studies [9•] [28, 7, 29, 30, 8, 31, 32] Sandvik et al. [10•] 2013 Medical birth registry review (Norway)
Authors
Table 1 Studies of hypertensive pregnancy disorders and future renal disease (in order of appearance)
484, Page 2 of 6 Curr Hypertens Rep (2014) 16:484
Curr Hypertens Rep (2014) 16:484
enhanced monitoring and consideration of ACE inhibition or angiotensin receptor blockade, both of which have been shown to slow the progression of diabetic renal disease [6]. Identification of a link between hypertensive pregnancy disorders and future microalbuminuria might provide a therapeutic window to apply targeted therapy aimed at slowing or preventing the development and progression of CKD. Several studies have shown an association between previous hypertensive pregnancies and later development of microalbuminuria. In a group of 48 women with preeclamptic pregnancies, albumin excretion was higher compared to 44 controls at 2–4 months after delivery as well as 3–5 years later [7]. The risk is not confined to women with a history of preeclampsia, as evidenced by a study of 49 women with gestational hypertension, 45 with preeclampsia, and 44 normotensive controls. In this 7-year follow-up study, the risk of microalbuminuria was markedly increased for those with a history of preeclampsia and gestational hypertension compared to controls, and was associated with systemic hypertension at follow-up [8]. Seven small studies were recently examined in a meta-analysis involving 273 preeclamptic and 333 normotensive pregnancies after 7 years of follow-up. Findings included a fourfold increased risk of microalbuminuria in women with a history of preeclampsia and an impressive eightfold risk in those with a history of severe preeclampsia [9•]. Considering the inherent limitations of meta-analytical methods, including publication bias and the small sample size even after combining several studies, larger studies were needed. Using data from the Medical Birth Registry in Norway, Sandvik et al. examined 89 women with preeclampsia and 69 normal controls 9 to 11 years after the index pregnancy [10•]. The authors found no association between microalbuminuria and prior preeclamptic pregnancy (p=0.54). Though larger than previous studies, this study remains relatively underpowered; it is interesting that the authors chose to limit their statistical power further by having a control group smaller than the preeclamptic group. In contrast, through the use of a pregnancy-history questionnaire, an analysis of the Family Blood Pressure Program Study between 2000 and 2004 (n= 3,015) defined 475 women with at least one prior hypertensive pregnancy [11•]. Compared to 2,199 women with normotensive pregnancies, the risk of microalbuminuria >25 mg/g was increased (OR 1.37) but with a relatively wide confidence interval (1.02–1.85, p=0.04). Large sample sizes are required to find small differences between heterogeneous groups. While it remains somewhat unclear, the majority of the studies seem to support an association between hypertensive pregnancy disorders and future microalbuminuria. Whether the microalbuminuria after hypertensive pregnancy is associated with future risk of CKD and ESRD is an entirely different question that has not been adequately investigated. It might be extrapolated from evidence linking microalbuminuria with
Page 3 of 6, 484
future CKD in other renal disorders such as diabetic nephropathy, which of course is a progressive systemic disease and not a fixed renal defect. With smaller studies such as that by Bar et al. showing microalbuminuria almost immediately after a hypertensive pregnancy, as well as many years later, it is possible that hypertensive pregnancy causes a fixed renal defect that may or may not progress to CKD or ESRD given that baseline data are often unavailable or incomplete, it is also possible that microalbuminuria might have been present before pregnancy and increased the risk of hypertensive pregnancy. In either case, identification of microalbuminuria increases a patient’s risk for future cardiovascular disease and therefore should be identified and managed appropriately. Regardless of whether hypertensive pregnancy is microalbuminuria’s chicken or egg, in order to understand whether hypertension during pregnancy increases the risk of CKD, we must progress past searching for risk factors such as microalbuminuria and examine CKD and ESRD risk directly. Hypertensive Pregnancies and Future Risk of CKD and ESRD Even if hypertensive pregnancy disorders impart a risk of future CKD and ESRD, the outcome will only be seen years after the insult. By the time CKD and ESRD develop, a history of preeclamptic pregnancy may have been either forgotten or lost in a sea of other CKD risk factors such as smoking, diabetes, chronic hypertension, obesity, and peripheral vascular disease. Linking CKD with a hypertensive pregnancy 10 or 20 years in the past is difficult at best. That said, there have been several recent studies showing an association between hypertensive pregnancy and future CKD and ESRD. The largest of these involved 570,433 women registered in the Medical Birth Registry of Norway who had a first singleton birth between 1967 and 1991 [12•]. These records were cross-referenced with the Norwegian Renal Registry, which tabulates all patients with ESRD since 1980. ESRD developed in 477 of these women. Of those with one or more pregnancies, the relative risk of ESRD was 4.7 in those with preeclampsia during the first pregnancy. Those with two or more pregnancies had a relative risk of 3.2 when preeclampsia occurred in the first pregnancy, 6.7 when during the second pregnancy, and 6.4 when both of the first two pregnancies were affected by preeclampsia. The overall rate of ESRD was low at just 3.7 per 100,000 women per year. However, when one considers the sheer number of women diagnosed with hypertensive pregnancy disorders every year, the contribution to ESRD might be substantial. Two studies from Taiwan’s National Health Insurance Research Database support an increased risk of ESRD after hypertensive pregnancy. The first of these examined 26,651 women with a history of at least one hypertensive pregnancy and found an unadjusted 10-fold risk of future ESRD; this was
484, Page 4 of 6
essentially unchanged after adjusting for urban status, CAD, congestive heart failure (CHF), hyperlipidemia, and placental abruption [13•]. However, the risk all but disappears after adjusting for hypertension and diabetes, falling to 2.72 (CI 1.76–4.22). One cannot help but conclude that the risk of ESRD after a hypertensive pregnancy might be due to shared risk factors rather than as a direct result of the hypertensive pregnancy itself. Women with preeclampsia had a 14-fold risk, while those with gestational hypertension had only a 9fold risk, indicating that the severity of the hypertensive condition might impact future renal risk. A very similar study of 13,633 women with a history of hypertensive pregnancy found a 10-fold risk of ESRD compared to women with only normotensive pregnancies [14•]. Interestingly, women with preeclampsia superimposed on chronic hypertension had the highest risk, with a hazard ratio of 44.72. This was higher than the risk of preeclampsia alone (p
