Preeclampsia and Onset of Renal Disorders in the Long-Term Period following Pregnancy

Authors: Nathalie Auger, Sam Amar, Gilles Paradis, Aimina Ayoub, Antoine Lewin, Amanda Maniraho, Brian J. Potter

Abstract

Introduction

Preeclampsia is associated with acute renal complications during pregnancy, but the risk of renal sequelae later in life is unclear. We determined if preeclampsia was associated with chronic renal complications in the long-term period following pregnancy.

Methods

We conducted a longitudinal cohort study of 1,431,156 pregnant women in QC, Canada with 25,598,024 person-years of follow-up between 1989 and 2023. The main exposure measure was preeclampsia, and outcomes included hospitalization for vascular and nonvascular renal complications up to 34 years after pregnancy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between preeclampsia and subsequent kidney complications using Cox regression models adjusted for patient characteristics.

Results

Patients with preeclampsia had a higher hospitalization rate for renal complications than patients without preeclampsia (29.4 vs. 19.5 per 10,000 person-years). Preeclampsia was associated with 1.45 times the risk of hospitalization for renal disease during follow-up (95% CI 1.40–1.50). Risks were particularly elevated for renal vascular disease (HR 3.74, 95% CI 3.21–4.37), diabetic kidney disease (HR 3.71, 95% CI 3.18–4.32), and glomerulopathy (HR 3.44, 95% CI 2.92–4.05). Associations were also present with obstructive uropathy (HR 1.44, 95% CI 1.30–1.58). Severe forms of preeclampsia, including early onset preeclampsia (HR 1.90, 95% CI 1.72–2.10) and superimposed preeclampsia (HR 2.52, 95% CI 2.22–2.85), were strongly associated with subsequent renal morbidity.

Conclusion

Preeclampsia, especially severe preeclampsia, is associated with the long-term risk of renal disease. Patients with preeclampsia may benefit from nephrological follow-up in the long-term period after pregnancy.

Introduction

Preeclampsia is a common cause of acute kidney injury in pregnancy [1], but little is known about the long-term risk of renal complications. Preeclampsia is a hypertensive disorder characterized by new onset of hypertension after 20 weeks of gestation [2]. Renal involvement is common, with most patients presenting with proteinuria caused by glomerular endothelial dysfunction and podocyte injury [3]. Severe cases may progress to acute renal failure or multi-organ dysfunction in the peripartum period [2]. Although the acute effects of preeclampsia on the kidney are believed to resolve following pregnancy [4], some sequelae have potential to persist and lead to chronic kidney complications over time [5]. However, the extent to which preeclampsia relates to the subsequent development of kidney disease is poorly understood.

Data are beginning to suggest that preeclampsia may be associated with end-stage renal disease [6–8]. A meta-analysis of more than 5 million patients from a range of countries found that preeclampsia increased the risk of end-stage kidney disease by up to 5 times compared with no preeclampsia [6]. The association appears to be stronger for preeclampsia than gestational hypertension, which was associated with only 3.6 times the risk of end-stage kidney disease in the same meta-analysis [6]. However, the specific renal disorders linking preeclampsia with end-stage kidney disease are unclear. Some studies suggest that diabetic nephropathy, interstitial nephritis, and glomerulonephritis may be common in patients with preeclampsia who later go on to develop end-stage kidney disease [7, 8]. Yet, hypertensive renal disease, renal artery disease, and other vascular disorders leading to end-stage renal disease have received limited attention despite the known influence of preeclampsia on endothelial cell function [2]. Our objective was to determine if preeclampsia was associated with the risk of developing vascular and nonvascular renal disease up to three decades after pregnancy.

Methods

Study Design and Population

We carried out a longitudinal cohort study of 1,437,755 women with deliveries in QC, Canada between April 1989 and March 2022. We obtained the cohort from the Maintenance and Use of Data for the Study of Hospital Clientele registry, which includes all hospitalized patients and 98% of deliveries in Quebec [9]. We included patients at their first delivery and used diagnostic codes from the ninth and tenth editions of the International Statistical Classification of Diseases and Related Health Problems to identify patients with a diagnosis of preeclampsia. Similarly, we used diagnostic codes to identify patients with kidney disease during subsequent hospitalizations (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000547538).

We began follow-up at the first delivery and ended at the first hospitalization for kidney disease, death, or the study end on March 31, 2023. Overall, we had up to 34 years of follow-up after pregnancy. We excluded patients who died at their first pregnancy since follow-up was not possible. We additionally excluded patients with prior hospitalizations for kidney disease before or during pregnancy, and patients with overt renal complications in the peripartum period.

Preeclampsia

The exposure measure was preeclampsia defined as hypertension (140/90 mm Hg) with new onset of proteinuria or end organ dysfunction at 20 weeks of gestation or later [2, 10]. We identified patients with preeclampsia at the first or any subsequent pregnancy. We determined the severity of preeclampsia (nonsevere, severe, superimposed). Nonsevere preeclampsia was defined as hypertension that did not reach 160/110 mm Hg [11]. Severe preeclampsia was defined as hypertension greater than or equal to 160/110 mm Hg and included eclampsia and the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) [10]. Superimposed preeclampsia was defined as resistant hypertension, new or worsening proteinuria, or other severe complications among women with preexisting chronic hypertension [11].

We further categorized preeclampsia as early versus late onset. Early onset is considered more severe and consists of preeclampsia occurring before 34 weeks of gestation, while late onset consists of preeclampsia occurring at or after 34 weeks [12]. We also identified patients with recurrent preeclampsia in more than one pregnancy. In multiparous women, recurrent preeclampsia is generally more severe than nonrecurrent preeclampsia [13].

Renal Outcomes

The outcome was hospitalization for renal disease anytime between the first delivery and the end of the study. We included diabetic renal disease, renal vascular disease (hypertensive renal disease, renal artery atherosclerosis or aneurysm, renal vein thrombosis), glomerulopathy (nephritic, nephrotic), acute or chronic pyelonephritis, obstructive uropathy, urolithiasis, acute or chronic renal failure, and dialysis or kidney transplant.

Covariates

We included covariates that were potential confounders of the relationship between preeclampsia and renal outcomes. Covariates consisted of age at first pregnancy (<25, 25–34, ≥35 years), multiple birth (yes, no), pregnancy comorbidity (gestational or preexisting type 1 and 2 diabetes, preexisting dyslipidemia, systemic lupus erythematosus, obesity, and tobacco, alcohol, or other substance use disorders), place of residence (rural, urban, unknown), socioeconomic disadvantage (yes, no, unknown), and time period (1989–1999, 2000–2010, 2011–2022). Socioeconomic disadvantage was defined as the lowest quintile of material deprivation, measured as an index of income, employment, and education at the neighborhood level [13].

Data Analysis

We began by assessing hospitalization rates for kidney disease per 100,000 person-years and plotting the cumulative incidence over time. In primary analyses, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between preeclampsia and subsequent risk of kidney disease using Cox proportional hazards regression models adjusted for age, multiple birth, comorbidity, place of residence, socioeconomic disadvantage, and time period. We used the number of days since the first delivery as the time scale and censored patients with short follow-up who delivered towards the end of the study, died, or were never hospitalized for kidney disease by the end of follow-up. We compared patients with preeclampsia against no preeclampsia, and stratified preeclampsia by severity, onset, and recurrence. We additionally examined the association of preeclampsia with kidney disorders at different points during follow-up using flexible parametric survival models [14]. In sensitivity analyses, we examined if associations persisted when we restricted the cohort to pregnancies occurring later in the study and when we excluded patients who developed diabetic renal disease.

We performed the analysis using SAS version 9.4 (SAS Institute Inc., Cary, NC). The data were anonymized and the study conformed to the Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans. The University of Montreal Hospital Centre Institutional Review Board waived ethics review as informed consent was not needed.

Results

Among 1,431,156 patients with deliveries between 1989 and 2022, 71,000 (5.0%) developed preeclampsia in at least one pregnancy (online suppl. Table S2). During a total of 25,598,024 person-years of follow-up, 3,352 (4.7%) patients with preeclampsia were hospitalized for renal disease, compared with 47,577 (3.5%) patients without preeclampsia. Patients with preeclampsia were more likely to be younger than 25 or older than 34 years, have a multiple birth or pregnancy comorbidity, and be socioeconomically disadvantaged compared with no preeclampsia.

Patients with preeclampsia had a modestly elevated renal hospitalization rate (Fig. 1). Cumulative incidence rates at 34 years of follow-up were 986.0 per 10,000 patients with preeclampsia versus 773.6 per 10,000 patients without preeclampsia. The cumulative incidence rate of renal vascular disease was 277.3 per 10,000 patients with preeclampsia versus 59.9 for no preeclampsia, while rates for glomerulopathy were 4.8 versus 1.7 per 10,000 and rates for renal failure were 983.5 versus 678.3 per 10,000 (online suppl. Fig. S1). Hospitalization rates increased more rapidly among women with preeclampsia beginning around 5 years after pregnancy.

Preeclampsia was associated with renal hospitalization (Table 1). Hospitalization rates for kidney disease were higher among women with superimposed (52.8 per 10,000 person-years), early onset (290.4 per 10,000), and recurrent preeclampsia (42.6 per 10,000) compared with no preeclampsia (19.5 per 10,000). Upon adjustment for confounders, patients with preeclampsia were 1.45 times more likely to be hospitalized for any renal disease (95% CI 1.40–1.50). Severe forms of preeclampsia, including superimposed (HR 2.52, 95% CI 2.22–2.85), early onset (HR 1.90, 95% CI 1.72–2.10), and recurrent preeclampsia (HR 2.02, 95% CI 1.84–2.22), were particularly associated with the risk of renal hospitalization.

Preeclampsia was associated with several renal complications in the long term (Table 2). Patients with preeclampsia were more likely to be hospitalized for diabetic renal disease (HR 3.71, 95% CI 3.18–4.32), renal vascular disease (HR 3.74, 95% CI 3.21–4.37), glomerulopathy (HR 3.44, 95% CI 2.92–4.05), acute renal failure (HR 1.79, 95% CI 1.67–1.92), and chronic renal failure (HR 2.89, 95% CI 2.61–3.19), compared with no preeclampsia. Patients with preeclampsia had up to 5 times the risk of admission for acute or chronic tubulointerstitial nephritis, urolithiasis, obstructive uropathy, and kidney procedures including dialysis and transplantation.

Severe forms of preeclampsia were more strongly associated with renal complications (online suppl. Table S3). Compared with no preeclampsia, superimposed preeclampsia was associated with admission for renal vascular disease (HR 13.84, 95% CI 9.90–19.33), glomerulopathy (HR 8.99, 95% CI 5.88–13.74), and kidney dialysis or transplant (HR 17.95, 95% CI 12.34–26.13). Severe preeclampsia was associated with around 5 times greater risk of these outcomes. Early onset and recurrent preeclampsia were associated with 8–12 times greater risk of renal vascular disease, glomerulopathy, and kidney dialysis or transplant.

Associations with renal vascular disease, glomerulopathy, and renal failure were strongest within 5 years of pregnancy but persisted throughout follow-up (Fig. 2). At 5 years of follow-up, preeclampsia was associated with 5.97 times greater risk of renal vascular disease (95% CI 4.72–7.55), 3.91 times greater risk of glomerulopathy (95% CI 3.16–4.84), and 2.41 times greater risk of renal failure (95% CI 2.16–2.69), compared with no preeclampsia. At 20 years of follow-up, preeclampsia was associated with 2.79 times greater risk of renal vascular disease (95% CI 2.24–3.49), 2.58 times greater risk of glomerulopathy (95% CI 2.01–3.33), and 1.91 times greater risk of renal failure (95% CI 1.78–2.05).

In sensitivity analyses, preeclampsia remained associated with the risk of renal hospitalization when we restricted the cohort to pregnancies between 2007 and 2022 (HR 1.42, 95% CI 1.32–1.52) and to pregnancies between 2012 and 2022 (HR 1.36, 95% CI 1.21–1.53) (online suppl. Table S4), and when we excluded women with diabetic renal disease (HR 1.40, 95% CI 1.35–1.45).

Discussion

In this cohort of 1.4 million patients, preeclampsia was associated with an increased risk of hospitalization for renal disease up to three decades after pregnancy. Preeclampsia was associated with a range of renal disorders, including renal vascular disease, diabetic nephropathy, glomerulopathy, and other complications leading to end-stage renal disease. Preeclampsia was also associated with urolithiasis, pyelonephritis, and tubulointerstitial nephritis, although the associations were weaker. Severe forms of preeclampsia, including early onset, severe, superimposed, and recurrent preeclampsia were particularly associated with renal morbidity. Associations persisted throughout follow-up but were strongest within 5 years of pregnancy. The associations were not driven by an acute effect of preeclampsia on the kidney, as patients with overt renal complications during pregnancy were excluded from the study. The findings suggest that the association between preeclampsia and end-stage renal disease is driven by both vascular and nonvascular renal disorders. Patients with preeclampsia may benefit from renal function monitoring to promptly detect kidney sequelae following pregnancy and prevent further complications.

What is currently known about the long-term impact of preeclampsia focuses primarily on end-stage renal disease. A meta-analysis of 5 studies with more than 5 million patients from North America, Europe, Asia, and Australia found that patients with preeclampsia were 5 times more likely to develop end-stage kidney disease than patients without preeclampsia [6]. The types of disorders that preceded the development of end-stage kidney disease were examined in only one study, an analysis of 1,366,441 patients from Sweden, where patients with preeclampsia were 3–9 times more likely to develop end-stage renal disease caused by diabetic nephropathy and glomerulonephritis [7]. Although other renal morbidities were not assessed [7], an analysis of 1 million patients from Denmark found that preeclampsia presenting before 34 weeks of gestation was additionally associated with tubulointerstitial nephritis and hypertensive kidney disease [15]. The findings point to the possibility that several pathways link preeclampsia with renal morbidity. Our findings suggest that preeclampsia may precede a range of renal disorders leading to end-stage kidney disease, including both vascular and nonvascular pathways.

Preeclampsia is an obstetric disorder with vascular etiology [16]. The underlying problem appears to be defective differentiation of cytotrophoblasts and spiral artery remodeling leading to placental insufficiency, oxidative stress, and imbalanced release of pro- and antiangiogenic factors [16, 17]. In patients with preeclampsia, the placenta releases higher levels of soluble fms-like tyrosine kinase-1, an antiangiogenic circulating biomarker that binds to pro-angiogenic placental growth factor and vascular endothelial growth factor, inhibiting their ability to support endothelial function [16]. Decreased availability of pro-angiogenic biomarkers is associated with inadequate angiogenesis, a pro-inflammatory environment, and inhibition of vasodilatory pathways [18]. Endothelial dysfunction ultimately leads to the clinical syndrome of preeclampsia manifested through hypertension and proteinuria [16]. Proteinuria results from glomerular endothelial dysfunction and is associated with acute renal damage in advanced stages [3]. Renal function typically resumes when pregnancy ends, but patients with a history of preeclampsia can continue to have elevated soluble fms-like tyrosine kinase-1 levels and endothelial dysfunction for several years [19]. Endothelial dysfunction is thought to explain why patients with preeclampsia have an elevated risk of cardiovascular disease later in life [13]. It is also possible that undiagnosed subclinical or preclinical conditions during pregnancy are involved. Subclinical tubular and glomerular dysfunction in pregnant patients with type 1 diabetes mellitus, for instance, may be associated with endothelial activation and has been found to predict preeclampsia [20].

Persisting endothelial dysfunction has the potential to affect the kidney over time. The kidney contains podocytes or specialized endothelial cells that are responsible for the integrity of the glomerular filtration barrier [21]. Podocytes are sensitive to angiogenic factors, especially vascular endothelial growth factor which helps prevent podocyte damage and podocyturia [21]. Podocyturia tends to be more prevalent in postpartum patients with preeclampsia [21, 22]. In an analysis of 13 renal biopsies taken 1 month postpartum, patients with preeclampsia were more likely to have signs of focal segmental glomerulosclerosis, a lesion associated with podocyturia, compared with normotensive patients [22]. Other studies have found that microalbuminuria, a marker of endothelial dysfunction and future development of renal disease, remains elevated years following preeclampsia [5, 23].

In our study, some of the strongest associations of preeclampsia were with renal vascular disease, especially hypertensive renal disease. Patients with preeclampsia are known to have a greater risk of hypertension over their lifetime [24]. A systematic review of 25 studies found that patients with preeclampsia were 3 times more likely to develop hypertension after pregnancy compared with no preeclampsia [24]. While endothelial dysfunction may explain some of this risk, patients with preeclampsia also tend to have reduced nitric oxide bioavailability during pregnancy [25]. Nitric oxide is a vasodilatory signaling molecule that helps maintain normotension [25, 26]. A study of 51 patients from Finland found that impaired vasodilation, measured by brachial artery flow in response to acetylcholine, was common in patients with a history of preeclampsia [26].

Preeclampsia was strongly associated with diabetic kidney disease. Similar to hypertension, patients with preeclampsia tend to be at risk of developing diabetes over their lifetime [25]. A review of 21 studies found that preeclampsia was associated with a 2.4-fold greater risk of developing diabetes more than 10 years after pregnancy compared with no preeclampsia [27], while an analysis of 1.4 million patients from Sweden found that preeclampsia was associated with a 9-fold greater risk of developing diabetic nephropathy [7]. An analysis of 26 patients from Taiwan suggested that patients with preeclampsia can have signs of insulin resistance as early as 2 months after pregnancy [28]. Our data indicate that preeclampsia may be just as strongly associated with the development of diabetic kidney disease as with renal vascular disease.

Glomerulopathy was another renal complication that was common after preeclampsia. Unlike hypertensive and diabetic kidney disease, glomerulopathy tends to be driven by inflammatory pathways [29]. Patients with preeclampsia tend to have laboratory signs of chronic immune activation during pregnancy [30], including increased production of the pro-inflammatory cytokines tumor necrosis factor alpha and interleukins (IL)-6 and IL-17, as well as a decrease in the anti-inflammatory cytokines IL-10 and IL-4 [25, 30]. While the extent to which imbalance in inflammatory cytokines persists after pregnancy is unclear, low-grade activation has potential to affect kidney function in the long term. Analyses of more than 3 million deliveries from Sweden and Denmark suggest that preeclampsia may be associated with up to 5 times greater risk of developing glomerulopathy following pregnancy [7, 15]. While neither study specified the types of disorders, patients with preeclampsia in our study were up to 4 times more likely to develop nephritic or nephrotic syndrome over their lifetime than patients without preeclampsia.

Preeclampsia was associated with a mild elevation in the risk of urolithiasis and obstructive uropathy, but the meaning of this finding is unclear as the biological connection may be indirect. During normal pregnancies, increased urinary calcium excretion and elevated urine pH can facilitate the formation of calcium phosphate stones [31]. Hormonal shifts with associated urinary relaxation and retention can further promote stone formation [31]. A study of 2,835 patients from the USA found that parous patients were 2.2 times more likely to have kidney stones up to a year after pregnancy compared with nonparous patients [31], but the association with preeclampsia has not been assessed to date.

Risk of renal complications was greatest for severe types of preeclampsia, especially early onset preeclampsia and preeclampsia superimposed on preexisting hypertension. Early onset preeclampsia is a particularly serious obstetric complication, with the onset of hypertension and proteinuria occurring early, typically before 34 weeks of gestation [12]. In a meta-analysis of studies of end-stage renal disease, patients with preterm onset of preeclampsia appeared to have greater risk of renal failure than patients with preeclampsia at term [6]. A retrospective cohort study of 1,094 women from Thailand found that early onset preeclampsia, compared with later onset, was associated with more laboratory evidence of renal dysfunction, including elevated creatinine levels and a high urine protein to creatinine ratio [32]. Patients with severe variants of preeclampsia may therefore benefit the most from kidney function screening after pregnancy.

This study had limitations. We used administrative hospital discharge data that may be subject to misclassification of exposures or outcomes due to coding errors. Hospitalized patients represent more advanced renal disease. We could not include mild or early stage renal morbidity managed in outpatient settings. We adjusted for potential confounders but did not have data on ethnicity, body mass index, and family history of kidney disease or hypertension. Obesity and smoking data may be incomplete or misclassified. We could not rule out the possibility that patients with preeclampsia had closer renal monitoring following delivery compared with patients without preeclampsia. We could not determine the extent to which diabetes and hypertension mediated the association between preeclampsia and kidney disease, although we were able to assess diabetic and hypertensive renal outcomes. Future research is needed to determine how preeclampsia relates to clinical endpoints such as microalbuminuria, proteinuria, and glomerular filtration rates. As the study was observational, the findings should be interpreted with caution. The data are representative of a large Canadian population, but it is unclear whether the findings can be generalized to other populations.

In this longitudinal study of 1.4 million pregnant patients followed for up to 34 years after pregnancy, preeclampsia was associated with a range of vascular and nonvascular renal complications. Associations were present with renal vascular disease, diabetic nephropathy, glomerulopathy, and obstructive uropathy. Risks were highest in the first 5 years following pregnancy and for severe forms of preeclampsia. The findings suggest that preeclampsia is an important risk factor for the development of vascular and nonvascular renal disease in the long term.

Statement of Ethics

This study protocol was exempted from review and from requiring informed consent by the University of Montreal Hospital Centre Institutional Review Board.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the Heart and Stroke Foundation of Canada (Grant No. G-22-0031974); and the Fonds de recherche du Québec-Santé (Grant No. 296785). The funders had no role in the design, data collection, data analysis, and reporting of this study.

Author Contributions

N.A., G.P., A.L., and B.P. conceived and designed the study. A.M. performed the data analysis, and N.A., S.A., and A.A. helped interpret the results. N.A., S.A., A.A., and A.M. drafted the manuscript, and G.P., A.L., and B.P. revised it critically for important intellectual content. All authors approved the version to be published.