Date Published: July 30, 2019
Publisher: Public Library of Science
Author(s): Ali S. Khashan, Marie Evans, Marius Kublickas, Fergus P. McCarthy, Louise C. Kenny, Peter Stenvinkel, Tony Fitzgerald, Karolina Kublickiene, Maarten W. Taal
Abstract: BackgroundPreeclampsia has been suggested to increase the risk of end-stage kidney disease (ESKD); however, most studies were unable to adjust for potential confounders including pre-existing comorbidities such as renal disease and cardiovascular disease (CVD). We aimed to examine the association between preeclampsia and the risk of ESKD in healthy women, while taking into account pre-existing comorbidity and potential confounders.Methods and findingsUsing data from the Swedish Medical Birth Register (MBR), women who had singleton live births in Sweden between 1982 and 2012, including those who had preeclampsia, were identified. Women with a diagnosis of chronic kidney disease (CKD), CVD, hypertension, or diabetes prior to the first pregnancy were excluded. The outcome was a diagnosis of ESKD, identified from the Swedish Renal Registry (SRR) from January 1, 1991, onwards along with the specified cause of renal disease. We conducted Cox proportional hazards regression analysis to examine the association between preeclampsia and ESKD adjusting for several potential confounders: maternal age, body mass index (BMI), education, native country, and smoking. This analysis accounts for differential follow-up among women because women had different lengths of follow-up time. We performed subgroup analyses according to preterm preeclampsia, small for gestational age (SGA), and women who had 2 pregnancies with preeclampsia in both. The cohort consisted of 1,366,441 healthy women who had 2,665,320 singleton live births in Sweden between 1982 and 2012. At the first pregnancy, women’s mean (SD) age and BMI were 27.8 (5.13) and 23.4 (4.03), respectively, 15.2% were smokers, and 80.7% were native Swedish. The overall median (interquartile range [IQR]) follow-up was 7.4 years (3.2–17.4) and 16.4 years (10.3–22.0) among women with ESKD diagnosis. During the study period, 67,273 (4.9%) women having 74,648 (2.8% of all pregnancies) singleton live births had preeclampsia, and 410 women developed ESKD with an incidence rate of 1.85 per 100,000 person-years. There was an association between preeclampsia and ESKD in the unadjusted analysis (hazard ratio [HR] = 4.99, 95% confidence interval [CI] 3.93–6.33; p < 0.001), which remained in the extensively adjusted (HR = 4.96, 95% CI 3.89–6.32, p < 0.001) models. Women who had preterm preeclampsia (adjusted HR = 9.19; 95% CI 5.16–15.61, p < 0.001) and women who had preeclampsia in 2 pregnancies (adjusted HR = 7.13, 95% CI 3.12–16.31, p < 0.001) had the highest risk of ESKD compared with women with no preeclampsia. Considering this was an observational cohort study, and although we accounted for several potential confounders, residual confounding cannot be ruled out.ConclusionsThe present findings suggest that women with preeclampsia and no major comorbidities before their first pregnancy are at a 5-fold increased risk of ESKD compared with parous women with no preeclampsia; however, the absolute risk of ESKD among women with preeclampsia remains small. Preeclampsia should be considered as an important risk factor for subsequent ESKD. Whether screening and/or preventive strategies will reduce the risk of ESKD in women with adverse pregnancy outcomes is worthy of further investigation.
Partial Text: The prevalence of chronic kidney disease (CKD) is estimated at 10% to 12% of the global population . Thus, kidney disease has evolved from a subspeciality concern to a global health problem [1,2]. More recently, the scientific community has become increasingly aware of sex-specific influences on the incidence and progression of renal disorders . Worldwide, it has been reported that the proportion of women with earlier stages of CKD is higher than that of men. This difference has been attributed to the longer life expectancy of women and/or potential CKD overdiagnosis due to differences in estimated glomerular filtration rate (GFR) equations [4,5]. Kidney function declines faster in men than in women, and estrogen has been suggested to play a protective role in females . Estrogen also has been suggested to play a protective role in the development of cardiovascular disease (CVD) in women compared with men with end-stage kidney disease (ESKD), although this survival benefit is smaller compared with the general population [7,8]. Moreover, women’s reproductive history seems to play an important role in the subsequent risk of developing CKD. Women who have had adverse pregnancy complications may be at risk of future CKD [9,10]; however, national guidelines are still lacking the support to address the link between pregnancy history and later renal dysfunction.
The study cohort consisted of 1,366,441 women (2,665,320 singleton live births) with no CKD, CVD, hypertension, or diabetes before the first pregnancy. During the study period, 4.9% of women (67,273/1,366,441) had at least 1 preeclampsia diagnosis (Fig 1). ESKD was diagnosed in 410 women.
This large, nationwide cohort study of healthy women followed up to 30 years after their first pregnancy suggests that women who have preeclampsia are at almost 5-fold increased risk to develop ESKD. The association is independent of a number of key potential confounders, including pre-existing CKD, CVD, diabetes, and hypertension. The highest risk of ESKD was observed among women with preterm preeclampsia, preeclampsia and SGA in the same pregnancy, and women who had preeclampsia in 2 pregnancies. The highest risk was associated with development of diabetic nephropathy. The population attributable fraction suggested that preeclampsia was responsible for 14% of all ESKD cases in parous women, although this estimate is based on the assumption that the association between preeclampsia and ESKD is causal. Restricting the analysis to women who had their first delivery from 1991 onwards resulted in a higher HR. Our results suggested that the risk of ESKD was increased in relation to preeclampsia in the first 5 years and the first 10-year follow-up (S5 Table), which may suggest that the increased HR could be due to missed ESKD diagnoses between 1982 and 1990 and that the true HR is likely to be larger than 5.