Adverse pregnancy outcomes and the long-term risk of maternal kidney disease

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Barrett, Peter M.
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University College Cork
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Background: Adverse pregnancy outcomes, including hypertensive disorders of pregnancy (HDP), preterm delivery, foetal growth restriction, gestational diabetes (GDM), and pregnancy loss, have been associated with the risk of maternal chronic disease, particularly cardiovascular disease. Less is known about the long-term risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in women who have experienced pregnancy complications. This thesis aims to examine associations between adverse pregnancy outcomes and the risk of maternal CKD and ESKD in later life. Structure and methods: This thesis begins with an introductory chapter (Chapter 1) followed by a systematic review and meta-analysis of the published literature, based on a pre-specified protocol (Chapter 2). A detailed methods chapter outlines the data sources, study design, exposure and outcome variables, and statistical approach used in each of the original observational studies conducted for this research (Chapter 3). Four population-based cohort studies are presented, and they focus on the risk of maternal kidney disease following preterm delivery (Chapter 4), stillbirth (Chapter 5), HDP (preeclampsia and gestational hypertension) (Chapter 6) and GDM (Chapter 7) respectively. In each study, data from the Swedish national registers are used, and analyses are based on Cox proportional hazard regression models with time-dependent covariates, adjusted for a wide range of medical, obstetric, and socio-demographic factors. In Chapter 8, an updated systematic review and meta-analysis is presented to reflect newly published literature on this topic. This is followed by a discussion and interpretation of the key findings, including consideration of the public health implications arising from this work (Chapter 9). Finally, conclusions of the thesis are presented in Chapter 10. Results: (i) Updated systematic review and meta-analysis - Overall, the published literature on this topic was sparse and most meta-analyses were based on small numbers (<5) of original studies. HDP and preterm delivery were associated with higher risk of long-term kidney disease in parous women. Preeclampsia was associated with a strongly increased risk of ESKD (adjusted risk ratio (aRR) 4.90; 95% CI, 3.56-6.74) and a modest increased risk of CKD (aRR 1.73, 95% CI 1.42-2.12). Gestational hypertension was associated with a strongly increased risk of ESKD (aRR, 3.64, 95% CI, 2.34-5.66), and more modest increased risk of CKD (aRR 1.48, 95% CI 1.38-1.58). Preterm delivery was associated with an increased risk of ESKD (aRR 2.19, 95% CI 1.93-2.47), but there were too few studies to determine the risk of CKD, or to separate the effects of iatrogenic vs. spontaneous preterm deliveries. No significant association was observed between GDM and CKD (aRR 1.04, 95% CI 0.76-1.41), but this meta-analysis was based on pooled estimates from just two studies. (ii) Original population-based cohort studies - Preterm delivery was associated with increased risk of both CKD and ESKD in our study. This association was strongest in women who experienced iatrogenic preterm delivery (due to preeclampsia or small for gestational age (SGA)), but the risk persisted in women who only had spontaneous preterm deliveries compared to women who delivered at term (for CKD, aHR 1.32, 95% CI 1.25-1.39; for ESKD, aHR 1.99, 95% CI 1.67-2.38). Separately, stillbirth was alsoassociated with an increased risk of both CKD (aHR 1.26, 95% CI 1.09–1.45) and ESKD (aHR 2.25, 95% CI 1.55-3.25) compared to women who only experienced live births. These associations persisted independent of preeclampsia, SGA or congenital malformations. Preeclampsia was associated with a higher risk of CKD during follow-up (vs. no preeclampsia, aHR 1.92, 95% CI 1.83–2.03), but this risk differed by CKD subtype and was greater for hypertensive CKD, diabetic CKD, and glomerular/proteinuric CKD. Women who experienced preterm preeclampsia, recurrent preeclampsia, or preeclampsia complicated by antenatal obesity were at particularly high risk of CKD. There was also a modest risk of CKD among women who experienced gestational hypertension (vs. none, aHR 1.49, 95% CI 1.38–1.61). GDM-diagnosed women were at increased risk of CKD and ESKD overall. However, when GDM was stratified according to those who developed post-pregnancy type 2 diabetes (T2DM), the associations between GDM alone (without later T2DM) and maternal kidney disease were non-significant (for CKD, 1.11, 95% CI 0.89-1.38; for ESKD, aHR 1.58, 95% CI 0.70-3.60). By contrast, strong associations were observed with CKD and ESKD in those who had GDM followed by subsequent T2DM. Conclusion: Adverse pregnancy outcomes, specifically preeclampsia, gestational hypertension, preterm delivery and stillbirth, are associated with increased risk of maternal CKD and ESKD. These associations persisted in a nationwide cohort after controlling for a wide range of confounders. Although the relative risk of future kidney disease is highest for ESKD, associations with CKD are likely to be of greater importance from a population perspective, given the high prevalence of CKD. Women who experience adverse pregnancy outcomes may warrant systematic follow-up to prevent onset or progression of future kidney disease, but the optimal format and timing of this follow-up requires further research.
Kidney disease , Pregnancy , Preeclampsia , Preterm delivery , Gestational diabetes , Chronic disease
Barrett, P. M. 2021. Adverse pregnancy outcomes and the long-term risk of maternal kidney disease. PhD Thesis, University College Cork.
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