The impact of maternal chronic hypertension and chronic kidney disease on the risk of adverse pregnancy outcomes and long-term cardiovascular disease: a population-based epidemiology study

Background and aims: The prevalence of chronic hypertension (CH) and chronic kidney disease (CKD) have increased among pregnant women in recent decades. Given the improvement in antenatal care over the last few decades, it is still unclear whether the risk of adverse pregnancy outcomes (APOs) among women with CH and/or CKD has decreased. There is limited evidence on the association between antihypertensive treatment and APOs in women with CH. Although there is evidence that women with a history of APOs have an increased risk of cardiovascular disease (CVD), it remains unclear whether pre-pregnancy hypertension and the occurrence of APOs would influence this association. The aim of this PhD project was to investigate the impact of maternal CH and/or CKD and antihypertensive treatment on the risk of APOs and long-term CVD. Structure and methods: This thesis includes eight chapters: Introduction, Methods, two systematic review articles on the impact of CH and CKD on APOs, three original research articles, and Discussion. Data from the Swedish National Registers were analysed to examine the associations between CH/CKD and the risk of APOs over the last three decades. Data from the UK CALIBER platform were used to investigate: i) the association between CH and APOs, with a focus on the role of antihypertensive treatment and control of hypertension, and ii) the associations between pre-pregnancy hypertension and subsequent diagnosis of 12 different CVDs, considering the role of APOs on these associations. Adverse pregnancy outcomes were pre-eclampsia, preterm birth, stillbirth, Caesarean section and small for gestational age (SGA). The statistical methods were done using logistic regression models for the Swedish data, logistic regression models with propensity score matching for the antihypertensive treatment analyses, while the associations between pre-pregnancy hypertension and CVD were analysed using stratified Cox models. All statistical models were adjusted for several potential confounders. Results: Systematic reviews and meta-analyses: CH was associated with 5-fold increased odds of pre-eclampsia and approximately 2-fold increased odds of stillbirth, preterm birth, and SGA, compared to women without CH. Women with treated CH (compared to untreated normotensive women) had higher odds of APOs. However, the results were inconsistent when outcomes were compared between treated and untreated women with CH; no increased odds of superimposed pre-eclampsia or other APOs were observed, except for 86% increased odds of SGA. Findings from the meta-analysis suggested that women with CKD had higher odds of pre-eclampsia, Caesarean section, preterm birth, very preterm birth, and SGA. All causes of CKD were associated with increased odds of pre-eclampsia, preterm birth, and SGA, with stronger associations in women with diabetic CKD, particularly for preterm birth [adjusted odds ratio (aOR): 4.76, (95% confidence interval (CI), 3.65–6.21)] and SGA [aOR: 4.50, (95% CI, 2.92–6.94)]. The findings according to the severity of kidney disease showed that later stages of CKD were associated with a greater odds of APOs than earlier stages. Swedish National Registers: The overall findings from this study suggested that the odds of APOs remain high in women with CH and/or CKD, and the odds persisted independent of parity, maternal age, and body mass index, among other potential confounders. No association was found between CKD and stillbirth. All causes of CKD were associated with higher odds of pre-eclampsia, emergency Caesarean section, and medically indicated preterm birth, and the ORs were higher in women with diabetic CKD, renovascular disease, and congenital kidney disease than other CKD subtypes. CALIBER studies: The results suggested a higher odds of APOs in women with CH (treated and untreated) compared to untreated normotensive women. In women with CH, those requiring treatment (versus untreated) had 17%, 25%, and 80% increased odds of superimposed pre-eclampsia, preterm birth, and fetal growth restriction (FGR), respectively. However, these results were mainly attributable to the level of blood pressure (BP) control among the treated group; as similar results were found between the untreated and treated women with CH who achieved tight control (BP<135/85 mmHg) for all assessed outcomes except for a 59% decreased odds of superimposed pre-eclampsia and a 55% increased odds of FGR. Pregnant women with CH who were prescribed methyldopa (versus β-blockers) had 43%, 59%, and 44% increased odds of superimposed pre-eclampsia, preterm birth, and very preterm birth, but 66% lower odds of FGR. No differences in outcomes were found in women who were prescribed calcium-channel-blockers (versus β-blockers) except for 94% increased odds of preterm birth. The magnitude of the associations increased with increasing BP, and the strongest associations were observed in women with severe hypertension (BP≥ 160/90 mmHg). In treated women with CH, less-tight (BP≥135/85 mmHg) versus tight (BP