Understanding the Association Between Hypertensive Disorders of Pregnancy and Peripartum Cardiomyopathy

This article refers to ‘Peripartum cardiomyopathy in Denmark: a retrospective, population-based study of incidence, management and outcome’, by A.S. Ersbøll et al. published in this issue on pages 1712–1720. Peripartum cardiomyopathy (PPCM) is an idiopathic form of cardiomyopathy presenting with heart failure secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found.1 The incidence of PPCM is variable, with the highest reported incidence of 1 in 102 deliveries in northwest Nigeria and the lowest reported incidence of 1 in 20 000 deliveries in Japan.2, 3 In the largest cohort of PPCM patients in the United States, the incidence was 1 in 968 live births.4 Advanced maternal age, African-American race, hypertensive disorders of pregnancy (HDP; including chronic hypertension, gestational hypertension, and pre-eclampsia), and multiple gestations are known risk factors for PPCM.5 In this issue of the Journal, Ersbøll et al.6 provide data on the incidence and outcomes of PPCM in Denmark. The authors linked the Danish National Birth Registry and the Danish National Patient Registry from 1 January 2005 to 31 December 2014 and identified 219 women with ICD-10 diagnosis code(s) for cardiomyopathy and/or heart failure in a period between 9 months before and 12 months after delivery. They retrieved and examined charts of 207 patients and identified 61 women with PPCM (incidence 1 in 10 149 deliveries) who met the EURObservational Programme PPCM registry inclusion criteria.7 The authors must be congratulated for a thorough and systematic approach for identifying patients with PPCM, thereby allowing them to provide a population-based estimate of the incidence of PPCM in Denmark. Complete recovery, defined as left ventricular ejection fraction (LVEF) ≥55% at 12 months or last available follow-up before 12 months, occurred in 52.5% of patients.6 Incidence of other major adverse events including death, mechanical circulatory support and/or heart transplantation, and persistent severe heart failure was 14.8%. Baseline LVEF predicted LVEF at 10–14 months, whereas cabergoline therapy was the only significant independent predictor of complete recovery in a multivariable logistic regression model.6 An interesting observation from the study by Ersbøll et al.6 is the association between HDP and clinical outcomes of PPCM. In their study, 54.1% of women with PPCM had HDP. Compared with women without HDP, those with HDP had higher baseline LVEF, were more often primiparous, had shorter duration of pregnancy and duration of admission, less need of inotropic therapy and/or mechanical circulatory support, and no major adverse events. More importantly, women with HDP were more likely to have complete recovery (66.7% vs. 35.7%, P = 0.016), and had higher mean LVEF at 12-month follow-up (55 ± 7 vs. 50 ± 9, P = 0.01), compared with those without HDP.6 In multivariable logistic regression, HDP had an adjusted odds ratio of 2.66 (95% confidence interval 0.75–9.43) for complete recovery, but was not statistically significant (P = 0.129), most likely due to the small sample size. Similar findings of HDP being associated with better outcomes have been reported previously in PPCM cohorts from Japan and Germany.3, 8 Whether HDP, particularly pre-eclampsia, and PPCM represent two distinct clinical entities or a spectrum of disease remains an ongoing conundrum. The Heart Failure Association of the European Society of Cardiology Working Group on PPCM has defined PPCM as a diagnosis of exclusion after eliminating all other known causes of peripartum heart failure, including hypertension.1 Ntusi et al.9 demonstrated significant differences in the time of onset of heart failure, clinical, electrocardiographic, and echocardiographic characteristics, and outcomes of hypertensive heart failure of pregnancy (HHFP) and PPCM. The onset of heart failure was post-partum in all PPCM patients, whereas it was antepartum in 85% of HHFP patients.9 Compared with HHFP, patients with PPCM had significantly lower LVEF, higher mortality (16.7% vs. 0%, P = 0.005) at 14-month follow-up, and were more likely to have chronic heart failure.9 On the other hand, the four-fold higher prevalence of pre-eclampsia and 1.5-fold higher prevalence of HDP in women with PPCM compared with controls, a common pathogenesis characterized by elevated levels of the vascular endothelial growth factor (VEGF) inhibitor soluble FLT1, and the fact that HDP is commonly associated with LV diastolic dysfunction and is not likely to cause severe LV systolic dysfunction (as seen in PPCM) have led experts to believe that HDP and PPCM may represent a spectrum of disorder.10, 11 Nonetheless, the observations that HDP is a risk factor for PPCM, but is associated with favourable outcome in patients with PPCM are counterintuitive. Whether this represents a true relationship between the two disease entities or is simply a manifestation of differential care of the two groups of patients (with and without HDP) remains to be determined. In the study by Ersbøll et al.,6 there were no significant differences in rates of medical therapy with beta-blockers, ACE inhibitor, or cabergoline between patients with and without HDP after the diagnosis of PPCM. However, compared with patients without complete recovery, those with complete recovery were more frequently treated with labetalol (43.8% vs. 17.2%, P = 0.026) during pregnancy.6 While the authors did not report the proportion of patients with and without HDP treated with labetalol during pregnancy, it is reasonable to speculate that the majority of patients receiving labetalol during pregnancy were those with HDP and that early beta-blockade may be associated with favourable outcomes, especially recovery of LVEF. Similarly, methyldopa, which according to the authors is the first choice for treatment of HDP in Denmark, has been shown to decrease soluble FLT1 and increase VEGF in in vitro studies.12 These observations may be viewed as hypothesis generating and future studies are needed to examine if the protective effect of HDP is in fact mediated via early treatment with labetalol and/or methyldopa during pregnancy. The Heart Failure Association of the European Society of Cardiology Study Group on PPCM recommends metoprolol succinate as the preferred beta-blocker for the treatment of patients with PPCM without cardiopulmonary distress.13 While Ersbøll et al.6 did not provide information on the type of beta-blocker used after the diagnosis of PPCM (specifically whether labetalol was switched to metoprolol succinate), their study highlights the gap between current evidence/guideline recommendations and clinical practice. Lastly, it is possible that women with HDP may have a closer follow-up and receive better care compared with those with a seemingly normal pregnancy until they develop PPCM. The study by Ersbøll et al.6 represents an important contribution to the literature on PPCM. Future prospective studies are needed to further explore the factors associated with complete recovery as well as to understand the influence of HDP on outcomes of patients with PPCM. The EURObservational Programme of the Heart Failure Association of the European Society of Cardiology Working Group on PPCM is an ongoing prospective, international, multicentre, observational registry which aims to collect information on 1000 patients with PPCM, and will provide important insights into the epidemiology, clinical characteristics, and outcome of patients with PPCM, as well as the impact of diagnostic and therapeutic processes on outcomes.7, 14 Conflict of interest: none declared.