Pulmonary arterial hypertension associated with congenital heart disease in children: clinical characterisation, outcomes and changes in demographics over time
Authors: Constantine A , Dimopoulos K , Condliffe R , Clift P , Chaplin G , Muthurangu V , Haworth S G , Moledina S 
Published: October 2021

Abstract

Background/Introduction
Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD) in children and is associated with significant morbidity and mortality. The impact of different phenotypes on management and survival remains unclear.

Purpose
To examine the clinical features, management and outcomes of paediatric PAH-CHD patients based on the 20-year experience of the UK National Paediatric Pulmonary Hypertension (PH) Service.

Methods
Consecutive PAH-CHD patients entering the service between January 2001 and January 2021 were included and classified into: Eisenmenger syndrome (ES, group A), PAH related to a significant systemic-pulmonary shunt (group B), PAH with small or co-incidental CHD (group C) and PAH following defect repair (group D). Incident patients (without pre-existing PAH) were included in survival analysis.

Results
Of the overall PH paediatric cohort of 1104 patients, 819 (74.2%) had co-existing CHD and 354 (32.1%) patients received a diagnosis of PAH-CHD: 57.1% female, median [IQR] 4.6 [1.7–10.9] years. Group D PAH-CHD was the commonest subgroup, accounting for 36%, while the least frequent subtype was group C (14%). Group A and group B PAH-CHD represented 26% and 24%, respectively. Down syndrome was present in over one third (122, 34.5%) of PAH-CHD patients and was more commonly associated with ES (p=0.02). PAH therapy was started in 79.9% of PAH-CHD patients. At the end of follow-up, patients with group C PAH-CHD were more likely to be on combination therapy than any other group (64.6% vs. 28.4%, p&lt;0.0001). Prostanoid therapy was used in a minority (11%) of patients.
The subgroup distribution of PAH-CHD at diagnosis changed from the early (2000–2005) to late (2015–2020) period (Figure 1). The proportion of ES patients decreased from 43.4% to 14.6% of PAH-CHD (p&lt;0.0001). The proportion of group B PAH-CHD patients increased (9.4% vs. 33.3%, p&lt;0.0001), with the majority (59.3%) deemed “operable” on specialist assessment. There was a trend for an increase in repaired PAH-CHD patients between the early and late era (31.1% vs. 43.8%, p=0.09).
Transplant-free survival in PAH-CHD was 90.9% (95% CI: 87.8–94%) at 1 year, 77.9% (95% CI: 73.1–83.1%) at 5 years, and 74.9% (95% CI: 69.6–80.7%) at 10 years (Figure 2). Group C PAH-CHD had a lower transplant-free survival than the other 3 groups (HR 2.54, 95% CI: 1.51–4.28, p=0.0005). There was no difference in outcome between group A and group D PAH-CHD (HR 1.19, 95% CI: 0.62–2.28, p=0.6).

Conclusions
Repaired PAH-CHD, not ES, was the most common subtype in this large paediatric cohort. Over time, there were fewer ES patients and more “operable” patients with left-right shunts, suggesting an improvement in early diagnosis and management. Despite widespread use of PAH therapy, PAH-CHD remains a life-limiting disease with the poorest outcomes in PAH with co-incidental CHD.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Constantine received a personal PhD fellowship grant (CHAMPION PhD Fellowship) Figure 1Figure 2