Abstract

Objective

     To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension in a large, multicenter pediatric pulmonary hypertension registry.

Study design

     We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with Down syndrome and children without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome.

Results

     Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. The median age at diagnosis of pulmonary hypertension in patients with Down syndrome was 0.49 year (IQR, 0.21-1.77 years), similar to that in patients without Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with Down syndrome and those without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%; repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). Pulmonary hypertension resolved in 43% after 3 years, associated with a diagnosis of pulmonary hypertension at age <6 months (54% vs 29%; P = .002) and a pretricuspid shunt (65% vs 38%; P = .02). Five-year transplantation-free survival was 88% (95% CI, 80%-97%). Tracheostomy (hazard ratio [HR], 3.29; 95% CI, 1.61-6.69) and reflux medication use (HR, 2.08; 95% CI, 1.11-3.90) were independently associated with a composite outcome of severe pulmonary hypertension.

Conclusions

     Despite high rates of cardiac and respiratory comorbidities that influence the severity of pulmonary hypertension, children with Down syndrome–associated pulmonary hypertension generally have a survival rate similar to that of children with non–Down syndrome–associated pulmonary hypertension. Resolution of pulmonary hypertension is common but reduced in children with complicated respiratory comorbidities.

Methods

     The PPHNet registry includes comprehensive clinical data from 8 centers in the US and Canada that enrolled patients between October 2014 and February 2018 and includes follow-up data submitted through May 18, 2020.20 The PPHNet registry was supported in part by a National Heart, Lung, and Blood Institute–funded U01 program (U01 HL12118; Data Fusion: A Sustainable, Open Source Registry Advancing Pediatric Pulmonary Vascular Disease Research; S.A. and K.M., principal investigators). The study protocol was approved by the Institutional Review Board of each participating center. Parents and/or guardians provided signed informed consent, and participants gave assent when appropriate, according to institutional guidelines.

Results

     Of the 1475 children enrolled in the PPHNet Registry, 158 (10.7%) were identified as subjects with Down syndrome.20 There was a slight preponderance of males in the Down syndrome group (53.8%). The proportion of patients with pulmonary hypertension with Down syndrome differed by study site, ranging from 6% to 22%. Compared with the non-Down syndrome cohort, patients with Down syndrome were less likely to be White and more likely to be Asian (P < .001). There were 12 deaths and no lung transplants in the Down syndrome cohort, which was followed for a median of 2.9 years. There was no difference in the proportion of patients with death/transplant for the Down syndrome and non-Down syndrome cohorts (Table I).

     The distribution of the primary WSPH classification of pulmonary hypertension differed between the Down syndrome and non-Down syndrome cohorts (P < .001). The Down syndrome cohort was more commonly group 1 (pulmonary arterial hypertension) compared with the non-Down syndrome cohort (69.6% vs 37.3%), and group 3 pulmonary hypertension (related to lung disease) was more common in the nonDown syndrome group (52.2% vs 20.9%) (Table I). Of the 110 patients with Down syndrome categorized as having group 1 pulmonary hypertension (pulmonary arterial hypertension), 109 were further classified: 103 (94.5%) with pulmonary arterial hypertension associated with CHD, 5 (4.6%) with idiopathic pulmonary arterial hypertension, and 1 (0.9%) with pulmonary arterial hypertension induced by drugs and toxins. Relatively few patients were classified as group 10 (pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis), group 100 (PPHN), and group 2 pulmonary hypertension (related to left heart disease), and prevalence was similar in children with Down syndrome and those without Down syndrome. No patients were classified as having chronic thromboembolic pulmonary hypertension (group 4). Group 5 (multifactorial) pulmonary hypertension was uncommon across the registry (Table I).