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. Author manuscript; available in PMC: 2026 Jun 26.
Published in final edited form as: Curr Opin Pulm Med. 2026 May 25;32(5):386–393. doi: 10.1097/MCP.0000000000001287

Association between Upper Airway Obstruction and Pulmonary Hypertension in Children with Down Syndrome

Kevin Guy 1, Amal Isaiah 1,2,3,4
PMCID: PMC13294707  NIHMSID: NIHMS2188412  PMID: 42199076

Abstract

Purpose of review:

Down syndrome (DS) is the most common non-lethal chromosomal aneuploidy, affecting 1 in 700 live births. Pulmonary hypertension (PH) occurs in approximately 25% of children with DS and contributes to a 10% mortality rate within 3 years of diagnosis. Despite obstructive sleep apnea (OSA) affecting up to 80% of children with DS, the specific contribution of upper airway obstruction to PH in this population remains poorly characterized. This review synthesizes current evidence to address that gap.

Recent findings:

Children with DS develop multilevel upper airway obstruction due to craniofacial dysmorphology, relative macroglossia, hypotonia, and reduced peripheral chemosensitivity. OSA-driven chronic hypoxemia promotes pulmonary vascular remodeling, with 87% of recurrent PH cases classified as WHO Group III. Echocardiographic diagnosis is limited by chronic lung disease. NT-proBNP is the most reliable biomarker in DS. Adenotonsillectomy reduces apnea severity, though evidence of a reduction in mean pulmonary arterial pressure in DS is lacking. Endothelin receptor antagonists show functional benefit, while sildenafil appears less effective in DS-specific analyses.

Summary:

No DS-specific PH staging system exists, representing a critical gap. Future research should quantify the impact of airway interventions on pulmonary hemodynamics, develop DS-tailored biomarkers, and optimize pharmacologic regimens in this molecularly distinct population.

Keywords: Pulmonary hypertension, Upper airway obstruction, Obstructive sleep apnea, adenotonsillectomy

Introduction

Trisomy 21, or Down Syndrome (DS), is the most common non-lethal aneuploidy, occurring in approximately 1 in 700 live births.1,2 Patients with DS are frequently affected by craniofacial abnormalities, growth retardation, and intellectual disability. While these are the typical phenotypic features, individuals with DS are also at increased risk of conditions that impact long-term survival, including obstructive sleep apnea (OSA), congenital heart disease (CHD), and pulmonary hypertension (PH). These disorders are common, with a prevalence of up to 80%, 50%, and 28%, respectively.3-5

DS impacts long-term survival, with PH contributing to mortality rates of 10% within 3 years of diagnosis.6 PH in DS is a complex entity subclassified by the World Health Organization (WHO) based on etiology, including pure pulmonary arterial hypertension (Group 1), left heart disease (Group 2), lung disease/hypoxia (Group 3), thromboembolic disease (Group 4), and multifactorial causes (Group 5).7 Notably, the majority (87%) of patients with recurrent PH are classified as WHO Group III, reflecting underlying respiratory disease, including OSA and other forms of upper airway obstruction.4

Epidemiology and Diagnosis

The prevalence of PH in the DS population is 25%, compared with 1% in the general population.4,8,9 Comorbid CHD is present in half of the children with DS and PH.4 In a large cohort study of 1,242 children with DS, the incidence of PH was 28% (n = 346).4 PH was classified as transient (resolved on serial echocardiograms; 70%), persistent (persisted on serial echocardiograms; 15%), or recurrent (resolved but then redeveloped evidence of PH on serial echocardiograms; 15%).

The development of PH in DS is multifactorial with intrinsic and extrinsic risk factors (Table 1).9,10 Intrinsic factors include abnormal lung development, including decreased alveolarization, pulmonary hypoplasia, and pulmonary vascular dysfunction. Extrinsic factors include congenital heart disease, upper airway obstruction, chronic aspiration, and recurrent pneumonia. Common comorbidities in the Pediatric Pulmonary Hypertension Network Registry are CHD (95%; repaired in 68%), OSA (56%), prematurity (49%), respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%).

Table 1. Clinical conditions associated with pulmonary hypertension (PH) in children with Down syndrome (DS), organized by World Health Organization (WHO) PH classification group, with estimated prevalence, prognostic significance, and recommended therapeutic approaches.

Pediatric DS-PH is predominantly driven by WHO Group I and Group III mechanisms. Group II (PH due to left heart disease) is not represented because clinically significant left-sided dysfunction in DS, including acquired valvular disease, mitral valve prolapse, and left ventricular diastolic dysfunction, arises predominantly in adulthood and reflects the aging cardiovascular phenotype rather than a primary pediatric driver of PH. Groups IV (chronic thromboembolic PH) and V (multifactorial/unclear etiology) are likewise uncommon in pediatric DS-PH and fall outside the scope of this review. Abbreviations: ASD, atrial septal defect; AVSD, atrioventricular septal defect; BiPAP, bilevel positive airway pressure; CHD, congenital heart disease; CPAP, continuous positive airway pressure; DS, Down syndrome; ERA, endothelin receptor antagonist; ES, Eisenmenger syndrome; GERD, gastroesophageal reflux disease; mPAP, mean pulmonary arterial pressure; NICU, neonatal intensive care unit; OSA, obstructive sleep apnea; PAH, pulmonary arterial hypertension; PDA, patent ductus arteriosus; PDE-5, phosphodiesterase-5; PH, pulmonary hypertension; PPHN, persistent pulmonary hypertension of the newborn; PPHNet, Pediatric Pulmonary Hypertension Network; PSG, polysomnography; PVR, pulmonary vascular resistance; RSV, respiratory syncytial virus; VSD, ventricular septal defect; WHO, World Health Organization.

Clinical
Condition		 WHO PH Group Prevalence in
DS		 Prognostic
Relevance		 Treatment
Options		 References
Congenital heart disease (CHD) Group I (PAH-CHD) CHD present in 40-50% of DS; PH prevalence up to 45% in those with CHD Primary driver of PH in infancy; CHD contributes to 13% of childhood and 23% of adult deaths; early repair reduces Eisenmenger risk from 53% to 1% Early surgical repair (ideally 1 year); lifelong echocardiographic surveillance; PAH-targeted pharmacotherapy if irreversible PH develops Peterson et al.9
Pierpont et al.48
Persistent pulmonary hypertension of the newborn (PPHN) Group I (transient) Accounts for 38% of initial PH diagnoses in DS; 12% recurrence rate Typically transient (median duration 8 months); 70% of all PH in DS is transient; recurrence risk 12-16% Inhaled nitric oxide; supplemental oxygen; supportive NICU care; surveillance for recurrence Peterson et al.9
Bush et al.4
Obstructive sleep apnea (OSA) Group III (lung disease/hypoxia) Up to 80-94% of children with DS; 56% among DS children with PH in the PPHNet registry Major driver of recurrent PH (87% of recurrent PH is WHO Group III); untreated OSA increases PH risk; persistent OSA after surgery in 30-70% Adenotonsillectomy (first-line; persistent OSA in 30-70%); CPAP/BiPAP; weight management; repeat PSG after intervention; lingual tonsil reduction or supraglottoplasty if needed Bush et al.4; Zalzal & Lawlor3; Seither et al.5; Hopper et al.6
Chronic aspiration / Dysphagia Group III Oral/pharyngeal dysphagia in 31-80% of DS children; aspiration in 31% of DS-PH cohort; >90% of aspiration is silent Associated with recurrent respiratory exacerbations and worsening PH severity; reflux medication use independently associated with severe PH Swallow evaluation; thickened feeds; anti-reflux therapy; Nissen fundoplication if refractory GERD; gastrostomy tube if severe Zalzal & Lawlor3; Hopper et al.6
Recurrent pneumonia / Lower respiratory tract infections Group III Respiratory exacerbations in 35% of DS-PH cohort Contributes to recurrent PH; more severe infections and prolonged hospitalizations in DS Aggressive infection treatment; immunization (influenza, pneumococcal, RSV prophylaxis); treatment of underlying aspiration and OSA Bush et al.4
Hopper et al.6
Pulmonary hypoplasia / Abnormal lung development Group III (developmental lung disease) Intrinsic to trisomy 21; alveolar simplification found in 100% and double capillary network persistence in 92% of DS autopsy specimens Reduces lung surface area and impairs gas exchange; contributes to baseline elevated pulmonary vascular resistance; worsens prognosis when combined with other comorbidities Supplemental oxygen for hypoxemia; PH-targeted pharmacotherapy (PDE-5 inhibitors, ERAs, prostacyclin analogues) in severe cases; multidisciplinary monitoring Peterson et al.9; Galambos et al.28
Obesity Group III (contributes to OSA/hypoventilation) Obesity prevalence 23-70% in DS across age groups; obese DS children are twice as likely to have OSA Exacerbates OSA severity and contributes to hypoventilation-related PH Weight management; dietary intervention; treatment of associated OSA Zalzal & Lawlor3; Bull MJ2
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The gold standard for diagnosing PH is right heart catheterization, indicating a mean pulmonary arterial pressure (mPAP) >20 mmHg, revised from >=25 mmHg by the 2018 World Symposium of Pulmonary Hypertension.11,12 Echocardiography helps evaluate right heart hemodynamics and stratify the likelihood of PH.13,14 Pulmonary arterial systolic pressure can be indirectly measured using echocardiographic findings of tricuspid regurgitation velocity, inferior vena cava dimensions, right atrial area, diastolic pulmonary regurgitation velocity, and pulmonary artery diameter. Other findings that suggest PH include flattening of the interventricular septum and a tricuspid annular plane systolic excursion.15,16

Diagnostic accuracy of TTE in pediatric DS is limited, especially due to the high prevalence of chronic lung disease.15 Factors such as pulmonary hyperinflation, thoracic cage expansion, and changes in cardiac position hinder the detection and measurement of tricuspid regurgitation velocity.

A registry from the Pediatric Pulmonary Hypertension Network reports 3- and 5-year survival for children with DS and PH approaches 90%.6 The risk of recurrence is up to 16% following resolution, often linked to comorbid respiratory conditions. Tracheostomy and reflux medications are independently associated with severe PH.4

Children with DS have anatomical risk factors for upper airway obstruction that predispose them to PH, categorized into craniofacial skeletal and soft tissue abnormalities.3 Airway management in patients with DS is complex due to smaller airway size and micrognathia. Craniofacial abnormalities such as midfacial and mandibular hypoplasia, a narrow nasopharynx, and a shortened palate reduce upper airway volume, increasing the risk of collapse during sleep. Relative macroglossia, in which the tongue appears disproportionately large relative to the oral cavity, is a key feature of DS. Patients may also have hypertrophy of the lingual tonsils and adenotonsillar tissues, along with generalized hypotonia, which contribute to glossoptosis, hypopharyngeal collapse, and laryngomalacia. The combination of hypotonia and anatomic crowding results in a multilevel pattern of upper airway obstruction.17,18

Drug-induced sleep endoscopy studies show that children with DS have multi-level obstruction, particularly at the base of the tongue and arytenoids.19 Beyond anatomical factors, children with DS exhibit decreased peripheral chemoreceptor sensitivity, contributing to nocturnal alveolar hypoventilation and compounding the risk of upper airway obstruction.17,20 OSA is the most common sleep-related breathing disorder in DS and occurs in up to 80% of this population, compared to 2-5% in the general pediatric population.5,20,21 Therefore, the American Academy of Pediatrics (AAP) recommends universal screening for OSA with polysomnography by 4.22,23

PH secondary to untreated OSA is driven by chronic hypoxemia, leading to pulmonary vasculature remodeling and vasoconstriction.24 Hypoxemia also activates inflammatory and proliferative pathways contributing to remodeling and decreased vascular caliber.25 Chronic hypoxia causes cardiac changes, shown by echocardiographic studies in patients with OSA.

Although there is a known strong association between untreated OSA and the development of PH in the DS population, there is a paucity of data detailing the prevalence of PH attributable specifically to OSA. However, the fact that 87% of patients with recurrent PH are classified as WHO Group III (PH associated with lung disease/hypoxia) strongly suggests that respiratory disease, including OSA, plays a major role.4

Sleep problems are common in children with DS, reported by parents in up to 65% of school-aged children.20 SDB in children with DS exacerbates sleep disruption compared to that of typically developing children.26 Children with DS and SDB have greater hypoxic exposure, more respiratory events during rapid eye movement sleep, higher total, delta, sigma, and beta power, and reduced slow-wave activity compared to typically developing children with similar SDB severity.

Laryngomalacia is a common source of upper airway obstruction in pediatric DS, characterized by the collapse of the supraglottic structures into the laryngeal inlet. The reported incidence of laryngomalacia in infants with DS is up to 50%.5,27 Other airway anomalies in DS include laryngotracheal cleft, tracheomalacia, subglottic and tracheal stenosis, complete tracheal rings, and tracheal bronchus. Presenting symptoms may include stridor, dyspnea, cough, recurrent respiratory infections, aspiration, and/or cyanosis or apnea.

Congenital subglottic stenosis is common and often asymptomatic in children with DS. They should be intubated with smaller endotracheal tubes. Higher prematurity and cardiac anomalies may require intubation in infancy, increasing the risk of acquired and posterior glottic stenosis.

CHD, present in up to 50% of children with DS, 11,15 is the most common cardiovascular condition and the leading cause of morbidity and mortality. PH occurs in up to 45% of DS patients with CHD and requires early treatment. Persistent pulmonary hypertension of the newborn (PPHN, or persistent fetal circulation, results from stimuli that delay the transition to extrauterine life, increasing pulmonary resistance. Children with DS are disproportionately affected, with a prevalence of 5% versus 0.2% in others. They also face a higher risk of intrinsic pulmonary vascular issues, including fewer endothelial progenitor cells, increased oxidative stress susceptibility, and smooth muscle dysfunction.28

Classification and Staging

The WSPH currently classifies PH into five categories based on the underlying etiology.17 These include pulmonary arterial hypertension (1), PH associated with left heart disease (2), PH associated with lung disease/hypoxia (3), PH associated with pulmonary artery obstruction (4), and, lastly, PH of multifactorial/unclear etiology (5). Children primarily affected by CHD or PPHN would be considered group 1, while those with upper airway obstruction or chronic lung disease would be placed in group 3; when multiple etiologies are present, these patients could be placed into group 5. While this staging system strongly categorizes PH by the underlying pathophysiology of the disease in the general population, its applicability to DS is questionable, particularly given the high prevalence of upper airway obstruction. The Pulmonary Vascular Research Institute also created a functional staging system for the pediatric population, subcategorized by age groups.29

Biomarkers also serve a role in the diagnosis and staging of PH. In particular, Interleukin-6 (IL-6), Galectin-3, IL-1 receptor 1, endostatin, hepatoma-derived growth factor, and N-terminal pro-hormone B-natriuretic peptide (NT-proBNP) have been shown to be associated with PH severity and survival.30 However, these biomarkers do not have the same applicability to the DS population.31 Specifically, Endostatin, galectin-3, HDGF, and IL-1 receptor 1 were elevated in the DS population regardless of PH status. NT-proBNP is the best marker for distinguishing PH status in the DS population.32

Several studies have attempted to categorize PH using echocardiography, but no consensus has emerged. Raymond et al. prospectively followed PH patients with WHO class III or IV, finding that pericardial effusion, right atrial enlargement, and septal displacement increased the risk of mortality or need for intervention transplantation.33 Other studies, such as Faqih et al., have used echocardiographic-based estimates of mPAP to stage PH into mild (35-50 mmHg), moderate (50-70 mmHg), and severe (>70 mmHg) sub-stages.34 To the best of our knowledge, there are no published echocardiographic guidelines for staging PH in the DS population. Similarly, little literature exists on staging based on right heart catheterization. Sugiyama et al. showed that an mPAP >40 versus <40 mmHg significantly impacts 1-, 3-, and 5-year survival (97.3% vs. 50.0%) in the general population, serving as a prognostic indicator and primary end-point in treatment PH.35 The applicability of this data to the DS population has not been published.

Treatment

PH treatment in DS involves identifying causes and a multidisciplinary approach. For OSA or airway obstruction, options include semi-invasive ventilation, surgery like adenotonsillectomy, or tracheostomy. CHD patients benefit from early surgical repair (within 3-6 months) to prevent PH. Medical therapies include calcium channel blockers, sildenafil, endothelin receptor antagonists, and prostacyclin agonists.

Adenotonsillectomy (AT) is the first-line treatment for children with DS and OSA.3 Although AT may reduce or cure OSA in some children with DS, 30% to 70% still have persistent OSA. A review of adenotonsillectomy in these children showed an average AHI decrease of 7.2 events/h and increased minimum oxygen saturation 3%.36 In another study, preoperative AHI improved from 13.8 to 3.5 postoperatively.37 Many patients will require repeated PSG testing after AT.

Cardiovascular parameters improved by adenotonsillectomy in the general population include improvements in ventricular function, blood pressure, and pulmonary artery pressure.38,39 However, these do not appear to be predicted by OSA severity.40 One study assessing the reduction in mPAP after adenotonsillectomy demonstrated a significant reduction of approximately 7 mmHg. Changes in mPAP following adenotonsillectomy in children with DS represents a knowledge gap.

Perioperative risks in children with DS are non-trivial, including increased length of stay, increased likelihood of respiratory complications, and increased time to tolerating adequate oral intake.41,42 While tracheostomy may significantly improve OSA, it paradoxically confers a worse prognosis for PH.6 This association likely reflects the severity of the underlying disease.

Supraglottoplasty is primarily used to treat moderate-to-severe laryngomalacia.43,44 Children with DS are more likely to experience treatment failure, which can include no improvement, worsening of aspiration or respiratory issues, or the need for tracheostomy. They are also likely to have multiple airway abnormalities and require tracheostomy. The prevalence of tracheomalacia is reported as 4.4%-7.1%, but among symptomatic DS patients undergoing endoscopic procedures, rates can reach 50%.5

While outside the scope of this review’s primary focus, surgical correction of CHD has demonstrated promise in the reduction of mPAP. The American Association for Thoracic Surgery clinical practice standards recommend surgical correction of CHD in infancy to facilitate normalization of PH.15,45,46 One study assessing the reduction in mPAP after surgical correction of atrioventricular and ventricular septal defects in DS found a mean decrease of 10 mmHg within 12 hours of surgery.47 Children with DS experience a significantly higher risk of longer hospital stays following cardiac surgery, as well as infections, respiratory complications, persistent PH, and need for a permanent cardiac pacemaker as compared to children without DS.48

Multiple vasoactive medical therapies are currently available for the treatment of PH in pediatric DS. Three classes of drugs have been extensively evaluated for the treatment of pediatric PH: prostanoids (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan, macitentan), and phosphodiesterase-5 inhibitors (sildenafil, tadalafil).15,49 Of these medication classes, endothelin receptor antagonists (ERAs) like bosentan have been the most heavily studied in the pediatric DS population and have shown the most promise in improving functional status.49,50 Tadalafil and macitentan are the most commonly used medications across all age groups in current practice.51 Sildenafil has been shown to improve peak oxygen consumption and functional class and reduce mean PAP and PVR.50 However, a post-hoc analysis of the STARTS-1 trial specifically examining children with DS and PH found that sildenafil treatment for 16 weeks had no significant effect on PVRI or mPAP in this subpopulation.52 Calcium channel blockers (amlodipine, diltiazem, nifedipine) are reserved for the subset of PAH patients who demonstrate acute vasoreactivity during right heart catheterization. Long-term responders, defined by sustained near-normalization of hemodynamics, have the most favorable prognosis. Close follow-up is essential, and PAH-targeted therapy should be added on top of CCB therapy if vasoreactivity is lost, hemodynamics worsen, or high-risk features emerge. These agents can decrease cardiac output and cause a significant drop in systolic blood pressure, limiting their use outside this responder phenotype.50 Combination therapies for CHD-PH are widely used, including for pediatric patients, with treatment decisions based on the clinical context and disease severity.51

Prognosis

The Pediatric Pulmonary Hypertension Network, which houses one of the largest published longitudinal cohorts of DS patients with PH, found 1- and 3-year mortality rates of 4% and 10%, respectively, after diagnosis of PH, similar to children without DS.6 Inversely, the 1- and 3-year PH resolution rates were 34% and 43%, respectively. PH resolved in 43% after 3 years, associated with a diagnosis of PH at age <6 months (54% vs. 29%) and a pretricuspid shunt (65% vs. 38%).4,6 Conversely, children with DS and aspiration, tracheostomy, history of gastroesophageal reflux, and male sex conferred a worse prognosis and higher severity of PH. Tracheostomy and reflux medication use were independently associated with a composite outcome of severe PH.6 Improved management of CHD has contributed to an increase in life expectancy for patients with DS, from 30 years in 1973 to 60 years by 2002.2

Areas for Further Research

This review examines literature on PH in pediatric DS, which is disproportionately affected by PH and OSA but lacks data on their interaction. A major gap is the absence of a DS-specific staging system. Current classifications (WSPH and Pulmonary Vascular Research Institute) categorize PH by cause for adults and children but are unsuitable for children with DS. The heterogeneous pathophysiology in DS complicates diagnosis and management, especially with multiple comorbidities. A DS-specific classification using physical exam, labs, polysomnogram, echocardiogram, and RHC data could better identify primary pathology and improve treatment. Future research should explore the roles of OSA and airway obstruction in PH, effects of airway surgeries like adenotonsillectomy on mPAP, develop DS-specific biomarkers for diagnosis and monitoring, optimize pharmacologic therapy due to reduced sildenafil responsiveness, and assess long-term outcomes.

Conclusion

PH disproportionately affects children with DS and carries significant mortality risks. Upper airway obstruction is a major potential contributor, driven by craniofacial dysmorphology resulting in multilevel airway obstruction. CHD, PPHN, and vascular pathology are common underlying causes that complicate treatment. No pediatric DS-specific staging exists, and current systems do not account for OSA despite its high prevalence. Treatment involves addressing the underlying pathology, including surgery for airway obstruction or CHD repair, both shown to lower mPAP. Selective vasodilators, such as ERAs, reduce mPAP and improve function, though children with DS may respond less to sildenafil. Despite comorbidities, survival rates are like those of non-DS PH, with 88% 5-year survival. PH resolution occurs in 43% at 3 years but is less common with respiratory comorbidities. More research is needed on the role of airway obstruction in PH and DS, as well as on DS-specific diagnostics and treatments.

Key points.

  1. Children with Down syndrome are disproportionately affected by obstructive sleep apnea (80%), congenital heart disease (50%), and pulmonary hypertension (28%).

  2. Although there is a strong association between upper airway obstruction and the development of pulmonary hypertension, there is a paucity of data detailing the prevalence of pulmonary hypertension associated with obstructive sleep apnea.

  3. Treatment for pulmonary hypertension in children with Down syndrome requires a multidisciplinary approach and identification of the dominant cause.

  4. Adenotonsillectomy is the first-line treatment for obstructive sleep apnea in children with Down syndrome; however, 30%-70% of patients continue to have clinically significant obstructive sleep apnea after the procedure.

  5. No current stratification or staging system exists for pulmonary hypertension in children with Down syndrome, despite this population being disproportionately affected by the disease.

Financial support and sponsorship

Research reported in this manuscript was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (award No. R01HL167012 to Dr. Isaiah). This article reflects the views of the authors and may not reflect the opinions or views of the National Institutes of Health.

Footnotes

Conflict of interest

Dr. Isaiah receives royalties and holds patents for the diagnosis and management of upper airway obstruction outside the submitted work. No other disclosures are reported.

References

  • 1.Antonarakis SE, Skotko BG, Rafii MS, et al. Down syndrome. Nat Rev Dis Primer. 2020;6(1):9. doi: 10.1038/s41572-019-0143-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bull MJ. Down Syndrome. N Engl J Med. 2020;382(24):2344–2352. doi: 10.1056/NEJMra1706537 [DOI] [PubMed] [Google Scholar]
  • 3.Zalzal HG, Lawlor CM. Down Syndrome for the Otolaryngologist: A Review. JAMA Otolaryngol-- Head Neck Surg. 2023;149(4):360–367. doi: 10.1001/jamaoto.2023.0001 [DOI] [PubMed] [Google Scholar]
  • 4.Bush D, Galambos C, Ivy DD, Abman SH, Wolter-Warmerdam K, Hickey F. Clinical Characteristics and Risk Factors for Developing Pulmonary Hypertension in Children with Down Syndrome. J Pediatr. 2018;202:212–219.e2. doi: 10.1016/j.jpeds.2018.06.031 [DOI] [PubMed] [Google Scholar]
  • 5.Seither K, Helm BM, Heubi C, Swarr D, Suhrie KR. Sleep Apnea in Children With Down Syndrome. Pediatrics. 2023;151(3):e2022058771. doi: 10.1542/peds.2022-058771 [DOI] [PubMed] [Google Scholar]
  • 6.Hopper RK, Abman SH, Elia EG, et al. Pulmonary Hypertension in Children with Down Syndrome: Results from the Pediatric Pulmonary Hypertension Network Registry. J Pediatr. 2023;252:131–140.e3. doi: 10.1016/j.jpeds.2022.08.027 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Condon DF, Nickel NP, Anderson R, Mirza S, de Jesus Perez VA. The 6th World Symposium on Pulmonary Hypertension: what’s old is new. F1000Research. 2019;8:F1000 Faculty Rev–888. doi: 10.12688/f1000research.18811.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Yin C, Deng C, Crespi CM, et al. The relation between Down syndrome and co-occurring conditions in children and young adults: A population-based cohort in Denmark, 1977–2016. Res Dev Disabil. 2025;167:105167. doi: 10.1016/j.ridd.2025.105167 [DOI] [PMC free article] [PubMed] [Google Scholar]; *This large Danish population-based cohort study spanning nearly four decades quantifies the prevalence of co-occurring conditions in DS across the lifespan, offering contemporary epidemiological benchmarks. The data reinforce the disproportionate burden of cardiovascular and respiratory comorbidity in this population and are directly relevant to understanding the PH risk context in DS.
  • 9.Peterson JK, Clarke S, Gelb BD, et al. Trisomy 21 and Congenital Heart Disease: Impact on Health and Functional Outcomes From Birth Through Adolescence: A Scientific Statement From the American Heart Association. J Am Heart Assoc Cardiovasc Cerebrovasc Dis. 2024;13(19):e036214. doi: 10.1161/JAHA.124.036214 [DOI] [PMC free article] [PubMed] [Google Scholar]; **This landmark AHA Scientific Statement provides the first comprehensive, evidence-based framework for monitoring and managing cardiovascular and multisystem health concerns in children with Trisomy 21 and congenital heart disease from birth through adolescence. It synthesizes the complex interactions between CHD, pulmonary hypertension, neurodevelopmental outcomes, and psychosocial health, and is essential reading for all clinicians caring for this population.
  • 10.Bush D, Galambos C, Dunbar Ivy D. Pulmonary hypertension in children with Down syndrome. Pediatr Pulmonol. 2021;56(3):621–629. doi: 10.1002/ppul.24687 [DOI] [PubMed] [Google Scholar]
  • 11.Hansmann G. Pulmonary Hypertension in Infants, Children, and Young Adults. J Am Coll Cardiol. 2017;69(20):2551–2569. doi: 10.1016/j.jacc.2017.03.575 [DOI] [PubMed] [Google Scholar]
  • 12.Kovacs G, Bartolome S, Denton CP, et al. Definition, classification and diagnosis of pulmonary hypertension. Eur Respir J. 2024;64(4):2401324. doi: 10.1183/13993003.01324-2024 [DOI] [PMC free article] [PubMed] [Google Scholar]; **Emerging from the 7th World Symposium on Pulmonary Hypertension, this paper provides updated hemodynamic definitions, a clinical classification system, and a diagnostic algorithm for PH. It refines the mPAP threshold and introduces the concept of exercise PH, directly informing how PH is classified and staged in children with Down syndrome.
  • 13.Ni JR, Yan PJ, Liu SD, et al. Diagnostic accuracy of transthoracic echocardiography for pulmonary hypertension: a systematic review and meta-analysis. BMJ Open. 2019;9(12):e033084. doi: 10.1136/bmjopen-2019-033084 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Ruopp NF, Cockrill BA. Diagnosis and Treatment of Pulmonary Arterial Hypertension: A Review. JAMA. 2022;327(14):1379–1391. doi: 10.1001/jama.2022.4402 [DOI] [PubMed] [Google Scholar]
  • 15.Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132(21):2037–2099. doi: 10.1161/CIR.0000000000000329 [DOI] [PubMed] [Google Scholar]
  • 16.Maron BA, Kovacs G, Vaidya A, et al. Cardiopulmonary Hemodynamics in Pulmonary Hypertension and Heart Failure: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;76(22):2671–2681. doi: 10.1016/j.jacc.2020.10.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Bokov P, Boujemla I, Dahan J, Dudoignon B, Delclaux C. Obstructive sleep apnea in children with Down syndrome: contribution of upper airway and chemosensitivity. Pediatr Res. 2023;94(6):1990–1997. doi: 10.1038/s41390-023-02718-8 [DOI] [PubMed] [Google Scholar]
  • 18.Lal C, White DR, Joseph JE, van Bakergem K, LaRosa A. Sleep-disordered breathing in Down syndrome. Chest. 2015;147(2):570–579. doi: 10.1378/chest.14-0266 [DOI] [PubMed] [Google Scholar]
  • 19.Hyzer JM, Milczuk HA, Macarthur CJ, King EF, Quintanilla-Dieck L, Lam DJ. Drug-Induced Sleep Endoscopy Findings in Children With Obstructive Sleep Apnea With vs Without Obesity or Down Syndrome. JAMA Otolaryngol-- Head Neck Surg. 2021;147(2):175–181. doi: 10.1001/jamaoto.2020.4548 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Horne RS, Wijayaratne P, Nixon GM, Walter LM. Sleep and sleep disordered breathing in children with down syndrome: Effects on behaviour, neurocognition and the cardiovascular system. Sleep Med Rev. 2019;44:1–11. doi: 10.1016/j.smrv.2018.11.002 [DOI] [PubMed] [Google Scholar]
  • 21.Lee CF, Lee CH, Hsueh WY, Lin MT, Kang KT. Prevalence of Obstructive Sleep Apnea in Children With Down Syndrome: A Meta-Analysis. J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med. 2018;14(5):867–875. doi: 10.5664/jcsm.7126 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Bull MJ, Trotter T, Santoro SL, et al. Health Supervision for Children and Adolescents With Down Syndrome. Pediatrics. 2022;149(5):e2022057010. doi: 10.1542/peds.2022-057010 [DOI] [PubMed] [Google Scholar]
  • 23.Knollman PD, Heubi CH, Wiley S, et al. Demographic and Clinical Characteristics Associated With Adherence to Guideline-Based Polysomnography in Children With Down Syndrome. Otolaryngol--Head Neck Surg Off J Am Acad Otolaryngol-Head Neck Surg. 2021;164(4):877–883. doi: 10.1177/0194599820954837 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Gocal W, Zeder K, Maron BA, Isaiah A. Cardiovascular complications in children with Down syndrome and sleep disordered breathing. Paediatr Respir Rev. Published online November 28, 2025:S1526-0542(25)00107-1. doi: 10.1016/j.prrv.2025.11.008 [DOI] [PMC free article] [PubMed] [Google Scholar]; *This review directly addresses the central thesis of the present article, synthesizing evidence on how sleep-disordered breathing drives cardiovascular complications, including pulmonary hypertension, in children with Down syndrome. It highlights the mechanistic links between OSA-mediated hypoxemia and pulmonary vascular remodeling and identifies critical gaps in the literature, making it the most topically aligned recent publication to this review.
  • 25.Maris M, Verhulst S, Wojciechowski M, Van de Heyning P, Boudewyns A. Prevalence of Obstructive Sleep Apnea in Children with Down Syndrome. Sleep. 2016;39(3):699–704. doi: 10.5665/sleep.5554 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Sibarani CR, Walter LM, Davey MJ, Nixon GM, Horne RSC. Sleep-disordered breathing and sleep macro- and micro-architecture in children with Down syndrome. Pediatr Res. 2022;91(5):1248–1256. doi: 10.1038/s41390-021-01642-z [DOI] [PubMed] [Google Scholar]
  • 27.Yahya MN, Goh BS, Mohammad Nasseri FZ, Kamal Nor NA, Wan Md Zin WN, Abdul Latif H. Spectrum of upper airway pathology in children with Down syndrome in a single tertiary centre. Acta Otolaryngol (Stockh). 2022;142(2):187–190. doi: 10.1080/00016489.2022.2028007 [DOI] [PubMed] [Google Scholar]
  • 28.Galambos C, Minic AD, Bush D, et al. Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension. PloS One. 2016;11(8):e0159005. doi: 10.1371/journal.pone.0159005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.del Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ. 2011;1(2):286–298. doi: 10.4103/2045-8932.83456 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Griffiths M, Simpson CE, Yang J, et al. Equivalency of Multiple Biomarkers to Clinical Pulmonary Arterial Hypertension Survival Risk Models. Chest. 2024;166(6):1511–1531. doi: 10.1016/j.chest.2024.06.3824 [DOI] [PMC free article] [PubMed] [Google Scholar]; *This study evaluates the equivalence of circulating biomarkers, including NT-proBNP, to established clinical risk models for predicting PAH survival. It is particularly relevant to the discussion of biomarker applicability in DS, given that NT-proBNP remains the most reliable marker for distinguishing PH status in this population, whereas other biomarkers, such as endostatin and galectin-3, are non-specifically elevated.
  • 31.Griffiths M, Yang J, Vaidya D, et al. Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension. J Pediatr. 2022;241:68–76.e3. doi: 10.1016/j.jpeds.2021.10.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Hirsch K, Nolley S, Ralph DD, et al. Circulating markers of inflammation and angiogenesis and clinical outcomes across subtypes of pulmonary arterial hypertension. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2023;42(2):173–182. doi: 10.1016/j.healun.2022.10.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39(7):1214–1219. doi: 10.1016/s0735-1097(02)01744-8 [DOI] [PubMed] [Google Scholar]
  • 34.Faqih SA, Noto-Kadou-Kaza B, Abouamrane LM, et al. Pulmonary hypertension: prevalence and risk factors. Int J Cardiol Heart Vasc. 2016;11:87–89. doi: 10.1016/j.ijcha.2016.05.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Sugiyama Y, Matsubara H, Shimokawahara H, Ogawa A. Outcome of mean pulmonary arterial pressure-based intensive treatment for patients with pulmonary arterial hypertension. J Cardiol. 2022;80(5):432–440. doi: 10.1016/j.jjcc.2022.04.003 [DOI] [PubMed] [Google Scholar]
  • 36.Li Y, Du J, Yin H, Wang Y. Efficacy and safety of adenotonsillectomy in the management of obstructive sleep apnea syndrome in children with Down syndrome: A systematic review and meta-analysis. J Sleep Res. 2024;33(2):e13946. doi: 10.1111/jsr.13946 [DOI] [PubMed] [Google Scholar]
  • 37.Farhood Z, Isley JW, Ong AA, et al. Adenotonsillectomy outcomes in patients with Down syndrome and obstructive sleep apnea. The Laryngoscope. 2017;127(6):1465–1470. doi: 10.1002/lary.26398 [DOI] [PubMed] [Google Scholar]
  • 38.Sun YL, Yuan B, Kong F, Li XM. Effects of adenoidectomy or adenotonsillectomy on the cardiovascular system in children: a meta-analysis. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol - Head Neck Surg. 2022;279(3):1147–1156. doi: 10.1007/s00405-021-06986-0 [DOI] [PubMed] [Google Scholar]
  • 39.Baker-Smith CM, Isaiah A, Melendres MC, et al. Sleep-Disordered Breathing and Cardiovascular Disease in Children and Adolescents: A Scientific Statement From the American Heart Association. J Am Heart Assoc. 2021;10(18):e022427. doi: 10.1161/JAHA.121.022427 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Teplitzky TB, Pereira KD, Isaiah A. Echocardiographic screening in children with very severe obstructive sleep apnea. Int J Pediatr Otorhinolaryngol. 2019;126:109626. doi: 10.1016/j.ijporl.2019.109626 [DOI] [PubMed] [Google Scholar]
  • 41.Xiao L, Barrowman N, Momoli F, Murto K, Bromwich M, Katz SL. Risk factors for respiratory adverse events after adenoidectomy and tonsillectomy in children with down syndrome: a retrospective cohort study. Eur J Pediatr. 2022;181(6):2399–2408. doi: 10.1007/s00431-022-04438-3 [DOI] [PubMed] [Google Scholar]
  • 42.Cottrell J, Zahr SK, Propst EJ, et al. Morbidity and mortality from adenotonsillectomy in children with trisomy 21. Int J Pediatr Otorhinolaryngol. 2020;138:110377. doi: 10.1016/j.ijporl.2020.110377 [DOI] [PubMed] [Google Scholar]
  • 43.Farhood Z, Ong AA, Nguyen SA, Gillespie MB, Discolo CM, White DR. Objective Outcomes of Supraglottoplasty for Children With Laryngomalacia and Obstructive Sleep Apnea: A Meta-analysis. JAMA Otolaryngol-- Head Neck Surg. 2016;142(7):665–671. doi: 10.1001/jamaoto.2016.0830 [DOI] [PubMed] [Google Scholar]
  • 44.van der Heijden M, Dikkers FG, Halmos GB. Treatment outcome of supraglottoplasty vs. wait-and-see policy in patients with laryngomalacia. Eur Arch Oto-Rhino-Laryngol Off J Eur Fed Oto-Rhino-Laryngol Soc EUFOS Affil Ger Soc Oto-Rhino-Laryngol - Head Neck Surg. 2016;273(6):1507–1513. doi: 10.1007/s00405-016-3943-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Miller JR, Stephens EH, Goldstone AB, et al. The American Association for Thoracic Surgery (AATS) 2022 Expert Consensus Document: Management of infants and neonates with tetralogy of Fallot. J Thorac Cardiovasc Surg. 2023;165(1):221–250. doi: 10.1016/j.jtcvs.2022.07.025 [DOI] [PubMed] [Google Scholar]
  • 46.Jone PN, Ivy DD, Hauck A, et al. Pulmonary Hypertension in Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circ Heart Fail. 2023;16(7):e00080. doi: 10.1161/HHF.0000000000000080 [DOI] [PubMed] [Google Scholar]
  • 47.Carvalho ES, Penha JG, Maeda NY, et al. Down syndrome and postoperative hemodynamics in patients undergoing surgery for congenital cardiac communications. Sci Rep. 2024;14(1):16612. doi: 10.1038/s41598-024-67097-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Pierpont ME, Brueckner M, Chung WK, et al. Genetic Basis for Congenital Heart Disease: Revisited. Circulation. 2018;138(21):e653–e711. doi: 10.1161/CIR.0000000000000606 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Ivy DD, Abman SH, Barst RJ, et al. Pediatric pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D117-126. doi: 10.1016/j.jacc.2013.10.028 [DOI] [PubMed] [Google Scholar]
  • 50.Ivy D, Rosenzweig EB, Abman SH, et al. Embracing the challenges of neonatal and paediatric pulmonary hypertension. Eur Respir J. 2024;64(4):2401345. doi: 10.1183/13993003.01345-2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Ishii T, Uchida K, Hosokawa S, et al. Pharmacological Treatment Practices for Patients With Congenital Heart Disease and Pulmonary Hypertension in Japan: Insights from the Japanese Association of Congenital Heart Disease Registry (JACPHR). Am J Cardiol. 2025;257:18–25. doi: 10.1016/j.amjcard.2025.07.035 [DOI] [PubMed] [Google Scholar]; *Drawing on a large national registry, this study characterizes real-world prescribing patterns for PH pharmacotherapy in children with CHD, including usage of endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and combination regimens. It provides important contemporary data to contextualize the treatment landscape discussed in this review, particularly the trend toward tadalafil and macitentan as first-line agents.
  • 52.Beghetti M, Rudzinski A, Zhang M. Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension. BMC Cardiovasc Disord. 2017;17(1):177. doi: 10.1186/s12872-017-0569-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

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