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variations.600,601 Additionally, 17% of children with PAH have other disorders known to be associated with PAH, including trisomy 21. Finally, 23% of children with PAH have copy number variations not previously associated with PH.600,602,603 Given the frequent association of paediatric PAH with chromosomal, genetic, and syndromic anomalies (for which the mechanistic basis for PAH is generally uncertain), genetic testing may be considered for defining aetiology and comorbidities, stratifying risk, and identifying family members at risk; however, this should be after appropriate expert genetic counselling for the child and family (see Section 5.1.13). The clinical PH classification (Table 6) is also followed for paediatric PH. To improve applicability of this classification in infants and children with PH, it has been adapted to give room to PH associated with various congenital cardiovascular and pulmonary diseases or specific paediatric conditions (Tables S5–S8).599

7.8.2 Diagnosis and risk assessment

Historically, the definition of PH in children aged .3 months has been the same as in adults. The definition for PH has now been redefined to mPAP .20 mmHg in adults as well as in children. The impact of an mPAP 21–24 mmHg on outcomes in children is unknown. However, in the interest of consistency and to facilitate transition from paediatric to adult PH care, it is recommended that the updated definition for PH also be followed in children. No treatment recommendations currently exist for this group of children (mPAP 21– 24 mmHg). Regarding the newly introduced criterion to include PVR .2 WU to identify pre-capillary PH in adults, PVR had previously been included in the definition for PAH in children. In children, blood flows are traditionally indexed assuming that systemic and pulmonary blood flows change proportionally with body size, while the transpulmonary pressure gradient does not. Since blood flow is the denominator in the equation for calculating PVR, the need for indexing of PVR in children is emphasized, and the criterion of pulmonary vascular resistance index (PVRI) ≥3 WU·m2 in the definition for PAH in children remains unchanged.599 Since the aetiology of paediatric PH is very diverse, a methodical and comprehensive diagnostic approach is crucial to reach an accurate diagnosis and treatment plan. As in adults, IPAH is a diagnosis ‘per exclusion’. A diagnostic work-up, similar to that in adults but customized for paediatric PH, is recommended.599 Pre-term infants with BPD should be screened for PH, since PH is prevalent in this population and seriously affects outcome.604 Also in children, RHC is the gold standard for definitively diagnosing and establishing the nature of PH, and provides important data for stratifying risk.604a,605 To identify those suitable for high-dose CCB treatment, acute vasoreactivity testing is recommended in children with IPAH/HPAH. The criteria used in adults for a positive acute response have identified children who will show sustained benefit from CCB therapy; however, these criteria do not define reversibility of PAH or operability in children with CHD. Since RHC in children with PH may be associated with major complications (in 1–3% of cases, especially in young infants and those in worse clinical condition), risks and benefits have to be balanced in the individual child.605 Heart catheterization in children with PAH should be exclusively performed in experienced paediatric PH centres. Indications for repeated RHC in children with PH are currently not well defined.

Treatment of children with PAH is based on risk stratification.599 Predictors of worse outcome in paediatric PAH are similar to those in adults, and include clinical evidence of RV failure, progression of symptoms, WHO-FC III–IV, certain echocardiographic parameters (e.g. TAPSE), and elevated serum NT-proBNP. A 6MWD ,350 m has also been suggested as a predictor of worse outcome in paediatric PH, but its value in young children is less established. Further prognosticators identified in paediatric PAH are failure to thrive and haemodynamic variables, such as RAP .10 mmHg, the ratio of mean pulmonary-to-systemic blood pressure .0.75, and PVRI .20 WU·m2.602,606,607 Paediatric risk-assessment tools based on these parameters have been retrospectively validated in observational paediatric registries.599,604a

7.8.3 Therapy

The ultimate goal of treatment should be to improve survival and facilitate normal childhood activities without limitations. In the absence of RCTs in paediatric PAH, recommended treatment algorithms are extrapolated from those in adults and enhanced with data from observational studies in children with PAH.599 Observational cohort studies support treatment algorithms designed for adults to be used for children (including the superiority of combination therapy over monotherapy).608 Drugs investigated in children, with or without formal approval by the European Medicines Agency (EMA) for treating children with PAH, are shown in Table 22. A paediatric treatment algorithm, derived from that for adults, is based on risk stratification, recommending general measures, highdose CCB therapy for responders to acute vasoreactivity testing (where close follow-up is mandatory, as some patients may fail longterm therapy), oral or inhaled combination therapy for children at low risk, and combination therapy with i.v./s.c. prostacyclin analogues for those at high risk.599 In the case of insufficient response to recommended drug therapy, or when drugs are unavailable, a Potts shunt (a surgical or interventional connection between the left PA and the descending aorta), BAS, or LTx may be considered in children with severe PH (see Sections 6.3.6.1 and 6.3.8).599 Reported clinical experience with Potts shunts is limited to just over 100 patients, predominantly children, with a mortality of 12–25% and long-term clinical benefit in a subset of children with long-term follow-up.456–459 Monitoring of treatment effect and disease course is pivotal in managing all patients with PAH (adults and in children). In children with PAH, clinical risk scores including WHO-FC, TAPSE, and serum NT-proBNP are potential treatment targets for goal-orientated treatment.604a,609 Contemporary treatment algorithms for infants with PPHN have been proposed but are outside the scope of these guidelines.610 The recommendations discussed above apply to children with PAH, whereas the specific group of infants with neonatal PVD, mostly classified as PH associated with developmental lung disease and with heterogeneous aetiology, require a distinct and customized approach (Figure 10). In pre-term infants with BPD and PH, the underlying lung disease should primarily be treated. Frequently, these infants are additionally Downloaded from academic.oup.com/eurheartj/article/43/38/3618/6673929 by guest on 07 October 2026