The goal of this clinical trial is to compare conservative wait-and-see management to elective surgical intervention, in asymptomatic Congenital Pulmonary Airway Malformation (CPAM) children.

Children assigned to the intervention group will undergo surgical resection of the CPAM between 6 and 9 months of age. Children assigned to the control group will be monitored conservatively. The follow-up scheme will be uniform for both treatment groups and last for 5 years.

The primary outcome is the difference in maximal endurance at five years of age between the surgical and conservative group. Secondary outcome measures are molecular genetic diagnostics, validated questionnaires - on parental anxiety, quality of life and health care consumption -, repeated imaging, and pulmonary morbidity during follow-up, as well as surgical complications and histopathology.

Study design: prospective multicentre randomized controlled trial. Duration: the total duration of the follow-up will be 5 years Setting: collaborating centres within the COllaborative Neonatal Network for the first European Congenital Pulmonary Airway Malformation (CPAM) Trial consortium (CONNECT)

Parents expecting a child with a prenatally diagnosed CPAM will be counselled and informed about the study prenatally. At the age of 6 months, each child will undergo a chest CT with intravenous contrast in order to confirm the diagnosis, as part of the standard of care. This chest CT will be evaluated according to a structured report. If the chest CT confirms the diagnosis CPAM and the child remains asymptomatic, the child is eligible for inclusion. After having obtained informed consent from parents or caregivers, randomisation to the surgical arm or the non-surgical arm will take place. At this point, the prenatal ultrasound images will be retrospectively evaluated according to a structured report.

In case of randomisation to the surgical arm, surgical resection will take place between 6 and 9 months of age. The type and extent of the surgical procedure is dependent on the lesion characteristics, local protocol and the surgeon's preference. Preferably, small lesions are treated with a segmentectomy; i.e., sub-lobar resection. Larger lesions are generally treated with lobectomy. Wedge resection is not advised due to higher risks of post-operative air leakage and residual disease. Surgical details will be documented according to a structured report.

Resected material will be sent to the local pathology department for analysis. The local pathologist will analyse the material, and document the results according to the Structured Pathology Report for Congenital Pulmonary Airway Malformation.

Genetic testing will be offered as part of routine diagnostic procedures. Standard information leaflets and informed consent forms of the department of clinical genetics will be offered to parents. If parental consent is obtained, blood (1-4ml, depending on availability/safety) will be drawn from the study subject, at the moment when an IV-needle is placed - in order to administer the IV-contrast - just before the diagnostic CT-scan). This material will be stored in a plastic Etheylenediaminetetraacetic acid (EDTA) vacutainer blood collector tube. Similarly, blood of both parents - if possible - (10 ml) will be drawn and stored in a plastic EDTA vacutainer blood collector tube. These parental samples will be sent for DNA isolation and genetic analysis to the local departments of Clinical Genetics, where the DNA will be stored. In this diagnostic procedure, trio single nucleotide polymorphism (SNP) array / whole exome sequencing or whole genome sequencing will be performed.

The follow-up program lasts 5 years, is uniform for all patients and consists of three assessments at the ages of 1 year, 2.5 years, and 5 years (with a margin of 2 months towards the patients' age for each assessment). This follow-up structure is standard of care in the majority of the participating centres. Patients assigned to the surgical arm will visit the hospital one additional time, 2-6 weeks after the surgery has taken place, for scar inspection, postoperative complaints and evaluation of the pathology report. At the second visit (at 2.5 years) a follow-up CT-scan will be performed, and during the last visit participants will perform a standardised exercise test using the BRUCE treadmill protocol, supervised by a certified paediatric physical therapist.

Furthermore, parents will be asked to complete several questionnaires, addressing anxiety, quality of life and medical costs.

The duration of the follow-up was set to 5 years to ensure enough time to observe potential differences in clinical outcome between the two study groups (i.e., the development of post-surgical complications or the development of symptoms in the conservative group). Another consideration was that the age of 5 years is the youngest age at which standardised endurance tests have been validated.

Inclusion Criteria:

• Lesion detected during routine prenatal ultrasound screening
• Delivery at term: gestational age ≥37 weeks
• Birthweight > -2SD or >P10
• Asymptomatic at birth defined as no prolonged respiratory distress or oxygen support (< 24 hours)
• Asymptomatic up to the moment of inclusion
• Confirmation of CPAM on postnatal chest CT-scan at 3-9 months of age, according to structured report form (34)
• Unilateral lesion occupying no more than one lung lobe as assessed on chest CT-scan at 3-9 months of age

Exclusion Criteria:

• Bilateral lesion
• Development of symptoms before randomization, considered by treating physician as caused by CPAM with reasonable certainty
• Complicated pregnancy defined as (pre-)eclampsia, pregnancy diabetes in mother, foetal hydrops or severe polyhydramnios on prenatal ultrasound
• Syndrome associated anomalies on genetic analysis confirmed by genetic expert
• Major associated malformations. Anomalies include cardiac malformations requiring surgical correction or follow-up by a paediatric cardiologist, congenital malformations requiring major surgical intervention, and anomalies that affect normal lung growth and development.
• Suspicion of malignancy on chest CT scan evaluation at the age of 3-9 months
• Participation in another randomised controlled trial

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