Summary

The MIRACLE Study is a multicentre collaborative research initiative led by the Montreal Children’s Hospital (MUHC–McGill University) and CHU Sainte-Justine (Université de Montréal) focused on understanding the long-term cardiopulmonary and multisystem health of adolescents born with congenital diaphragmatic hernia (CDH). Although survival of children with CDH has significantly improved over recent decades, many survivors may continue to experience subtle but important long-term effects involving the heart, lungs, pulmonary circulation, exercise tolerance, growth, kidney and vascular health, metabolism, and quality of life. These outcomes remain incompletely understood, particularly during adolescence and transition toward adulthood. The MIRACLE Study aims to better characterize these long-term trajectories through an innovative “deep phenotyping” approach integrating advanced cardiovascular imaging, pulmonary assessment, vascular and renal evaluation, functional testing, biomarkers, and patient-reported outcomes. The project will recruit adolescents aged 14–18 years and adults 18-25 with CDH from the Montreal Children’s Hospital and CHU Sainte-Justine, alongside matched healthy friend controls of similar age and sex. Participants will undergo a comprehensive multidisciplinary assessment including:

• Advanced 2D and 3D echocardiography 

• Pulmonary function testing 

• Renal and vascular ultrasound with Doppler imaging 

• Blood pressure and vascular health assessments 

• Exercise capacity evaluation (6-minute walk test) 

• Bioimpedance and anthropometric measurements 

• Blood and urine biomarker profiling 

• Quality-of-life and health behavior questionnaires

A major objective of the study is to identify early subclinical markers of long-term vulnerability in CDH survivors, particularly among those with more severe neonatal disease phenotypes. The MIRACLE Study also seeks to establish the first Quebec multicentre adolescent CDH deep-phenotyping platform and generate the infrastructure and pilot data necessary for future national and international life-course studies in congenital diaphragmatic hernia.

Non-scientific Summary

Children born with congenital diaphragmatic hernia (CDH), a defect of the diaphragm (the muscle that separates the chest from the abdomen) that allows organs to move into the chest, often survive but may face hidden heart, lung, and overall health challenges later in life. We will study adolescents and young adults aged 14–25 years with CDH and compare them with similar-age friends. Using medical assessments and questionnaires, we aim to improve long-term follow-up and care for CDH survivors.

Project Description

The problem: Congenital diaphragmatic hernia (CDH) causes thoracic herniation of abdominal content and disrupts lung, pulmonary vascular and cardiac development. Although survival has improved, the long-term multisystem morbidity of CDH survivors (cardiopulmonary, renal-vascular, metabolic, functional, and quality-of-life [QOL]) remains poorly characterized beyond pediatric follow-up and is rarely assessed with appropriate controls1,2. Prior studies, including from our group, suggest persistent pulmonary hypertension (PH), altered ventricular size/function, systemic hypertension and reduced QOL in infantile subgroups of CDH survivors3-5. Our preliminary echocardiographic follow-up work suggests that children with CDH and liver herniation may have smaller left ventricular dimensions/mass across childhood4.

The needs: A feasible deep-phenotyping model is needed to define adolescent and young adult CDH trajectories and to identify high-risk phenotypes associated with increased vulnerability to adverse cardiopulmonary and multisystem outcomes.

Hypothesis: Adolescents and young adults with CDH have persistent, subclinical multisystem alterations compared with age- and sex-matched controls, including differences in cardiac structure/function, pulmonary function, renal-vascular health, cardiometabolic biomarkers, functional capacity and QOL. These differences will be more pronounced among individuals with greater neonatal disease severity (those with intrathoracic liver).

Objectives

1. Primary: Assess feasibility of a multicentre deep-phenotyping study in adolescents and young adults with CDH, including recruitment yield, acceptability of the “friend control” model, completion rates across phenotyping domains, data completeness, and participant burden.

2. Secondary: Compare CDH survivors and controls across (a) cardiovascular structure and function (2D/3D echocardiography, blood pressure, vascular Doppler; associations with neonatal disease severity), (b) pulmonary, renal-vascular, and cardiometabolic profiles (PFTs, imaging, biomarker panels), and (c) functional capacity, body composition, respiratory symptoms, health behaviours, and health-related QOL.

Methods: 

Prospective, multicentre, matched case-control pilot study at Montreal Children’s Hospital/MUHC and CHU Sainte-Justine/CHUSJ. Eligible participants will include adolescents (14–18 years) and young adults (18–25 years) recruited from established CDH clinical cohorts and follow-up/surgical programs. We will recruit 30 CDH adolescent participants, 30 CDH adult participants and 30 controls. Each CDH participant will identify a same-sex, similar-age friend control to reduce socioeconomic and lifestyle confounders6. Age will be treated as a continuous variable in analyses. Participants will complete one structured visit including: anthropometrics and bioimpedance; standardized blood pressure; 2D/3D-echocardiography (ventricular dimensions, volumes, systolic/diastolic indices, strain and PH markers); PFT; 6-minute walk test; renal ultrasound with Dopplers; carotid intima–media thickness and vascular distensibility (as markers of vascular structure and elasticity); urine albumin/creatinine ratio and urine biobanking; blood biobanking; cardiometabolic profile (ex: CRP, NT-proBNP, glucose, lipid profile). Participants will complete QOL, lung-health and health-status/habit questionnaires capturing medication use, smoking/vaping/substance exposure, sports/physical activity, school/work participation and healthcare utilization. Neonatal and surgical variables will be abstracted.

Analyses: Characteristics will be summarized by liver herniation status, a postnatal severity marker. Matched comparisons will use paired tests or regression models accounting for matching, with adjustment for age, sex, body size and centre when appropriate. Feasibility outcomes will include recruitment rate, control identification, testing completion, and missingness. We will compare cardiac, pulmonary, renal-vascular, biomarkers, functional and QOL outcomes between groups. Secondary analyses will examine associations between neonatal severity markers and later phenotypes using multivariable linear or logistic regression. Effect sizes and confidence intervals will inform future CIHR/FRQS/HSF applications.

Feasibility/Expected results: We identified a substantial cohort of CDH survivors within the target age range who are followed at MUHC and anticipate a similar number from the CHUSJ cohort. Assuming a conservative 65% re-enrollment rate, consistent with prior HAPI cohort experience, we expect to recruit 60 CDH participants. We anticipate demonstrating the feasibility of deep phenotyping of adolescent and young adult CDH survivors and matched friend controls across two centres. We expect to identify subclinical differences in CDH survivors, including among clinically stable participants, and that neonatal disease severity will define a subgroup with greater long-term vulnerability. This project will establish the first Quebec multicentre adolescent and young adult CDH deep-phenotyping platform, generate effect sizes for a larger life-course study, and support transition pathways from pediatric to adult care for CDH survivors.

Potential Impact: This project targets adolescents and young adults born with congenital diaphragmatic hernia (CDH), a rare condition affecting approximately 2.6 per 10,000 births7 and associated with pulmonary hypertension, cardiac dysfunction, respiratory disease, and long-term morbidity beginning in childhood8-13. We will include up to 60 CDH survivors aged 14–25 years from MCH/MUHC and CHUSJ, along with 30 matched friend controls. The immediate impact will be to identify hidden heart, lung, kidney, vascular, metabolic, functional, and quality-of-life challenges in survivors who may appear clinically stable, informing transition from pediatric to adult care. Findings will directly inform long-term surveillance and follow-up strategies for current and future individuals born with CDH. By leveraging existing Quebec clinics, low-burden assessments, local personnel, and friend controls, the project is sustainable and socially relevant, with potential to reduce future health-care costs and improve equity for a rare-disease population. This pilot will generate feasibility data, matched-control infrastructure and effect sizes needed for CIHR/FRQS/Heart & Stroke applications on life-course outcomes after CDH. It will formalize the MCH–CHUSJ adolescent and young adult CDH cohort, strengthen multidisciplinary collaborations, support trainee projects and create a scalable surveillance model linking neonatal severity to adolescent and young adult cardiopulmonary, renal-vascular, metabolic and quality-of-life health.

Projected timeline

Estimated project duration: 24 months, from September 1, 2026 to August 31, 2028.

• Months 1–3: Finalize study protocol and harmonize procedures across MCH/MUHC and CHU Sainte-Justine. Confirm questionnaires (with team experts and parent-partner input), data dictionary, and standardized operating procedures. Obtain or amend ethics approvals, train research staff, and establish coordinated recruitment pathways with CDH clinics, follow-up programs (nursing), surgical teams, and adult transition collaborators.

• Months 4–15: Active recruitment of adolescents and young adults with CDH (14–25 years) and matched friend controls across both centres by recalling participants from nursing staff and established CDH programs. Conduct comprehensive study visits including echocardiography (2D/3D), pulmonary function testing, renal and vascular ultrasound, blood and urine collection, bioimpedance, 6-minute walk test, questionnaires, and abstraction of neonatal and surgical variables. Ongoing monitoring of recruitment rates, feasibility of control matching, and participant retention.

• Months 12–20: Data cleaning and integration across sites, including imaging analysis, laboratory data processing, and quality assurance. Evaluate feasibility outcomes (recruitment yield, completeness of phenotyping, participant burden), and ensure harmonization of datasets for multicentre analyses.

• Months 18–24: Final statistical analyses and interpretation in collaboration with co-investigators and patient/family partners. Preparation of conference abstracts, manuscripts, and bilingual lay summaries. Dissemination through clinical networks and NeoCardioLab platforms. Use effect size estimates and feasibility metrics to develop competitive applications to CIHR, FRQS, and Heart & Stroke for a larger multicentre life-course study.

• Expected deliverables: Ethics approval and harmonized study manual by month 3; recruitment feasibility report by month 15; cleaned and integrated multicentre dataset by month 20; preliminary results, conference abstracts, family-facing materials, and major grant submission plan by month 24.

Detailed Knowledge Translation (KT)

Knowledge translation (KT) will implement a comprehensive, multi-level dissemination and mobilization strategy targeting clinicians, researchers, patients, families, and policy stakeholders in congenital diaphragmatic hernia (CDH) care across childhood, adolescence, and young adulthood.

• Scientific dissemination and open-access publication: Study findings will be disseminated through presentations at major international and national conferences (e.g., PAS, CPS, ATS, CDH conference) and through publication in high-impact, peer-reviewed journals in neonatology, pediatric cardiology, adult congenital/life-course medicine, and respiratory medicine. Open-access publication will be prioritized to ensure unrestricted access to results, particularly for multidisciplinary CDH teams and international collaborators.

• Digital knowledge mobilization and global reach: A key strength of this program is the established NeoCardioLab platform (www.neocardiolab.com), which reaches over 70,000 users annually across more than 200 countries, with over 230,000 page views per year. Study findings will be translated into dedicated CDH content modules, including interactive summaries, visual algorithms, and clinical interpretation tools. Dissemination will also occur through NeoCardioLab mobile applications and professional platforms (LinkedIn, ResearchGate, ORCID, X/Twitter), maximizing global accessibility and rapid uptake.

• Podcast and multimedia dissemination: The project will leverage established KT channels, including The Incubator Podcast (global neonatal audience) and L’Incubateur Néonat, a French-language podcast hosted by the Nominated Principal Applicant. Dedicated episodes focused on long-term CDH outcomes and cardiopulmonary health across adolescence and young adulthood will be developed to ensure broad dissemination and accessibility to both English- and French-speaking audiences.

• Engagement with CDH patient and family organizations: Collaboration with international and national patient organizations, including CDH International and the French-speaking association APEHDIA (Association des Parents d’Enfants porteurs de Hernie Diaphragmatique), will support the co-development and dissemination of lay summaries, webinars, and interactive discussions. These activities will ensure meaningful and accessible communication of findings to families. All materials will be developed in both French and English to maximize accessibility and equity. Mrs. Ode Lunardi, a mother of a child with CDH, will be actively involved in KT activities, contributing her lived experience to the co-development of family-facing materials and ensuring that dissemination strategies align with the priorities and needs of affected families. She has also reviewed the grant and study protocol and provided valuable feedback from a parent perspective. In addition, she will contribute, alongside Dr. Brossard-Racine (expert in patient-reported outcomes), to the selection of relevant questionnaires and surveys to ensure they are meaningful and appropriate for participants.

• Development of educational tools and clinician resources: High-yield educational materials, including infographics, clinical algorithms, and case-based modules, will be developed for neonatal, pediatric, and adult providers. These resources will facilitate the translation of deep phenotyping findings into clinical reasoning, risk stratification, transition planning, and long-term follow-up strategies for CDH survivors.

• Foundation for future multicentre research and collaboration: KT activities will include structured dissemination to research networks and collaborators (MUHC, CHU Sainte-Justine, and international CDH networks), enabling integration of findings into future multicentre studies and collaborative research initiatives. This will include preparation of reports, presentations, and collaborative discussions to support the development of larger-scale life-course studies.

• Equity, Diversity, Inclusion, and Accessibility (EDI-A): EDI-A principles are central to the design and conduct of this study. Recruitment will occur across two major pediatric centres (MCH/MUHC and CHU Sainte-Justine) serving socioeconomically and culturally diverse populations, with intentional efforts to include underrepresented and vulnerable groups. The “friend control” design helps reduce socioeconomic and environmental confounding, enhancing equity in comparisons. Study materials and dissemination outputs will be available in both French and English to ensure linguistic accessibility, and participant reimbursement will minimize financial barriers to participation.

• Collaboration with patient advocacy groups, including CDH International and APEHDIA, ensures that patient and family perspectives are embedded throughout the project. Together, these elements ensure that the study is inclusive, accessible, and responsive to the diverse population of adolescents and young adults living with CDH, while promoting generalizable and impactful findings.

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