Urinary and Sexual Symptoms in Patients With Hirschsprung Disease

• Study Design

This research is a Category 3 human research study (non-interventional research involving human participants). It is a multicenter, prospective, observational, and descriptive study combining a retrospective review of clinical and surgical data extracted from medical records with a prospective collection of patient-reported outcomes using standardized self-administered questionnaires. No additional procedures, examinations, or study visits are required. All clinical and surgical data are obtained from routine medical records, while the only study-specific procedure consists of completing online questionnaires.

Eligible patients are identified from the databases of the five participating university hospitals (Grenoble, Lyon, Saint-Étienne, Clermont-Ferrand, and Marseille) using procedural codes for pull-through surgery (French CCAM codes including HJFA001, HJFA002, HJFA004, HJFA005, HJFA007, HJFA011, HJFA017, and HJFC031) together with the diagnosis code for Hirschsprung disease (ICD-10: Q43.1). Electronic medical records are subsequently reviewed to confirm eligibility based on histopathological findings, operative reports, and the absence of syndromic forms, total colonic aganglionosis, or small-bowel aganglionosis.

• Study Procedures

The participant pathway consists of the following steps:

An initial telephone call from the local investigator to provide oral information about the study (up to three contact attempts).

For participants who provide oral agreement, an email containing the participant information sheet, a non-opposition form, and secure links to age- and sex-specific online questionnaires.

Completion of the questionnaires through the secure REDCap platform during a clinically stable period, outside any acute episode that could influence symptom reporting.

Up to three reminder emails sent at one-week intervals, followed by one additional telephone reminder after one month if no response has been received.

Study inclusion is considered complete upon receipt of the completed questionnaires. No longitudinal follow-up is planned after this single assessment.

No in-person study visits are scheduled.

• Data Collection

Two complementary data sources are used:

A- Retrospective data extracted from medical records:

Demographic characteristics (sex, date of birth, weight, height) Surgical technique (Swenson, Duhamel, or Soave procedure) Surgical approach (open surgery, laparoscopic surgery, or transanal approach) Length of aganglionosis based on histopathological examination Date of surgery Other clinically relevant perioperative data

B. Prospectively collected patient-reported outcomes:

Questionnaire responses are automatically transferred into the REDCap electronic case report form (eCRF) without manual transcription and include:

ICIQ questionnaires (urinary symptoms) IIEF-5 or FSFI questionnaires (sexual function) PedsQL 4.0 (health-related quality of life) Bowel Function Score (Rintala score) (bowel function)

• Data Management and Quality Assurance

Data quality is ensured through manual verification, automated validation checks within the REDCap eCRF, and a final review before database lock. The database will be locked after complete validation by the Principal Investigator (Dr. Pierre-Yves Rabattu) and subsequently approved by the study sponsor.

Each participating center designates a single local investigator responsible for data entry, identification of eligible patients, family contact, questionnaire distribution, and extraction of clinical data from medical records. Clinical data are entered into the eCRF using single data entry with source verification. Questionnaire responses are automatically imported into the database, eliminating transcription errors.

Source documents include patients' medical records (operative reports, hospitalization records, consultation notes, complementary investigations, and medical correspondence) together with the original electronic questionnaire responses collected through REDCap, which constitute the source data for patient-reported outcomes.

A local study coordinator is designated at each participating center to oversee study conduct. A centralized tracking log records questionnaire distribution, reminders, and responses for each participant. The eCRF is managed and monitored by the study coordinator (Amandine Juge).

Reasons for study discontinuation (withdrawal of non-opposition, failure to meet eligibility criteria, or non-response despite reminders) are systematically documented in the eCRF, together with the date and reason. Individual participants will not be replaced; however, additional eligible participants may be recruited if necessary to achieve the target sample size.

• Sample Size

The sample size calculation is based on the primary descriptive objective of estimating the prevalence of urinary symptoms. Assuming a prevalence of 10%, consistent with published estimates ranging from 7% to 25%, a precision of ±5%, and a two-sided 95% confidence interval, 556 evaluable participants are required.

The source population is estimated at approximately 720 patients who underwent surgery between 2000 and 2018 across the five participating centers. Assuming an 80% response rate (20% expected non-response), the required sample size is expected to be achieved.

• Missing Data

Participants who do not return the questionnaires despite the planned reminders will be considered non-responders rather than withdrawals. The primary analysis will be conducted as a complete-case analysis, including only participants who completed the questionnaires.

• Statistical Analysis

Statistical analyses will be performed once, at the end of the study, after all questionnaires have been received. No interim analyses are planned.

Continuous variables will be summarized using means and standard deviations or medians and interquartile ranges, depending on data distribution. Categorical variables will be presented as frequencies and percentages.

The primary outcome, the overall ICIQ score (age- and sex-specific version), will be analyzed as a continuous variable.

Overall descriptive analyses will be complemented by subgroup analyses according to surgical technique (Swenson, Duhamel, or Soave), with adjustment for the length of aganglionosis determined from histopathological findings.

Comparisons of continuous variables will be performed using the Student's t-test or the Mann-Whitney U test, depending on distribution. Comparisons of categorical variables will use the Chi-square test or Fisher's exact test, as appropriate. Multivariable analyses (linear or logistic regression models) may be conducted where appropriate after verification of statistical assumptions.

Statistical significance will be defined as a two-sided p-value < 0.05. Where multiple comparisons are performed, Bonferroni or Holm corrections may be applied.

A participant flow diagram will describe all patients who underwent surgery between 2000 and 2018, exclusions (total colonic aganglionosis, small-bowel aganglionosis, syndromic forms), the telephone contact and reminder process, and the final number of participants included in the analyses.

All statistical analyses will be performed at Grenoble Alpes University Hospital by Amandine Juge, with methodological review by Dr. Alexandre Bellier, using R and/or SPSS or Stata software.

Inclusion criteria

• Biopsy-confirmed Hirschsprung disease treated surgically between 2000 and 2018, regardless of the pull-through technique used.
• Surgery performed at one of the five participating university hospitals (Grenoble, Lyon, Saint-Étienne, Clermont-Ferrand, or Marseille).
• Male or female participants.
• Aged 7 to 25 years at the time of study inclusion.
• No objection to participation obtained from the participant or, for minors, from the legal representative, in accordance with French regulations.
• Affiliation with the French national health insurance system.

Exclusion criteria

• Syndromic Hirschsprung disease (e.g., Down syndrome, Waardenburg syndrome, or Multiple Endocrine Neoplasia type 2).
• Total colonic aganglionosis.
• Small-bowel aganglionosis.
• Major congenital urogenital malformation unrelated to Hirschsprung disease (e.g., bladder exstrophy or posterior urethral valves).
• Deceased before study inclusion.
• Unable to be contacted despite repeated attempts.
• Individuals not eligible for biomedical research under Articles L1121-5 to L1121-8 of the French Public Health Code.