Brainstem Dysfunction Involvement in the Pathogenesis of Pierre Robin Sequence (DYSROBIN)

Introduction Pierre Robin Sequence, PRS, incidence is about one hundred births per year in France. The main neonatal clinical manifestations are secondary to airway obstruction and food difficulties related to swallowing disorders. Despite recent progress, the pathogenesis of PRS is not fully understood.

The hypothesis is that brainstem dysfunction, BSD, plays a central role in the pathogenesis of PRS.

The purpose of the study is to achieve a complete evaluation of BSD to specify its role in the pathogenesis of PRS.

The primary objective is to compare central apnea index (CAI) of infants with PRS with those of infants with isolated airway obstruction (AWO) and those of healthy infants in order to clarify the direct role of BSD.

Material and Methods This prospective interventional study will be carried out in Lyon at the Hôpital Femme-Mère-Enfant and in Paris at the Hôpital Necker-Enfants Malades for 2 years. 3 groups of patients will be studied: PRS, 50 patients, AWO, 50 patients and healthy, 30 patients, included before 2 months of life. Infants will be followed for a maximum of 10 months. The evaluations will be carried out for 48 hours between birth and 2 months of life and then for 24 hours between 6 and 10 months of life for PRS and AWO group. Concerning the healthy group, the evaluation will be carried out during 48h during a single hospitalization before 2 months. Polysomnography, holter-ECG, 24h gas exchange, impedance-pH monitoring and mental region EEG will be performed. The central apnea index (mean number per hour), obstructive apnea index, non-nutritive swallowing index (NNS), gastroesophageal reflux and NNS-respiration coordination will be assessed for each stage of sleep and compared between the three groups of patients.

Study Overview

• Status: Completed
• Conditions: Pierre Robin Sequence; Brainstem Dysfunction
• Intervention / Treatment: Other: Recording of data; Other: Recording of data

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Philippe REIX, Pr; Phone Number: +33 4 72 12 94 37; Email: phlippe.reix@chu-lyon.fr
• Study Contact Backup: Name: Lauriane Couturier; Phone Number: +33 4 27 85 59 69; Email: lauriane.couturier@chu-lyon.fr

Study Locations

• France
  • Bron, France, 69500
    • Hôpital Femme Mère Enfant
  • Paris, France, 75015 Paris
    • APHP-Necker

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 2 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for the group 1

- infants with PRS

Inclusion Criteria for the group 2 - infant with isolated airway obstruction

Inclusion Criteria for the group 3

- healthy infant : siblings of sudden unexpected death of the infant or with any known pathology

Inclusion Criteria for the 3 groups

• During one hospitalization or program for one hospitalization
• Parental consent
• Social safety affiliation

Exclusion Criteria:

• Birth before 37 SA
• Neonatal complication
• Group 2 only: AWO with neurological disease including brainstem dysfunction
• Group 3 only : AWO, ENT disease or syndromic disease, neurological disease including brainstem dysfunction, Intra uterine growth retardation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Pierre Robin sequence; Infants with PRS : retrognathism, glossoptosis, cleft palate Group 1a : isolated PRS Group 1b : PRS with bone disease or collagen disease (Stickler) Group 1c : syndromic PRS or associated PRS without bone disease or collagen disease	Other: Recording of data; Recording during one hospitalization of 48 hours between birth and 2 months of life and one hospitalization of 24 hours between 6 and 10 months of life; General data: age, term of birth, birth weight, gender, diseases, weight and size at recording, cranial perimeter, food, drugs : first and second visit; Respiratory rate, respiratory signs, stridor : first and second visit; 24h holter-ECG : first and second visit; 24h impedance pH-metry : first visit; Nocturne polysomnography : 50% prone position, 50% supine : sleep analyze, obstructive apnea hypopnea index (OAHI), central apnea index (CAI), periodical breathing, micro arousals index, non-nutritive swallowing analyze,(mental region electromyogram) : first and second visit; 24 h gaz exchanges : mean, maximal PtcCO2 and % of time spent above 50 mmHg , SpO2 under 90%, 85% et 80% and desaturations index : first and second visit; succimetry procedure : at first visit only between birth and 2 months; Other: Recording of data; Recording during one hospitalization of 48 hours between birth and 2 months of life; General data: age, term of birth, birth weight, gender, diseases, weight and size at recording, cranial perimeter, food, drugs; Respiratory rate, respiratory signs, stridor; 24h holter-ECG; 24h impedance pH-metry; Nocturne polysomnography : 100% supine position : sleep analyze, obstructive apnea hypopnea index (OAHI), central apnea index (CAI), periodical breathing, micro arousals index, non-nutritive swallowing analyze,(mental region electromyogram); 24 h gas exchanges : mean, maximal PtcCO2 and % of time spent above 50 mmHg , SpO2 under 90%, 85% et 80% and desaturations index; Succimetry procedure : at first visit only between birth and 2 months
Other: Superior airway obstruction, AWO; Infants with AWO : laryngomalacia, tracheal stenosis, laryngeal stenosis, others etiology	Other: Recording of data; Recording during one hospitalization of 48 hours between birth and 2 months of life and one hospitalization of 24 hours between 6 and 10 months of life; General data: age, term of birth, birth weight, gender, diseases, weight and size at recording, cranial perimeter, food, drugs : first and second visit; Respiratory rate, respiratory signs, stridor : first and second visit; 24h holter-ECG : first and second visit; 24h impedance pH-metry : first visit; Nocturne polysomnography : 50% prone position, 50% supine : sleep analyze, obstructive apnea hypopnea index (OAHI), central apnea index (CAI), periodical breathing, micro arousals index, non-nutritive swallowing analyze,(mental region electromyogram) : first and second visit; 24 h gaz exchanges : mean, maximal PtcCO2 and % of time spent above 50 mmHg , SpO2 under 90%, 85% et 80% and desaturations index : first and second visit; succimetry procedure : at first visit only between birth and 2 months; Other: Recording of data; Recording during one hospitalization of 48 hours between birth and 2 months of life; General data: age, term of birth, birth weight, gender, diseases, weight and size at recording, cranial perimeter, food, drugs; Respiratory rate, respiratory signs, stridor; 24h holter-ECG; 24h impedance pH-metry; Nocturne polysomnography : 100% supine position : sleep analyze, obstructive apnea hypopnea index (OAHI), central apnea index (CAI), periodical breathing, micro arousals index, non-nutritive swallowing analyze,(mental region electromyogram); 24 h gas exchanges : mean, maximal PtcCO2 and % of time spent above 50 mmHg , SpO2 under 90%, 85% et 80% and desaturations index; Succimetry procedure : at first visit only between birth and 2 months
Other: Healthy infants; Healthy infants : siblings of sudden unexpected death of the infant	Other: Recording of data; Recording during one hospitalization of 48 hours between birth and 2 months of life and one hospitalization of 24 hours between 6 and 10 months of life; General data: age, term of birth, birth weight, gender, diseases, weight and size at recording, cranial perimeter, food, drugs : first and second visit; Respiratory rate, respiratory signs, stridor : first and second visit; 24h holter-ECG : first and second visit; 24h impedance pH-metry : first visit; Nocturne polysomnography : 50% prone position, 50% supine : sleep analyze, obstructive apnea hypopnea index (OAHI), central apnea index (CAI), periodical breathing, micro arousals index, non-nutritive swallowing analyze,(mental region electromyogram) : first and second visit; 24 h gaz exchanges : mean, maximal PtcCO2 and % of time spent above 50 mmHg , SpO2 under 90%, 85% et 80% and desaturations index : first and second visit; succimetry procedure : at first visit only between birth and 2 months; Other: Recording of data; Recording during one hospitalization of 48 hours between birth and 2 months of life; General data: age, term of birth, birth weight, gender, diseases, weight and size at recording, cranial perimeter, food, drugs; Respiratory rate, respiratory signs, stridor; 24h holter-ECG; 24h impedance pH-metry; Nocturne polysomnography : 100% supine position : sleep analyze, obstructive apnea hypopnea index (OAHI), central apnea index (CAI), periodical breathing, micro arousals index, non-nutritive swallowing analyze,(mental region electromyogram); 24 h gas exchanges : mean, maximal PtcCO2 and % of time spent above 50 mmHg , SpO2 under 90%, 85% et 80% and desaturations index; Succimetry procedure : at first visit only between birth and 2 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Central apnea index (CAI) (mean number per hour)	To compare central apnea index (CAI) (mean number per hour), according to the ASSM guidelines 2007, recording by one nocturne polysomnography, between 3 groups of infants by sleep step, between birth and 2 months of life, in order to clarify the direct role of BSD. According to the ASSM guidelines 2007, the central apnea index is measured : mean number of central apnea per hour.	2 months of life during one nocturne polysomnography

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Obstructive apnea hypopnea index (OAHI)(mean number per hour)	To compare obstructive apnea hypopnea index (OAHI)(mean number per hour) according to the guidelines ASSM 2007, recording by one nocturne polysomnography, between 3 groups of infants by sleep step, between birth and 2 months of life According to the ASSM guidelines 2007, the obstructive apnea hypopnea index is measured: mean number of obstructive apnea and hypopnea per hour.	2 months
Comparison of OAHI(mean number per hour) and CAI	To compare obstructive apnea hypopnea index (OAHI)(mean number per hour) and central apnea index (CAI) (mean number per hour), between PRS group and AWO group by sleep step between 6 and 10 months of life According to the ASSM guidelines 2007, the obstructive apnea hypopnea index, mean number of obstructive apnea and hypopnea per hour, and the central apnea index are measured, mean number of central apnea per hour.	between 6 and 10 months of life
Micro arousals index (mean number per hour)	To compare micro arousals index (mean number per hour) between the 3 groups by sleep step between birth and 2 months of life and between PRS group and AWO group between 6 and 10 months of life to clarify the role of BSD in sleep microstructure According to the ASSM guidelines 2007, micro arousals index (mean number per hour) are measured.	up to 2 months of life
Micro arousals index (mean number per hour)	To compare micro arousals index (mean number per hour) between the 3 groups by sleep step between birth and 2 months of life and between PRS group and AWO group between 6 and 10 months of life to clarify the role of BSD in sleep microstructure According to the ASSM guidelines 2007, micro arousals index (mean number per hour) are measured.	up to 10 months of life
Non-nutritive swallowing index (NNS) and apnea secondary to non-nutritive swallowing	To compare non-nutritive swallowing index (NNS) and apnea secondary to non-nutritive swallowing between the 3 groups by sleep step between birth and 2 months of life and between PRS group and AWO group between 6 and 10 months of life to clarify the role of BSD in swallowing disorders and NNS-respiration coordination non-nutritive swallowing index (NNS), mean number per hour, and apnea secondary to non-nutritive swallowing, mean number per hour, monitoring by the mental region EEG and the one nocturne polysomnography	up to 2 months of life
Non-nutritive swallowing index (NNS) and apnea secondary to non-nutritive swallowing	To compare non-nutritive swallowing index (NNS) and apnea secondary to non-nutritive swallowing between the 3 groups by sleep step between birth and 2 months of life and between PRS group and AWO group between 6 and 10 months of life to clarify the role of BSD in swallowing disorders and NNS-respiration coordination non-nutritive swallowing index (NNS), mean number per hour, and apnea secondary to non-nutritive swallowing, mean number per hour, monitoring by the mental region EEG and the one nocturne polysomnography	up to 10 months of life
Positive and negative pressures, their temporal organizations evaluated using succimetry procedure between the 3 groups of patients at 0 and 2 months of life	Compare the positive and negative pressures, their temporal organizations evaluated using succimetry procedure between the 3 groups of patients at 0 and 2 months of life.	up to 2 months of life

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): May 24, 2018
• Primary Completion (Actual): March 23, 2023
• Study Completion (Actual): March 23, 2023

Study Registration Dates

• First Submitted: January 12, 2018
• First Submitted That Met QC Criteria: January 30, 2018
• First Posted (Actual): February 6, 2018

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: apnea; pathogenesis; swallowing; Brainstem; Pierre Robin sequence
• Additional Relevant MeSH Terms: Congenital Abnormalities; Musculoskeletal Diseases; Stomatognathic Diseases; Stomatognathic System Abnormalities; Jaw Abnormalities; Jaw Diseases; Maxillofacial Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Pierre Robin Syndrome
• Other Study ID Numbers: 69HCL17_0816

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No