ENOrphanet Journal of Rare Diseases | Intranasal Oxytocin in Infancy Improves Swallowing Function and Disease Trajectory in Prader-Willi Syndrome
Date: March 08, 2026
Classification: Frontiers
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This study presents the first multicenter randomized controlled trial of intranasal oxytocin (OT) in infants with Prader-Willi syndrome (PWS), demonstrating that early OT treatment significantly improves swallowing function and shows long-term advantages in neurodevelopment and behavior, suggesting its potential as a disease-modifying therapy.
Literature Overview
The article 'Oxytocin in infants with Prader-Willi syndrome to improve dysphagia and disease trajectory,' published in Orphanet Journal of Rare Diseases, reviews and summarizes the results of a multicenter, randomized, double-blind, placebo-controlled trial (OTBB3) and its long-term follow-up study (OTBB3-FUP) evaluating intranasal oxytocin (OT) in infants with Prader-Willi syndrome (PWS) during the neonatal critical period. The study assessed the short-term efficacy of OT on feeding skills and its long-term impact on disease trajectory, finding that although the primary endpoint was not significant, key secondary endpoints showed significant improvement in swallowing function, and a 3-year follow-up revealed sustained advantages in motor development, adaptive behavior, and comorbidity severity. This study provides important clinical evidence for early intervention in PWS.Background Knowledge
Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder caused by the silencing of paternally inherited genes in the 15q11-q13 region, characterized by neonatal hypotonia, feeding difficulties, and growth retardation, followed later by pathological hyperphagia and obesity. Infants with PWS exhibit significant suck-swallow dysfunction, leading to malnutrition and risk of aspiration. Studies indicate that PWS-related genes (e.g., MAGEL2 and SNORD116) are involved in the development of oxytocin (OT) neurons, and animal models show that a single early postnatal OT injection rescues suckling behavior and adult cognitive function in Magel2-knockout mice. Previous phase II trials suggested that intranasal OT improves sucking, social interaction, and mother-infant bonding in PWS infants. Thus, OT is considered a potential disease-modifying therapy for PWS. However, there has been a lack of multicenter phase III trials to confirm its efficacy and long-term safety. This study fills that gap by systematically evaluating the short- and long-term effects of early OT treatment through a rigorously designed double-blind RCT and prospective cohort follow-up, bridging mechanistic insights with clinical translation for neurodevelopmental intervention in PWS.
Methods and Experiment
The research team conducted a phase III, multicenter, double-blind, randomized, placebo-controlled OTBB3 trial across Europe, enrolling 52 PWS infants with a median age of 2.2 months, randomly assigned 1:1 to receive daily 4 IU intranasal OT or placebo for 4 weeks. The primary endpoint was the proportion achieving normalized Neonatal Oral-Motor Scale (NOMAS) scores (≤10) at week 4. Key secondary endpoints included the proportion with normalization of two abnormalities on videofluoroscopic swallowing study (VFSS) linked to high aspiration risk: pharyngeal propulsion and airway protection. Resting-state fMRI (rs-fMRI) was used to assess changes in brain functional connectivity. All infants underwent a second randomization after the initial phase to ensure at least 4 weeks of OT exposure. Subsequently, a prospective cohort study (OTBB3-FUP) was conducted at a center in France, comparing 40 children who had received OT treatment (exposed cohort) with 24 untreated PWS children (unexposed cohort) at approximately 3 years of age to evaluate long-term safety and comorbidity severity.Key Conclusions and Findings
Significance and Outlook
This study provides the first high-quality clinical evidence in PWS that early intranasal OT treatment improves swallowing function, reduces aspiration risk, and may alter the long-term disease trajectory. VFSS, as a sensitive biomarker, may be more suitable than NOMAS for evaluating intervention effects in PWS infants. The findings support the disease-modifying role of OT during the critical neurodevelopmental window, consistent with animal models showing OT promotes neural circuit maturation. Future studies should further explore the optimal dosage, timing, and duration of OT treatment, as well as its long-term effects on core PWS symptoms such as appetite regulation.
Conclusion
This study systematically evaluated the efficacy and safety of intranasal oxytocin (OT) in infants with Prader-Willi syndrome (PWS) through a rigorous multicenter European randomized controlled trial and long-term follow-up. Although the primary endpoint (NOMAS score) showed no significant difference between groups, key secondary VFSS results demonstrated that 4 weeks of OT treatment significantly improved swallowing function and reduced the incidence of high-risk complications. Brain imaging further revealed that OT may achieve this effect by modulating prefrontal functional connectivity. More importantly, approximately 3 years of follow-up showed that children with early OT exposure consistently outperformed unexposed children in motor development, behavioral adaptation, and comorbidity severity, suggesting OT may act as a disease-modifying therapy that reshapes the developmental trajectory of PWS. This study not only provides strong clinical evidence for early intervention in PWS but also offers new therapeutic insights for other neurodevelopmental disorders associated with neonatal hypotonia and feeding difficulties. Future research should focus on optimizing treatment protocols and exploring its potential application in broader populations.
