Understanding the impact of growth hormone on ventilatory control stability in children with Prader-Willi syndrome

A hallmark of Prader-Willi syndrome (PWS) is hypothalamic-pituitary axis dysfunction, which can result in reduced growth hormone (GH) production. While GH replacement therapy is common in children with PWS, it has also been implicated in the development of obstructive sleep apnoea (OSA) in some children. The mechanisms underlying this development are poorly understood but may be related to alterations in ventilatory control. Our study investigated the impact of GH treatment on ventilatory control stability during sleep in children with PWS. Polysomnographic data pre- and post-GH therapy in 25 children (aged 2mo-18y) were used to assess ventilatory control using a validated method that estimates loop gain (dimensionless ratio) from ventilation changes following spontaneous sighs during sleep. Data were analysed using linear mixed-effects modelling with GH as a fixed effect and participant as a random intercept. Covariates that could impact loop gain including age, obstructive-apnoea hypopnoea index (OAHI) and central apnoea-hypopnoea index (CAHI) were each added separately to the base model in a stepwise, manual forward selection approach. Loop gain was not altered by GH treatment (β = 0.003, 95% CI: [-0.042, 0.049], p = 0.878, Cohen's d = 0.031). Age, OAHI and CAHI did not alter the impact of GH on loop gain. No difference in sleep or respiratory characteristics were found, however 20% of children developed OSA post-GH.

Initiation of GH therapy was not associated with a change in loop gain, suggesting that changes in ventilatory control are unlikely to contribute to the development of OSA in children with PWS.

• Prader-Willi syndrome is associated with abnormal ventilatory control and increased risk of sleep-disordered breathing. • Growth hormone therapy may influence respiratory physiology but its effect on the stability of ventilatory control (loop gain) remains unclear.

• In this cohort of children with Prader-Willi syndrome, growth hormone therapy did not alter loop gain despite inter-individual variability. • Our findings suggest that any sleep-disordered breathing that emerges following growth hormone therapy is likely driven by mechanisms other than altered loop gain.