Early oxytocin treatment in infants with Prader-Willi syndrome is safe and is associated with better endocrine, metabolic and behavioral outcomes

Abstract

Background: Oxytocin (OT) plays an important role in modulating behavior, social interactions and feeding. Prader-Willi syndrome (PWS), a rare genetic neurodevelopmental disorder, is a model of hypothalamic disorder including OT dysfunction. We previously showed that infants with PWS who had received an early short course (7 days) of intranasal OT treatment improved their oral and social skills. We aim to document the long-term tolerance and effects of early intranasal OT treatment on the disease trajectory.

Methods: We performed a comparative clinical trial including the 17 children who had received OT as infants in our previous study and compared them to 17 PWS non-exposed children at 3-4 years old. Primary endpoint was the total communication score on the Vineland Adaptive Behavior Scales-2nd edition (VABS-II). Secondary endpoints were the other domains of VABS-II, behavior scored by the Child Behavior Checklist, feeding skills, endocrine and metabolic profiles, and brain connectivity on functional magnetic resonance imaging.

Results: We documented the long-term safety of early OT treatment. The VABS-II communication score was not different between the two groups, defined as OT-exposed and non-exposed, whereas a trend toward a higher socialization score was found in the OT-exposed children (p = 0.06). Circulating IGF-1 and HDL cholesterol were significantly higher in the OT-exposed group (p < 0.05). OT-exposed children had normal acylated ghrelin levels, which were lower than those observed in non-exposed children (p = 0.06), and they displayed higher connectivity of the orbitofrontal cortex brain region.

Conclusion: Early OT treatment in infants with PWS is safe up to 3-4 years of age. OT-exposed children display better social, endocrine and metabolic outcomes. This study documents for the first time in human the biological window of opportunity of early OT treatment, which may change the trajectory of the PWS condition.

Trial registration: Clinical trial NCT03081832 Retrospectively registered https://clinicaltrials.gov/search?cond=NCT03081832 .

Keywords: Behavior; Brain connectivity; Infants; Long-term effects; Metabolism; Oxytocin; Prader–Willi syndrome.

Fig. 1

VABS II total scores and subscores of communication and socialization domains. VABS total scores and subscores of communication (A, B) and socialization (C, D) in OT-exposed (gray) and non-exposed (white) groups. Horizontal dotted lines represent the thresholds above which scores were considered as low, moderately low and adequate scores

Fig. 2

CBCL subscores in the OT-exposed and non-exposed groups according to genetic subtype groups (deletion vs. non-deletion). This figure shows the forest plot comparing the difference between the two genetic subtype groups (deletion vs. non-deletion) within the OT-exposed and non-exposed groups for each subscore. In the deletion subtype group, there were significant differences or trends between the OT-exposed group and the non-exposed group in subscores adjusted for age

Fig. 3

Circulating AG (A), UAG (B) and AG/UAG ratio (C) levels in OT-exposed (gray box) and non-exposed (white box) PWS children and age-matched healthy controls (dotted box). The healthy control group comprises 29 children, mean age 3.5 years, from a previous study [12]

Fig. 4

Brain connectivity studies in fMRI in the OT-exposed and non-exposed groups. Brain region connectivity in the orbitofrontal network (A, B) and default mode network (DMN) (C, D) are shown. High connectivity regions in each network are shown in red (A, C). B and D showed higher connectivity Z-score in the OT-exposed children compared to non-exposed children in red (B) and in yellow (D); Correlations between connectivity Z-score of parahippocampus and VABS-II socialization score (E). Correlations between connectivity Z-score of frontal cortex and UAG level in DMN (F)