Discussion
The purpose of the study was to assess SDB burden among I-DS referred to
sleep center. All I-DS had OSA with majority exhibiting severe OSA.
Hypoxemia and hypoventilation were also common. Among those who
underwent AT, short term outcome shows marked improvement of OSA.
A high prevalence of OSA in children with DS has been described. A
recent meta-analysis of 18 studies including 2,000 children with DS
showed the prevalence of OSA to be about 50% by the conventional
diagnostic threshold,(Lee et al. 2018) which represents a 10-fold higher
risk than in the general pediatric population.(Marcus et al. 2012)
Studies exclusively examining SDB in infant have been rare. Similar to
our study, a previous single center study revealed virtually all I-DS
who underwent sleep study manifested OSA and, alike our study, with a
great proportion exhibiting severe OSA.(Goffinski et al. 2015) In our
study severe OSA was present in 80% of I-DS. Thus, it is possible that
the severity of OSA in infants may be higher than older children with
DS.(Nerfeldt and Sundelin 2020) While the true prevalence of OSA is
difficult to assess from clinical setting due to selection bias, it is
reasonable to believe that the OSA risk is at its extreme even at a very
young age in I-DS. Because all included infants met OSA criteria with
most of them exhibiting severe OSA, we were unable to explore factors
associated with OSA or severity of OSA. Not surprisingly, OSA was more
severe in I-DS who underwent split study (vs. diagnostic) as young
children with more severe OSA or anticipated to be more severe OSA tend
to undergo O2 titration study in clinical practice.
In addition to OSA, CSA was also highly prevalent in I-DS. CSA during
sleep is common in the preterm, newborn period and during infancy.(S et
al. 2014) In healthy children, short duration (<20 s) CSAs in
sleep are considered physiologic in the setting of a sigh, REM sleep and
movement.(S et al. 2014) However, there is paucity of studies examining
CSA in unselected infant population. Regardless, we suspect that high
occurrence of CSA events noted in our study may not be unique to I-DS. A
study by Fan et al. showed that CSA (as measured by CAI) was associated
with younger age in the very youngest cohort (0-3 yrs old) in their
review of children with DS who underwent PSG.(Fan et al. 2017) They
reasoned that the improvement of CSA may be due to maturity of the
respiratory control system with aging in younger children. However, such
a relationship with age was not demonstrated in our study.
Sleep hypoxemia was also common affecting nearly 30% of I-DS in our
study. As expected, hypoxemia was more common among those who exhibited
hypoventilation and severe OSA in our study. Despite the notion that
individuals with DS are at risk for hypoventilation, studies examining
this very aspect in DS has been rare. A recent case control study by
Richard et al. including children with and without DS revealed that
children with DS have increased TCCO2 regardless of the presence of OSA
and its severity.(Richard et al. 2020) In that study, investigators
noted correlation between BMI and maximum CO2 speculating that obesity
might be a contributing factor to the hypoventilation. Our study is the
first to closely inspect hypoventilation exclusively in I-DS. In our
study, 25% of I-DS met the criteria for hypoventilation. Interestingly,
we found that I-DS with comorbid hypothyroidism had about 5 times higher
odds of having hypoventilation, albeit borderline statistical
significance likely related to small sample size. This alludes to the
fact that hypotonia resulting from hypothyroidism, may play an important
role in hypoventilation. The incidence of hypothyroidism in children
with DS is 5.5%–10% but higher in the first year of life.(King et al.
2014) We did not examine the association of body habitus with
hypoventilation given the limited variability of the BMI in our cohort.
In the subcohort of I-DS who underwent AT, we observed marked
improvement in the severity of OSA as measured by oAHI and minO2sat.
This is consistent with previous studies mainly including older children
(older than infant age) that showed improvement of OSA following the
AT.(Abdel-Aziz et al. 2017; Maris et al. 2017; Nerfeldt and Sundelin
2020) Average reduction in AHI was reportedly about 50% according to
the systematic review.(Nation and Brigger 2017) Despite this, AT is not
entirely curative in most cases and residual OSA is common.(Galluzzi and
Garavello 2021) Moreover, complication rates of AT is higher in children
with DS.(Goldstein et al. 1998; Yumusakhuylu et al. 2016) Thus, despite
the marked improvement in OSA shown in our study, long term outcome and
safety of AT in infants should be investigated in the future study.
OSA leads to poor sleep by frequent sleep disruption and deprivation of
restful sleep. Poor sleep resulting from OSA in turn leads to daytime
sleepiness, fatigue, mood change(Sánchez et al. 2009), and deficits in
memory(Wallace and Bucks 2013), cognition(Pierobon et al. 2008), and
executive function(Saunamäki et al. 2009), all of which may have more
significant implications in I-DS given the inherent intellectual,
cognitive, and emotional challenges associated with DS.(Sánchez et al.
2009) Moreover, gas exchange abnormality associated with SDB can
unavoidably impact on the risk of cardiovascular disease including
pulmonary hypertension in individuals with DS.(Bush et al. 2018) Thus,
in view of our study findings, early screening of SDB as early as
infants should be considered. This will become more feasible with the
advance and emergency of more convenient technology that enables SDB
evaluation in the home setting.
The strengths of this study are the exclusive investigation of infants
and the comprehensive evaluation of all spectrum of SDB including
hypoventilation. Moreover, to our knowledge this is the first study that
examined the change in SDB metrics following the AT in I-DS. The main
limitation of the study is related to inherent weakness of the
retrospective study including selection bias. Such bias could have
impacted the severity of SDB and the treatment outcome following the AT.
In conclusion, we report the excessively high burden of SDB among I-DS
referred to tertiary sleep center.
OSA was present in the entire
cohort and was mostly severe in nature. In addition to OSA and CSA,
sleep hypoxemia and hypoventilation were all common. There was
significant improvement in OSA following AT in a subcohort. These
findings propel us to consider early screening of SDB and possibly AT in
this population.
Acknowledgement: We thank pediatric sleep specialists in our sleep
center who cared for patients included in this study.
Grant support: YK is supported by grants from NIH (R01 HL158765, R21
AG070576, R21 HL150502).
Financial Disclosure: none. Non-financial or conflicts of interest that
could be relevant in this context: none