Obstructive Sleep Apnea in Individuals with Down Syndrome: A Meta-Analytic Literature Review

Twenty three studies examining OSA among 1,469 people with DS were found. Among ten studies using community referred samples, 71.5% of people with DS had OSA, compared to 69.6% in referred community samples suspected of having respiratory events. There was an inverse relationship between apnea hypopnea index (AHI) cutoffs and OSA prevalence as higher cutoffs were associated with somewhat lower prevalence. Examining age groups, adults had a higher prevalence of OSA (90.0%) compared to infants (66.5%) and children between 2-21 years of age (69.9%). Oxygen desaturation and gender did not affect prevalence. Although surgery had less effect on successfully treating OSA among DS individuals compared to those without DS in prior studies, lingual tonsillectomy had the greatest effect (mean AHI decrease of 9.0).


Introduction
Down syndrome (DS), also known as trisomy 21, is a common genetic disorder with an incidence of 1 per 660 live births. DS is caused by a full or partial extra airway infections, nasal secretions, hypothyroidism, and a higher incidence of obesity [2]. In a study including 303 children with DS, 47.8% were obese compared to 12.1% of age-and gender-matched controls in the general population [3]. However, although obesity presents a risk factor for developing OSA in nongenetically affected individuals, it is not consistently associated with increased prevalence of SDB [4]. Studies also suggest a higher prevalence of sleep issues among males with DS compared to females. Similarly, there are sporadic case reports on adults with DS noting a higher prevalence of OSA, hypoxemia, hypoventilation, and sleep fragmentation [5]. Examining surgical treatment, although adenotonsillar hyperplasia plays an important role in children with OSA, studies of children with DS suggest only partial improvements in their breathing after adenotonsillectomy [6].
The high prevalence of SDB in people with DS is unquestioned. In a study involving 16 adults, an estimated 88% of subjects with DS had an Apnea Hypopnea Index (AHI) ≥ 15/h compared to only 9% of non-DS adults in a population-based study, while 75% of subjects with DS had a saturation nadir < 85% compared to 8% of the non-DS population [5]. Since untreated OSA could increase the risk for cardiovascular and neurological complications, early diagnosis and treatment of OSA can significantly improve quality of life.
PSG remains the gold standard in diagnosing OSA. With greater awareness of OSA in recent years, however, the OSA-18 questionnaire has been increasingly utilized to screen and diagnose OSA [7].
Though often administered, the OSA-18 was found to have poor sensitivity in identifying OSA among a sample of 225 children, as most children with severe OSA were not correctly diagnosed [8]. In a study examining 56 children with DS, the positive predictive value for parental-based diagnoses of OSA was 36.4% (4/11), while the negative predictive value was 45.8% (11/24) [4]. In addition, while the use of in-home sleep studies and overnight pulse oximetry has been rising, especially when there is a lack of or inability to conduct PSG, their accuracy in diagnosing OSA remains questionable [9]. In a review assessing the accuracy of oximetry in 25 published studies involving normal children, oximetry use accurately identified those individuals with moderate to severe OSA [10]. However, less is known about its efficacy in identifying OSA in children with DS. An underestimation of the prevalence of OSA was found in study comparing laboratory PSG (n = 8) to in home PSG (n = 36), a lower prevalence of OSA was found in the home PSG (56%) compared to the in laboratory method (88%) [11].
Since the prevalence of OSA may vary depending on the assessment method used, our present review aims to identify the prevalence of OSA in the DS population using the gold-standard method of laboratory  [29]; three studies were excluded due to their use of pulse oximetry, a less accurate indicator of OSA [9], [30], [31] and/or in-home sleep studies [11]; 24 studies were eliminated because only partial or incomplete information was provided [2], [32]- [40], [27], [41]- [53]; three were excluded due to imaging of the airway [54]- [56]; another three that used endoscopy [27]- [29]; two other studies were excluded due to their focus on adenotonsillectomy outcome which held a selection  [58];. and another study was eliminated as it contained data already included in a larger study [59].
Due to largely overlapping data, two more studies were eliminated [24], [60]. Finally, one study used primarily in home PSG, with a small subgroup using in laboratory PSG; however, separate statistics were not provided for the laboratory PSG subgroup so this study was eliminated [61]. A final set of 10 studies were included that examined non-referred (e.g., who were not referred for a sleep study due to concern about sleep problems, upper airway obstruction, or other potentially comorbid problems) community samples of people with DS, containing 443 individuals [4]- [6], [59], [62]- [67]. In addition, 13 studies of 1,026 individuals were included to examine the prevalence of OSA among referred samples (see Table 1 for a summary of included studies) [3], [11], [68]- [78].

Prevalence of OSA and Potential Moderators
Overall Prevalence of OSA among People with Down Syndrome. The pooled prevalence of OSA across the 10 studies using non-referred samples was 71 Table 3).
To address heterogeneity across studies, subgroup analyses were conducted. Given the high degree of similarity in prevalence rate across non- Prevalence of OSA as a Function of Severity Criterion. The Apnea Hypopnea Index (AHI) is a sleep measure commonly used to diagnose the severity of OSA; it is the sum of apneas (≥ 90% reduction of airflow for ≥ 10 seconds or equivalent to two breaths in children) and hypopneas (≥ 50% reduction in respiratory effort with ≥ 3 or 4% oxygen desaturation or followed by arousals) per hour of sleep [79]. Studies use variable AHI cutoff points (≥ 1, ≥ 1.5, or ≥ 2) to diagnose and categorize the severity of OSA [79]. We identified eight studies with 235 individuals using an AHI ≥ 1.0 cutoff for OSA among people with DS; these studies indicate an OSA prevalence of 78.7% (95% CI: 64.0 to 90.6) [11], [62], [65], [68], [71], [74]- [76].
Age Group and OSA Prevalence. To assess the effect of young age on the prevalence of OSA, the studies were divided into those of children below two years of age versus those with children and adolescents who were predominantly between age 2 and 21 years.  Note. Under sample, "non-referred" refers to study recruitment in which participants were not referred for a sleep study secondary to concern for sleep problems or associated risk factors. Obstructive Sleep Apnea Prevalence  Note. LCI = lower confidence interval; HCI = higher confidence interval.  [72], [74], [76]. In comparison, among the eight studies using a 4% cutoff the prevalence of OSA was 69.1% (54.5 to 82.1), suggesting that desaturation cutoff did not substantially affect the prevalence of OSA [4]- [6], [43], [63], [68], [73], [77].
Study Geographical Region and OSA Prevalence.
One study utilized an AHI of 5 and showed normalization of the AHI in 48% of individuals (12/25) [85]. However, it is important to note that these prior studies used different inclusion criteria (i.e., cutoffs and oxygen desaturations) and sometimes included additional surgeries besides the four that we focus on above.
Collectively, however, individuals with DS tend to exhibit a mild to moderate degree of improvement in OSA symptoms following surgery.

Discussion
This meta-analytic review indicates that approximately 70% of individuals with DS have OSA.  [6], [62], [65], [67], [70], [77]. As in community samples without DS, males tend to have a higher prevalence of OSA compared to females, especially in adults, possibly due to protective effects of female hormones [91].
Given the high prevalence of OSA among individuals with DS, it is imperative to note that OSA is related to cognitive problems (for example, lack of concentration), as well as strokes, myocardial infarction, hypertension and diabetes mellitus [92]. It is unknown, but possible, that OSA might contribute to the known early onset of dementia and increased death at a younger age in this population [93]. Thus, diagnosing OSA using PSG should be indicated in various stages of life in this population, followed by subsequent treatment if needed.
In analyzing the effect of adenotonsillectomy as well as lingual tonsillectomy, the biggest change in AHI was found in the lingual tonsillectomy group (a mean average decrease in AHI of 9.0), compared to 8.0 in the AT group. Tonsillectomy and adenoidectomy showed the smallest decreases in AHI (5.7 and 6.7 respectively).
The slightly greater improvement with adenoidectomy than tonsillectomy possibly highlights a greater role of a narrow nasal passage and the effects the adenoids exert than tonsils in this group (i.e., with the oropharynx being larger than the nasopharynx, the adenoids might cause more obstruction).  [94], [95]. Finally, it is well known that individuals with DS tend to die earlier, possibly in part due to untreated OSA. Thus, early detection and treatment is required to best manage OSA in this population.