Longitudinal Analysis of Sleep-disordered Breathing and Cognitive Outcomes in Children Living with Sickle Cell Anaemia

Longitudinal Analysis of Sleep-disordered Breathing and Cognitive Outcomes in Children Living with Sickle Cell Anaemia | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Clinical Otolaryngology This is a preprint and has not been peer reviewed. Data may be preliminary. 28 February 2025 V1 Latest version Share on Longitudinal Analysis of Sleep-disordered Breathing and Cognitive Outcomes in Children Living with Sickle Cell Anaemia Authors : Shifa Hamdule , Melanie Koelbel , Johanna C. Gavlak , Fenella Jane Kirkham 0000-0002-2443-7958 [email protected] , and Anna M. Hood 0000-0002-7213-1179 Authors Info & Affiliations https://doi.org/10.22541/au.174071721.18195185/v1 Published Clinical Otolaryngology Version of record Peer review timeline 318 views 144 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Objectives: Sleep-disordered breathing (SDB) and cognitive challenges are commonly observed in children living with sickle cell anaemia (SCA). This study investigated the longitudinal change in polysomnographic outcomes and the association with cognitive functions in children living with SCA. Method: Data from the Sleep Asthma Cohort (SAC 1, 2 and 3) included participants living with SCA (aged 4-18 years) who were initially recruited between 2006-2009, with follow-up studies conducted through until 2019. Polysomnographic indices (PSG indices), i.e., obstructive apnoea hypopnoea index (OAHI), central apnoea index (CAI), mean overnight oxygen saturation and total sleep time were assessed over two visits. Additional analyses assessed the impact of PSG indices on cognitive outcomes collected at Visit 3. Results: Ninety-two participants (91 HbSS, 1HbSβ) completed a PSG at Visit 1 and 56 participants returned for Visit 2, 40 of whom returned for the Visit 3 cognitive assessment; mean ages were 9.9 (3.8), 14.7 (3.69), and 17.7 (4.64) years, respectively. Total sleep time significantly decreased between the two visits, while overall PSG indices remained stable. Mean overnight oxygen saturation at Visit 1 significantly predicted working memory at Visit 3. In addition, CAI at Visit 2 was associated with lower scores on the verbal comprehension index and self or caregiver-reported measures of executive function. Conclusions: PSG indices did not change significantly over time; however, routine PSG screening is recommended, given the complexity of sickle pathology. Overnight oxygen saturation levels and central apnoea influence cognitive outcomes for children living with SCA. not-yet-known not-yet-known not-yet-known unknown Abstract: Objectives: Sleep-disordered breathing (SDB) and cognitive challenges are commonly observed in children living with sickle cell anaemia (SCA). This study investigated the longitudinal change in polysomnographic outcomes and the association with cognitive functions in children living with SCA. Method: Data from the Sleep Asthma Cohort (SAC 1, 2 and 3) included participants living with SCA (aged 4-18 years) who were initially recruited between 2006-2009, with follow-up studies conducted through until 2019. Polysomnographic indices (PSG indices), i.e., obstructive apnoea hypopnoea index (OAHI), central apnoea index (CAI), mean overnight oxygen saturation and total sleep time were assessed over two visits. Additional analyses assessed the impact of PSG indices on cognitive outcomes collected at Visit 3. Results: Ninety-two participants (91 HbSS, 1HbSβ) completed a PSG at Visit 1 and 56 participants returned for Visit 2, 40 of whom returned for the Visit 3 cognitive assessment; mean ages were 9.9 (3.8), 14.7 (3.69), and 17.7 (4.64) years, respectively. Total sleep time significantly decreased between the two visits, while overall PSG indices remained stable. Mean overnight oxygen saturation at Visit 1 significantly predicted working memory at Visit 3. In addition, CAI at Visit 2 was associated with lower scores on the verbal comprehension index and self or caregiver-reported measures of executive function. Conclusions: PSG indices did not change significantly over time; however, routine PSG screening is recommended, given the complexity of sickle pathology. Overnight oxygen saturation levels and central apnoea influence cognitive outcomes for children living with SCA. Keywords: Sickle cell; Obstructive sleep apnoea; Sleep-disordered breathing; Polysomnography; Cognition; Oxygen saturation. Key points: The study investigated longitudinal PSG data and the impact on cognition in children living with SCA. Data was collected between 2004 and 2019; the initial recruitment age was between 4 and 18 years. Total sleep time was significantly lower at Visit 2. However, other PSG indices remained stable over time. Mean overnight oxygen saturation levels and central apnoea index predicted cognition, including executive function. Monitoring overnight oxygen saturation levels and routine PSG screening is recommended to enhance cognitive care for children living with SCA. INTRODUCTION Sickle cell anaemia (SCA) is an inherited condition affecting the beta-globin chain of haemoglobin. Haemoglobin (HbS) polymerises in hypoxic conditions, leading to rigid, sickle-shaped red blood cells with reduced oxygen-carrying capacity. Reduced oxygen delivery leads to multiorgan complications, including neurological sequelae such as stroke, silent cerebral infarction (SCI) (1) and cognitive dysfunction (2). Cognitive deficits are often observed, including slowed processing speed (3), attention deficits, and executive dysfunction (2) associated with poor academic performance, employability, and lower quality of life (4). Although stroke and SCI increase the likelihood of cognitive deficits, individuals living with SCA without SCI or stroke may still experience cognitive challenges related to reduced oxygen delivery (5). Sleep-disordered breathing (SDB) is a common complication for children living with SCA. SDB disrupts breathing at night, leading to a lower nocturnal oxygen supply, increased sympathetic activity and intermittent hypoxia, which can be observed as obstructive sleep apnoea (OSA) through polysomnography (PSG) (6). Up to 40% of children living with SCA experience OSA, with 43% of those children showing signs of severe OSA (OSA index >5) (7). In the general population, compromised cerebral oxygen delivery may contribute to cognitive and executive dysfunction, such as reduced attention, low processing speed, and overall cognitive decline (8). However, very few studies have investigated the association between SDB and cognition in individuals living with SCA (9-12). The studies conducted found that the apnoea-hypopnoea index (AHI) was correlated with processing speed (11), while mean overnight oxygen saturation predicted executive function (8), working memory and verbal comprehension in youth living with SCA (10). However, these studies did not examine longitudinally collected PSG data in association with cognitive outcomes, limiting the understanding of the long-term consequences of SDB on cognitive outcomes in this population. Objectives Given the paucity of previous research, we investigated the association between PSG outcomes and cognition in children living with SCA. We hypothesised that a) PSG outcomes would worsen over time and b) PSG outcomes would predict lower cognitive performance. METHODS Participants This study analyses data from the Sleep Asthma Cohort (SAC) (9), which investigated asthma, sleep abnormalities and disease-related morbidity in young people living with SCA in one UK and 2 US cities (i.e., London, UK, St Louis, Missouri and Cleveland, Ohio). Participants were homozygous for sickle cell haemoglobin (HbSS) or compound heterozygotes for sickle b thalassemia zero (HbSβ0) aged 4 to 18 years and were enrolled without regard to past morbidity from or symptoms of sleep-disordered breathing history, presence of adenotonsillar hypertrophy, and a history of adenoidectomy or tonsillectomy. Exclusion criteria included receiving long-term blood transfusions or continuous positive airway pressure therapy, participating in another clinical trial, or having a history of smoking or chronic lung disease other than asthma or HIV positivity. Participants had two study visits with PSG: SAC-1; 2005-2009 and SAC-2 2011-2013 Cognitive data were collected between 2016-19 from the London, UK site; these data are presented here. Ethical Considerations Ethical approval was provided for each site: London: Brent (05/Q0408/42) and East Midlands-Leicester (11/EM/0084). Written informed consent was obtained from participants aged 16 to 18 years and their parents/guardians. Children under 16 years provided assent and their parents/guardians consented. Haematological variables Medical history was obtained from electronic medical records, including the haemoglobin level closest to each study visit from the six months before. Socioeconomic variables The Index of Multiple Deprivation (IMD), open-source data, was used to estimate the participants’ socioeconomic status (SES). The IMD uses the participants’ home postcode to determine SES by defining deprivation as a composite of seven domains. Polysomnography PSG was conducted in the laboratory using the Embla N-7000. Data collected included total sleep time, obstructive apnoea hypopnoea index (OAHI- count of all obstructive apnoeas and hypopnoeas divided by total sleep time), central apnoea index (CAI – count of central apnoeas) and mean overnight oxygen saturation. Data was scored by trained and blinded sleep technicians using the Academy of Sleep Medicine’s scoring manual (9, 12). PSG data was collected from habitual bedtime and ended when the child woke up spontaneously or, at the latest, by 7 am (9). Cognitive variables Age-appropriate Wechsler Intelligence Scale for Children (WISC-4) and Wechsler Adult Intelligence Scales (WAIS-4) (for participants full-scale intelligence quotient (FSIQ), working memory index (WMI), perceptual reasoning index (PRI), processing speed index (PSI) and verbal comprehension index (VCI). Given the robust correlations between these editions of the Wechsler scales, we included both in our analyses (13). The Delis Kaplan Executive Function System (D-KEFS) Tower subtest is a spatial planning measure of executive function. The Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire is a subjective measure of executive function completed by participants or caregivers. All tests were double-scored by trained assessors. In case of disagreement or ambiguity, an independent assessor’s opinion was sought. Statistical Analysis All statistical analyses were conducted using SPSS v.28. The normality of the variables was visually inspected using Q-Q plots and histograms, as well as the skewness of the variables. Non-normally distributed variables (i.e., OAHI, CAI and oxygen saturation) were log-transformed for analysis. To investigate PSG changes over time, we used a paired samples t-test. Models compared total sleep time, OAHI, CAI, and mean overnight oxygen saturation between the two study visits. We also examined categorical changes using clinical cut-offs for each PSG parameter to derive clinically meaningful differences and compared whether participants changed clinical categories over time. For this analysis, we used age-appropriate mean values derived from typically developing children using the means reported in Scholle et al. (14) Change over time was also categorised as “If PSG Visit 2 PSG Visit 1 (Worsened),” and reported the proportions of participants in each group. Further, we also compared the clinical severity and probability of improvement for the participants by using an ANOVA model where the numerical difference between indices (PSG Visit 2- PSG Visit1) was the dependent variable, and the clinical categories at Visit 1 were the independent variables. Correlational analysis and visual inspection of scatterplots were employed to test associations between PSG and cognitive outcomes, followed by multiple linear regression models to test if PSG indices predicted cognitive outcomes, controlling for age, sex, and body mass index (BMI). RESULTS Demographics: Table 1 describes participant characteristics. Ninety-two participants (91 HbSS, 1HbSβ genotype), 49 (51%) females, completed a PSG at Visit 1. Fifty-six participants returned for Visit 2, and 40 of the 56 participants returned for the Visit 3 cognitive assessment. The mean ages for the patients at Visits 1, 2, and 3 were 9.9 (3.8) years, 14.7 (3.69) years, and 17.7 (4.64) years, respectively. PSG outcomes: PSG outcomes are summarised in Table 1; only total sleep time significantly decreased from Visit 1 to Visit 2 (mean decrease ~ 50 minutes). None of the other PSG outcomes significantly differed between visits. However, all mean indices for PSG outcomes at both visits were higher than the age-matched means for typically developing children. The mean of the mean overnight oxygen saturation remained within the normal range (14), although around a third had mild and around 10% had moderate hypoxaemia (Table 2). Table 2 summarises the number of participants in each clinical cutoff category. We cross-tabulated the age group recommended total sleep times at Visits 1 and 2 with age, summarised in Table 2 (15). We found that no children between 4 and 6 years slept over the recommended 10 hours for their age group, and about half slept 7 to 10 hours per night. At Visit 2, most children were sleeping below 7 hours. We tested if individuals changed categories across visits. We found that about 35% (20/56) improved and had OAHI within the normal to acceptable range, 32% (18/56) remained the same, and another 32% (18/56) worsened over time. A smaller change was seen in CAI, with over 90% (50/56) remaining in the no-change group. Similarly, 75% (42/56) remained in the no-change group for mean overnight oxygen saturation (Table 2). To investigate improvement based on clinical severity, we used a one-way ANOVA model to compare numerical changes in PSG indices across visits. Most improvements in PSG indices from Visit 1 to 2 were seen in participants in the severe categories for OAHI and CAI (Table 3). Cognitive outcomes Mean cognitive scores are summarised in Table 1. Cognitive scores were lower than general population norms. Correlation analyses demonstrated significant associations for (1) total sleep time at Visit 1 and BRIEF Metacognition Index (MI), (2) OAHI at Visit 1 and VCI, and (3) mean oxygen saturation at Visit 1 and PSI and WMI. At Visit 2, total sleep time was associated with FSIQ, PRI, and WMI; CAI was associated with VCI and all three BRIEF indices (Table 4). Associations between PSG and cognitive outcomes Multiple linear regression analyses were conducted for the significantly correlated variables only. Separate models were generated for each cognitive outcome and each PSG index. All models were corrected for age, sex, BMI, and SES. Mean overnight oxygen saturation at Visit 1 significantly predicted WMI and independently predicted FSIQ (Supplementary figure 1). Similarly, CAI at Visit 2 independently predicted VCI, the BRIEF Behaviour Regulation Index (BRIEF BRI), and the BRIEF Global Executive Composite (BRIEF GEC) (Tables 5 and 6, Supplementary figure 2). DISCUSSION Comparison to other studies Our study examined the longitudinal change in respiratory indices measured by PSG and their associations with cognitive outcomes in children living with SCA. Our analyses revealed several key findings. Total sleep time showed a significant decrease over time, which may indicate that children living with SCA sleep less than recommended, in addition to the decline in sleep time with age seen in the general population. Despite reduced sleep time, the overall PSG indices (i.e., OAHI, CAI, and mean overnight oxygen saturation) remained stable across two study visits. The classification of SDB also did not change significantly over time. Interestingly, participants categorised as severe based on their PSG index at Visit 1 tended to have improved clinical severity at Visit 2. These findings are in line with SCA and general population literature (14) (16). As reduction in PSG indices with age is common in the general population, including PSG assessment in clinical practice for those living with SCA may be beneficial, especially within the context of sickle pathology where other comorbidities, such as acute chest syndrome, change in body weight, and nasal congestion may impact the severity of SDB (6, 17). Previous studies examining risk factors for SDB in young children living with SCA report associations with habitual snoring, lower oxygen saturation (12), and pain crises (18). Therefore, slight elevations in PSG indices could potentially trigger worse clinical outcomes, which might be mitigated by intervention following routine screening for SDB. Consistent with previous literature (9, 19), our findings suggest that reduced mean overnight oxygen saturation predicts cognition (i.e., working memory). Working memory involves temporarily storing and manipulating information. It is highly dependent on the structural connectivity within the white matter regions in the brain, which are known to be vulnerable to hypoxic insults not only due to sickle pathology but can also be further compromised due to nocturnal hypoxaemia (3, 20). Sustained and intermittent hypoxaemia, measured by reduced oxygen saturation levels, may also contribute to other sequelae, such as SCI commonly seen in the deep white matter of the frontal and parietal lobe (21) in children living with SCA, which together can exacerbate cognitive challenges. Additionally, we found that CAI, a measure of apnoea where the brain fails to send appropriate signals to the respiratory muscles, showed the smallest change at Visit 2 and was associated with verbal comprehension and executive function. Brain regions implicated in central breathing control, including a network of the brain stem, cerebellar lobes and the middle cingulate gyrus, are also regions implicated in behavioural control (22). Potential damage to these regions could be due to sickle pathology that may contribute to the incidence of central apnoea and poor behavioural regulation (22, 23). However, this association remains to be established and needs further investigation. Our study focused on the respiratory PSG indices. However, there is further complexity to sleep (e.g., sleep quality and sleep architecture- the basic organisation of the structure of sleep), which also likely plays a crucial role in cognitive function (24). Disruptions in sleep architecture have been associated with impaired memory consolidation and executive function in the general population (25). People living with SCA are also vulnerable to other clinical complications, such as periodic limb movement disorders, enuresis, and pain, which significantly impact sleep quality and may exacerbate cognitive issues associated with SDB (16). An integrated assessment approach considering sleep disruptions and sleep quality alongside SDB could provide a more comprehensive understanding of the impact of sleep on cognitive outcomes. An integrated framework for interventions for sleep in SDB has the potential to identify sleep challenges and improve cognitive health. Clinical implications Our findings suggest regular monitoring of oxygen saturation levels and early management of SDB, such as the use of oral devices or nasal continuous positive airway pressure, may both have neuroprotective benefits for people living with SCA. SDB interventions could focus on prioritising oxygen delivery during sleep. Additionally, tailored interventions that provide a more in-depth view of sleep architecture and SDB could influence cognitive outcomes and improve the quality of life of people living with SCA. Education of families so that they know the importance of adequate sleep will also be important. Limitations and future directions We did not include a control group of typically developing children or children living with SCA without SDB. The study does not account for the management or treatment of SDB, which may influence cognitive outcomes. Some of our multiple regression analyses were likely underpowered to detect an effect if present. Future research could use neuroimaging techniques to explore the underlying mechanism between oxygen saturation and cognitive outcomes in a larger sample. There is also a scope to investigate associations between sleep quality indices and other non-clinical factors (e.g., housing, employment, and air quality) in conjunction with SDB and its effect on cognitive outcomes. CONCLUSION Our longitudinal study highlighted the predictive ability of oxygen saturation and the stability of PSG indices over time whilst providing insights into the respiratory factors affecting cognition. Building on our findings, future research could investigate PSG indices alongside sleep architecture and sleep quality, which may provide a bigger picture of cognitive health in individuals with SCA. List of tables Participant Characteristics for General Demographics and Polysomnography Indices Categorisation of PSG variables, categorisation of total sleep time based on age, and change in PSG indices over time Clinical severity for PSG variables Correlations between PSG indices and cognitive outcomes Multiple linear regressions: overnight oxygen saturation predicting working memory index and Full-scale IQ Multiple linear regressions: CAI predicting verbal comprehension index, BRIEF Behavioural regulation index, and BRIEF Global executive composite List of Supplementary Figures a: Mean overnight oxygen saturation x Working memory index, b: Mean overnight oxygen saturation x Full Scale IQ a: Central Apnoea Index x Verbal comprehension index, b: Central Apnoea Index x BRIEF Behavioural regulation index, c: Central Apnoea Index x BRIEF Global executive composite References: 1. Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review. Jama. 2022;328(1):57-68.2. 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Supplementary Material File (sdb, cognition tables fjk final- tables 6 edited sh (1).docx) Download 57.75 KB Information & Authors Information Version history V1 Version 1 28 February 2025 Peer review timeline Published Clinical Otolaryngology Version of Record 22 Feb 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Clinical Otolaryngology Authors Affiliations Shifa Hamdule University College London Great Ormond Street Institute of Child Health View all articles by this author Melanie Koelbel University College London Great Ormond Street Institute of Child Health View all articles by this author Johanna C. Gavlak University College London Great Ormond Street Institute of Child Health View all articles by this author Fenella Jane Kirkham 0000-0002-2443-7958 [email protected] University College London Great Ormond Street Institute of Child Health View all articles by this author Anna M. Hood 0000-0002-7213-1179 University College London Great Ormond Street Institute of Child Health View all articles by this author Metrics & Citations Metrics Article Usage 318 views 144 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shifa Hamdule, Melanie Koelbel, Johanna C. Gavlak, et al. Longitudinal Analysis of Sleep-disordered Breathing and Cognitive Outcomes in Children Living with Sickle Cell Anaemia. Authorea . 28 February 2025. DOI: https://doi.org/10.22541/au.174071721.18195185/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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