Introduction Childhood obstructive sleep apnoea (OSA) is a highly prevalent disorder that may directly contribute to the development of obesity, hypertension and renal injury. Although those associations seem to be clearer in adults, studies in children have revealed conflicting results and updated synthesis of the evidence is lacking. The aim of this systematic review is to summarise the available evidence on the effect of OSA on obesity, systemic blood pressure and kidney function, to help to elucidate whether respiratory interventions to correct OSA would have the potential to improve those outcomes.
Methods and analysis A systematic literature review search was created by a medical librarian and peer-reviewed by a second librarian prior to running. Ovid Medline, Ovid Embase, CINAHL via EbscoHOST, Wiley Cochrane Library and ProQuest Dissertations and Theses Global were searched on 25 February 2020. Titles and abstracts will be screened by two independent reviewers for inclusion, followed by full-text screening of relevant articles. Studies in children will be included if they report data on OSA and weight, systemic blood pressure or kidney parameters. The extracted data will be combined for analysis and the information subcategorised in groups based on outcome. Risk of bias will be determined using tools specific to study methodology and certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach.
Ethics and dissemination This study will provide essential information for healthcare professionals to better understand the relationship between childhood OSA and changes in body mass index, systemic blood pressure and kidney function indicators. Our findings will be disseminated through conferences and publications. The results of this review may guide the initiation of new strategies and the development of future research studies. This research did not involve human subjects and therefore did not undergo research ethical review.
PROSPERO registration number CRD42020171186.
- paediatric thoracic medicine
- paediatric nephrology
- sleep medicine
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Strengths and limitations of this study
Methodological and information experts were engaged to enable high-quality assessment and transparency.
No language restrictions or time limits will be applied to the search strategy.
Risk of bias and certainty of the evidence will be rigorously determined.
Availability of primary studies may be limited, especially for the kidney function outcome.
There may be low certainty of the evidence from observational studies.
Childhood obstructive sleep apnoea (OSA) is characterised by recurrent events of partial or complete upper airway obstruction during sleep, resulting in disruption of normal ventilation and sleep patterns.1 It has become a highly prevalent disorder with rates up to 5.7%2 due in part to the dramatic increase in prevalence and severity of obesity in children and adolescents worldwide.3–7 In adults, it has been clearly demonstrated that OSA, the associated intermittent nocturnal hypoxemia and other sleep disturbances, has deleterious clinical consequences contributing to obesity, metabolic syndrome and cardiovascular and renal diseases8–12 with some of this evidence previously synthesised.13–16 In children, emerging data over the past few years also suggest these associations although available studies have revealed conflicting results17–31 and evidence synthesis is less available.
Childhood obesity is a widely recognised risk factor for the development of OSA32 33 and the presence of OSA has also been found to promote or aggravate obesity and associated morbidities in observational studies.2 34 35 Moreover, OSA and obesity may interact and potentiate each other amplifying their adverse consequences.18 36 37 Evidence showing the implications of treating obesity to ameliorate OSA has started to emerge.38 39 As well, the effect of treating OSA on obesity management has also been explored by more recent studies,30 40–43 justifying the need of a systematic review.
Cardiovascular morbidity of OSA in children include, among others, changes in systemic blood pressure and cardiac structure by echocardiography.44 45 Thus, several studies have demonstrated the association between OSA, high blood pressure and left ventricular hypertrophy.46–50 A recent meta-analysis synthesised the available evidence on the impact of OSA on echocardiogram parameters as a surrogate of cardiovascular disease.23 Updated high-quality systematic reviews summarising the evidence on the association between OSA and changes in blood pressure are however lacking.51–55
The association between OSA and adverse renal outcomes in children is less clear than in adults15 but there are growing concerns among paediatric specialists about early initiation of kidney damage in children with OSA. Children and adolescents with OSA who are found to have high blood pressure in paediatric respiratory and sleep clinics settings are frequently referred to paediatric nephrology specialists for evaluation and management. These patients may also have subclinical or clinical renal alterations such as proteinuria, hyperfiltration or decreased glomerular filtration rate (GFR) as OSA may contribute to renal vascular dysfunction, inflammation and dysregulation of the renin–angiotensin–aldosterone system.56–58 Likewise, OSA may contribute to renal dysfunction by promoting classical risk factors for kidney disease such as obesity and diabetes mellitus.56 59 Varlami et al did not find a significant difference in urine albumin-to-creatinine ratio between children with mild OSA, moderate to severe OSA and a control group. Conversely, there is evidence of a high prevalence of sleep-disordered breathing in children with chronic kidney disease.60 A systematic review summarising the emerging evidence on the impact of OSA on renal outcomes in children will be useful for clinicians working with this population.
The aim of this systematic review is to summarise the current evidence available on the effect of childhood OSA on obesity, systemic blood pressure and kidney function. This synthesis will help to elucidate whether respiratory interventions to correct OSA will have the potential to improve those outcomes.
Methods and analysis
The protocol for this systematic review was designed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines.61 The study protocol has been registered in PROSPERO. We have created an advisory team that includes an expert in systematic review methodology, an information specialist, two paediatric respirologists and sleep specialists and a paediatric nephrologist to advise on the search strategy, sources of information and methodology and discussion of the results. This approach will enable a rational high-quality assessment and transparency in the report of the available evidence on the role of OSA in children and adolescents on body mass index (BMI), blood pressure changes and kidney injury.
Terms referring to OSA, obesity, systemic hypertension and renal function were combined for a comprehensive search strategy that captures all publications available on the topic. A previously established paediatric filter in children62 was incorporated to the search (see online supplementary appendix for the full search strategy). Study design restrictions were applied to exclude letters to the editor, comments, reviews and case reports as well as studies in animals. No language restrictions or time limits were applied to the search strategy.
A comprehensive search strategy with described terms was built in Ovid Medline and translate into Ovid Embase, CINAHL via EbscoHOST and Wiley Cochrane Library (including the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database and the National Health Service Economic Evaluation Database). The reference lists of the included studies will be screened to identify any relevant studies that were not detected by the search. Search of grey literature will include ProQuest Dissertations and Theses Global and published abstracts from relevant international conference proceedings such as the International Pediatric Nephrology Association conference and the Scientific Meeting of the European Society for Paediatric Nephrology.
We will include studies of children and adolescents (0–18 years of age) with OSA syndrome, defined by the American Academy of Sleep Medicine (snoring and at least one other symptom of OSA including night time symptoms, daytime symptoms and physician examination) and/or the presence of an apnoea-hypopnoea index greater than 1.5 events/hours in children over 2 years of age and greater than three events/hour in children under the age of 2 years by night polysomnography.17 63 Studies that contain data from both adults and children will be included if children data are reported separately.
Studies will be included if they report data on weight, BMI, systemic blood pressure or parameters of kidney function. We will use percentiles and/or Z scores to compare data regarding anthropometric measurements and percentiles for blood pressure data. Definitions of overweight/obesity will include BMI above 85/95th percentile based on Centers for Disease Control and Prevention (CDC) growth charts64 or +1SD/2SD based on WHO standards (www.who.int/growthref). CDC standards will be used for potential meta-analysis. Elevated blood pressure/hypertension will be defined based on current guidelines: elevated blood pressure as blood pressure above the 90th percentile for age or greater than 120/80 mm Hg and hypertension as blood pressure above the 95th percentile or greater than 130/80 mm Hg.65 We will include studies that report renal outcomes according to the status of albuminuria/proteinuria or the estimated GFR. Chronic kidney disease will be defined as a GFR below 90 mL/min/1.73 m2 and/or albuminuria above 30 mg/24 hours (or urine albumin to creatinine ratio greater than 30 mg/g or 3 mg/μmol) for more than 3 months according to internationally accepted criteria, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines.66 The estimated GFR may be calculated by any of the accepted formulas (Schwartz or Cystatin C). Original studies will be included as far as they provide a clear description of their definitions for overweight/obesity, elevated blood pressure/hypertension or renal abnormalities.
Observational and intervention studies will be considered for inclusion, including controlled before–after studies, cross-sectional studies, longitudinal observational studies, case–control studies, retrospective cohorts research and case series with seven or more cases. Case reports and case series with less than seven subjects, comments, editorials, letters and reviews will be excluded.
Records identified by the search strategy will be imported into an EndNote (V.X9, Clarivate Analytics) library for management and screening.
Titles and abstracts of the citations identified by the search will be screened by two independent reviewers for eligibility based on our inclusion criteria. For all potentially relevant articles, full text will be retrieved and evaluated for eligibility independently by the two reviewers. Any discrepancies will be resolved through discussion between the reviewers and, if not consensus reached, a third member of the research team will be invited into the discussion. Reasons for exclusion will be recorded for articles that underwent full-text screening.
Data extraction process
Using a predesigned standardised form, one reviewer will extract the data and enter it into Microsoft Excel database (Microsoft, Redmond, Washington, USA). Verification of 20% of the data extraction will be done by a second reviewer. If agreement does not meet 80%, additional verification of the data will occur, reviewing all the important data columns. One article per data set will be retained to avoid double counting of the same data published in more than one publication.
The extracted data will be collected and combined for a narrative and numerical analysis of included studies. We will present a narrative description of the author, year and country of the publication, study design, participant characteristics, sample size, intervention type, control group description, outcome measures and timeframe for follow-up duration. The information will be subcategorised to include different groups based on outcome (changes in BMI/weight gain, blood pressure, kidney function parameters). Given the potential collinearity between these conditions, we will perform a stratified analysis based on the collinearity assessments of the original studies. Meta-analysis will be attempted for those studies reporting same outcomes with heterogeneity measured using the I2 statistics.
Quality assessment (risk of bias and certainty of the evidence)
Risk of bias and methodological quality will be determined for each study independently by two reviewers using tools specific to the study methodology. Quantitative studies included in our review will be assessed using the Quality Assessment Tool for Quantitative Studies67 and qualitative studies using the Critical Appraisal Skills Programme (CASP) Qualitative Research Checklist.68 The Cochrane Risk of Bias tool69 will be used to evaluate randomised controlled trials if any. Discrepancies in decisions will be resolved through discussion.
The reviewers will also use the Grading of Recommendations, Assessment, Development and Evaluations approach70 to assess the certainty of the evidence at the outcome level: very low, low, moderate and high.
Patient and public involvement
No patient involved.
Ethics and dissemination
This study will provide essential information for healthcare professionals to better understand the relationship between childhood OSA and changes in BMI, systemic blood pressure and kidney function indicators. Our findings will be disseminated through conferences and publications. The results of this review may guide the initiation of new strategies and may also provide information for the development of future research studies. This research did not involve human subjects and therefore did not undergo research ethical review.
There is a clinical need to systematically summarise the emerging literature around the association between childhood OSA and deleterious outcomes such as obesity, hypertension and kidney injury. This will facilitate the work of researchers and clinicians looking after this increasing group of children and adolescents and will also help to elucidate whether potential respiratory interventions to correct OSA are helpful to ameliorate those outcomes.
Contributors SR-L, CG and MLC-C conceived the idea of the study and designed the methodology. SR-L, SP and MLC-C wrote the manuscript. MS and DK-L developed the search strategy and performed a preliminary literature review. SR-L, SP, MS, DK-L, CG and MLC-C reviewed the protocol. All authors read and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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