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Abstract
Objective To determine the prevalence of sleep-disordered breathing (SDB) symptoms and respiratory events during sleep in infants with cleft lip and/or palate (CL/P).
Design Prospective observational study.
Setting Cleft palate clinic, tertiary care paediatric hospital, before palate surgery.
Patients Consecutive newborn infants with CL/P.
Main outcome measures Demographics, clinical history, sleep symptoms, facial measurement and polysomnography (PSG; sleep study) data.
Results Fifty infants completed PSG at 2.7±2.3 months; 56% were male, and 30% had a clinical diagnosis of Pierre Robin sequence (PRS) or a syndrome. The majority of infants (75%) were reported to snore frequently or constantly, while 74% were reported to have heavy or loud breathing during sleep. The frequency of parent-reported difficulty with breathing during sleep was 10% for infants with isolated CL/P, 33% for those with syndrome, and 43% for PRS (χ2 16.1, p<0.05). All infants had an Obstructive–Mixed Apnoea–Hypopnoea Index (OMAHI) >1 event/h, and 75% had an OMAHI >3 events/h. Infants with PRS had higher OMAHI (34.3±5.1) than infants with isolated CL/P (7.6±1.2) or infants with syndromes (15.6±5.7, F stat, p<0.001). Multivariate analysis showed that PRS was associated with higher OMAHI (B 0.53±0.22, p=0.022), but the majority of the variance for SDB was unexplained (constant B 1.31±0.55, p=0.024).
Conclusions The results highlight that infants across the spectrum of CL/P have a high risk of SDB symptoms and obstructive respiratory events before palate surgery. Clinicians should enquire about symptoms of SDB and consider investigation with polysomnography in all infants with CL/P.
- Syndrome
- Sleep
- Respiratory
- Congenital Abnormalities
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What is known about this topic
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Infants with Pierre Robin sequence have a high risk of sleep-disordered breathing (SDB).
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Infants with all forms of cleft lip and/or palate have smaller upper airway measurements.
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The risk of SDB across the spectrum of cleft lip and/or palate is unknown.
What this study adds
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▸ Infants across the spectrum of cleft lip and/or palate have a high risk of symptoms of SDB before palate surgery.
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▸ Elevated obstructive respiratory event rates are not limited to infants with Pierre Robin sequence.
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▸ Symptom reports do not predict the variance in respiratory event rates in infants with cleft lip and/or palate.
Introduction
Infants with cleft palate in the context of Pierre Robin sequence (PRS) are known to have anatomical features that predispose to airway obstruction in early infancy.1–4 Airway obstruction can range from life-threatening events that necessitate intubation or tracheostomy to the occurrence of intermittent airway obstruction during sleep. Although the palatal clefts of PRS have different anatomical features from other forms of cleft lip and/or palate (CL/P) reflecting glossoptosis, children with CL/P also have smaller airway calibre and an increased risk of sleep-disordered breathing (SDB) compared with children without clefts.5–7 However, little information is available regarding the risk of SDB in infants before surgical intervention across the spectrum of CL/P. One study, using a mouse model of CL/P, reported cyanosis in 40% of newborns, and the authors concluded that the cyanosis was related to airway obstruction.8 In a retrospective review of children with clefts who had undergone polysomnography (PSG), 24% had undergone PSG under 9 months of age.9 Young age and study timing before palate repair were independent risk factors for more severe SDB.
Respiratory events associated with SDB in children result in comorbidities secondary to their effects on sleep and cardiovascular function. Sleep disruption or fragmentation is thought to be responsible, at least in part, for poor neurocognitive outcomes in children with SDB,10 ,11 while obstructive respiratory events are associated with both acute and chronic changes in blood pressure and heart rate in children.12–15 Experimentally induced sleep deprivation in infants is associated with an increase in basal heart rate and a shift on spectral analysis of heart rate consistent with increased sympathetic tone.16 Infants born with CL/P have higher rates of cognitive difficulties17 ,18 as well as an increased risk of mortality,19 but it is unknown whether SDB in early life contributes to these important health outcomes.
The aim of this study was to determine the prevalence of SDB in a population of infants with CL/P before palate surgery and to examine identifiable clinical characteristics as predictors of SDB. Our hypothesis was that SDB is common among infants with all forms of CL/P, but that severity of SDB could be predicted by clinical characteristics. Results from this study have been published in abstract form.20–22
Methods
The families of newborn infants referred to the cleft team were approached for participation in a prospective study of sleep and breathing in infants with CL/P. After their first contact with the cleft team, families were approached for participation, and the infant was scheduled for PSG. Infants were excluded if a cleft was not confirmed, if they were medically unstable, or if they required medical interventions that precluded the performance of a diagnostic PSG before palate surgery. The timing of palate surgery was determined by each infant's managing plastic surgeon based on individual characteristics of the infants, with the majority of infants undergoing palate surgery between 6 and 9 months of age. Infants under the age of 3 months with usual daytime sleep periods of >4 h were offered daytime studies. Infants over 3 months, those with short daytime sleep, or where the parent/guardian preferred the overnight schedule underwent overnight studies. The study protocol was approved by the institutions’ research ethics committees.
After providing informed consent to participate in the study, the parent/guardian completed a brief medical questionnaire; additional information was obtained from the medical record when necessary. Cleft classification and syndrome status were documented by members of the cleft team, with referral of the infant to medical genetics where appropriate. Growth parameters were measured and converted to z-scores based on the formula available from the Centre for Disease control (http://www.cdc.gov/growthcharts/). A sleep and breathing research questionnaire (composite of two previously published scales for obstructive sleep apnoea (OSA) questionnaires)23 ,24 was used to systematically assess symptoms of SDB. Direct facial measures (figure 1) were completed at the time of PSG.
Facial measurements included the following. (1) L-OBIN/R-OBIN: distance from otobasion inferius (OBI) to soft tissue nasion (N), left and right sides. (2) L-OBIGn/R-OBIGn: distance from OBI to soft tissue gnathion (Gn), left and right sides. (3) TFH (total facial height): linear distance from N to menton (Me). (4) LFH (lower facial height): linear distance from anterior nasal spine (ANS) to Me. (5) Mandibular length: L-OBIGn+R-OBIGn. (6) Jaw index: mean L-OBIN/L-OBIGn+R-OBIN/R-OBIGN. (7) Facial height ratio: TFH/LFH.
PSG was completed using a standard infant protocol. This included determination of sleep state using an EEG (C4-M1, C3-M2, O1-M2, O2-M1), electro-oculogram (ROC/M1, LOC/M2) and submental electromyogram. For infants with positional plagiocephaly, F4-M1 and F3-M2 were added at set-up to ensure four satisfactory EEG recording channels. Channels to evaluate respiratory status included pulse oximetry, nasal/oral airflow by thermistor, nasal pressure, chest and abdominal wall movement using respiratory inductance plethysmography, and diaphragm and abdominal muscle activity by trans-diaphragmatic electromyography. Carbon dioxide was monitored using transcutaneous CO2 (TcCO2). Cardiac monitoring included the pulse signal from the oximeter and ECG.
PSG data were analysed by a single experienced scorer using the criteria of the American Academy of Sleep Medicine (AASM).25 Sleep staging for infants <6 months of age was completed using the criteria outlined by Anders et al,26 with AASM criteria applied for those ≥6 months. Obstructive apnoea was defined as the cessation of airflow (<10% of baseline level) for a minimum duration of two missed breaths with evidence of ongoing respiratory efforts. Central apnoea was defined as the cessation of airflow (<10% of baseline level) for a minimum of two missed breaths if followed by an arousal, awakening or ≥3% oxygen desaturation, or for ≥20 s in the absence of any associated events. Mixed apnoeas included central and obstructive components in the same event. Hypopnoeas were defined on the basis of a decrease in airflow of 10–50% of baseline that was associated with an arousal, awakening or ≥3% oxygen desaturation. The Apnoea–Hypopnoea Index (AHI) was calculated on the basis of the number of apnoeas and hypopnoeas during sleep divided by the total sleep time (TST). The Obstructive–Mixed AHI (OMAHI) excluded central respiratory events. The Oxygen Desaturation Index (ODI) was calculated on the basis of the number of oxygen desaturation events ≥3% during sleep divided by the TST. AHI and ODI are considered markers of SDB severity. An OMAHI of 3 events/h was considered the upper limit of normal on the basis of previous studies of respiratory events in normal infants.27 ,28 This cut-off point is probably conservative and hence may falsely classify infants with a mildly elevated OMAHI as normal.
Data were entered into a database (Microsoft Office Access 2003). Statistical analysis was performed using SPSS V.13.0.1. A p value of ≤ 0.05 was considered to indicate a significant result. Descriptive analyses were used for demographic information and sleep parameters, as well as arousal and respiratory events. Logarithmic transformation was applied to PSG variables without normal distribution, including AHI, OMAHI and ODI. Categorical data were compared using χ2 analysis, with Student's t test and analysis of variance used for continuous variables. A modified Bonferroni correction was made for multiple comparisons. Linear regression was used for multivariate analysis to examine predictors of SDB severity.
Results
A total of 52 families consented to participate in the study. Two infants were excluded from analysis, the first because PSG was not undertaken until after 12 months of age and the second because raw PSG data were not available for analysis as the study was performed in another laboratory. The mean birth weight for the final group of 50 infants was 3.3±0.7 kg at 38.5±2.3 weeks’ gestational age. Forty per cent of the infants were referred for respiratory or sleep medicine review before study enrolment. Additional description of the cohort is included in table 1.
Demographic features of the cohort
Symptoms of SDB were common in infants with cleft lip and/or palate (table 2). The majority of infants were reported by parents to frequently or constantly snore (75%), and 74% had heavy or loud breathing during sleep. Struggling to breathe during sleep was the only symptom that differed by syndrome status. Family history of sleep problems (8%), breathing problems (12%) and SDB (2%) were uncommon. Growth parameters at the time of PSG included weight of −0.61±1.5 z-score, length of −0.74±1.9 z-score, and head circumference of −0.65±1.8 z-score.
Clinical symptoms of sleep-disordered breathing as reported by parents on standardised questionnaires in infants with cleft lip and/or palate by syndrome status
Infants underwent PSG at 2.7±2.3 months (range 0.1–8.9 months chronological age, all >37 weeks’ gestational age). Daytime studies were completed for 54% of infants. Compared with infants who had overnight PSG, infants who underwent daytime studies were younger (1.5±0.7 vs 4.0±2.8 months, p<0.001). In addition, they had shorter total sleep time (3.7±0.9 vs 7.2±1.5 h, p<0.001) and poorer sleep efficiency (67.5±10.4% vs 78.8±10.5%, p<0.001); these differences were expected given the parameters for daytime testing. Respiratory event rates, however, did not differ between the two groups (eg, AHI: 23.7±19.7 vs 21.9±17.0 events/h, p=ns; OMAHI: 14.7±14.8 vs 10.9±12.5 events/h, p=ns; ODI: 24.2±21.8 vs 24.5±18.8 events/h, p=ns); therefore all infants were combined for further analyses.
Sleep was recorded for a mean of 5.3±2.1 h (range 2.28–9.40 h) with a mean sleep efficiency of 74±11%. Infants had a mean of 16±7 stage changes, 6±3 awakenings and 4±3 REM periods per hour of sleep. Sleep state distribution was 40% active sleep/rapid eye movement (REM), 40% quiet sleep/slow wave sleep, and 20% indeterminate sleep/stage 1–2. The mean Arousal Index was 17.3±6.2 events/h.
Infants showed a predominance of obstructive events; all infants had an OMAHI >1 event/h, and 75% had an OMAHI >3 events/h. OAMHI was >3 events/h in 69% of infants with isolated CL/P, 86% of infants with syndromes and 100% of infants with PRS (χ2=3.9, p=ns). Two (4%) infants had a baseline oxygen saturation during sleep that was <92%. Eighty per cent of infants (40 infants) had at least one episode of periodic breathing during sleep with a mean duration of 1.8±2.5% of TST. Respiratory event rates differed by syndrome status (table 3). Post hoc comparisons with Bonferroni correction showed infants with PRS had higher AHI, OMAHI and ODI compared with infants with an isolated cleft and syndromes, but markers of oxygenation and carbon dioxide did not differ between these groups. A similar pattern of results was seen for respiratory findings by cleft classification such that infants with cleft of the hard and soft palates had higher AHI and OMAHI than infants with other forms of cleft (data not shown). For this reason, syndrome status was reclassified as PRS or non-PRS for linear regression analysis with cleft classification reclassified as cleft of the hard and soft palate or other forms of cleft.
Summary of respiratory findings by syndrome status
The presence of snoring was associated with higher AHI (34.9±22.3 vs 16.5±14.0 events/h, p<0.01), OMAHI (19.2±17.1 vs 8.5±11.0 events/h, p<0.05) and ODI (35.9±25.0 vs 21.0±17.3 events/h, p<0.05). Snoring did not distinguish infants with a normal OMAHI from those with an elevated obstructive index (snorers vs non-snorers 41.9% vs 58.1%, χ2=2.4, p=ns). The same pattern was seen for the other symptoms of OSA.
Linear regression was used to examine associations between multiple infant characteristics and measures of SDB. The outcome variable with the strongest model was OMAHI based on the highest adjusted R2. Variables were analysed in four groups to determine possible predictors for a final model of OMAHI: demographic features (age, gender, cleft classification, and syndrome status), growth parameters, symptoms of SDB and facial measurements. From these analyses, five variables were included in the final analysis (table 4): age, cleft classification, syndrome status, mandibular length and snoring. Multivariate analysis demonstrated that only syndrome status was an independent predictor of OMAHI, with infants with PRS showing more severe respiratory abnormalities. However, unidentified factors account for the majority of variance in OMAHI.
Result of linear regression, with Obstructive–Mixed Apnoea–Hypopnoea Index as the outcome variable and infant characteristics as predictors
Recommendations for clinical care were determined by the treating physician. No change in clinical care was recommended for 22 infants (44%); of these, only one had been referred for clinical review before PSG. The remaining infants were recommended for clinical follow-up (13 infants, 26%), side or prone positioning during sleep (three infants, 6%), oxygen during sleep (one infant, 2%), continuous positive airway pressure (10 infants, 20%) or mandibular distraction (one infant, 2%). Infants who were recommended for treatment or clinical follow-up had higher AHI (31.4±20.0 vs 11.9±6.4 events, p<0.001) and ODI (33.6±22.6 vs 12.6±6.6 events/h, p<0.001), but similar age at the time of the study (2.6±2.4 vs 2.8±2.2 months, p=ns) compared with infants who were recommended for no treatment.
Discussion
This study reports PSG findings in a prospectively recruited group of infants across the spectrum of CL/P with PSG performed before palate surgery. The results show that infants with CL/P, regardless of cleft classification or syndrome status, have a high frequency of symptoms of SDB and obstructive respiratory events. Symptoms of SDB, including snoring, are common in this group, but do not distinguish between infants with normal or elevated numbers of respiratory events. With the exception of syndrome status, clinical characteristics do not predict the severity of OMAHI. While PRS is associated with a higher number of respiratory events, infants with isolated CL/P (ie, without PRS) also had demonstrable, albeit less severe, airway obstruction. The presence of PRS explains only a small proportion of the variance in respiratory disturbance in infants with CL/P.
The results from this study highlight a need for clinicians to look for symptoms and consider investigating for SDB regardless of syndrome status in infants with CL/P. Several recent studies of cleft clinic populations have described high rates of SDB. In a study of 248 preschool children from a single cleft clinic, 31% of children met criteria for a questionnaire diagnosis of OSA, but only 30% had undergone investigation for these symptoms.29 Symptoms of SDB were identified on medical record review in two other cleft clinic populations, with rates of 22% in children over 3 years of age30 and 37% in children who had undergone cleft repair.31 While not all children with SDB symptoms underwent PSG, SDB was confirmed by PSG in 87%,9 85%31 and 98%30 of children from three separate cohorts. While the rates of SDB and OSA were higher in children with syndromes, the rates across all children with CL/P were higher than population rates. The present study extends these findings to infants and shows that infants across the spectrum of CL/P have elevated rates of SDB symptoms and obstructive respiratory events.
One of the challenges for investigating SDB in infants is that there are currently no accepted criteria for the diagnosis of SDB on PSG in infants. Several studies provide indices of respiratory events in normal infants,27 ,28 ,32–34 but all preceded use of the current AASM scoring criteria.25 What is clear from these studies is that, in normal infants, the number of both obstructive central respiratory events decreases with increasing age,27 ,28 the number and range of central respiratory events is greater than for obstructive respiratory events,33–35 and respiratory events are more common in active sleep/REM than in non-REM sleep.28 ,35–37 These relationships make it challenging to determine pathological respiratory event limits in infants. Previous authors have chosen different cut-offs for defining SDB in infants: for example, Respiratory Disturbance Index >5/h of sleep;38 Mixed Plus Obstructive Apnoea Index >2/h of sleep37; and OSA defined as AHI>2 unless>25% of events were central.39 We defined the upper limit of normal for OMAHI as 3 events/h based on the results of normative data and recognise that this does not define SDB but rather identifies infants with a definitely higher than normal number of obstructive respiratory events. Even with this potentially conservative cut-off, 76% of infants in our study had OMAHI that was higher than normal.
Snoring, a cardinal symptom of SDB, has been studied more actively than SDB in infants. Estimates of prevalence are complicated by differences in the definition of significant snoring. In a population study, snoring in the last 2 weeks was reported for 26% of infants <1 year of age.40 Male gender and maternal smoking were associated with an increased risk of snoring, while side sleep position, compared with both supine and prone position, was protective. In one community sample, habitual snoring (≥3 nights/week) was reported by parents in 9% of infants 0–3 weeks of age.41 Habitual snoring was associated with exclusive formula feeding since birth, restless sleep, and increased maternal concerns about the child's breathing during sleep. More infants aged 2–3 months were reported to habitually snore than younger infants. In another community sample of infants, mothers reported habitual snoring in 5% of infants, noisy breathing other than snoring in 24%, and snoring and noisy breathing in 6.5% of infants aged 2–4 months.42 In the present study, there were no significant differences between snoring and non-snoring infants with respect to infant or maternal characteristics, including feeding and maternal smoking. Given these estimates for snoring in population and community samples, our sample of infants with CL/P have a higher rate of snoring than expected, regardless of syndrome status.
The long-term effects of SDB in infancy, including infants with CL/P, are largely unknown. Several studies have documented comorbidity associated with SDB in infancy. Studies of SDB in infants with PRS have demonstrated an improvement in growth and feeding with successful treatment of SDB43 or, conversely, failure to thrive associated with residual SDB despite treatment.44 Studies of neurocognitive outcomes for infants with SDB demonstrate associations with abnormal movements,45 behavioural changes46 and decreased neurological status.47 Finally, SDB has been associated with sudden infant death syndrome both through the effects of intermittent hypoxia48 ,49 and from autonomic changes associated with sleep disruption.16 ,50 Cumulatively, this evidence suggests that SDB in infancy is associated with poor health outcomes. Whether these poor outcomes are confined to infancy or may extend to childhood, adolescence and possibly even to adulthood is unknown.
Limitations of this study must be considered. Our study did not include a control group of healthy infants against which to compare respiratory event rates. Event rates from historical control data are based on different scoring criteria, and therefore comparison with our results is limited. There is no accepted standard event rate for the diagnosis of SDB in infants, and individual clinicians differ on criteria required to diagnose SDB in infants. Therefore we have elected to report on objective measures that could be applied in other clinics. The group of infants with syndromes including a cleft is heterogeneous. Given the small size of this sample in the present study, conclusions with regard to this subset of infants with clefts are limited. Finally, as this is a cross-sectional study, it does not report follow-up or outcomes, and such data will be required to evaluate the levels of disease that would mandate treatment intervention.
In summary, we have documented that infants across the CL/P spectrum have an increased risk of symptoms of SDB and elevated obstructive respiratory event rates. While respiratory event rates are higher in infants with PRS, the presence of PRS explains only a small proportion of the variance in PSG findings. Clinicians should enquire about sleep-related symptoms and consider the role of PSG, as reported symptoms do not identify all infants with high rates of obstructive respiratory events. The long-term risk of SDB in infants with CL/P is unknown and should be the focus of future research.
Acknowledgments
We would like to thank Ms Nicole Coburn (cleft team nurse) and Dr Peter Hayward (head of the cleft team) for their assistance with this study.
References
Footnotes
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Contributors JEM was the principal investigator and responsible for all aspects of the study including preparation of the manuscript. DF, DAF and KAW contributed to the study design, review of the results and manuscript editing. All authors made a significant contribution to warrant authorship.
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.