SLEEP OUTCOMES IN CHILDREN WITH SINGLE-SUTURE CRANIOSYNOSTOSIS
COMPARED WITH UNAFFECTED CONTROLS
by
Baiyang Sun
BMed, Sichuan University, China, 2013
Submitted to the Graduate Faculty of
Epidemiology
Graduate School of Public Health in partial fulfillment
of the requirements for the degree of
Master of Public Health
University of Pittsburgh
2015
UNIVERSITY OF PITTSBURGH
GRADUATE SCHOOL OF PUBLIC HEALTH
This essay is submitted
by
Baiyang Sun
on
April 22, 2015
and approved by
Essay Advisor:
Yona Keich Cloonan, PhD
Assistant Professor
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Essay Reader:
Ping Guo Tepper, MD, MS, PhD
Assistant Professor
Department of Epidemiology
Graduate School of Public Health
University of Pittsburgh
Essay Reader:
David N. Finegold, MD, PhD
Professor
Department of Pediatrics
School of Medicine
Department of Human Genetics
Graduate School of Public Health
University of Pittsburgh
______________________________________
______________________________________
______________________________________
ii
Copyright © by Baiyang Sun
2015
iii
Yona Keich Cloonan, PhD
SLEEP OUTCOMES IN CHILDREN WITH SINGLE-SUTURE
CRANIOSYNOSTOSIS COMPARED WITH UNAFFECTED CONTROLS
Baiyang Sun, MPH
University of Pittsburgh, 2015
ABSTRACT
Public Health Significance
Craniosynostosis refers to premature closure of the cranial sutures during the perinatal
period. Isolated single-suture craniosynostosis (SSC) is a non-syndromic form impacting only
one suture. There is evidence that children with craniofacial anomalies have a higher risk for
SDB as compared with unaffected children; however, it is not known whether this also applies to
isolated SSC. Sleep-disordered breathing (SDB) occurs in 0.7% to 13.0% of children and is
associated with behavioral, neurocognitive and cardiovascular consequences. We compared
parent-reported SDB-related symptoms in children with and without isolated SSC, hypothesizing
that those with SSC would have increased SDB-related symptoms as compared with controls.
This preliminary study may have implications for clinical care by identifying a treatable
condition (i.e. SDB) in an already vulnerable pediatric population.
Method
Among children with and without SSC, 6 SDB symptoms were assessed by parent report:
restless sleep, arousal, snoring, snorting/gasping, apneas, and daytime sleepiness. Current sleep
problems (yes/no) and ever sleep problems (yes/no) were identified based on the constellation of
SDB-related outcomes. Snoring, the most common symptom of SDB, was categorized as never,
0-1 nights/week, and 2+ nights/week. Logistic and multinomial logistic regression models were
iv
applied to assess the association between sleep outcomes and SSC, adjusted for sex, age,
race/ethnicity and family socioeconomic status (SES).
Results
Current sleep problems were reported slightly more often in children with SSC (19%)
than in controls (14%; adjusted odds ratio (aOR)=1.6, 95% CI 0.9-2.8). There was no difference
in report of having ever had sleep problems between cases and controls. In the multinomial
regression model, the overall association of SSC and SDB was statistically significant (p=0.02).
Snoring was more often reported as 2+ nights/week by parents of SSC cases (13%) than controls
(4%) (versus never, aOR=3.4, 95% CI=1.4-7.9); while snoring 0-1 nights/week was reported
similarly in both groups.
Conclusion
Children with SSC had significantly increased presence of snoring during sleep compared
to controls. This suggests that children with isolated SSC may be at increased risk for SDB and
further suggests that awareness and clinical evaluation of SDB are important for children with
SSC. Further study using standardized assessments of SDB are needed.
v
TABLE OF CONTENTS
1.0
INTRODUCTION ........................................................................................................ 1
1.1
CRANIOSYNOSTOSIS ...................................................................................... 1
1.2
SLEEP-DISORDERED BREATHING ............................................................. 2
1.3
SLEEP DISORDERED BREATHING AND CRANIOSYNOSTOSIS ......... 3
1.4
PRESENT STUDY .............................................................................................. 4
2.0
METHODS ................................................................................................................... 5
2.1
PARTICIPANTS ................................................................................................. 5
2.2
DATA COLLECTION ........................................................................................ 6
2.3
STATISTICAL ANALYSES .............................................................................. 6
3.0
RESULTS ..................................................................................................................... 9
4.0
DISCUSSION ............................................................................................................. 17
BIBLIOGRAPHY ....................................................................................................................... 21
vi
LIST OF TABLES
Table 1. Sociodemographic Characteristics of SSC Cases and Controls at Follow-Up ............... 10
Table 2. Results of Logistic Regression Comparing the Odds of Current and Ever Sleep
Problems in SSC Cases versus Controls ....................................................................................... 11
Table 3. Results of Multinomial Logistic Regression to Assess the Association between Snoring
and SSC......................................................................................................................................... 11
Table 4. Comparison of Fit Statistics for Model Selection in Latent Class Analysis ................... 14
Table 5. Latent Classes Identified for Participants with SSC Cases and Controls ....................... 15
vii
LIST OF FIGURES
Figure 1. Current / Ever Sleep Problem across Suture Involvement ............................................ 12
Figure 2. Snoring across Suture Involvement ............................................................................... 13
viii
1.0
1.1
INTRODUCTION
CRANIOSYNOSTOSIS
Craniosynostosis is a craniofacial anomaly defined as premature fusion of cranial sutures
(e.g. sagittal, coronal, metopic, and/or lambdoidal) during the perinatal period, affecting the
growth of the face and head. It is usually diagnosed by computed tomography (CT) scans and
three-dimensional reconstruction, along with medical history evaluation and careful physical
examination.
Craniosynostosis is classified as syndromic or non-syndromic/isolated. Syndromic
craniosynostosis manifests as part of a congenital syndrome such as Crouzon, Apert, Pfeiffer,
and Saethre-Chotzen syndromes, which may include additional abnormal development and
appearance of the jaw, lip/palate, eye and/or trunk.1,2 Some known causal genetic mutations are
associated with syndromic craniosynostosis, including FGFR-1, FGFR-2, FGFR-3, TWIST-1
and EFNB-1, though not always identified.1,3 In comparison, non-syndromic/isolated
craniosynostosis
typically
occurs
without
other
congenital
anomalies.4
Meanwhile,
craniosynostosis is classified as single-suture or multiple-suture, depending on the number of
cranial sutures involved. Isolated craniosynostosis may impact only one suture5, in which case it
is called isolated single-suture craniosynostosis (SSC). Among sutures, sagittal is the most
commonly impacted in SSC6. Although estimates vary in different populations, prevalence of all
1
types of craniosynostosis ranges from 3 to 14 per 10,000 live births, and single-suture
craniosynostosis is present in approximately 5 in 10,000 live births7,8.
Craniosynostosis does not only result in abnormal appearance of the head, but also causes
functional impairment. Several studies indicated that SSC was associated with neurocognitive,
psychological and behavioral problems9,10. Surgical treatment, usually a single cranioplasty, is
commonly performed for children with isolated SSC, before 1 year of age to release the fused
suture11. Ideally, both children using surgical or non-surgical treatment should be managed by a
multidisciplinary team4.
1.2
SLEEP-DISORDERED BREATHING
Sleep-disordered breathing (SDB) refers to several chronic conditions categorized by
partial or complete breathing obstruction or cessation during sleep, which affects functional
ability and quality of life12,13,14. Studies indicate that childhood SDB is not only associated with
behavioral and neurocognitive problems, such as decreased attention, learning difficulties, and
anxious/depressive symptoms, but also long-term cardiovascular consequences15,16,17,18.
There is a wide range of the estimated prevalence of SDB in children, ranging from 0.7%
to 13.0%19 depending on diagnostic method. Polysomnography is the gold standard to measure
and diagnose sleep disorders objectively. However, polysomnography is not feasible to be used
to identify sleep problems in large pediatric epidemiological studies, because of its high price
and time burden for participants. Thus, validated parent-report questionnaires, such as the
Pediatric Sleep Questionnaire20 and Sleep Disturbance Scale for Children21, are commonly
employed to identify children with suspected SDB22.
2
Diverse manifestations are present for children with SDB, such as nighttime snoring,
daytime sleepiness, restless sleep, frequent arousals, snorting/gasping, witness apneas, dry
mouth/mouth breathing23. The constellation of symptoms change with age; yet nighttime snoring
is regarded as the most common presentation of SDB at any age among children.
The causes of SDB are multifactorial. One main reason is the narrow airway structure
due to enlarged adenoids or/and tonsils, overweight, or insufficient maxillary growth, which may
obstruct air flow during sleep24,25. Meanwhile, neuromuscular activation and inflammation can
also lead to the development of SDB23. Compared to the general population, individuals with
craniofacial and neuromuscular anomalies have an increased risk of SDB23.
For children, the most common treatment of SDB is adenoidectomy and tonsillectomy.
After adenoidectomy and tonsillectomy, children should be followed up using polysomnography.
If SDB is not sufficiently treated and residual SDB occurs, other orthodontic treatment, distractor
or expansion can be applied according to individual’s situation26,27.
1.3
SLEEP DISORDERED BREATHING AND CRANIOSYNOSTOSIS
There is evidence that children with craniofacial anomalies have a higher risk for SDB as
compared with unaffected children; however, the literature is sparse, and focuses on cleft
lip/palate, craniofacial microsomia, and syndromic craniosynostosis28,29,30,31,32. Few published
studies have examined sleep outcomes in children with either non-syndromic craniosynostosis or
isolated SSC. One previous study indicated that both children with syndromic and nonsyndromic craniosynostosis had increased risk of developing of SDB33. However, this study is
limited by the small sample size (4 with syndromic, and 10 with non-syndromic
3
craniosynostosis), no comparison group, and referral bias. To our knowledge, there are no
studies comparing sleep outcomes in children with SSC as compared with unaffected children
and thus the association between SSC and SDB is yet to be clarified.
1.4
PRESENT STUDY
The current study aimed to assess whether children with isolated SSC are at higher risk
for SDB as compared with controls. We hypothesized that those with SSC would have increased
SDB-related symptoms as compared with controls. We compared parent-reported SDB-related
symptoms in children with and without isolated SSC in a multi-center cohort.
4
2.0
2.1
METHODS
PARTICIPANTS
This cross-sectional study includes 184 children with isolated SSC and 184 unaffected
controls. These children are participants in an ongoing, multisite, follow-up study of
neurodevelopment in children with and without isolated SSC34,35. When initially enrolled in the
original study, cases were infants diagnosed (by computed tomographic scans) with one of the
following types of isolated SSC: sagittal, metopic, right unicoronal, left unicoronal and
lambdoid. Controls were healthy infants without congenital anomalies. Cases and controls were
frequency matched by age, sex, race/ethnicity, and family socioeconomic status (SES).
Exclusion criteria for the original enrollment included age >30 months, gestational age <34
weeks, major medical comorbidities (e.g. cardiac defects, seizure disorders), co-occurrence of
major malformations, or >3 minor congenital anomalies36. Informed consent was obtained before
enrollment with approval of institutional review boards (IRB) of each four site (Seattle, Chicago,
St. Louis and Atlanta). Participation in the current cross-sectional analysis was limited to those
who enrolled in the original study and completed the follow-up visit.
5
2.2
DATA COLLECTION
SDB-related outcomes, sleep-related medical history and demographic information were
obtained by staff-administered interview. First, parents of all participants were asked whether
their child had sleep problems and whether these problems were new, continuing or reported at
the previous study visit. For those who reported new or continuing sleep problems, 6
supplemental questions related to SDB symptoms were further assessed, including restless sleep,
arousal, snoring, snorting/gasping, apneas, and daytime sleepiness. Choices for each response
were “usually: 5-7 times per week”, “sometimes: 2-4 times per week”, “rarely: 0-1 time per
week”, and “never”. Demographic information, such as sex, date of birth, race/ethnicity, site and
family SES, was collected at baseline and updated by parent report at follow-up. Additionally,
sleep-related medical history regarding airway intervention (tonsillectomy and adenoidectomy)
and respiratory diseases, including asthma, allergies, and respiratory infections (e.g., bronchitis,
bronchiolitis, and pneumonia) was obtained during the interview.
2.3
STATISTICAL ANALYSES
Descriptive analyses were used to illustrate the sociodemographic characteristics of
children with and without SSC, including age, sex, race/ethnicity, family SES and site of data
collection. Among the children with SSC, type of suture involvement (e.g., sagittal, metopic,
right and left unicoronal, lambdoid), and sociodemographic characteristics by suture involvement
were assessed as well. Counts and percentages were calculated for discrete variables. Means,
standard deviations, medians and ranges were calculated for continuous variables.
6
Logistic regression and multinomial logistic regression were performed to explore
whether children with SSC have increased risk to have sleep problems than unaffected children.
For the purpose of analyses, current sleep problems (yes/no) were identified based on
endorsement of ‘having new or continuing sleep problems’, or endorsement of at least one SDB
symptom. Meanwhile, we classified participants as having ever sleep problems (yes/no) if the
child had current sleep problems or previously reported sleep problems. Besides the above two
outcome variables, we also separately assessed whether snoring was associated with SSC.
Participants with “sometimes” and “usually” responses were combined into one group to avoid
the issue of small cell sizes; therefore, snoring was recoded as never, 0-1 night/week, and 2+
nights/week. To compare the odds of sleep problems between case and control groups, logistic
regression was conducted for binary variables (current sleep problem and ever sleep problem).
Multinomial logistic regression model was used for multi-level outcome variable (snoring) with
“Never” as the reference group. For all adjusted regression models, potential confounding
variables (sex, race/ethnicity, age, and SES) were included as covariates. Odds ratios and their
95% confidence intervals (CIs) were computed. P-values less than 0.05 were regarded as
statistically significant.
To identify whether reported snoring frequency was distributed similarly among cases
with different cranial suture involvement (sagittal, metopic, right and left unicoronal, lambdoid),
proportions of snoring frequency responses were compared across suture type using Fisher’s
exact test, taking into account that expected counts in some cells were less than 5.
Latent class analysis37 was employed to explore the underlying structure of the sleep
patterns among children with and without isolated SSC based on the 6 reported SDB-related
items. To determine the number of latent classes, we fitted a model with two classes and repeated
7
with one additional class iteratively to compare the fit statistics, including the likelihood-ratio G2
statistic, Akaike’s Information Criterion (AIC) and Bayesian Information Criterion (BIC). The
optimal latent class model and the composition of each class were described.
Sensitivity Analyses
To assess potential bias introduced by specific conditions, sensitivity analyses were
conducted by excluding children who had probable and known causal mutations, suffered from
respiratory diseases (e.g., asthma, allergy, respiratory infections), and had ever undergone airway
interventions (tonsillectomy and adenoidectomy), respectively. We repeated the main regression
analyses in the subsamples successively, and then compared the results obtained in the
subsamples and in the full sample.
All analyses above were performed using SAS 9.4. PROC LCA developed by the
Pennsylvania State University was used for latent class analysis.
8
3.0
RESULTS
Participants included 184 children with isolated SSC and 184 unaffected controls, with
the mean age of 7.5 and 7.4 years, respectively. (Table 1) As the SSC case and control groups
were frequency matched by sex, race/ethnicity and family SES, these characteristics were
distributed similarly in the two groups. In both SSC cases and controls, of the majority were
male (64%, 63%) and white (80%, 74%). Also, most SSC cases and controls had high family
SES, classified as I or II based on Hollingshead Classification (71%, 85%).
Within case group, sagittal synostosis (42%) was the most common form, whereas
lambdoid (7%) was the least common. (Table 1) Sociodemographic characteristics differed by
suture type: there were more females among children with left and right unicoronal SSC, but
more males for other types of SSC. Race/ethnicity and age were similar across different suture
types. The composition of family SES were overall similar, though the proportion of children
with high family SES (I or II) in left unicoronal group (55%) was lower than other suture types.
No children with left unicoronal were enrolled in St. Louis and Atlanta.
9
Table 1. Sociodemographic Characteristics of SSC Cases and Controls at Follow-Up
Total
Controls
N (%)++
184
Total
Cases
N (%)
184
Sagittal
Metopic
N (%)
77 (42)
N (%)
49 (27)
Right
Unicoronal
N (%)
24 (13)
Left
Unicoronal
N (%)
22 (12)
Number
Age
Mean (SD)
7.4 (0.5)
7.5 (0.6)
7.5 (0.7) 7.4 (0.3) 7.4 (0.3)
7.4 (0.3)
Range
7.0: 11.1
6.9: 11.5
7.0: 11.5 7.0: 8.4
7.0: 8.5
6.9: 8.1
Sex
Female
69 (38)
67 (36)
18 (23)
14 (29)
13 (54)
17 (77)
Male
115 (63)
117 (64)
59 (77)
35 (71)
11 (46)
5 (23)
Race/Ethnicity
White
137 (74)
148 (80)
64 (83)
38 (78)
20 (83)
16 (73)
Non-White
47 (26)
36 (20)
13 (17)
11 (22)
4 (17)
6 (27)
SES+
I:55-60 (high)
54 (29)
44 (24)
21 (27)
11 (22)
3 (13)
5 (23)
II:40-54
103 (56)
86 (47)
33 (43)
24 (49)
17 (71)
7 (32)
III:30-39
14 (8)
32 (17)
13 (17)
9 (18)
3 (13)
4 (18)
IV:20-29
10 (5)
20 (11)
10 (13)
4 (8)
1 (4)
5 (23)
V:8-19 (low)
3 (2)
2 (1)
0 (0)
1 (2)
0 (0)
1 (5)
Site
Seattle
72 (39)
76 (41)
34 (44)
20 (41)
6 (25)
12 (55)
Chicago
76 (41)
66 (36)
16 (21)
21 (43)
14 (58)
10 (45)
St. Louis
9 (5)
17 (9)
12 (16)
1 (2)
3 (13)
0 (0)
Atlanta
27 (15)
25 (14)
15 (19)
7 (14)
1 (4)
0 (0)
+
SES, socioeconomic status, Hollingshead Four Factor Index of social status (Hollingshead, 1975)
++
Percentages may not add up to 100% because of rounding.
Lambdoid
N (%)
12 (7)
8.1 (0.8)
7.2: 9.3
5 (42)
7 (58)
10 (83)
2 (17)
4 (33)
5 (42)
3 (25)
0 (0)
0 (0)
4 (33)
5 (42)
1 (8)
2 (17)
Current / Ever Sleep Problems
Current sleep problems were reported slightly more often in children with SSC (19%)
than in controls (14%; adjusted odds ratio (aOR)=1.6, 95% CI 0.9-2.8, p=0.13) (Table 2). There
was no difference in report of having ever had sleep problems between cases (25%) and controls
(23%; aOR=1.1, p=0.59).
10
Table 2. Results of Logistic Regression Comparing the Odds of Current and Ever Sleep Problems
in SSC Cases versus Controls
Current Sleep
Problem
Ever Sleep
Problem
+
Control
N (%)
Case
N (%)
No
159 (86)
149 (81)
Yes
25 (14)
34 (19)
No
142 (77)
138 (75)
Yes
42 (23)
45 (25)
Crude
Odds Ratio
(95% CI)
Adjusted
Odds Ratio+
(95% CI)
p-value++
1.5 (0.8, 2.5)
1.6 (0.9, 2.8)
0.13
1.1 (0.7, 1.8)
1.1 (0.7, 1.9)
0.59
Adjusted for sex, age, race/ethnicity and family SES
P-value based on the adjusted regression models
++
Snoring
The overall association of SSC and snoring was statistically significant (p=0.02) in the
multinomial regression model. Snoring was more often reported as 2+ nights/week by parents of
children with SSC (13%) than controls (4%) (aOR vs. never=3.4, 95% CI=1.4-7.9, p=0.01);
Snoring was reported as 0-1 night/week in 5% and 8% of cases and controls, respectively (aOR
vs. never=0.8, 95% CI=0.3-2.0, p=0.62). (Table 3)
Table 3. Results of Multinomial Logistic Regression to Assess the Association between Snoring and
SSC
Snoring
Control
N (%)
Case
N (%)
Crude
Odds Ratio
(95% CI)
Adjusted
Odds Ratio+
(95% CI)
p-value++
Never
161 (88)
149(82)
Referent
Referent
-
0-1 nights/week
14 (8)
9(5)
0.7 (0.3, 1.7)
0.8 (0.3, 2)
0.62
2+ nights/week
8 (4)
23(13)
3.1(1.3, 7.2)
3.4(1.4, 7.9)
0.01
Note: P-value for the overall model based on Walt test was 0.02.
+
Adjusted for sex, age, race/ethnicity and family SES
++
P-value based on the adjusted regression models
11
Comparison by Suture Involvement
Among children with isolated SSC, there were no statistically significant overall
differences in the proportions of children with current sleep problems, ever sleep problems, and
snoring frequency across suture involvement, and the p-values of the overall test (Fisher’s exact
test) were 0.07, 0.39 and 0.52, respectively. However, it is notable that children with left
unicoronal SSC had a higher proportion of sleep-related problems than other suture types. 41%
of children with left unicoronal SSC were reported having current sleep problem and ever sleep
problem, and 37% of children with left unicoronal SSC were reported having snoring symptoms.
(Figures 1, 2)
100%
90%
80%
59% 59%
70%
Percentage
60%
82%
75%
85%
79%
92%
50%
83%
83%
75%
40%
30%
41% 41%
20%
10%
18%
25%
15%
21%
8%
0%
Sagittal
N=77
Metopic
N=49
17%
Right
Unicoronal
N=24
17%
Left
Unicoronal
N=22
25%
Lambdoid
N=12
Suture Involvement
Having current sleep problem
Not having current sleep problem
Having ever sleep problem
Not having ever sleep problem
Figure 1. Current / Ever Sleep Problem across Suture Involvement
12
100%
90%
80%
Percentage
70%
60%
64%
83%
85%
83%
91%
50%
40%
30%
20%
10%
0%
14%
4%
7%
7%
2%
6%
6%
Sagittal
N=77
Metopic
N=49
never
rarely
sometimes
usually
14%
8%
4%
4%
9%
8%
Right
Unicoronal
N=24
Left
Unicoronal
N=22
Lambdoid
N=12
Suture Involvement
Figure 2. Snoring across Suture Involvement
Latent Class Analysis
In latent class analysis evaluating the underlying pattern of SDB-related symptoms
among children with and without isolated SSC, the two-class model had the smallest BIC.
Though Likelihood Ratio G2 and AIC decrease after increasing the number of latent classes, the
probability of one class was too small. Thus, the two-class model was selected (Table 5). For the
pattern of SDB-related symptoms among all participants with and without SSC, two main classes
were identified: normal (85%), and abnormal (15%) (Table 6). Children in the normal class
reported “never” to at least 4 of 6 SDB-related symptoms, whereas all children in the abnormal
13
class reported at least 0-1 night/week for all 6 SDB-related symptoms. In the abnormal class, the
majority of participants reported “0-1 nights/week” to arousal (64%), snorting/gasping (83%),
apneas (90%), and daytime sleepiness (75%). 63% and 57% reported restless sleep and snoring
2+ nights/week, respectively. Therefore, for children with abnormal sleep, symptoms such as
arousal, snorting/gasping, apneas, and daytime sleepiness were less frequent, while snoring and
restless sleep were reported more frequently.
Table 4. Comparison of Fit Statistics for Model Selection in Latent Class Analysis
No. of Classes
Likelihood Ratio G2
Degree of Freedom
AIC
BIC
2
86.66
703
136.66
234.09
3
39.97
690
115.97
264.07
4
26.50
677
128.50
327.25
14
Table 5. Latent Classes Identified for Participants with SSC Cases and Controls
Normal
%
Abnormal
%
85.4
14.6
Never
99.7
0.0
0-1 nights/week
0.0
37.7
2+ nights/week
0.3
62.3
100.0
0.0
0-1 nights/week
0.0
64.2
2+ nights/week
0.0
35.9
Never
99.7
0.0
0-1 nights/week
0.0
43.4
2+ nights/week
0.3
56.6
100.0
0.0
0-1 nights/week
0.0
82.7
2+ nights/week
0.0
17.3
100.0
0.0
0-1 nights/week
0.0
90.2
2+ nights/week
0.0
9.8
100.0
0.0
0-1 nights/week
0.0
75.0
2+ nights/week
0.0
25.0
Class probability
Child is restless and moves a lot during sleep
Child wakes up more than once during the night
Never
Child snores during sleep
Child snorts and/or gasps during sleep
Never
Child seems to stop breathing during sleep
Never
Child seems sleepy during daytime
Never
15
Sensitivity Analyses
When excluding 18 children with identified genetic mutations associated with
craniosynostosis, the ORs for current sleep problem (aOR=1.5, 95% CI 0.7-2.5, p=0.37) and ever
sleep problem (aOR=1, 95% CI 0.6-1.7, p=0.96) were slightly lower as compared with
regression analyses in the full sample. The aOR for snoring 2+nights/week versus never was
slightly lower (aOR=2.8, 95% CI 1.1-6.8, p=0.03), and the overall association of SSC and
snoring was marginally significant (p=0.0508). The ORs for current sleep problems and ever
sleep problems were not affected by excluding participants with asthma, allergy or respiratory
infections. However, the overall association of SSC and SDB was no longer significant (p=0.06).
The association of snoring 2+ times per week (vs. never) remained (aOR=4.5, 95% CI=1.3-15.3,
p=0.02). After excluding 31 participants who had a history of tonsillectomy or adenoidectomy,
the results were comparable to that using the full sample.
16
4.0
DISCUSSION
In our study, SSC was not significantly associated with higher parent report of current or
ever sleep problems, adjusted for child sex, age, ethnicity and family SES, however, SSC was
associated with higher presence of snoring compared with unaffected controls. Thus, these
preliminary results suggested that children with isolated SSC may be at increased risk for SDB.
Additionally, though we observed a higher proportion of sleep problems in children with left
unicoronal SSC than other suture types, no statistically significant difference was found across
all suture involvement. Considering only 22 children with left unicoronal SSC were included in
our study, future study with larger sample size can be conducted to explore whether children
with left unicoronal SSC have a higher risk for sleep problems compared with other suture types.
Though there are several studies indicating that children with craniofacial anomalies have
increased risk for SDB, few have focused on children with isolated SSC. In a 2012 study, SDB
was present in 50% of children with isolated craniosynostosis, with no apparent association
between the number of sutures affected and the presence of SDB.33 However, due to the lack of a
comparison group, it remains unknown whether children with SSC have a higher risk for sleep
problems as compared with unaffected controls. To our knowledge, our study was the first to
compare the occurrence of SDB in children with isolated SSC as compared with a control group.
Though preliminary, our results suggest that children with isolated SSC may have higher risk for
17
SDB, which is consistent with previous study of many other craniofacial anomalies (e.g. cleft/lip
palate, craniofacial microsomia and syndromic craniosynostosis) 28,29,30,31,32.
The multi-center design of the study with relatively large number of children with
isolated SSC is a strength of our study. There were most children with sagittal synostosis (42%)
and least with lambdoid, which is consistent with the general distribution of craniosynostosis
suture types in epidemiological studies6. Also, the frequency matched sociodemographic
characteristics made cases and controls more comparable. As for suture-specific sex predilection,
there were more females among children with unicoronal SSC, but fewer females for other
suture types in our study. This is not quite consistent with previous literature, indicating that
there is a higher proportion of females in children with sagittal or unicoronal synostosis, but no
sex predilection exists in metopic or lambdoidal synostosis5,38.
In our study, we both compared the sleep outcomes based on the constellations of SDBrelated symptoms and snoring, which is the most common symptom in SDB, between SSC cases
and controls. Meanwhile, we also did latent class analysis to explore the underlying pattern of
sleep in these children. Two latent classes were identified as normal and abnormal, and children
in abnormal class were reported having snoring and restless sleep more frequently than other
SDB-symptoms.
One particular limitation of this study is the lack of a standardized and validated
questionnaire (e.g., Pediatric Sleep Questionnaire) to identify SDB. There is no evidence of the
validity of the items used in for the current study (specificity and sensitivity) as compared with
polysomnography, the gold standard. Thus, it is difficult to estimate the validity of our results
and compare our findings to other studies which have used standardized assessments.
Furthermore, since parent-report symptoms largely depend on parental awareness and sleep
18
habits (e.g., co-sleeping), supplemental questions for parent awareness are need to assess
whether parents of participants with isolated SSC may put more attention or have closer
observation for their children’s sleep compared with parents of unaffected controls.
Another limitation is a lack of BMI information. It is well known that overweight is a
significant risk factor for SDB. Without this information, results may be biased due to
imbalanced distribution of BMI across groups.
For latent class analyses, the only assumption is that the observed variables are
independent within a latent class. In this study the 6 SDB-related symptoms were correlated; we
expected the dependence between the 6 observed SDB-related symptoms, and assumed that the
latent class variable could account for these interrelations39.
Further study using standardized questionnaires of SDB with supplemental questions
about parental awareness is needed. After sufficient evidence based on parent-report
questionnaires indicate an increased risk for SDB in children with isolated SSC, further study
using polysomnography can be conducted to confirm the association between SSC and objective
SDB. Meanwhile, other relevant clinical information (e.g., BMI) should be included in future
studies.
Many studies have shown that untreated SDB can result in poor growth, mood disorders,
learning
difficulties,
memory
impairment
and
even
long
term
cardiovascular
complications15,16,17,18,23. Early diagnosis and treatment are required for the particularly
vulnerable group of children. What’s more, ample evidence has confirmed that children with
SSC have higher risk for such adverse neurodevelopmental outcomes40,41. It is possible that the
poor neurodevelopmental outcomes in children with SSC can be partially attributable to the
higher prevalence of SDB, besides the common hypothesized reasons such as cerebral
19
abnormalities, increased intracranial pressures and cranial vault distortion9,33. Future longitudinal
studies are needed to understand the pattern of SDB in children with SSC, and to evaluate its
health-related consequences.
Children with craniosynostosis are vulnerable to both health-related and psychological
problems, and are followed up and managed by multidisciplinary team. SDB is a treatable
condition and is associated with multiple health-related consequences. Our study indicated that
children aged 7-11 years with isolated SSC may have an increased risk for SDB as compared
with controls. This preliminary study may have implications for clinical care for SDB in an
already vulnerable pediatric population. Once the hypothesis confirmed, routine screening of
sleep problems for children with isolated SSC should be recommended.
20
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