pii: sp- 00326-15
http://dx.doi.org/10.5665/sleep.5618
PEDIATRICS
Perinatal Risk Factors Associated with the Obstructive Sleep Apnea Syndrome in School-Aged Children Born Preterm Ignacio E. Tapia, MD, MS1; Justine Shults, PhD2; Lex W. Doyle, MBBS3; Gillian M. Nixon, MBChB4; Christopher M. Cielo, DO1; Joel Traylor1; Carole L. Marcus, MBBCh1; Caffeine for Apnea of Prematurity – Sleep Study Group Sleep Center, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania; 3Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Melbourne, Australia; 4 Melbourne Children’s Sleep Centre, Monash Children’s, Monash University, Melbourne, Australia
1
Study Objectives: The obstructive sleep apnea syndrome (OSAS) is more prevalent in ex-preterm children compared to the general pediatric population. However, it is unknown whether OSAS in ex-preterm children is associated with specific perinatal risk factors. This multicenter cohort study aimed to determine perinatal factors associated with OSAS at school age. Methods: 197 ex-preterm (500–1,250 g) children aged 5–12 y who participated as neonates in a double-blind, randomized clinical trial of caffeine versus placebo (Caffeine for Apnea of Prematurity) underwent comprehensive ambulatory polysomnography. A negative binomial regression model was used to identify perinatal risk factors associated with OSAS. Results: 19 children had OSAS (9.6%). Chorioamnionitis and multiple gestation were positively associated with OSAS with P values of 0.014 and 0.03, respectively. Maternal white race (P = 0.047) and maternal age (P = 0.002) were negatively associated with OSAS. Other risk factors, such as birth weight, Apgar score at 5 min, antenatal corticosteroids, delivery route, and sex were not significant. Conclusions: OSAS is very frequent, and is associated with chorioamnionitis and multiple gestation in ex-preterm children. Those born to older white mothers appear to be protected. We speculate that the former may be due to systemic inflammation and the latter to a higher socio-economic status. Commentary: A commentary on this article appears in this issue on page 721. Keywords: OSAS, preterm, school-aged, risk factors Citation: Tapia IE, Shults J, Doyle LW, Nixon GM, Cielo CM, Traylor J, Marcus CL. Perinatal risk factors associated with the obstructive sleep apnea syndrome in school-aged children born preterm. SLEEP 2016;39(4):737–742. Significance Pediatricians need to be aware of the increased prevalence of OSAS in former preterm children and screen them for OSAS in order to avoid OSASrelated complications.
INTRODUCTION The obstructive sleep apnea syndrome (OSAS) affects 1% to 4% of children and has been associated with several risk factors, such as adenotonsillar hypertrophy, hypotonia, craniofacial anomalies, obesity, and history of prematurity, among others.1 Prematurity was first associated with OSAS by Rosen et al. in 2003.2 Since then, other investigators have highlighted the association between OSAS, during childhood and adulthood, and prematurity.3–5 However, it is unknown whether former preterm infants have specific perinatal risks factors associated with OSAS. This question is important because perinatal care has significantly progressed over the years, resulting in greater numbers of surviving former preterm individuals.6 Therefore, it is important for clinicians to know whether there are key elements of the patient’s history that could help determine who requires polysomnography, as symptoms of OSAS are often not reported by caregivers.7 The Caffeine for Apnea of Prematurity-Sleep study (CAPS) followed a cohort of children, now aged 5–12 years, born preterm in Canada and Australia, who participated in the Caffeine for Apnea of Prematurity study.8,9 All children underwent polysomnography. For the current study, birth and demographic data from CAPS were analyzed in respect to the polysomnographic findings at school age with the aim of determining perinatal factors associated with OSAS at school age.
follow up cohort have been described elsewhere in detail.10,11 In brief, four CAP sites were selected to participate in this study based on cohort size and geographic proximity. The Institutional Review Board at Children’s Hospital of Philadelphia and at each clinical site approved the study and written informed consent was obtained from parents/guardians. 201 children born preterm, with birth weights of 500–1,250 g and without major congenital anomalies or syndromes, were enrolled. Subjects were initially enrolled in CAP if their clinicians considered them to be candidates for methylxanthine therapy during the first 10 days of life, either to prevent apnea, treat apnea, or facilitate extubation. They were randomized to placebo or caffeine. Forty percent of children in the caffeine group and 40% of those in the placebo group had documented apnea of prematurity. Subjects completed comprehensive unattended ambulatory polysomnography at school age (5–12 years) as previously described in detail.11 Briefly, ambulatory polysomnography was performed at the child’s usual sleep times. A technologist went to the child’s home to place the following leads (Siesta 802, Compumedics): electroencephalograms (C4/M1, C3/M2, F4/ M1, F3/M2, O2/M1, O1/M2), electro-oculograms, submental and tibial electromyograms, chest and abdominal wall movement by inductance plethysmography, electrocardiogram, airflow (nasal pressure and oronasal thermistor), and arterial oxygen saturation with pulse waveform. Because of the difficulty of obtaining adequate signals in an unattended setting, capnometry was not performed. Studies were scored using
METHODS This study was a prospective follow-up of the Caffeine for Apnea of Prematurity (CAP) study 8,9 and the methods of this SLEEP, Vol. 39, No. 4, 2016
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Figure 1—Incidence rate ratio of maternal age at delivery associated with obstructive sleep apnea syndrome at school age. Second, third, and fourth maternal age quartiles are referenced to the first quartile. The closed circles represent the incidence rate ratio and the open circles the 5th and 95th confidence intervals. Values below 1 are protective. First age quartile: 20.8–27.6 y, second age quartile: 27.6–31.6 y, third age quartile: 31.7–34.9 y, fourth age quartile: 35–47 y. Children born to older mothers had a lower incidence rate ratio of obstructive sleep apnea syndrome at school age.
standard pediatric rules.12 Two definitions of OSAS were used to investigate risks factors associated with OSAS at school age. (1) OSAS was defined as an obstructive apnea-hypopnea index (AHI) ≥ 2 events per hour on polysomnography,13–16 and (2) OSAS was defined as an AHI ≥ 2 events per hour and/or history of adenoidectomy/tonsillectomy. This classification was used because OSAS is the most common indication for adenotonsillectomies in children and therefore, it is probable that participants who underwent these surgical procedures had OSAS at the time of the surgery.17,18 Statistical Analysis Two analyses were performed based on the two definitions of OSAS. Because the AHI was similar between participants treated with caffeine or placebo,10 both groups were pooled for these analyses. First, clinical data from the CAP study were evaluated to investigate the relationship with OSAS at age 5–12 y and defined as an obstructive AHI ≥ 2 events per hour.13–16 Negative binomial regression models were fitted, for which outcome was the count of obstructive events, defined as the sum of obstructive apnea, hypopnea, and mixed apnea events per child adjusted per hour of sleep. The original regression models included the clinical data present in the database: maternal race, maternal age, maternal education, presence of chorioamnionitis, multiple gestation, birth weight, sex, Apgar score at 5 min, antenatal corticosteroids, and delivery route. Data on respiratory support were not part of the parent study. Clinical variables that were not significantly associated with the outcome variable were removed one at a time, in a manual stepwise approach that removed variables with the largest P value first. The fit of the final model was assessed using the countfit command in Stata, which indicated SLEEP, Vol. 39, No. 4, 2016
that the fit of a negative binomial model was superior to that of a Poisson regression model.19 Incidence rate ratios higher than 1 were considered risk factors and those lower than 1, protective factors. For example, the incidence rate ratio of 1.7 for multiple gestation indicated that the rate of events in those children who were product of a multiple gestation was 1.7 times greater than in those who were a product of a single gestation. Next, logistic regressions were performed defining OSAS as an AHI ≥ 2 events per hour and/or history of adenoidectomy/ tonsillectomy. OSAS was defined as a categorical variable for this analysis to avoid a floor effect as most of these participants had normal AHI at ages 5–12 years. Variables present in the database were included in multivariable logistic regression models. Variables that were not significantly associated with the outcome variable were removed one at a time, using the same manual stepwise approach as for the negative binomial regression models. The hypothesis of adequate fit was tested using the Hosmer-Lemeshow test. All statistical analyses were performed using Stata 13.0 (StataCorp. 2013. College Station, TX). A two-sided P = 0.05 was considered statistically significant. RESULTS Two hundred one participants underwent comprehensive ambulatory polysomnography, which was successful in 197 participants whose characteristics are presented in Table 1.11 There was no difference in age between participants with and without OSAS defined solely on the AHI. Five children with OSAS, with AHI ranging between 5.3 and 22.1 events per hour, and 33 children without OSAS, had a history of tonsillectomy and/ or adenoidectomy. Nineteen participants met the AHI-based OSAS definition, and 52 met the AHI and/or history of tonsillectomy/adenoidectomy OSAS definition. Three percent of the participants of this study had moderate to severe cerebral palsy. The negative binomial regression model showed that maternal age and maternal White race were independent protective factors for OSAS at age 5–12 years (Table 2). Considering there was a wide range of maternal ages, these were further grouped into quartiles to ascertain whether a specific age group was responsible for this protective effect. The fourth quartile only, mothers aged 35–47 years at delivery, was strongly associated with absence of OSAS at age 5–12 years (Figure 1). Chorioamnionitis and multiple gestation were significant risk factors for OSAS in these school-aged children (Table 2). Birth weight, Apgar score at 5 min, antenatal corticosteroids, delivery route, and sex were not significant risk or protective factors for OSAS in this cohort. There was no significant correlation between maternal age and education in children with and without OSAS. Specifically, children with OSAS had an r of −0.15 with P = 0.53, and children without OSAS an r of −0.14 with P = 0.063. The logistic regression model using a broader definition of OSAS (AHI ≥ 2 events per hour and/or history of adenoidectomy/tonsillectomy), showed that only a birth weight ≤ 10th percentile was associated with OSAS at age 5–12 y, with an odds ratio of 2.8 compared to those with birth weights > 10th percentile (P = 0.033, 95% confidence interval [CI] 1.1 to 7.2). 738
Perinatal Risk Factors of OSAS—Tapia et al.
Table 1—Demographic, perinatal, and polysomnographic data. OSAS (n = 19) 9.5 (8.3–9.8)
Age, median (IQR), y Male, n (%) Maternal race, n (%) White Black Asian Other Maternal education, n (%) Did not finish high school High school graduate Attended college or university College or university graduate Unknown Perinatal data Gestational age, mean ± SD, w Birth weight, mean ± SD, g Chorioamnionitis, n (%) Cesarean section, n (%) Antenatal corticosteroids, n (%) Multiple gestation, n (%) Apgar at 5 min, mean ± SD, points Maternal age at delivery, mean ± SD, years Polysomnographic data Apnea-hypopnea index, median (IQR), n/h SpO2 nadir, median (range), % Time with SpO2 < 90%, median (IQR), % TST
Non-OSAS (n = 178) 9.2 (7.7–11.2)
P 0.89
9 (31.0)
105 (59.0)
0.34
14 (73.7) 1 (5.3) 4 (21.0) 0 (0)
150 (84.3) 10 (5.6) 16 (9.0) 2 (1.1)
0.33 1.00 0.11 1.00
2 (10.5) 5 (26.3) 7 (36.9) 5 (26.3) 0 (0)
30 (16.9) 41 (23) 38 (21.3) 65 (36.6) 4 (2.2)
0.74 0.77 0.15 0.46 1.00
27.6 ± 1.6 944 ± 185.6 4 (21.1) 12 (63.2) 17 (89.5) 8 (42.1) 8.2 ± 1.5 30.9 ± 5.1
27.2 ± 1.7 973.9 ± 169.0 25 (14.0) 116 (65.2) 158 (88.8) 65 (36.5) 7.9 ± 1.3 31.7 ± 5.4
0.38 0.47 0.49 1.00 1.00 0.63 0.36 0.56
5.3 (3.5–12.8) 89 (85–91) 0 (0–0.1)
0.2 (0.1–0.6) 92 (91–94) 0 (0–0)
< 0.0001 < 0.0001 < 0.0001
IQR, interquartile range; OSAS, obstructive sleep apnea syndrome defined as an apnea-hypopnea index ≥ 2 events per hour; SD, standard deviation; SpO2, oxyhemoglobin saturation; TST, total sleep time.
Table 2—Factors associated with obstructive sleep apnea in former preterm infants at age 5–12 y. Protective factors Maternal age 4th quartile (35.2–47.4 y) Maternal white race Risk factors Chorioamnionitis Multiple gestation
IRR
SE
z
P
IRR 95% CI
0.36 0.53
0.12 0.17
−3.15 −1.99
0.002 0.047
0.19–0.68 0.28–0.99
2.30 1.70
0.78 0.41
2.45 2.17
0.014 0.030
1.18–4.50 1.05–2.73
CI, confidence interval; IRR, incidence rate ratio; SE, standard error.
DISCUSSION This study has identified perinatal protective and risk factors in a cohort of school-aged children born preterm. Importantly, the factors reported here are practical, easily obtainable, and key components of children’s birth history that can guide clinicians in the assessment of OSAS in ex- preterm patients. The study has also confirmed a greater incidence of OSAS in children born preterm compared to the general pediatric population.1 Children born preterm are at increased risk for bronchopulmonary dysplasia, retinopathy of prematurity, and developmental delay, among other complications.20–24 Recently, OSAS has also been identified as a complication in this expanding SLEEP, Vol. 39, No. 4, 2016
group of children.3,5,6,25 This is particularly relevant as OSAS has been associated with negative outcomes when left untreated, such as growth failure,26 systemic27–29 and pulmonary hypertension,30,31 endothelial dysfunction,32,33 and cognitive and behavioral deficits.13,34–38 Moreover, it has been reported that the association between cognitive impairment and OSAS is stronger in children born preterm compared to those born at term.39 Therefore, it is important for pediatricians to recognize major elements of the perinatal history associated with protection or risk of the development of OSAS at school age. A previous study in an urban area of the United Stated showed that minority children, children born to single mothers, and children exposed to preeclampsia were at higher risk for OSAS 739
Perinatal Risk Factors of OSAS—Tapia et al.
at birth may have been able to predict increased incidence of OSAS at school age. Race classification was based on maternal race and most mothers were White. Further research in other races previously identified as at risk are warranted. In addition, there was lack of data on perinatal intubation, ventilatory support, and degree of apnea at birth. Finally, comprehensive ambulatory polysomnography is not the gold standard to diagnose OSAS. A broader definition of OSAS (AHI ≥ 2 events per hour and/or history of adenoidectomy/tonsillectomy) was used to account for children who may have been previously treated for OSAS. The indications for adenotonsillectomy in these participants were not available. However, the most frequent adenotonsillectomy indication is obstructed breathing.18 Specifically in the United States, 59% to 69% of tonsillectomies are performed for obstruction, and about 30% are performed for recurrent throat infection.55 Hence, it is reasonable to infer that most participants who underwent adenotonsillectomy had OSAS at that time. However, as definitive data on indications for adenotonsillectomy were not available, this second definition was used only for secondary analyses.
defined as an obstructive apnea index ≥ 1 per hour or an AHI ≥ 5 per hour at ages 8–11 years.40 Previous data in adults and children have shown that race is an independent risk factor for OSAS. Specifically, African Americans appeared to be more likely to have OSAS compared to Caucasians.2,41,42A large sample of 399 children found that African American children were 3.5 times more likely to have OSAS than Caucasian children, even after adjusting for obesity and asthma.2 The results presented here confirm that race is an important factor for OSAS as participants born to white mothers appeared to be protected. The data reported here showed that children born to older mothers were protected from OSAS. It is possible that older mothers had better socioeconomic status. However, there was no correlation between maternal education, as a marker of socioeconomic status, and maternal age in children with and without OSAS. Interestingly and in contrast to this research finding, advanced maternal age has typically been associated with poorer outcomes such as fetal death, miscarriage, preeclampsia, small for gestational age, and gestational diabetes mellitus even after adjusting for socioeconomic status.43–45 Other longitudinal studies may be needed to further clarify the association reported here. Chorioamnionitis and multiple gestation were found to be risk factors for OSAS. Chorioamnionitis is characterized by inflammation of the chorioamniotic membranes and has been associated with adverse neonatal outcomes such as sepsis, cerebral palsy, low birth weight, preterm birth, neonatal mortality, and developmental delay.46,47 It has also been associated with elevated inflammatory markers in pregnant women, such as elevated neutrophil to lymphocyte ratio and C-reactive protein.48,49 Hence, it is possible that infants born to mothers with chorioamnionitis were exposed to inflammation in utero. OSAS has been associated with elevated inflammatory markers when untreated.50 However, to the best of our knowledge there is no known link between perinatal inflammation exposure and OSAS. One plausible theory is that children perinatally exposed to inflammation have greater tonsillar and adenoidal tissue later in life. Alternatively, children born to mothers with chorioamnionitis may have other risk factors for OSAS, such as cerebral palsy. However, only 3% the participants of this study had moderate to severe cerebral palsy.10 Multiple gestation has not been linked to OSAS previously to the best of our knowledge. However, infants of multiple gestation are at increased risk for prolonged neonatal intensive care unit stay, developmental delay, and respiratory complications.51,52 Therefore, they may be prone to prolonged intubation and complications derived from there, such as a high arched palate,53 which can cause a small upper airway, a known risk factor for OSAS.54 Future longitudinal multicenter studies targeting multiple births are needed to further evaluate this association. Importantly, the best age for screening ex-preterm children for OSAS is unknown. Therefore, we suggest that pediatricians do clinical screening (especially history of snoring) at all ages as part of the well-child visits.
CONCLUSIONS Maternal age and maternal white race are independent protective factors for OSAS at ages 5–12 y in former preterm children. Chorioamnionitis and multiple gestation are significant risk factors for OSAS in these school-aged children. Based on the increased prevalence of OSAS in former preterm children, we recommend that pediatricians screen children born preterm for OSAS in order to avoid OSAS-related complications. Further research is needed to more precisely define the subpopulation at risk and the age at which OSAS is likely to present. REFERENCES 1. Lumeng JC, Chervin RD. Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc 2008;5:242–52. 2. Rosen CL, Larkin EK, Kirchner HL, et al. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 2003;142:383–9. 3. Paavonen EJ, Strang-Karlsson S, Raikkonen K, et al. Very low birth weight increases risk for sleep-disordered breathing in young adulthood: the Helsinki Study of Very Low Birth Weight Adults. Pediatrics 2007;120:778–84. 4. Calhoun SL, Vgontzas AN, Mayes SD, et al. Prenatal and perinatal complications: is it the link between race and SES and childhood sleep disordered breathing? J Clin Sleep Med 2010;6:264–9. 5. Raynes-Greenow CH, Hadfield RM, Cistulli PA, Bowen J, Allen H, Roberts CL. Sleep apnea in early childhood associated with preterm birth but not small for gestational age: a population-based record linkage study. Sleep 2012;35:1475–80. 6. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012;379:2162–72. 7. Carroll JL, McColley SA, Marcus CL, Curtis S, Loughlin GM. Inability of clinical history to distinguish primary snoring from obstructive sleep apnea syndrome in children. Chest 1995;108:610–8. 8. Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007;357:1893–902. 9. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112–21.
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Bhattacharjee, MD, University of Chicago, Chicago, IL; Lorrie Costantini, McMaster University, Hamilton, Ontario, Canada; Margot Davey, MBBS, Monash University, Melbourne Australia; Joanne Dix, RN, MSN, McMaster University, Hamilton, Ontario, Canada, Indra Narang, MBBCh. University of Toronto, Toronto, Ontario, Canada.
51. van Baaren GJ, Peelen MJ, Schuit E, et al. Preterm birth in singleton and multiple pregnancies: evaluation of costs and perinatal outcomes. Eur J Obstet Gynecol Reprod Biol 2015;186:34–41. 52. Mendez-Figueroa H, Dahlke JD, Viteri OA, et al. Neonatal and infant outcomes in twin gestations with preterm premature rupture of membranes at 24-31 weeks of gestation. Obstet Gynecol 2014;124:323–31. 53. Macey-Dare LV, Moles DR, Evans RD, Nixon F. Long-term effect of neonatal endotracheal intubation on palatal form and symmetry in 8-11-year-old children. Eur J Orthod 1999;21:703–10. 54. Arens R, McDonough JM, Corbin AM, et al. Upper airway size analysis by magnetic resonance imaging of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2003;167:65–70. 55. Boss EF, Marsteller JA, Simon AE. Outpatient tonsillectomy in children: demographic and geographic variation in the United States, 2006. J Pediatr 2012;160:814–9.
SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication June, 2015 Submitted in final revised form August, 2015 Accepted for publication September, 2015 Address correspondence to: Ignacio E. Tapia, MD, MS, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, office 11403, Philadelphia, PA 19104; Tel: (267) 426-5842; Fax: (267) 426-9234; Email: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. Funding was supplied by a National Institutes of Health grant R01 HL098045 and Canadian Institutes of Health Research grant MCT 13288. Dr. Marcus has received research support from Philips Respironics in the form of loaned equipment. The other authors have indicated no financial conflicts of interest.
ACKNOWLEDGMENTS Members of the Caffeine for Apnea of Prematurity - Sleep Study Group: Elizabeth Asztalos, MD, University of Toronto, Toronto, Ontario, Canada; Sarah Biggs, PhD, Monash University, Melbourne Australia; Rakesh
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http://dx.doi.org/10.5665/sleep.5618
PEDIATRICS
Perinatal Risk Factors Associated with the Obstructive Sleep Apnea Syndrome in School-Aged Children Born Preterm Ignacio E. Tapia, MD, MS1; Justine Shults, PhD2; Lex W. Doyle, MBBS3; Gillian M. Nixon, MBChB4; Christopher M. Cielo, DO1; Joel Traylor1; Carole L. Marcus, MBBCh1; Caffeine for Apnea of Prematurity – Sleep Study Group Sleep Center, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania; 3Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Melbourne, Australia; 4 Melbourne Children’s Sleep Centre, Monash Children’s, Monash University, Melbourne, Australia
1
Study Objectives: The obstructive sleep apnea syndrome (OSAS) is more prevalent in ex-preterm children compared to the general pediatric population. However, it is unknown whether OSAS in ex-preterm children is associated with specific perinatal risk factors. This multicenter cohort study aimed to determine perinatal factors associated with OSAS at school age. Methods: 197 ex-preterm (500–1,250 g) children aged 5–12 y who participated as neonates in a double-blind, randomized clinical trial of caffeine versus placebo (Caffeine for Apnea of Prematurity) underwent comprehensive ambulatory polysomnography. A negative binomial regression model was used to identify perinatal risk factors associated with OSAS. Results: 19 children had OSAS (9.6%). Chorioamnionitis and multiple gestation were positively associated with OSAS with P values of 0.014 and 0.03, respectively. Maternal white race (P = 0.047) and maternal age (P = 0.002) were negatively associated with OSAS. Other risk factors, such as birth weight, Apgar score at 5 min, antenatal corticosteroids, delivery route, and sex were not significant. Conclusions: OSAS is very frequent, and is associated with chorioamnionitis and multiple gestation in ex-preterm children. Those born to older white mothers appear to be protected. We speculate that the former may be due to systemic inflammation and the latter to a higher socio-economic status. Commentary: A commentary on this article appears in this issue on page 721. Keywords: OSAS, preterm, school-aged, risk factors Citation: Tapia IE, Shults J, Doyle LW, Nixon GM, Cielo CM, Traylor J, Marcus CL. Perinatal risk factors associated with the obstructive sleep apnea syndrome in school-aged children born preterm. SLEEP 2016;39(4):737–742. Significance Pediatricians need to be aware of the increased prevalence of OSAS in former preterm children and screen them for OSAS in order to avoid OSASrelated complications.
INTRODUCTION The obstructive sleep apnea syndrome (OSAS) affects 1% to 4% of children and has been associated with several risk factors, such as adenotonsillar hypertrophy, hypotonia, craniofacial anomalies, obesity, and history of prematurity, among others.1 Prematurity was first associated with OSAS by Rosen et al. in 2003.2 Since then, other investigators have highlighted the association between OSAS, during childhood and adulthood, and prematurity.3–5 However, it is unknown whether former preterm infants have specific perinatal risks factors associated with OSAS. This question is important because perinatal care has significantly progressed over the years, resulting in greater numbers of surviving former preterm individuals.6 Therefore, it is important for clinicians to know whether there are key elements of the patient’s history that could help determine who requires polysomnography, as symptoms of OSAS are often not reported by caregivers.7 The Caffeine for Apnea of Prematurity-Sleep study (CAPS) followed a cohort of children, now aged 5–12 years, born preterm in Canada and Australia, who participated in the Caffeine for Apnea of Prematurity study.8,9 All children underwent polysomnography. For the current study, birth and demographic data from CAPS were analyzed in respect to the polysomnographic findings at school age with the aim of determining perinatal factors associated with OSAS at school age.
follow up cohort have been described elsewhere in detail.10,11 In brief, four CAP sites were selected to participate in this study based on cohort size and geographic proximity. The Institutional Review Board at Children’s Hospital of Philadelphia and at each clinical site approved the study and written informed consent was obtained from parents/guardians. 201 children born preterm, with birth weights of 500–1,250 g and without major congenital anomalies or syndromes, were enrolled. Subjects were initially enrolled in CAP if their clinicians considered them to be candidates for methylxanthine therapy during the first 10 days of life, either to prevent apnea, treat apnea, or facilitate extubation. They were randomized to placebo or caffeine. Forty percent of children in the caffeine group and 40% of those in the placebo group had documented apnea of prematurity. Subjects completed comprehensive unattended ambulatory polysomnography at school age (5–12 years) as previously described in detail.11 Briefly, ambulatory polysomnography was performed at the child’s usual sleep times. A technologist went to the child’s home to place the following leads (Siesta 802, Compumedics): electroencephalograms (C4/M1, C3/M2, F4/ M1, F3/M2, O2/M1, O1/M2), electro-oculograms, submental and tibial electromyograms, chest and abdominal wall movement by inductance plethysmography, electrocardiogram, airflow (nasal pressure and oronasal thermistor), and arterial oxygen saturation with pulse waveform. Because of the difficulty of obtaining adequate signals in an unattended setting, capnometry was not performed. Studies were scored using
METHODS This study was a prospective follow-up of the Caffeine for Apnea of Prematurity (CAP) study 8,9 and the methods of this SLEEP, Vol. 39, No. 4, 2016
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Figure 1—Incidence rate ratio of maternal age at delivery associated with obstructive sleep apnea syndrome at school age. Second, third, and fourth maternal age quartiles are referenced to the first quartile. The closed circles represent the incidence rate ratio and the open circles the 5th and 95th confidence intervals. Values below 1 are protective. First age quartile: 20.8–27.6 y, second age quartile: 27.6–31.6 y, third age quartile: 31.7–34.9 y, fourth age quartile: 35–47 y. Children born to older mothers had a lower incidence rate ratio of obstructive sleep apnea syndrome at school age.
standard pediatric rules.12 Two definitions of OSAS were used to investigate risks factors associated with OSAS at school age. (1) OSAS was defined as an obstructive apnea-hypopnea index (AHI) ≥ 2 events per hour on polysomnography,13–16 and (2) OSAS was defined as an AHI ≥ 2 events per hour and/or history of adenoidectomy/tonsillectomy. This classification was used because OSAS is the most common indication for adenotonsillectomies in children and therefore, it is probable that participants who underwent these surgical procedures had OSAS at the time of the surgery.17,18 Statistical Analysis Two analyses were performed based on the two definitions of OSAS. Because the AHI was similar between participants treated with caffeine or placebo,10 both groups were pooled for these analyses. First, clinical data from the CAP study were evaluated to investigate the relationship with OSAS at age 5–12 y and defined as an obstructive AHI ≥ 2 events per hour.13–16 Negative binomial regression models were fitted, for which outcome was the count of obstructive events, defined as the sum of obstructive apnea, hypopnea, and mixed apnea events per child adjusted per hour of sleep. The original regression models included the clinical data present in the database: maternal race, maternal age, maternal education, presence of chorioamnionitis, multiple gestation, birth weight, sex, Apgar score at 5 min, antenatal corticosteroids, and delivery route. Data on respiratory support were not part of the parent study. Clinical variables that were not significantly associated with the outcome variable were removed one at a time, in a manual stepwise approach that removed variables with the largest P value first. The fit of the final model was assessed using the countfit command in Stata, which indicated SLEEP, Vol. 39, No. 4, 2016
that the fit of a negative binomial model was superior to that of a Poisson regression model.19 Incidence rate ratios higher than 1 were considered risk factors and those lower than 1, protective factors. For example, the incidence rate ratio of 1.7 for multiple gestation indicated that the rate of events in those children who were product of a multiple gestation was 1.7 times greater than in those who were a product of a single gestation. Next, logistic regressions were performed defining OSAS as an AHI ≥ 2 events per hour and/or history of adenoidectomy/ tonsillectomy. OSAS was defined as a categorical variable for this analysis to avoid a floor effect as most of these participants had normal AHI at ages 5–12 years. Variables present in the database were included in multivariable logistic regression models. Variables that were not significantly associated with the outcome variable were removed one at a time, using the same manual stepwise approach as for the negative binomial regression models. The hypothesis of adequate fit was tested using the Hosmer-Lemeshow test. All statistical analyses were performed using Stata 13.0 (StataCorp. 2013. College Station, TX). A two-sided P = 0.05 was considered statistically significant. RESULTS Two hundred one participants underwent comprehensive ambulatory polysomnography, which was successful in 197 participants whose characteristics are presented in Table 1.11 There was no difference in age between participants with and without OSAS defined solely on the AHI. Five children with OSAS, with AHI ranging between 5.3 and 22.1 events per hour, and 33 children without OSAS, had a history of tonsillectomy and/ or adenoidectomy. Nineteen participants met the AHI-based OSAS definition, and 52 met the AHI and/or history of tonsillectomy/adenoidectomy OSAS definition. Three percent of the participants of this study had moderate to severe cerebral palsy. The negative binomial regression model showed that maternal age and maternal White race were independent protective factors for OSAS at age 5–12 years (Table 2). Considering there was a wide range of maternal ages, these were further grouped into quartiles to ascertain whether a specific age group was responsible for this protective effect. The fourth quartile only, mothers aged 35–47 years at delivery, was strongly associated with absence of OSAS at age 5–12 years (Figure 1). Chorioamnionitis and multiple gestation were significant risk factors for OSAS in these school-aged children (Table 2). Birth weight, Apgar score at 5 min, antenatal corticosteroids, delivery route, and sex were not significant risk or protective factors for OSAS in this cohort. There was no significant correlation between maternal age and education in children with and without OSAS. Specifically, children with OSAS had an r of −0.15 with P = 0.53, and children without OSAS an r of −0.14 with P = 0.063. The logistic regression model using a broader definition of OSAS (AHI ≥ 2 events per hour and/or history of adenoidectomy/tonsillectomy), showed that only a birth weight ≤ 10th percentile was associated with OSAS at age 5–12 y, with an odds ratio of 2.8 compared to those with birth weights > 10th percentile (P = 0.033, 95% confidence interval [CI] 1.1 to 7.2). 738
Perinatal Risk Factors of OSAS—Tapia et al.
Table 1—Demographic, perinatal, and polysomnographic data. OSAS (n = 19) 9.5 (8.3–9.8)
Age, median (IQR), y Male, n (%) Maternal race, n (%) White Black Asian Other Maternal education, n (%) Did not finish high school High school graduate Attended college or university College or university graduate Unknown Perinatal data Gestational age, mean ± SD, w Birth weight, mean ± SD, g Chorioamnionitis, n (%) Cesarean section, n (%) Antenatal corticosteroids, n (%) Multiple gestation, n (%) Apgar at 5 min, mean ± SD, points Maternal age at delivery, mean ± SD, years Polysomnographic data Apnea-hypopnea index, median (IQR), n/h SpO2 nadir, median (range), % Time with SpO2 < 90%, median (IQR), % TST
Non-OSAS (n = 178) 9.2 (7.7–11.2)
P 0.89
9 (31.0)
105 (59.0)
0.34
14 (73.7) 1 (5.3) 4 (21.0) 0 (0)
150 (84.3) 10 (5.6) 16 (9.0) 2 (1.1)
0.33 1.00 0.11 1.00
2 (10.5) 5 (26.3) 7 (36.9) 5 (26.3) 0 (0)
30 (16.9) 41 (23) 38 (21.3) 65 (36.6) 4 (2.2)
0.74 0.77 0.15 0.46 1.00
27.6 ± 1.6 944 ± 185.6 4 (21.1) 12 (63.2) 17 (89.5) 8 (42.1) 8.2 ± 1.5 30.9 ± 5.1
27.2 ± 1.7 973.9 ± 169.0 25 (14.0) 116 (65.2) 158 (88.8) 65 (36.5) 7.9 ± 1.3 31.7 ± 5.4
0.38 0.47 0.49 1.00 1.00 0.63 0.36 0.56
5.3 (3.5–12.8) 89 (85–91) 0 (0–0.1)
0.2 (0.1–0.6) 92 (91–94) 0 (0–0)
< 0.0001 < 0.0001 < 0.0001
IQR, interquartile range; OSAS, obstructive sleep apnea syndrome defined as an apnea-hypopnea index ≥ 2 events per hour; SD, standard deviation; SpO2, oxyhemoglobin saturation; TST, total sleep time.
Table 2—Factors associated with obstructive sleep apnea in former preterm infants at age 5–12 y. Protective factors Maternal age 4th quartile (35.2–47.4 y) Maternal white race Risk factors Chorioamnionitis Multiple gestation
IRR
SE
z
P
IRR 95% CI
0.36 0.53
0.12 0.17
−3.15 −1.99
0.002 0.047
0.19–0.68 0.28–0.99
2.30 1.70
0.78 0.41
2.45 2.17
0.014 0.030
1.18–4.50 1.05–2.73
CI, confidence interval; IRR, incidence rate ratio; SE, standard error.
DISCUSSION This study has identified perinatal protective and risk factors in a cohort of school-aged children born preterm. Importantly, the factors reported here are practical, easily obtainable, and key components of children’s birth history that can guide clinicians in the assessment of OSAS in ex- preterm patients. The study has also confirmed a greater incidence of OSAS in children born preterm compared to the general pediatric population.1 Children born preterm are at increased risk for bronchopulmonary dysplasia, retinopathy of prematurity, and developmental delay, among other complications.20–24 Recently, OSAS has also been identified as a complication in this expanding SLEEP, Vol. 39, No. 4, 2016
group of children.3,5,6,25 This is particularly relevant as OSAS has been associated with negative outcomes when left untreated, such as growth failure,26 systemic27–29 and pulmonary hypertension,30,31 endothelial dysfunction,32,33 and cognitive and behavioral deficits.13,34–38 Moreover, it has been reported that the association between cognitive impairment and OSAS is stronger in children born preterm compared to those born at term.39 Therefore, it is important for pediatricians to recognize major elements of the perinatal history associated with protection or risk of the development of OSAS at school age. A previous study in an urban area of the United Stated showed that minority children, children born to single mothers, and children exposed to preeclampsia were at higher risk for OSAS 739
Perinatal Risk Factors of OSAS—Tapia et al.
at birth may have been able to predict increased incidence of OSAS at school age. Race classification was based on maternal race and most mothers were White. Further research in other races previously identified as at risk are warranted. In addition, there was lack of data on perinatal intubation, ventilatory support, and degree of apnea at birth. Finally, comprehensive ambulatory polysomnography is not the gold standard to diagnose OSAS. A broader definition of OSAS (AHI ≥ 2 events per hour and/or history of adenoidectomy/tonsillectomy) was used to account for children who may have been previously treated for OSAS. The indications for adenotonsillectomy in these participants were not available. However, the most frequent adenotonsillectomy indication is obstructed breathing.18 Specifically in the United States, 59% to 69% of tonsillectomies are performed for obstruction, and about 30% are performed for recurrent throat infection.55 Hence, it is reasonable to infer that most participants who underwent adenotonsillectomy had OSAS at that time. However, as definitive data on indications for adenotonsillectomy were not available, this second definition was used only for secondary analyses.
defined as an obstructive apnea index ≥ 1 per hour or an AHI ≥ 5 per hour at ages 8–11 years.40 Previous data in adults and children have shown that race is an independent risk factor for OSAS. Specifically, African Americans appeared to be more likely to have OSAS compared to Caucasians.2,41,42A large sample of 399 children found that African American children were 3.5 times more likely to have OSAS than Caucasian children, even after adjusting for obesity and asthma.2 The results presented here confirm that race is an important factor for OSAS as participants born to white mothers appeared to be protected. The data reported here showed that children born to older mothers were protected from OSAS. It is possible that older mothers had better socioeconomic status. However, there was no correlation between maternal education, as a marker of socioeconomic status, and maternal age in children with and without OSAS. Interestingly and in contrast to this research finding, advanced maternal age has typically been associated with poorer outcomes such as fetal death, miscarriage, preeclampsia, small for gestational age, and gestational diabetes mellitus even after adjusting for socioeconomic status.43–45 Other longitudinal studies may be needed to further clarify the association reported here. Chorioamnionitis and multiple gestation were found to be risk factors for OSAS. Chorioamnionitis is characterized by inflammation of the chorioamniotic membranes and has been associated with adverse neonatal outcomes such as sepsis, cerebral palsy, low birth weight, preterm birth, neonatal mortality, and developmental delay.46,47 It has also been associated with elevated inflammatory markers in pregnant women, such as elevated neutrophil to lymphocyte ratio and C-reactive protein.48,49 Hence, it is possible that infants born to mothers with chorioamnionitis were exposed to inflammation in utero. OSAS has been associated with elevated inflammatory markers when untreated.50 However, to the best of our knowledge there is no known link between perinatal inflammation exposure and OSAS. One plausible theory is that children perinatally exposed to inflammation have greater tonsillar and adenoidal tissue later in life. Alternatively, children born to mothers with chorioamnionitis may have other risk factors for OSAS, such as cerebral palsy. However, only 3% the participants of this study had moderate to severe cerebral palsy.10 Multiple gestation has not been linked to OSAS previously to the best of our knowledge. However, infants of multiple gestation are at increased risk for prolonged neonatal intensive care unit stay, developmental delay, and respiratory complications.51,52 Therefore, they may be prone to prolonged intubation and complications derived from there, such as a high arched palate,53 which can cause a small upper airway, a known risk factor for OSAS.54 Future longitudinal multicenter studies targeting multiple births are needed to further evaluate this association. Importantly, the best age for screening ex-preterm children for OSAS is unknown. Therefore, we suggest that pediatricians do clinical screening (especially history of snoring) at all ages as part of the well-child visits.
CONCLUSIONS Maternal age and maternal white race are independent protective factors for OSAS at ages 5–12 y in former preterm children. Chorioamnionitis and multiple gestation are significant risk factors for OSAS in these school-aged children. Based on the increased prevalence of OSAS in former preterm children, we recommend that pediatricians screen children born preterm for OSAS in order to avoid OSAS-related complications. Further research is needed to more precisely define the subpopulation at risk and the age at which OSAS is likely to present. REFERENCES 1. Lumeng JC, Chervin RD. Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc 2008;5:242–52. 2. Rosen CL, Larkin EK, Kirchner HL, et al. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 2003;142:383–9. 3. Paavonen EJ, Strang-Karlsson S, Raikkonen K, et al. Very low birth weight increases risk for sleep-disordered breathing in young adulthood: the Helsinki Study of Very Low Birth Weight Adults. Pediatrics 2007;120:778–84. 4. Calhoun SL, Vgontzas AN, Mayes SD, et al. Prenatal and perinatal complications: is it the link between race and SES and childhood sleep disordered breathing? J Clin Sleep Med 2010;6:264–9. 5. Raynes-Greenow CH, Hadfield RM, Cistulli PA, Bowen J, Allen H, Roberts CL. Sleep apnea in early childhood associated with preterm birth but not small for gestational age: a population-based record linkage study. Sleep 2012;35:1475–80. 6. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012;379:2162–72. 7. Carroll JL, McColley SA, Marcus CL, Curtis S, Loughlin GM. Inability of clinical history to distinguish primary snoring from obstructive sleep apnea syndrome in children. Chest 1995;108:610–8. 8. Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007;357:1893–902. 9. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112–21.
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Bhattacharjee, MD, University of Chicago, Chicago, IL; Lorrie Costantini, McMaster University, Hamilton, Ontario, Canada; Margot Davey, MBBS, Monash University, Melbourne Australia; Joanne Dix, RN, MSN, McMaster University, Hamilton, Ontario, Canada, Indra Narang, MBBCh. University of Toronto, Toronto, Ontario, Canada.
51. van Baaren GJ, Peelen MJ, Schuit E, et al. Preterm birth in singleton and multiple pregnancies: evaluation of costs and perinatal outcomes. Eur J Obstet Gynecol Reprod Biol 2015;186:34–41. 52. Mendez-Figueroa H, Dahlke JD, Viteri OA, et al. Neonatal and infant outcomes in twin gestations with preterm premature rupture of membranes at 24-31 weeks of gestation. Obstet Gynecol 2014;124:323–31. 53. Macey-Dare LV, Moles DR, Evans RD, Nixon F. Long-term effect of neonatal endotracheal intubation on palatal form and symmetry in 8-11-year-old children. Eur J Orthod 1999;21:703–10. 54. Arens R, McDonough JM, Corbin AM, et al. Upper airway size analysis by magnetic resonance imaging of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2003;167:65–70. 55. Boss EF, Marsteller JA, Simon AE. Outpatient tonsillectomy in children: demographic and geographic variation in the United States, 2006. J Pediatr 2012;160:814–9.
SUBMISSION & CORRESPONDENCE INFORMATION Submitted for publication June, 2015 Submitted in final revised form August, 2015 Accepted for publication September, 2015 Address correspondence to: Ignacio E. Tapia, MD, MS, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, office 11403, Philadelphia, PA 19104; Tel: (267) 426-5842; Fax: (267) 426-9234; Email: [email protected]
DISCLOSURE STATEMENT This was not an industry supported study. Funding was supplied by a National Institutes of Health grant R01 HL098045 and Canadian Institutes of Health Research grant MCT 13288. Dr. Marcus has received research support from Philips Respironics in the form of loaned equipment. The other authors have indicated no financial conflicts of interest.
ACKNOWLEDGMENTS Members of the Caffeine for Apnea of Prematurity - Sleep Study Group: Elizabeth Asztalos, MD, University of Toronto, Toronto, Ontario, Canada; Sarah Biggs, PhD, Monash University, Melbourne Australia; Rakesh
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