Abstract
Background
Preterm birth (gestational age <37 weeks) has previously been associated with cardiometabolic and neuropsychiatric disorders into adulthood, but has seldom been examined in relation to sleep disorders. We conducted the first population-based study of preterm birth in relation to sleep-disordered breathing (SDB) from childhood into mid-adulthood.
Methods
A national cohort study was conducted of all 4 186 615 singleton live births in Sweden during 1973–2014, who were followed for SDB ascertained from nationwide inpatient and outpatient diagnoses through 2015 (maximum age 43 years). Cox regression was used to examine gestational age at birth in relation to SDB while adjusting for other perinatal and maternal factors, and co-sibling analyses assessed for potential confounding by unmeasured shared familial factors.
Results
There were 171 100 (4.1%) persons diagnosed with SDB in 86.0 million person-years of follow-up. Preterm birth was associated with increased risk of SDB from childhood into mid-adulthood, relative to full-term birth (39–41 weeks) [adjusted hazard ratio (aHR), ages 0–43 years: 1.43; 95% confidence interval (CI), 1.40, 1.46; P <0.001; ages 30–43 years: 1.40; 95% CI, 1.34, 1.47; P <0.001]. Persons born extremely preterm (<28 weeks) had more than 2-fold risks (aHR, ages 0–43 years: 2.63; 95% CI, 2.41, 2.87; P <0.001; ages 30–43 years: 2.22; 95% CI, 1.64, 3.01; P <0.001). These associations affected both males and females, but accounted for more SDB cases among males (additive interaction, P = 0.003). Co-sibling analyses suggested that these findings were only partly due to shared genetic or environmental factors in families.
Conclusions
Preterm-born children and adults need long-term follow-up for anticipatory screening and potential treatment of SDB.
Keywords: Premature birth, sleep, sleep apnoea syndromes
Key Messages
Preterm birth has been associated with cardiometabolic and neuropsychiatric disorders into adulthood, but has rarely been examined in relation to sleep-disordered breathing (SBD), a potential mediator for many of those same disorders.
In a large national cohort study, preterm birth and extremely preterm birth were associated with 1.4- and 2.6-fold risks of SDB, respectively, from birth up to age 43 years.
Preterm-born children and adults need long-term follow-up for anticipatory screening and potential treatment of SDB.
Introduction
Preterm birth (gestational age <37 weeks) has a worldwide prevalence of 11%,1 and has been associated with cardiometabolic2–8 and neuropsychiatric9–12 disorders into adulthood. Sleep-disordered breathing (SDB) is a common risk factor or potential mediator for many of those same disorders,13–17 but has seldom been examined in preterm birth survivors. SDB is characterized by intermittent upper airway obstruction that disrupts normal ventilation during sleep, with symptoms ranging in severity from primary snoring to obstructive sleep apnoea (OSA).18,19 SDB may potentially play a role in mediating the increased risks of cardiometabolic or neuropsychiatric disorders in preterm-born children and adults. If so, preventive efforts in these patients should include screening, detection and treatment of the underlying sleep disorder. A better understanding of SDB risks in preterm survivors is critically needed to facilitate more effective long-term care of these patients.
A few earlier studies have reported associations between preterm birth and SDB in infancy20 and childhood.21–23 However, it is unknown whether an increased risk of SDB persists later in life. The only study to date that included preterm-born adults was a small case-control study that reported a 2-fold risk of chronic snoring in young adults aged 18–27 years who were born preterm with very low birth weight.24 No population-based cohort studies have examined preterm birth in relation to SDB, and the risks later in adulthood remain unknown.
We conducted a national cohort study of 4.1 million persons in Sweden to examine preterm birth in relation to SDB risk from childhood into mid-adulthood. Our goals were to provide the first population-based risk estimates for SDB associated with gestational age at birth, assess for sex-specific differences and explore the potential influence of shared familial (genetic and/or environmental) factors on these associations using co-sibling analyses. The results may help guide long-term surveillance for SDB in preterm-born children and adults, and inform future investigations of its role as a potential mediator of other chronic disease risks.
Methods
Study population
The Swedish Birth Registry contains prenatal and birth information for nearly all births nationwide since 1973.25 Using this registry, we identified 4 195 249 singleton live births in Sweden during 1973–2014. We excluded 8634 (0.2%) births that had missing information for gestational age, leaving 4 186 615 births (99.8% of the original cohort) for inclusion in the study. This study was approved by the Ethics Committee of Lund University in Sweden.
Ascertainment of gestational age at birth and sleep-disordered breathing
Gestational age at birth was identified from the Swedish Birth Registry, based on maternal report of last menstrual period in the 1970s and on ultrasound estimation in the 1980s and later. This was examined alternatively as a continuous variable or categorical variable with six groups: extremely preterm (22–27 weeks), very preterm (28–33 weeks), late preterm (34–36 weeks), early-term (37–38 weeks), full-term (39–41 weeks, used as the reference group) and post-term (≥42 weeks). In addition, the first three groups were combined to provide summary estimates for preterm birth (<37 weeks).
The study cohort was followed up for the earliest diagnosis of SDB from birth through 31 December 2015 (maximum age 43 years), using inpatient and outpatient clinical diagnoses. SDB has no specific diagnostic code in Sweden; instead, sleep apnoea and adenotonsillar hypertrophy are regularly used as proxies.26–29 SDB was therefore identified in the Swedish Hospital Registry and Swedish Outpatient Registry using International Classification of Diseases (ICD) codes for sleep apnoea (ICD-9: 327.2, 780.51, 780.53, 780.57; ICD-10: G47.3) and adenotonsillar hypertrophy (ICD-8: 500; ICD-9: 474B, ICD-10: J35.1, J35.3). The Swedish Hospital Registry contains all primary and secondary hospital discharge diagnoses from six populous counties in southern Sweden starting in 1964, and with nationwide coverage starting in 1987; and the Swedish Outpatient Registry contains outpatient diagnoses from all specialty clinics nationwide starting in 2001. To our knowledge, there are no previous validation studies for sleep apnoea and adenotonsillar hypertrophy diagnoses in these registries; however, diagnoses in the Swedish Hospital Registry have been reported to have positive predictive values of at least 85–95% for a wide range of other common conditions.30
Other study variables
Other perinatal and maternal characteristics that may be associated with gestational age at birth and SDB risk were identified using the Swedish Birth Registry and national census data, which were linked using an anonymous personal identification number. The following were included as adjustment variables: birth year (continuous), sex, birth order (1, 2, ≥3), congenital anomalies (yes/no, identified using codes 740–759 in ICD-8/9 and Q00-Q99 in ICD-10), maternal age (continuous), maternal education level (<10, 10–12, >12 years), maternal body mass index (BMI; continuous), maternal smoking (0, 1–9, ≥10 cigarettes/day), preeclampsia (ICD-8: 637; ICD-9: 624.4–624.7; ICD-10: O14-O15) and diabetes mellitus during pregnancy (ICD-8: 250; ICD-9: 250, 648.0; ICD-10: O24, E10-E14). Maternal preeclampsia and diabetes were examined because they have been associated with preterm delivery31 and maternal SDB,32,33 though it is unclear whether they are also associated with SDB in the offspring.
Maternal BMI and smoking were assessed at the beginning of prenatal care starting in 1982, and were available for 61.0% and 74.2% of women, respectively. Data were >99% complete for all other variables. Missing data for each covariate were imputed using a standard multiple imputation procedure based on the variable’s relationship with all other covariates and SDB.34
Statistical analysis
Cox proportional hazards regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between gestational age at birth and risk of SDB. These associations were examined across the entire age range of 0–43 years and in narrower age ranges (0–9, 10–19, 20–29, 30–43 years) among persons still living in Sweden and without a previous diagnosis of SDB at the beginning of the respective age range. Attained age was used as the Cox model time axis. Individuals were censored at death as identified in the Swedish Death Registry (n = 42 696; 1.0%), or at emigration as determined by absence of a Swedish residential address in census data (n = 252 788; 6.0%). Emigrants and non-emigrants had a similar gestational duration (median, 40 1/7 weeks for both groups), and thus it was unlikely that emigration introduced any substantial bias. Analyses were conducted both unadjusted and adjusted for covariates (as above). The proportional hazards assumption was assessed by examining log-log plots,35 and was met in each model.
Sex-specific differences were assessed by performing sex-stratified analyses and examining interactions between gestational age at birth and sex in relation to SDB risk on both the additive and the multiplicative scales. Additive interactions were tested using the ‘relative excess risk due to interaction’ (RERI), which is computed for binary variables as: RERIHR = HR11 − HR10 – HR01 + 1.36,37 Multiplicative interactions were tested using the ratio of HRs: HR11 / (HR10 HR01).37
Co-sibling analyses were performed to assess for potential confounding effects of unmeasured shared familial (genetic and/or environmental) factors. These analyses used stratified Cox regression with a separate stratum for each family as identified by the mother’s anonymous identification number. A total of 3 504 900 individuals (83.7% of the cohort) had at least one sibling and were included in these analyses. In the stratified Cox model, each set of siblings has its own baseline hazard function that reflects the family’s shared genetic and environmental factors, and thus comparisons of different gestational ages at birth are made within the family. In addition, these analyses were further adjusted for the same covariates as in the main analyses.
In secondary analyses, we further adjusted for fetal growth (defined as birthweight standardized for gestational age and sex based on Swedish reference intrauterine growth curves38) to explore the effects of gestational age at birth on SDB risk independent of fetal growth. We also examined diagnostic codes more specific for sleep apnoea as a secondary outcome (ICD-9: 327.2, 780.51, 780.53, 780.57; ICD-10: G47.3; i.e. excluding adenotonsillar hypertrophy diagnoses). In addition, we examined other perinatal and maternal characteristics (as above) to identify other early-life risk factors for SDB. All statistical tests were two-sided and used an α-level of 0.05. All analyses were conducted using Stata version 15.1.
Results
Table 1 shows perinatal and maternal characteristics by gestational age at birth. Preterm infants were more likely than term infants to be male or firstborn, or have congenital anomalies; and their mothers were more likely to be at the extremes of age, have low education level or high BMI, smoke or have preeclampsia or diabetes during their pregnancy.
Table 1.
Characteristics of study participants by gestational age at birth, Sweden, 1973–2014
| Extremely preterm | Very preterm | Late preterm | Early-term | Full-term | Post-term | |
|---|---|---|---|---|---|---|
| (22–27 wks) | (28-33 wks) | (34-36 wks) | (37-38 wks) | (39-41 wks) | (≥42 wks) | |
| N = 8129 | N = 43 516 | N = 155 626 | N = 737 412 | N = 2 895 746 | N = 346 186 | |
| n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | |
| Child characteristics | ||||||
| Sex | ||||||
| Male | 4435 (54.6) | 24 286 (55.8) | 84 696 (54.4) | 379 645 (51.5) | 1 471 045 (50.8) | 188 354 (54.4) |
| Female | 3694 (45.4) | 19 230 (44.2) | 70 930 (45.6) | 357 767 (48.5) | 1 424 701 (49.2) | 157 832 (45.6) |
| Birth order | ||||||
| 1 | 4094 (50.4) | 22 513 (51.7) | 77 533 (49.8) | 296 887 (40.3) | 1 218 861 (42.1) | 172 698 (49.9) |
| 2 | 2292 (28.2) | 12 211 (28.1) | 46 346 (29.8) | 269 837 (36.6) | 1 087 327 (37.5) | 111 056 (32.1) |
| ≥3 | 1743 (21.4) | 8792 (20.2) | 31 747 (20.4) | 170 688 (23.1) | 589 558 (20.4) | 62 432 (18.0) |
| Congenital anomalies | 219 (2.7) | 1115 (2.6) | 1775 (1.1) | 2733 (0.4) | 5024 (0.2) | 944 (0.3) |
| Maternal characteristics | ||||||
| Age (years) | ||||||
| <20 | 356 (4.4) | 2056 (4.7) | 6464 (4.2) | 22 060 (3.0) | 84 018 (2.9) | 12 962 (3.7) |
| 20-24 | 1554 (19.1) | 8868 (20.4) | 33 037 (21.2) | 138 918 (18.8) | 580 804 (20.1) | 76 288 (22.0) |
| 25-29 | 2378 (29.3) | 13 488 (31.0) | 50 748 (32.6) | 242 523 (32.9) | 1 018 704 (35.2) | 121 282 (35.0) |
| 30-34 | 2206 (27.1) | 11 552 (26.6) | 40 970 (26.3) | 210 743 (28.6) | 821 392 (28.4) | 92 811 (26.8) |
| 35-39 | 1280 (15.7) | 6012 (13.8) | 19 826 (12.7) | 100 289 (13.6) | 330 684 (11.4) | 36 880 (10.7) |
| ≥40 | 355 (4.4) | 1540 (3.5) | 4581 (2.9) | 22 879 (3.1) | 60 144 (2.1) | 5963 (1.7) |
| Education (years) | ||||||
| ≤9 | 1369 (16.8) | 7229 (16.6) | 24 216 (15.6) | 103 813 (14.1) | 367 744 (12.7) | 48 593 (14.0) |
| 10-12 | 3867 (47.6) | 20 812 (47.8) | 73 689 (47.3) | 337 757 (45.8) | 1 304 617 (45.1) | 157 016 (45.4) |
| >12 | 2893 (35.6) | 15 475 (35.6) | 57 721 (37.1) | 295 842 (40.1) | 1 223 385 (42.2) | 140 577 (40.6) |
| Body mass index | ||||||
| <18.5 | 137 (1.7) | 1118 (2.6) | 4767 (3.1) | 21 727 (2.9) | 65 593 (2.3) | 4649 (1.3) |
| 18.5-24.9 | 6006 (73.9) | 33 733 (77.5) | 120 397 (77.4) | 565 433 (76.7) | 2 279 136 (78.7) | 275 210 (79.5) |
| 25.0-29.9 | 1381 (17.0) | 5935 (13.6) | 21 157 (13.6) | 107 005 (14.5) | 404 104 (14.0) | 46 599 (13.5) |
| ≥30.0 | 605 (7.4) | 2730 (6.3) | 9305 (6.0) | 43 247 (5.9) | 146 913 (5.1) | 19 728 (5.7) |
| Smoking (cigarettes/day) | ||||||
| 0 | 5904 (72.6) | 30 588 (70.3) | 113 066 (72.6) | 562 247 (76.3) | 2 215 716 (76.5) | 247 294 (71.4) |
| 1-9 | 1731 (21.3) | 10 181 (23.4) | 33 600 (21.6) | 138 227 (18.7) | 567 319 (19.6) | 87 933 (25.4) |
| ≥10 | 494 (6.1) | 2747 (6.3) | 8960 (5.8) | 36 938 (5.0) | 112 711 (3.9) | 10 959 (3.2) |
| Preeclampsia | 1027 (12.6) | 7775 (17.8) | 15 822 (10.2) | 39 087 (5.3) | 94 678 (3.3) | 11 831 (3.4) |
| Diabetes mellitus | 88 (1.1) | 902 (2.1) | 3867 (2.5) | 11 940 (1.6) | 16 748 (0.6) | 710 (0.2) |
Gestational age at birth and risk of SDB
There were 171 100 (4.1%) SDB cases identified in 86.0 million person-years of follow-up, yielding an overall incidence rate of 199.00 per 100 000 person-years across the entire age range examined (0–43 years). The corresponding incidence rates were 281.63 among those born preterm, 220.35 among those born at early term and 191.50 among those born at full term (Table 2).
Table 2.
Associations between gestational age at birth and risk of sleep-disordered breathing (SDB), Sweden, 1973–2015
| All |
Males |
Females |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Unadjusted |
Adjusted
a
|
Adjusted
a
|
Adjusted
a
|
||||||||||
| Cases | Rate b | HR (95% CI) | HR (95% CI) | P | Cases | Rate b | HR (95% CI) | P | Cases | Rate b | HR (95% CI) | P | |
| Attained ages 0-43 years | |||||||||||||
| Preterm (<37 weeks) | 11 364 | 281.63 | 1.49 (1.46, 1.52) | 1.43 (1.40, 1.46) | <0.001 | 6725 | 303.69 | 1.43 (1.40, 1.47) | <0.001 | 4639 | 254.81 | 1.42 (1.38, 1.47) | <0.001 |
| Extremely preterm (<28 weeks) | 506 | 640.30 | 3.51 (3.22, 3.83) | 2.63 (2.41, 2.87) | <0.001 | 306 | 750.24 | 2.82 (2.52, 3.16) | <0.001 | 200 | 523.02 | 2.39 (2.08, 2.75) | <0.001 |
| Very preterm (28-33 weeks) | 2812 | 354.27 | 1.88 (1.81, 1.96) | 1.76 (1.70, 1.83) | <0.001 | 1663 | 377.60 | 1.74 (1.66, 1.83) | <0.001 | 1149 | 325.19 | 1.79 (1.69, 1.90) | <0.001 |
| Late preterm (34-36 weeks) | 8046 | 254.44 | 1.34 (1.31, 1.37) | 1.31 (1.28, 1.34) | <0.001 | 4756 | 274.40 | 1.31 (1.27, 1.35) | <0.001 | 3290 | 230.23 | 1.30 (1.25, 1.35) | <0.001 |
| Early-term (37-38 weeks) | 32 067 | 220.35 | 1.18 (1.16, 1.19) | 1.12 (1.10, 1.13) | <0.001 | 17 953 | 236.38 | 1.11 (1.10, 1.13) | <0.001 | 14 114 | 202.85 | 1.12 (1.10, 1.14) | <0.001 |
| Full-term (39-41 weeks) | 113 862 | 191.50 | Reference | Reference | 63 005 | 208.55 | Reference | 50 857 | 173.88 | Reference | |||
| Post-term (≥42 weeks) | 13 807 | 174.10 | 0.86 (0.84, 0.87) | 0.95 (0.94, 0.97) | <0.001 | 8209 | 196.28 | 0.97 (0.94, 0.99) | 0.004 | 5598 | 149.35 | 0.94 (0.91, 0.97) | <0.001 |
| Per additional week (trend) | 0.93 (0.93, 0.93) | 0.95 (0.95, 0.95) | <0.001 | 0.95 (0.95, 0.95) | <0.001 | 0.95 (0.94, 0.95) | <0.001 | ||||||
| Attained ages 0-9 years | |||||||||||||
| Preterm (<37 weeks) | 5773 | 336.02 | 1.57 (1.53, 1.61) | 1.51 (1.47, 1.55) | <0.001 | 3430 | 365.96 | 1.49 (1.44, 1.55) | <0.001 | 2343 | 300.07 | 1.53 (1.47, 1.60) | <0.001 |
| Extremely preterm (<28 weeks) | 366 | 906.14 | 4.26 (3.84, 4.72) | 3.06 (2.76, 3.39) | <0.001 | 229 | 1083.02 | 3.25 (2.85, 3.70) | <0.001 | 137 | 711.82 | 2.77 (2.34, 3.28) | <0.001 |
| Very preterm (28-33 weeks) | 1482 | 431.46 | 2.02 (1.92, 2.13) | 1.88 (1.78, 1.98) | <0.001 | 877 | 461.12 | 1.81 (1.69, 1.94) | <0.001 | 605 | 394.66 | 1.98 (1.82, 2.15) | <0.001 |
| Late preterm (34-36 weeks) | 3925 | 294.18 | 1.38 (1.33, 1.42) | 1.35 (1.30, 1.39) | <0.001 | 2324 | 320.15 | 1.33 (1.28, 1.39) | <0.001 | 1601 | 263.20 | 1.37 (1.30, 1.44) | <0.001 |
| Early-term (37-38 weeks) | 16 047 | 252.61 | 1.18 (1.16, 1.20) | 1.12 (1.10, 1.14) | <0.001 | 9209 | 281.40 | 1.13 (1.11, 1.16) | <0.001 | 6838 | 222.01 | 1.11 (1.08, 1.14) | <0.001 |
| Full-term (39-41 weeks) | 53 704 | 213.84 | Reference | Reference | 30 623 | 240.43 | Reference | 23 081 | 186.48 | Reference | |||
| Post-term (≥42 weeks) | 5782 | 188.45 | 0.88 (0.86, 0.91) | 0.98 (0.96, 1.01) | 0.23 | 3680 | 222.45 | 1.00 (0.96, 1.03) | 0.87 | 2102 | 148.68 | 0.96 (0.92, 1.00) | 0.07 |
| Per additional week (trend) | 0.93 (0.92, 0.93) | 0.94 (0.94, 0.95) | <0.001 | 0.94 (0.94, 0.95) | <0.001 | 0.94 (0.94, 0.95) | <0.001 | ||||||
| Attained ages 10-19 years | |||||||||||||
| Preterm (<37 weeks) | 1241 | 100.57 | 1.13 (1.07, 1.20) | 1.14 (1.08, 1.21) | <0.001 | 602 | 89.10 | 1.25 (1.15, 1.36) | <0.001 | 639 | 114.45 | 1.06 (0.97, 1.14) | 0.19 |
| Extremely preterm (<28 weeks) | 31 | 132.79 | 1.50 (1.06, 2.14) | 1.27 (0.89, 1.81) | 0.18 | 16 | 133.69 | 1.55 (0.95, 2.54) | 0.08 | 15 | 131.85 | 1.07 (0.64, 1.77) | 0.80 |
| Very preterm (28-33 weeks) | 256 | 105.56 | 1.19 (1.05, 1.34) | 1.19 (1.05, 1.35) | 0.006 | 136 | 101.47 | 1.40 (1.18, 1.66) | <0.001 | 120 | 110.60 | 1.02 (0.85, 1.22) | 0.85 |
| Late preterm (34-36 weeks) | 954 | 98.55 | 1.11 (1.04, 1.18) | 1.13 (1.05, 1.20) | <0.001 | 450 | 84.97 | 1.20 (1.09, 1.33) | <0.001 | 504 | 114.95 | 1.06 (0.97, 1.16) | 0.18 |
| Early-term (37-38 weeks) | 4416 | 99.03 | 1.11 (1.08, 1.15) | 1.07 (1.04, 1.11) | <0.001 | 1759 | 75.84 | 1.05 (0.99, 1.11) | 0.08 | 2657 | 124.15 | 1.09 (1.05, 1.14) | <0.001 |
| Full-term (39-41 weeks) | 16 075 | 88.88 | Reference | Reference | 6461 | 70.39 | Reference | 9614 | 107.93 | Reference | |||
| Post-term (≥42 weeks) | 1656 | 70.79 | 0.80 (0.76, 0.84) | 0.92 (0.88, 0.97) | 0.002 | 715 | 57.86 | 0.90 (0.84, 0.98) | 0.01 | 941 | 85.28 | 0.94 (0.88, 1.00) | 0.05 |
| Per additional week (trend) | 0.96 (0.95, 0.96) | 0.97 (0.97, 0.98) | <0.001 | 0.96 (0.95, 0.98) | <0.001 | 0.98 (0.97, 0.99) | <0.001 | ||||||
| Attained ages 20-29 years | |||||||||||||
| Preterm (<37 weeks) | 2172 | 281.57 | 1.52 (1.45, 1.59) | 1.36 (1.30, 1.42) | <0.001 | 1328 | 310.79 | 1.34 (1.26, 1.42) | <0.001 | 844 | 245.29 | 1.40 (1.30, 1.50) | <0.001 |
| Extremely preterm (<28 weeks) | 67 | 573.59 | 3.23 (2.54, 4.10) | 2.34 (1.84, 2.98) | <0.001 | 37 | 631.28 | 2.27 (1.64, 3.14) | <0.001 | 30 | 515.50 | 2.43 (1.70, 3.48) | <0.001 |
| Very preterm (28-33 weeks) | 540 | 362.77 | 1.97 (1.80, 2.14) | 1.69 (1.55, 1.85) | <0.001 | 311 | 374.79 | 1.56 (1.39, 1.75) | <0.001 | 229 | 347.64 | 1.91 (1.68, 2.18) | <0.001 |
| Late preterm (34-36 weeks) | 1565 | 256.20 | 1.38 (1.31, 1.45) | 1.26 (1.19, 1.32) | <0.001 | 980 | 289.55 | 1.26 (1.18, 1.35) | <0.001 | 585 | 214.77 | 1.24 (1.14, 1.35) | <0.001 |
| Early-term (37-38 weeks) | 5972 | 220.36 | 1.19 (1.16, 1.23) | 1.06 (1.03, 1.09) | <0.001 | 3494 | 242.52 | 1.04 (1.00, 1.08) | 0.03 | 2478 | 195.21 | 1.08 (1.04, 1.13) | <0.001 |
| Full-term (39-41 weeks) | 20 948 | 185.76 | Reference | Reference | 12 245 | 212.63 | Reference | 8703 | 157.71 | Reference | |||
| Post-term (≥42 weeks) | 2437 | 150.81 | 0.79 (0.76, 0.83) | 1.05 (1.00, 1.09) | 0.04 | 1488 | 178.00 | 1.05 (0.99, 1.11) | 0.08 | 949 | 121.66 | 1.04 (0.97, 1.11) | 0.24 |
| Per additional week (trend) | 0.92 (0.92, 0.93) | 0.96 (0.96, 0.97) | <0.001 | 0.97 (0.96, 0.98) | <0.001 | 0.96 (0.95, 0.97) | <0.001 | ||||||
| Attained ages 30-43 years | |||||||||||||
| Preterm (<37 weeks) | 2178 | 698.93 | 1.53 (1.46, 1.60) | 1.40 (1.34, 1.47) | <0.001 | 1365 | 783.25 | 1.38 (1.31, 1.46) | <0.001 | 813 | 591.94 | 1.44 (1.34, 1.55) | <0.001 |
| Extremely preterm (<28 weeks) | 42 | 1163.65 | 2.51 (1.85, 3.40) | 2.22 (1.64, 3.01) | <0.001 | 24 | 1323.90 | 2.14 (1.43, 3.19) | <0.001 | 18 | 1001.94 | 2.38 (1.50, 3.78) | <0.001 |
| Very preterm (28-33 weeks) | 534 | 906.91 | 1.98 (1.82, 2.16) | 1.82 (1.67, 1.98) | <0.001 | 339 | 1020.53 | 1.80 (1.62, 2.00) | <0.001 | 195 | 759.84 | 1.84 (1.59, 2.12) | <0.001 |
| Late preterm (34-36 weeks) | 1602 | 643.04 | 1.41 (1.34, 1.48) | 1.29 (1.23, 1.36) | <0.001 | 1002 | 719.60 | 1.27 (1.19, 1.36) | <0.001 | 600 | 546.03 | 1.33 (1.23, 1.45) | <0.001 |
| Early-term (37-38 weeks) | 5632 | 546.38 | 1.21 (1.17, 1.24) | 1.12 (1.09, 1.15) | <0.001 | 3491 | 620.83 | 1.11 (1.07, 1.15) | <0.001 | 2141 | 457.02 | 1.13 (1.08, 1.19) | <0.001 |
| Full-term (39-41 weeks) | 23 135 | 464.42 | Reference | Reference | 13 676 | 539.05 | Reference | 9459 | 386.96 | Reference | |||
| Post-term (≥42 weeks) | 3932 | 433.44 | 0.90 (0.87, 0.94) | 0.95 (0.92, 0.99) | 0.007 | 2326 | 509.81 | 0.96 (0.92, 1.01) | 0.11 | 1606 | 356.17 | 0.94 (0.89, 0.99) | 0.02 |
| Per additional week (trend) | 0.93 (0.93, 0.94) | 0.95 (0.95, 0.96) | <0.001 | 0.95 (0.95, 0.96) | <0.001 | 0.95 (0.94, 0.96) | <0.001 | ||||||
Adjusted for child characteristics (birth year, sex, birth order, congenital anomalies) and maternal characteristics (age, education, BMI, smoking, preeclampsia, diabetes).
Incidence rate per 100 000 person-years.
Across the entire age range (0–43 years), gestational age at birth was inversely associated with SDB risk (adjusted HR per additional week of gestation, 0.95; 95% CI, 0.95, 0.95; P <0.001; Table 2). Preterm and early-term birth were associated with 43% and 12% increased risks of SDB, respectively, relative to full-term birth (adjusted HR, 1.43; 95% CI, 1.40, 1.46; P <0.001; and 1.12; 95% CI, 1.10, 1.13; P <0.001). Higher risks were observed at earlier gestational ages (Table 2). Persons born extremely preterm had a 2.6-fold risk of SDB (adjusted HR, 2.63; 95% CI, 2.41, 2.87: P <0.001). Similar associations were observed among males and females (e.g. adjusted HR comparing preterm to full-term, males: 1.43; 95% CI, 1.40, 1.47; P <0.001; females: 1.42; 95% CI, 1.38, 1.47; P <0.001).
In analyses of narrower age intervals, preterm birth was strongly associated with increased risk of SDB in early childhood (ages 0–9 years: adjusted HR, 1.51; 95% CI, 1.47, 1.55; P <0.001). This association was weaker in later childhood/adolescence (ages 10–19 years: 1.14; 95% CI, 1.08, 1.21; P <0.001), then strengthened again in adulthood (ages 20–29 years: 1.36; 95% CI, 1.30, 1.42; P <0.001; ages 30–43 years: 1.40; 95% CI, 1.34, 1.47; P <0.001). A similar pattern was observed among both males and females (Table 2). Figure 1 shows the adjusted HRs (fitted by cubic spline) for SDB risk by attained age for different gestational age groups.
Figure 1.
Adjusted hazard ratios for sleep-disordered breathing (SDB) by gestational age at birth relative to full-term birth, Sweden, 1973–2015.
Interactions between preterm or early-term birth and sex in relation to SDB risk are shown in Supplementary Table 1, available as Supplementary data at IJE online. Across the entire age range (0–43 years), preterm-born males had the highest overall SDB incidence rate, which was substantially higher relative to preterm-born females (303.69 vs 254.81 per 100 000 person-years; adjusted HR, 1.20; 95% CI, 1.16, 1.25; P <0.001). Furthermore, a moderately positive additive interaction was found between preterm birth and male sex (i.e. the combined effect of these factors on SDB risk exceeded the sum of their separate effects; P = 0.003; Supplementary Table 1, available as Supplementary data at IJE online), indicating that preterm birth accounted for more SDB cases among males.
Co-sibling analyses to control for unmeasured shared familial factors resulted in attenuation of risk estimates by an average of ∼8% (Table 3), suggesting that the observed associations were only partly due to shared genetic or environmental factors in families. In analyses of the entire age range (0–43 years), the risk estimates decreased only modestly. For example, the adjusted HR for SDB associated with preterm birth was 1.43 (95% CI, 1.40, 1.46) in the main analysis and 1.35 (95% CI, 1.29, 1.40) in the co-sibling analysis.
Table 3.
Co-sibling analyses of gestational age at birth in relation to risk of sleep-disordered breathing (SDB), Sweden, 1973–2015
| All |
Males |
Females |
||||
|---|---|---|---|---|---|---|
| HR (95% CI) a | P | HR (95% CI) a | P | HR (95% CI) a | P | |
| Attained ages 0-43 years | ||||||
| Preterm (<37 weeks) | 1.35 (1.29, 1.40) | <0.001 | 1.34 (1.25, 1.44) | <0.001 | 1.32 (1.21, 1.43) | <0.001 |
| Early-term (37-38 weeks) | 1.05 (1.02, 1.07) | <0.001 | 1.04 (1.00, 1.08) | 0.08 | 1.07 (1.03, 1.13) | 0.002 |
| Full-term (39-41 weeks) | Reference | Reference | Reference | |||
| Per additional week | 0.96 (0.95, 0.96) | <0.001 | 0.96 (0.95, 0.97) | <0.001 | 0.96 (0.95, 0.97) | <0.001 |
| Attained ages 0-9 years | ||||||
| Preterm (<37 weeks) | 1.41 (1.34, 1.48) | <0.001 | 1.44 (1.32, 1.57) | <0.001 | 1.35 (1.22, 1.51) | <0.001 |
| Early-term (37-38 weeks) | 1.04 (1.01, 1.07) | 0.004 | 1.06 (1.00, 1.11) | 0.03 | 1.04 (0.98, 1.10) | 0.25 |
| Full-term (39-41 weeks) | Reference | Reference | Reference | |||
| Per additional week | 0.96 (0.95, 0.96) | <0.001 | 0.95 (0.94, 0.96) | <0.001 | 0.97 (0.95, 0.98) | <0.001 |
| Attained ages 10-19 years | ||||||
| Preterm (<37 weeks) | 1.10 (0.99, 1.21) | 0.07 | 1.16 (0.96, 1.41) | 0.12 | 1.09 (0.92, 1.31) | 0.32 |
| Early-term (37-38 weeks) | 1.04 (0.99, 1.10) | 0.15 | 0.93 (0.84, 1.04) | 0.23 | 1.16 (1.06, 1.27) | 0.002 |
| Full-term (39-41 weeks) | Reference | Reference | Reference | |||
| Per additional week | 0.98 (0.97, 0.99) | 0.003 | 0.98 (0.96, 1.01) | 0.25 | 0.98 (0.95, 1.00) | 0.03 |
| Attained ages 20-29 years | ||||||
| Preterm (<37 weeks) | 1.18 (1.06, 1.32) | 0.003 | 1.13 (0.94, 1.37) | 0.20 | 1.21 (0.95, 1.54) | 0.12 |
| Early-term (37-38 weeks) | 1.01 (0.95, 1.08) | 0.74 | 0.98 (0.88, 1.09) | 0.71 | 1.07 (0.93, 1.23) | 0.34 |
| Full-term (39-41 weeks) | Reference | Reference | Reference | |||
| Per additional week | 0.98 (0.96, 0.99) | 0.004 | 0.99 (0.96, 1.01) | 0.27 | 0.96 (0.93, 0.99) | 0.02 |
| Attained ages 30-43 years | ||||||
| Preterm (<37 weeks) | 1.14 (0.97, 1.35) | 0.12 | 1.09 (0.84, 1.42) | 0.51 | 1.00 (0.65, 1.55) | 0.99 |
| Early term (37-38 weeks) | 1.06 (0.96, 1.17) | 0.28 | 1.09 (0.93, 1.28) | 0.28 | 0.96 (0.73, 1.27) | 0.80 |
| Full-term (39-41 weeks) | Reference | Reference | Reference | |||
| Per additional week | 0.97 (0.95, 0.99) | 0.01 | 0.98 (0.95, 1.02) | 0.28 | 0.98 (0.92, 1.04) | 0.53 |
Adjusted for shared familial (genetic and/or environmental) factors, and additionally for specific child characteristics (birth year, sex, birth order, congenital anomalies) and maternal characteristics (age, education, BMI, smoking, preeclampsia, diabetes).
Secondary analyses
Further adjustment for fetal growth had a negligible effect on any of the risk estimates. A strong inverse association remained between gestational age at birth and SDB risk (e.g. adjusted HR per additional week of gestation, ages 0–43 years: 0.95; 95% CI, 0.95, 0.95; P <0.001; ages 30–43 years: 0.95; 95% CI, 0.94, 0.95; P <0.001) and an increased risk for preterm relative to full-term births (e.g. adjusted HR, ages 0–43 years: 1.43; 95% CI, 1.40, 1.45; P <0.001; ages 30–43 years: 1.42; 95% CI, 1.36, 1.48; P <0.001).
When more specific diagnostic codes for sleep apnoea were examined (i.e. by excluding adenotonsillar hypertrophy diagnoses), the overall findings were similar to those for SDB (Supplementary Table 2, available as Supplementary data at IJE online). For example, preterm birth was associated with more than a 1.4-fold risk of sleep apnoea across ages 0–43 years, relative to full-term birth (adjusted HR, 1.45; 95% CI, 1.38, 1.53; P <0.001). Associations with sleep apnoea were even stronger than for SDB in childhood and adolescence, but weaker in adulthood, though an increased risk was still observed at ages 30–43 years (adjusted HR, 1.15; 95% CI, 1.03, 1.28; P = 0.01; Supplementary Table 2, available as Supplementary data at IJE online).
Analyses of other perinatal and maternal characteristics identified several other risk factors for SDB from birth to age 43 years, in addition to preterm birth and male sex (Table 4). After adjusting for all other factors, congenital anomalies were associated with more than a 3-fold risk of SDB. High maternal BMI and maternal smoking also were associated with increased SDB risk in the offspring. Maternal age was positively associated with SDB risk before adjusting for other factors, but inversely associated after adjusting for birth year. No association was found between maternal preeclampsia or diabetes and SDB risk in the offspring, after adjusting for other factors (Table 4).
Table 4.
Associations between perinatal or maternal characteristics and risk of sleep-disordered breathing (SDB) from birth to age 43 years, Sweden, 1973–2015
| SDB |
Unadjusted |
Adjusted
a
|
||||
|---|---|---|---|---|---|---|
| Cases | Rate b | HR (95% CI) | P | HR (95% CI) | P | |
| Child characteristics | ||||||
| Gestational age at birth | ||||||
| Preterm (<37 weeks) | 11 364 | 281.63 | 1.49 (1.46, 1.52) | <0.001 | 1.43 (1.40, 1.46) | <0.001 |
| Extremely preterm (<28 weeks) | 506 | 640.30 | 3.51 (3.22, 3.83) | <0.001 | 2.63 (2.41, 2.87) | <0.001 |
| Very preterm (28-33 weeks) | 2812 | 354.27 | 1.88 (1.81, 1.96) | <0.001 | 1.76 (1.70, 1.83) | <0.001 |
| Late preterm (34-36 weeks) | 8046 | 254.44 | 1.34 (1.31, 1.37) | <0.001 | 1.31 (1.28, 1.34) | <0.001 |
| Early-term (37-38 weeks) | 32 067 | 220.35 | 1.18 (1.16, 1.19) | <0.001 | 1.12 (1.10, 1.13) | <0.001 |
| Full-term (39-41 weeks) | 113 862 | 191.50 | Reference | Reference | ||
| Post-term (≥42 weeks) | 13 807 | 174.10 | 0.86 (0.84, 0.87) | <0.001 | 0.95 (0.94, 0.97) | <0.001 |
| Sex | ||||||
| Male | 95 892 | 216.93 | 1.20 (1.19, 1.22) | <0.001 | 1.21 (1.19, 1.22) | <0.001 |
| Female | 75 208 | 180.03 | Reference | Reference | ||
| Birth order | ||||||
| 1 | 77 169 | 212.58 | Reference | Reference | ||
| 2 | 59 495 | 187.88 | 0.89 (0.88, 0.90) | <0.001 | 0.94 (0.93, 0.95) | <0.001 |
| ≥3 | 34.436 | 191.21 | 0.92 (0.91, 0.93) | <0.001 | 1.00 (0.99, 1.02) | 0.60 |
| Congenital anomalies | ||||||
| Yes | 627 | 538.34 | 2.69 (2.49, 2.91) | <0.001 | 3.54 (3.27, 3.83) | <0.001 |
| No | 170 473 | 198.54 | Reference | Reference | ||
| Maternal characteristics | ||||||
| Age (years) | ||||||
| <20 | 6656 | 199.71 | 0.94 (0.92, 0.97) | <0.001 | 1.13 (1.10, 1.16) | <0.001 |
| 20-24 | 40 729 | 201.77 | 1.01 (1.00, 1.02) | 0.19 | 1.11 (1.09, 1.12) | <0.001 |
| 25-29 | 60 657 | 193.83 | Reference | Reference | ||
| 30-34 | 42 926 | 198.75 | 1.06 (1.04, 1.07) | <0.001 | 0.88 (0.87, 0.90) | <0.001 |
| 35-39 | 16 972 | 209.58 | 1.13 (1.11, 1.15) | <0.001 | 0.82 (0.80, 0.83) | <0.001 |
| ≥40 | 3160 | 215.25 | 1.16 (1.12, 1.20) | <0.001 | 0.77 (0.75, 0.80) | <0.001 |
| Education (years) | ||||||
| ≤9 | 23 553 | 183.95 | 0.81 (0.80, 0.83) | <0.001 | 0.94 (0.93, 0.96) | <0.001 |
| 10-12 | 86 999 | 209.69 | Reference | Reference | ||
| >12 | 60 548 | 191.10 | 0.93 (0.92, 0.94) | <0.001 | 0.81 (0.80, 0.82) | <0.001 |
| Body mass index | ||||||
| <18.5 | 3638 | 191.74 | 1.29 (1.25, 1.33) | <0.001 | 0.94 (0.90, 0.97) | <0.001 |
| 18.5-24.9 | 132 321 | 178.34 | Reference | Reference | ||
| 25.0-29.9 | 24 919 | 334.85 | 2.24 (2.21, 2.28) | <0.001 | 1.14 (1.13, 1.16) | <0.001 |
| ≥30.0 | 10 222 | 418.34 | 2.77 (2.71, 2.82) | <0.001 | 1.21 (1.19, 1.24) | <0.001 |
| Smoking (cigarettes/day) | ||||||
| 0 | 133 187 | 189.45 | Reference | Reference | ||
| 1-9 | 24 338 | 208.41 | 1.08 (1.06, 1.09) | <0.001 | 1.31 (1.29, 1.33) | <0.001 |
| ≥10 | 13 575 | 199.14 | 1.02 (1.00, 1.04) | 0.04 | 1.35 (1.32, 1.38) | <0.001 |
| Preeclampsia | ||||||
| Yes | 7891 | 184.27 | 0.85 (0.83, 0.87) | <0.001 | 0.99 (0.97, 1.01) | 0.47 |
| No | 163 209 | 199.78 | Reference | Reference | ||
| Diabetes mellitus | ||||||
| Yes | 1513 | 333.63 | 1.65 (1.57, 1.74) | <0.001 | 1.00 (0.95, 1.05) | 0.95 |
| No | 169 587 | 198.29 | Reference | Reference | ||
Adjusted for birth year and all other variables included in the table.
SDB incidence rate per 100 000 person-years.
Discussion
In this large national cohort study, we found a strong inverse association between gestational age at birth and risk of SDB from childhood into mid-adulthood. After adjusting for other perinatal and maternal factors, preterm birth was associated with more than a 40% increased risk of developing SDB. Persons born extremely preterm had more than 2-fold risks. These associations weakened from childhood into adolescence, but strengthened again in adulthood. Both males and females were affected, although preterm birth accounted for more SDB cases among males.
This is by far the largest study of preterm birth in relation to SDB risk, and the first to examine this risk from childhood into mid-adulthood. Previous smaller studies have reported associations between preterm birth and SDB in infancy20 and childhood,21–23 as well as other sleep-related disorders in childhood, including irregular sleep patterns39 and periodic limb movement disorder.40,41 The largest of these was an Australian cohort study of 398 961 children that reported that low gestational age at birth (but not small for gestational age) was associated with increased risk of sleep apnoea at ages 1 to 6 years (adjusted HR, <32 vs >36 weeks: 2.74; 95% CI, 2.16, 3.49).22 To our knowledge, only one previous study has examined preterm birth in relation to SDB symptoms in adulthood. A Finnish case-control study of 158 preterm-born adults and 169 term-born controls aged 18–27 years found that preterm birth with very low birthweight was associated with >2-fold odds of chronic snoring (adjusted OR, 2.21; 95% CI, 1.07, 4.54).24 The present study advances earlier evidence by providing the first population-based risk estimates for SDB associated with gestational age at birth. Our findings from a large cohort show that preterm-born children and adults have a substantially increased SDB risk that extends into the mid-adulthood period.
In addition to preterm birth, our findings identified or confirmed several other risk factors for SDB, including male sex, congenital anomalies, high maternal BMI and maternal smoking. Maternal preeclampsia and diabetes were not associated with SDB risk in the offspring. These findings are largely consistent with previous studies that have reported associations with male sex42,43 and maternal smoking,24,44 but not preeclampsia.24 Obesity is also a well-established risk factor for SDB or sleep apnoea.42,45 The present study lacked BMI measures in the offspring later in life; however, the association we observed between high maternal BMI and SDB risk may potentially be explained by correlation of BMI between mothers and offspring.
The mechanisms underlying our findings may include craniofacial and upper airway soft tissue abnormalities that are more common in preterm-born children and adults46 and have been linked with SDB risk.42 Preterm birth has been associated with facial asymmetry as measured in sagittal occlusal relationships,46 which may predispose to SDB through altered airway dimensions. Shared genetic factors are also possible, as sleep apnoea is known to have a substantial genetic basis,47 partly mediated through differences in craniofacial structure.48 However, our co-sibling analyses suggested that shared familial factors, either genetic or environmental, only partly explained the associations between preterm birth and SDB risk.
SDB has been associated with a wide range of adverse outcomes including neurocognitive and behavioural disorders in childhood,49–51 and cognitive impairment, depression, metabolic syndrome and cardiovascular disease in adulthood.13–17 Given the high prevalence of preterm birth (currently 10% in the USA52 and 11% worldwide1), even a modest association with SDB risk may have large clinical and public health impacts because of the wide-ranging downstream effects on other chronic conditions. Our findings suggest that preterm-born children and adults need long-term follow-up for anticipatory screening and targeted treatment for SDB. Future studies will be needed to elucidate the potential role of SDB in mediating other chronic disorders in preterm-born childen and adults.
A major strength of the present study was the ability to examine preterm birth in relation to SDB in a large population-based cohort with follow-up into the fifth decade of life, using highly complete birth and medical registry data. This study design minimizes potential selection or ascertainment biases and provides more robust risk estimates. The results were controlled for other perinatal and maternal factors, as well as unmeasured shared familial factors using co-sibling analyses.
Limitations include the lack of polysomnography or other clinical data to verify diagnoses. Diagnoses in the Swedish Hospital Registry have been reported to have high validity for a wide range of conditions, including cardiovascular diseases, diabetes, asthma and mental disorders.30 However, to our knowledge, sleep apnoea and adenotonsillar hypertrophy diagnoses have not been specifically validated. Undiagnosed SDB or sleep apnoea is common in the general population, especially for mild cases.53 In the present study, outpatient diagnoses were unavailable before 2001, which further contributed to under-reporting. It is possible that persons born prematurely are more likely to be diagnosed with SDB because of increased contact with the health care system. However, Sweden’s universal health care system may also reduce any differences in health care access or use compared with countries that lack universal health coverage. Although we controlled for maternal BMI and smoking, we lacked data on BMI or smoking in the offspring later in life. Lastly, despite having the longest follow-up to date (up to 43 years), this was still a relatively young Swedish cohort. Additional follow-up will be needed to examine preterm birth in relation to SDB risk in later adulthood as well as in other diverse populations.
In summary, this large cohort study provides the first population-based risk estimates for SDB associated with gestational age at birth. We found that preterm birth is a strong, independent risk factor for the development of SDB from childhood into mid-adulthood. Preterm-born children and adults need long-term follow-up for screening, detection and potential treatment of SDB.
Funding
This work was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health [R01 HL139536 to C.C. and K.S.]; the Swedish Research Council; the Swedish Heart-Lung Foundation; and ALF project grant, Region Skåne/Lund University, Sweden. The funding agencies had no role in the design or conduct of the study; in the collection, analysis or interpretation of the data; or in the preparation, review or approval of the manuscript.
Supplementary Material
Author Contributions
J.S. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: all authors. Acquisition of data: J.S., K.S. Analysis and interpretation of data: all authors. Drafting of the manuscript: C.C. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: C.C., J.S. Obtained funding: C.C., J.S.,K.S.
Conflict of interest: None declared.
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