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Both very and late preterm infants have worse respiratory health in childhood and adolescence.
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Very preterm survivors have worse lung function, particularly airway obstruction, in childhood up to young adulthood.
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BPD in the newborn period is associated with worse respiratory outcomes in childhood and later years.
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More research is required into the effects of cigarette smoking on later lung function in preterm survivors.
Preterm birth continues to be a significant problem in the developed world. Preterm birth rates peaked at 13% in 2006 in the United States and have since declined to approximately 10%. “Late preterm” infants, with gestational ages from 34 to 36 completed weeks, represent the majority of preterm births. Moreover, survival rates for preterm neonates, particularly those born very preterm (<32 completed weeks) have increased because of technologic and therapeutic advances, such as antenatal administration of corticosteroids and postnatal administration of exogenous surfactant, combined with a greater willingness to offer intensive care before and after birth. Unfortunately, preterm infants are more susceptible to adverse sequelae than are term infants, and the lungs of preterm infants are particularly vulnerable to injury. Despite advances in care, respiratory problems remain the major cause of mortality in extremely preterm (<28 completed weeks) infants in the surfactant era. Of those who survive the neonatal period, some experience bronchopulmonary dysplasia (BPD), both “old” and “new” forms, with prolonged oxygen dependency, occasionally for years. Although most preterm survivors have no ongoing oxygen dependency or respiratory distress in early childhood, their pulmonary function should be determined, because they are more prone to respiratory ill health in late childhood and adulthood.
Controversies
Some of the controversies regarding pulmonary outcomes of preterm birth are as follows:
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What are the pulmonary outcomes for the late preterm infants, who make up the majority of preterm survivors?
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What are the pulmonary outcomes for the very preterm infants, including hospital readmissions, respiratory health problems, pulmonary function in childhood and later life, and exercise tolerance?
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What are the effects of exogenous surfactant, cigarette smoking, and BPD in the newborn period on outcomes in very preterm infants?
This chapter reviews long-term pulmonary outcomes for preterm infants. If data by gestational age are not available, data by birth weight are substituted, with the assumption that birth weight less than 1500 g is equivalent to gestational age less than 32 weeks, and birth weight less than 1000 g to gestational age less than 28 weeks.
What Are the Long-Term Pulmonary Outcomes for Late Preterm Infants?
There are two published reviews of studies reporting long-term respiratory morbidity of late preterm infants. Some studies have also included infants born “moderately preterm” (between 32 and 33 completed weeks of gestation). In total, there were 34 studies reporting respiratory outcomes of late preterm infants between 2000 and 2014. Rates of readmission to hospital after first discharge home were higher in the late preterm group compared with term controls. Data from the U.K. Millennium Cohort Study reported higher rates of hospital admissions for late preterm infants and children compared with term born controls (39–41 weeks). In the first 9 months after birth, the mean adjusted odds ratio (OR) of three or more hospital admissions for late preterm infants was 5.1 (95% confidence interval [CI] 3.0–8.8). The hospital admission rates decreased as the children became older. However, late preterm children up to 5 years in that study were still at increased risk of hospital admissions compared with term children (adjusted OR 1.9, 99% CI 1.3–2.7). The major reason for rehospitalization was respiratory illness. In a study enrolling infants born in Manitoba, Canada, during 1997 to 2001, preterm birth was a significant risk factor for readmission to the hospital in the first 6 weeks after discharge. On the basis of birth weights, gestational ages for the majority of the infants in that study would have been 32 to 36 weeks. The most common cause for readmission during the 6 weeks was respiratory illness (22%), which was more than twice as common as the next leading cause. Both reviews reported substantial respiratory morbidity caused by respiratory syncytial virus (RSV). One study reported that rates of hospital admission for RSV were 57 per 1000 in late preterm infants, which exceeded that of term controls (30 per 1000) but were close to that of very preterm infants (66–70 per 1000). A similar trend was noticed in a regional study of preterm children in the Netherlands, where the rates of hospitalization in the first year owing to RSV were 4% in those born between 32 and 36 weeks of gestation, compared with 3% in those born before 32 weeks and 1% in the full-term children.
It has become clearer that respiratory morbidity for late preterm children persists beyond infancy. Many studies report an increased prevalence of asthma, bronchiolitis, or wheezing illnesses in this group of children compared with term controls. A large retrospective study of 7925 infants using electronic health data from 31 practices affiliated with an academic center in the United States reported associations between late preterm birth and persistent asthma to 18 months (adjusted OR 1.68, 95% CI 1.20–2.29) and inhaled corticosteroid use (adjusted OR 1.66, 95% CI 1.01–2.80). A large observational study between 1989 and 2008 in Finland also reported a similar increase in asthma risk with lower gestation at birth (adjusted OR 1.7, 95% CI 1.4–2.0). In the United Kingdom, the increased rates of asthma or wheezing illnesses persisted up to 5 years, with an adjusted OR of being prescribed any asthma-related medication of 2.2 (95% CI 1.6–3.1). However, data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) did not show a significantly increased risk of asthma in late preterm infants. Data were available from 6187 singletons of gestational ages 34 to 41 weeks who were between 2 and 83 months old at the time of the survey; the 537 late preterm (34–36 weeks) children had a slightly higher rate of physician-diagnosed asthma than the 5650 children who were born at term, but the increase was not statistically significant (adjusted hazard ratio 1.3; 95% CI 0.8–2.0).
There are now several reports of pulmonary function in late preterm children, all of which report more airway obstruction in late preterm infants compared with controls. One study from Brazil reported on 26 infants born with a mean gestational age of 32.7 weeks (range 30–34 weeks) who did not have substantial respiratory distress in the neonatal period. Pulmonary function tests performed at a mean age of 10 weeks and repeated at a mean age of 64 weeks showed more airway obstruction in these infants compared with 24 term controls, with no evidence of improvement between the two tests. The investigators concluded that preterm birth per se resulted in abnormal lung development, but late preterm children clearly need to be reassessed later in childhood and into adulthood to determine whether lung function abnormalities are permanent. A more recent study of a cohort of 31 infants born at 33 to 36 weeks of gestation with no clinical respiratory disease and 31 race- and sex-matched term controls also reported abnormal pulmonary function at term corrected age in the late preterm group compared with term controls. The late preterm group had decreased respiratory compliance, decreased expiratory flow ratio, and increased respiratory resistance compared with term controls. A decrease in expiratory flow ratio in the newborn period is thought to be a reflection of expiratory airflow limitation and predicts subsequent wheezing. Kotecha et al. reported respiratory function at 8 to 9 years and 14 to 17 years from the Avon Longitudinal Study of Parents and Children. Participants were divided into 4 gestational age groups (i.e., <32 weeks, 33–34 weeks, 35–36 weeks, and term). Of the 6705 children with lung function at 8 to 9 years, those born at 33 to 34 weeks had poorer spirometry measures (forced expiratory volume at 1 second [FEV 1 ], forced vital capacity [FVC], forced expiratory flow in the middle of the exhaled volume [FEF 25–75 ], and the FEV 1 /FVC ratio) than term children. There was attenuation of differences in FEV 1 and FVC between those born at 33 to 34 weeks and term controls by the time the children were reassessed at 14 to 17 years. Interestingly, the spirometry measures of the “late preterm group” (35–36 weeks’ gestation) were similar to term controls at all time points. In a recent study from Sweden, lung function data of 149 children born at 32 to 36 weeks were compared at 8 and 16 years of age with 2472 children born at term at 8 and 16 years of age. At 8 years of age FEV 1 was lower only in preterm girls compared with girls born at term, but by 16 years of age airflow was lower in both sexes compared with controls. In addition to these studies, Northway and colleagues reported respiratory function at a mean age of 18.3 years of subjects who would have mostly been late preterm; this study is discussed further in the section “Pulmonary Function in Adolescence or Early Adulthood.”
What Are the Long-Term Pulmonary Outcomes for Very Preterm Infants, and What Is the Effect of BPD on These Outcomes?
Hospital Readmissions for Respiratory Illness
Rates of rehospitalization of very preterm infants are several fold higher than in term controls, and rates of hospital readmission have risen as survival rates of more very preterm infants have increased over time. For example, the UK Millennium Cohort Study reported an adjusted OR of 13.7 (95% CI 6.5–29.2) for 3 or more admissions to the hospital for very preterm infants up to 9 months, which decreased with age (adjusted OR 6.0, 95% CI 3.2–11.4) between 9 months and 5 years of age. Respiratory illnesses are the most common cause of rehospitalization in these early years, and they occur more frequently in preterm survivors who had BPD, especially those who were discharged home while receiving oxygen treatment. However, as the rate of hospital readmission declines later in childhood, those who had BPD are no more likely to be readmitted to the hospital for respiratory or other reasons by the time they reach mid-adolescence.
Respiratory Health Problems
Very preterm children have more ill health than term children over the first few years of life, particularly upper and lower respiratory tract illnesses. Rates of morbidity are further increased in those who had BPD. Asthma or recurrent wheezing is more prevalent later in life in those born very tiny or preterm than in those not born preterm or very tiny in some but not all studies. Those who had BPD have even higher rates of asthma than those who did not.
Pulmonary Function in Childhood
Before the widespread availability of antenatal corticosteroids and exogenous surfactant therapy in the 1990s, very preterm survivors had more abnormalities in pulmonary function in childhood than term controls ( Table 9.1 ). Very preterm survivors with BPD had even more abnormalities in childhood pulmonary function than did very preterm survivors without BPD.
| Study (Year Published) | Age Studied | Very Preterm (N) and Definition | Controls (N) | Main Findings |
|---|---|---|---|---|
| Children Born Before the 1990s | ||||
| Chan et al. (1989) | 7 yr | 130; <2000 g | 120 | Airway obstruction |
| Kitchen et al. (1992) | 8–9 yr | 240; <1000 g or <28 wk | 208 | Airway obstruction; worse with BPD |
| McLeod et al. (1996) | 8–9 yr | 300; <1500 g | 590 | Airway obstruction with exercise |
| Kennedy et al. (2000) | 11 yr | 102; <1501 g | 82 | Airway obstruction and air trapping |
| Anand et al. (2003) | 15 yr | 128 <1500 g | 128 | Airway obstruction |
| Siltanen et al. (2004) | 10 yr | 72; <1501 g | 65 | Airway obstruction |
| Children Born After 1990 | ||||
| Hjalmarson and Sandberg (2002) | Term corrected age | Mean 32 a (range 25–33) wk | 53 | Reduced compliance; higher resistance |
| Thunqvist et al. (2015) | 6 and 18 mo | 55; ≤30 wk | 0 | Airflow limitation (relative to published norms) |
| Korhonen et al. (2004) | 7–8 yr | 34 BPD; 34 no BPD; all <1500 g | 34 | Airway obstruction |
| Doyle et al. (2006) | 8–9 yr | 240; <1000 g or <28 wk | 208 | Airway obstruction; worse with BPD |
| Fawke et al. (2010) | 11 yr | 182; <26 wk | 161 | Airway obstruction; worse with BPD |
| Fortuna et al. (2016) | 8 and 12 yr | 48; <28 wk and <1000 g | 27 | Airway obstruction; worse with BPD, deterioration between 8 and 12 years |
| MacLean et al. (2016) | 8–12 yr | 103; ≤28 wk | 65 | Airway obstruction; worse with BPD |
After 1990 pulmonary function was still worse in very preterm survivors than in controls (see Table 9.1 ). However, survivors from later eras of neonatal care are, on average, more immature and weigh less at birth than those in earlier eras and hence are more at risk for abnormal pulmonary function. There may have been some improvement in pulmonary function with antenatal corticosteroids and exogenous surfactant that has been offset by the survival of higher-risk survivors. Children with the new BPD in later eras still have the reductions in airflow and increased gas trapping observed before the widespread availability of surfactant and antenatal corticosteroids. Fawke and associates measured lung function data with portable devices at 11 years of age in 59% of survivors born before 26 weeks of gestation from the EPICure study of births in the United Kingdom in 1995. They reported large differences in several variables reflecting airway obstruction between these very preterm survivors and term controls. However, the differences reported were wider between preterm survivors and term controls than differences reported in another study of preterm survivors born in the 1990s and evaluated at 8 to 9 years of age; this study measured pulmonary function using standard laboratory tests. A more recent study reported deterioration in spirometry between age 8 and 12 years in a subgroup of children with BPD compared with controls. It will be important to reassess pulmonary function later in life in such extremely immature infants, particularly to determine the effects of environmental hazards, such as cigarette smoking.
Pulmonary Function in Adolescence or Early Adulthood
Several studies have reported respiratory function data in the second and third decades of life for very preterm subjects and controls. Results for FEV 1 , reported as percentage of predicted for age, height, and sex, are shown in Table 9.2 for those studies in which data are available separately for preterm subjects with BPD and without BPD as well as for controls. All subjects in these studies were born before exogenous surfactant was available for clinical use.
Study (Year Published) | FEV 1 in Preterm Groups Data are Mean (SD) Unless Otherwise Specified | FEV 1 in NBW Controls | |
|---|---|---|---|
| BPD | No BPD | ||
| Northway et al. (1990) | 74.8 (14.5); n = 25 b | 96.6 (10.2); n = 26 | 100.4 (10.9); n = 53 |
| Halvorsen et al. (2004) | 87.8 (13.8); n = 12 c | 97.7 (12.9); n = 34 | 108.1 (13.8); n = 46 |
| Doyle et al. (2006) | 81.6 (18.7); n = 33 b | 92.9 (12.8); n = 114 | 99.4 (9.5); n = 37 |
| Vrijlandt et al. (2006) | 90.1 (19.8); n = 8 d | 99.2 (17.9); n = 12 e | 109.6 (13.4); n = 48 |
| Wong et al. (2008) | 89.0 (22.6–121.9) e ; n = 21 | ||
| Gough et al. (2014) | 81.9 (15.9); n = 72 | 97.0 (15.2); n = 57 | 101.2 (11.4); n = 78 |
| Gibson et al. (2015) ( z scores) | –1.37 (2.21); n = 24 | –0.47 (1.30); n = 63 | 0.38 (0.79); n = 19 |
| Vollsaeter et al. (2015) | 84.1 (75.8–92.3) f ; n = 11 | 93.6 (85.0–102.3); n = 12 | 100.4 (95.5–105.3); n = 39 |
| Caskey et al. (2016) | 88.2 (15.2); n = 25 | 102.0 (14.9); n = 24 | 109.4 (11.8); n = 25 |
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