Long-term pulmonary outcome of preterm infants

Controversies

Some of the controversies regarding pulmonary outcomes of preterm birth are as follows:

• What are the pulmonary outcomes for the late preterm infants, who make up the majority of preterm survivors?

• 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?

• What are the effects of having had BPD in the newborn period and of active cigarette smoking on outcomes in very preterm infants?

• Are we improving expiratory airflow in survivors born extremely preterm over time in the post-surfactant era?

• Is there a role for caffeine in the newborn period?

• What further research is required?

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 assumptions that birth weight <1500 g is approximately equivalent to gestational age <32 weeks, and birth weight <1000 g to gestational age <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 following first discharge home were higher in the late preterm group compared with term controls. Data from the UK Millenium cohort reported higher rates of hospital admissions for late preterm infants and children compared with controls born 39 to 41 weeks’ gestation. In the first 9 months after birth, the mean adjusted odds ratio (OR) for three or more hospital admissions for late preterm infants was 5.1 (95% confidence interval [CI] 3.0, 8.8) compared with controls. The hospital admission rates decreased with increasing age. However, late preterm children up to 5 years of age in that study were still at increased risk of hospital admissions compared with term-born children (adjusted OR 1.9 [1.3, 2.7]). The major reason for rehospitalization was for respiratory illnesses. In a study enrolling infants born in Manitoba, Canada, during 1997 to 2001, preterm birth was a significant risk factor for readmission to 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 reported in a regional study of preterm children in the Netherlands, where the rates of hospitalizations in the first year due to RSV were 4% in those born between 32 and 36 weeks’ gestation, compared with 3% in those born <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 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% 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 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 term, but the increase was not statistically significant (adjusted hazard ratio 1.3; 95% CI 0.8–2.0). In a systematic review and meta-analyses that included 52 studies, there was a significant increase in hospital admissions for RSV or bronchiolitis in late preterm infants compared with term controls during infancy and early childhood (up to 6 years). Admissions for asthma were elevated until 6 years of age (hazard ratio [95% CI] of 1.22 [1.13, 1.32]) but not after that. Admissions for any respiratory problems fell with age, from a risk ratio (95% CI) of 2.25 (1.75, 2.89) within 28 days of hospital discharge to 1.24 (1.11, 1.40) from 12 to 18 years.

There are several registry studies from Scandinavia that report adult respiratory outcomes of infants born 32 to 36 weeks. There was heterogeneity of the gestational age range, and in the ascertainment of asthma in the different studies. Not all studies consistently reported an increased risk of asthma in adulthood. Damgaard et al. reported outcomes of a national cohort in Denmark born between 1980 and 2009 in which those born at 32 to 36 weeks had an OR (95% CI) for purchase of asthma medication of 1.59 (1.43, 1.77) in infancy, 1.21 (1.12, 1.31) for 12 to 17 years, and persisting at 1.31 (1.25, 1.38) at 25 to 31 years. Crump et al. reported outcomes of 25 to 35 years from the Swedish Medical Birth Register of births between 1973 and 1979. There were no associations between being born at 33 to 36 weeks and being prescribed asthma medications in adulthood.

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 of 64 weeks later 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 early lung function abnormalities are permanent. A more recent study of 31 infants born at 33 to 36 weeks’ 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 four gestational age groups, i.e., <32 weeks, 33 to 34 weeks, 35 to 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 flow in 1 second [FEV ₁ ], forced vital capacity [FVC], forced expiratory flow in the middle of the exhaled volume [FEF _{25 – 75} ], and the ratio of FEV ₁ /FVC) 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 with 2472 children born at term at 8 and 16 years of age. At 8 years of age, expiratory airflow (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. The 13- to 14-year follow-up of the LOLLIPOP study in the Netherlands reported only mild lung function abnormalities (lower peak expiratory flow, and maximum expiratory flow at 75% FVC) in the adolescents born at 32 to 36 weeks compared with controls. However, the study was underpowered, with only a 47% follow-up (37 in the preterm group and 34 controls).

What are the long-term pulmonary outcomes for very preterm infants, and what is the effect of having BPD on these outcomes?