INTRODUCTION
Preterm infants form a significant portion of total births, and the number of these infants surviving to adulthood is increasing. Current neonatal intensive care practices such as antenatal corticosteroids, gentler mechanical ventilation and postnatal surfactant have improved the long-term survival of preterm infants over recent years. On average, 10% of all worldwide births each year are preterm (<37 weeks’ gestation). This translates into over 56,000 and 480,000 preterm births each year in the United Kingdom and in the United States respectively. In 2011, 7.1% of births were preterm in England and Wales [1]. Of the 7.1% of births that were preterm (<37 weeks’ gestation), 5.0% were extremely preterm (<28 weeks’ gestation), 11.2% were very preterm (between 28 and 31 weeks’ gestation) and 83.8% were born between 32 and 36 weeks’ gestation [1]. It is increasingly recognised that late preterm birth, often classified as between 32 and 36 weeks’ gestation, is associated with long-term respiratory morbidity.
An understanding of the long–term respiratory consequences of premature birth is essential. Bronchopulmonary dysplasia (BPD) or chronic lung disease (CLD) of prematurity is a chronic respiratory disease which is a sequelae of preterm birth and is a consequence of perinatal and/or neonatal lung injury. BPD has been diagnosed in several ways on the basis of the need for supplemental oxygen. The most commonly used are the need for supplemental oxygen at 36 weeks postmenstrual age (PMA) or the need for supplemental oxygen for at least 28 days after birth. Our recent systematic review showed decreased lung function [forced expiratory volume in 1 second (FEV1)] in subjects born preterm (<37 weeks’ gestation), with and without BPD during childhood and beyond [2]. The mean differences [95% confidence interval (CI)] for percentage predicted FEV1 (%FEV1) compared with term-born controls were −7.2% (–8.7%, −5.6%) for the preterm-born group without BPD, and −18.9% (–21.1%, −16.7%) for the preterm-born group with BPD (defined as supplemental oxygen dependency until at least 36 weeks PMA). Children and adults who did not develop BPD in their infancy are at risk of long-term deficits in lung function. Children born preterm – whether they have BPD in their infancy or not – also have increased respiratory symptoms when compared with children born at term [3].
Sailesh Kotecha PhD FRCPCH, Department of Child Health, Cardiff University School of Medicine, Cardiff, UK. Email: kotechas@cardiff.ac.uk (for correspondence)
A large proportion of preterm-born school-aged children have parentally reported respiratory symptoms, such as wheeze, cough and dyspnoea, during the last 12 months.
Since lung function is thought to track throughout life, there are concerns that airway obstruction established in early childhood in this large vulnerable group of the population will lead to later development of chronic obstructive pulmonary disease. Filippone et al found that maximal flow at functional residual capacity (Vmax FRC) measured at 2 years of age showed a significant positive correlation with lung function at a mean age of 8.8 years in children who had BPD [4]. Figure 1.1 shows the positive correlation with lung function at the two time points.
This review will discuss the following:
- The short- and long-term respiratory outcomes of preterm births
- The impact of respiratory infections and atopy on respiratory consequences
- The treatment and management of respiratory consequences of premature birth
RESPIRATORY MORBIDITY IN THE NEONATAL PERIOD
It is well documented that infants born extremely/very preterm have increased rates of admission to the neonatal intensive care unit, increased respiratory morbidity and increased health care utilisation in early life compared to term-born infants. The health care utilisation is even greater for preterm-born infants with BPD who are discharged on supplemental home oxygen [5].
In the United States, data collected retrospectively over 200,000 deliveries between 2002 and 2008 were used to compare term-born and late preterm-born subjects (34–36 weeks’ gestation) for short-term respiratory morbidity.
Figure 1.1: Relationship between Vmax FRC at 24 months and postbronchodilator forced expiratory volume in 1 second and forced expiratory flow 25–75% at school age. The solid line is the regression line, and dotted lines are 95% confidence intervals. Reproduced from Filippone M, et al. [4] with permission from Elsevier.
3The late preterm-born infants were more likely to be admitted to a neonatal intensive care unit compared to the term-born infants (36.5% and 7.2% respectively). In addition, of those admitted to the neonatal intensive care unit, the late preterm-born infants were more likely to be admitted due to respiratory compromise than the term-born infants (28.8% and 15.6% of those admitted respectively). The late preterm-born infants had increased respiratory morbidity in the neonatal period compared to the term-born infants, in particular, respiratory distress syndrome, transient tachypnoea of the newborn and pneumonia [6].
EARLY INFECTION
As mentioned previously, there are many reports of increased hospitalisation and increased respiratory symptoms of preterm-born children both extremely/very preterm and moderate/late preterm. Boyce et al, in a large retrospective cohort study, estimated the number of respiratory syncytial virus (RSV) hospitalisations during the first year of life per 1000 children was 70 for children born ≤28 weeks’ gestation, 66 for children born at 29 to <33 weeks, 57 for children born at 33 to <36 weeks and 388 for children with BPD, compared to 30 for children born at term without underlying medical condition [7]. However, the rates of hospitalisation due to RSV were no higher after 12 months of age for the preterm-born children compared to term-born children without underlying medical conditions who were <12 months old. A large Swedish study noted that a respiratory infection requiring hospitalisation in the first year of life is associated with an increased risk of asthma after the age of 5. The association between infection and later asthma risk was present across all the gestational groups, but the greatest association was in the most preterm-born subjects (<28 weeks’ gestation) [8]. It is, therefore, clear that preterm birth is associated with increased hospitalisation.
THE SHORT- AND LONG-TERM LUNG FUNCTION OUTCOMES OF VERY/EXTREMELY PREMATURE BIRTHS
Traditionally, research studies and many reviews have focussed on respiratory outcomes of those who develop the neonatal lung disease, BPD, often also called CLD, and/or those preterm-born subjects who were born at <32 weeks’ gestation. Preterm-born infants who develop BPD may require supplementary oxygen at home for several months or longer.
Chronic respiratory morbidity is a common consequence of preterm birth prior to 32 weeks’ gestation, especially if the child had BPD in infancy [5]. As already stated in our recent systematic review [2], preterm-born subjects with BPD have greater deficits in lung function than preterm-born subjects without BPD. In the systematic review, we did note that %FEV1 for the preterm-born subjects with BPD defined as supplemental oxygen dependency until at least 28 days of life may have improved over the years, but it was unclear if there was any selection bias to explain this improvement (Figure 1.2). There is evidence that during the first 2 years of life, lung function abnormalities are common and these may persist into school age and beyond. The EpiCure study, a large cohort study in the United Kingdom and Ireland, analysed children born at ≤25 weeks’ gestation at 11 years of age and observed that 56% of survivors had abnormal spirometry when compared with controls. The lung function deficits were greater in the preterm-born children who had BPD than in the preterm-born children who did not have BPD [9]. Vrijlandt et al, in a prospective nationwide Dutch study of preterm-born subjects at <32 weeks’ gestation and/or a birth weight under 1500 g at 19 years, noted that preterm birth was associated with lower FEV1 and exercise capacity than term controls [10].4
Figure 1.2: Effect of year of birth on percentage predicted forced expiratory volume in 1 second (FEV1) for the bronchopulmonary dysplasia (BPD) group (supplemental oxygen dependency at 28 days) and the term control group. BPD group supplemental oxygen dependency at 28 days (closed circles) and the term control group (open circles). Weighting was based on two separate models, one for the BPD group and one for the term control group. Weighting was defined by variance which differs for the term control and BPD group. Bubble sizes show relative contributions based on individual weighting of term control and BPD group. The E-numbers refer to references which are given in the online data supplement. Reproduced from Kotecha SJ, et al. [2] with permission from BMJ Publishing Group Ltd.
They did not find any significant differences in lung function or exercise capacity between the preterm-born young adults who had BPD and the preterm-born adults who did not have BPD. They conclude that ‘subtle but possibly important lung function abnormalities after preterm birth may persist into adulthood’. This may have an impact in later life, since it has been shown that young adults with submaximal lung function will reach the danger zone of impaired lung function in old age more quickly [10].
THE SHORT- AND LONG-TERM LUNG FUNCTION OUTCOMES OF MODERATE/LATE PRETERM BIRTHS
Traditionally, there has been a paucity of research on the long-term outcomes of children and adults born at >32 weeks’ gestation. These infants were not perceived to be at risk of short- or long-term consequences of their preterm birth. However, recently there has been much interest in this large group of the population of preterm-born survivors and an awareness that these children and adults are at risk of short- and long-term respiratory morbidity.
In one study, healthy infants born at 33–36 weeks’ gestation were compared at 40 weeks PMA to healthy term infants and were noted to have altered lung function [11]. The late preterm-born infants have decreased passive respiratory system compliance and time to peak tidal expiratory flow to expiratory time; increased respiratory resistance and a higher tidal volume when compared to the term control group. These results suggest that even 5healthy infants born at 33–36 weeks’ gestation may have abnormal or delayed pulmonary development when compared to term-born infants. Friedrich et al studied healthy infants born at 30–34 weeks’ gestation in the first and second years of life and reported decreased forced expiratory flows and normal forced vital capacities [12]. Using the Avon Longitudinal Study of Parents and Children, we noted that children of 8–9 years of age born at 33–34 weeks’ gestation had lower measures of forced expiratory spirometry compared to children born at term. These measures are of a similar magnitude to those observed in the extremely/very preterm (25–32 weeks’ gestation) group [13]. Children born at 35–36 weeks’ gestation had measures which were more similar to the term-born children. Interestingly, by 14–17 years, measures of airway function in children born at 33–34 weeks’ gestation were similar to those in the term-born children with the exception of forced mid-expiratory flow between 25% and 75% of vital capacity (FEF25–75; Figure 1.3). These data suggest that even birth at late preterm is associated with longer-term lung function deficits.
RESPIRATORY SYMPTOMS
When assessing symptoms in preterm-born children or reporting them in the medical journals, the phrase ‘doctor diagnosed asthma’ is frequently used, but we and others have questioned the accuracy of this phrase. Been et al conducted a systematic review and meta-analysis of preterm birth and childhood wheezing disorders using data from >1.5 million children, noting that preterm birth was associated with 1.71 times greater risk of childhood wheezing disorders compared to term-born children [an unadjusted odds ratio (OR) of 1.71 (95% CI 1.57–1.87)] [14]. When they studied very preterm born (<32 weeks’ gestation), they had three times increased risk of childhood wheezing disorders compared to term-born children (an unadjusted OR of 3.00). Another systematic review and meta-analysis reported that preterm-born children have approximately 7% higher risk of asthma compared to term-born children [15]. The authors noted that the effect of prematurity on the risk of asthma decreases in later life and appeared to be strongest at a younger age. A recent article investigated if respiratory morbidity during the first year of life can be predicted by lung function tests performed at near term age (44 weeks PMA) in pretermborn infants (mean 29 weeks’ gestation standard deviation ± 3 weeks’ gestation). There was a significant association between tidal volume, time to peak expiratory flow/expiratory time ratio and respiratory rate with subsequent wheeze. However, when lung function was compared to standard clinical predictors, it did not improve prediction of later respiratory morbidity in individual children.
Figure 1.3: Changes in lung spirometry between 8–9 and 14–17 years for children in the Avon Longitudinal Study of Parents and Children cohort born at 33–34 weeks. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; FEF, forced expiratory *P<0.05. Reproduced from Kotecha SJ, et al. [13] with permission from BMJ Publishing Group Ltd.
They summarised that they would recommend tidal lung function testing as a way to gain further knowledge and understanding of respiratory pathophysiology but did not recommend its use to predict respiratory symptoms during the first year of life [16]. Recent publications have also reported that late preterm-born infants and children have increased respiratory symptoms. An association between extremely preterm birth and later respiratory morbidity has been well reported previously. Boyle et al [17] in a large longitudinal study in the United Kingdom of infants born between 2000 and 2002 noted that preterm-born children born at 32–36 weeks’ gestation may experience increased respiratory symptoms, often reported as asthma; have increased reported inhaled drug use and increased health utilisation, including hospitalisation, especially in early childhood. The cohort studied and hence the data are representative of the UK population. Goyal et al conducted a retrospective cohort analysis studying preterm-born infants (34–42 weeks’ gestation) born in 2007. They reported that late preterm birth (34–36 completed weeks’ gestation) compared to term birth (39–42 weeks’ gestation) was associated with significant increases in persistent asthma diagnoses (an adjusted OR of 1.68) when they monitored children from birth to 18 months [18]. In addition, late preterm birth compared to term birth was associated with significant increases in inhaled corticosteroid use (an adjusted OR of 1.66) and the number of acute respiratory visits (an incidence rate ratio of 1.44).
ATOPY
Preterm-born children have increased wheeze often reported as increased rates of asthma. Increased atopy may explain the increased rates of reported asthma. Siltanen at al compared this incidence of atopy among 166 adults aged 18–27 years who were born preterm and at a very low birth weight (≤1500 g) and 172 term-born controls [19]. They reported that the young adults who were born prematurely with a very low birth weight had a lower incidence of atopy than the controls. About 45.5% of the preterm-born adults had a positive skin prick test to at least one of the six common aeroallergens compared to 57.9% of the control group (crude OR of 0.61; 95% CI 0.39–0.93 P = 0.023). In a previous publication, Siltanen et al compared respiratory symptoms and lung function in relation to atopy in two groups of 10-year-old children: preterm-born children with birth weights of <1501 g and full-term children with birth weights >2500 g. Preterm-born children had more respiratory symptoms, e.g. lifetime prevalence of wheezing was 43% compared to 17% in the term-born group. However, in the term-born group, wheezing was associated with atopy, with 64% of wheezers having atopy, whereas in the preterm-born group only 23% of wheezing was associated with atopy. When lung function was measured, the preterm-born group, as in many other studies, had lower spirometry values compared to the term-born group. The lower spirometry values in the preterm-born group were associated with reported asthma, wheezing and low gestational age, but not with atopy. About 62% of children in the preterm-born group who wheezed and still wheezed at 10 years of age were atopic compared to 9% of the children in the preterm-born group who wheezed but no longer had wheezing at 10 years of age [20]. In agreement, a recent Polish publication reported that extremely low birth weight children (<1000 g) at a mean age of 6.7 years had more frequent wheezing compared to term-born children (64% compared to 25% respectively) and were diagnosed with asthma more often (32% compared to 7.5% respectively). About 60% of the extremely low birth weight children required hospitalisation ever due to respiratory problem compared to 10% of term-born children. However, the extremely low birth weight children were not different to the term-born children in the 7case of occurrence of allergy symptoms. The need for rehospitalisation in the first 2 years of life was an important risk factor for respiratory morbidity in the future. The need for rehospitalisation was a more important risk factor than the diagnosis of BPD or allergy and perinatal factors [21]. Atopy rates in preterm-born children are not different to term-born children, hence are unlikely to explain the increased wheezing reported in preterm-born children.
TREATMENT AND MANAGEMENT
It is apparent that there is a large population of preterm-born children and adults who have lung function deficits and respiratory symptoms which, in many cases, are underinvestigated and not treated. One can speculate that failure to institute treatment may be due to the possible absence of evidence of symptoms of ‘classical’ asthma including atopy in preterm-born children. In addition, the reluctance to instigate regular treatment is probably because we do not understand the underlying disease process, which, thus, needs careful evaluation to determine. In summary, the underlying mechanisms are unknown; this may lead to under or inappropriate treatment of preterm-born children with wheeze.
The EpiCure study reported that 56% of children born extremely preterm, <26 weeks’ gestation, had abnormal baseline spirometry and 27% had a positive bronchodilator response, but less than half of those having lung function impairments were receiving any medication at 11 years of age [9]. Joshi et al showed marked reversible exercise-induced bronchoconstriction in preterm-born children who had BPD in their infancy at 8–12 years of age, but a few children were receiving any treatment. These children also had more respiratory symptoms than term-born controls [22]. In contrast, a large Swedish study reported over a million children aged 6–19 years and their retrieval of at least one prescription of an inhaled corticosteroid during 2006; in total 4.89% of the men and 3.78% of the women had purchased inhaled corticosteroids. They reported preterm-born children had increased inhaled corticosteroid usage. Compared to the control group–children born between 39 and 41 weeks’ gestation – the OR for inhaled corticosteroid use increased with prematurity, an OR of 1.10 for children born at 37–38 weeks to 2.28 for children born between 23 and 28 weeks, this was after adjustment for confounders. The use was similar in men and women, and decreased as age increased [23A]. In another systematic review [23B] remove review and put in paper, as otherwise it reads review we have reviewed, we have reviewed the short- and long-term effect of bronchodilator administration on %FEV1 in preterm-born children and adults. The studies mainly reported short-term effects after a single dose administration of a bronchodilator with a majority reporting an improvement. Disappointingly, we only found one study investigating the longer-term effects of bronchodilator administration, 2 weeks, which reported an improvement in lung function [24]. There is a paucity of date on the effect of inhaled steroid administration on the lung function of preterm-born subjects. We are aware of two studies which reported the effect of inhaled steroids on the lung function of preterm-born subjects in childhood. The inhaled steroids did not have a significant effect on spirometry [25,26] but in one study may have decreased bronchial liability [25].
There may be many reasons for the lack of treatment of the deficits in lung function observed in preterm-born children and adults. Failure to treat may be owing to the absence of evidence of ‘classical’ asthma symptoms including atopy in preterm-born children. Possibly, a lack of understanding of the underlying mechanism of the disease process has also impeded the management of these children and, perhaps a perception that airway 8obstruction in the preterm-born subjects is due to an irreversible, structural airway injury. The underlying mechanisms is likely to be either inflammatory as suggested by a study reporting neutrophilic airway inflammation [27] and increased oxidant stress assessed by measuring 8-isoprostane concentration in exhaled breath condensate [28] or due to smooth muscle hypertrophy, as suggested by pathological studies of preterm infants dying from respiratory failure.
Further research is needed to identify the underlying mechanisms of the deficits in lung function and to identify possible treatments.
CONCLUSION
In conclusion, children and adults born preterm are at risk of long-term respiratory consequences. It is not just those who are born extremely/very preterm but also those who are born late preterm have respiratory symptoms and deficits in lung function. More studies are needed particularly with regard to the children and adult who were born late preterm as they had not been studied to as greater an extent as extremely/very preterm-born children and adults. It is important to identify the mechanisms of the symptoms and the pulmonary function deficits that have been observed; and following on from this to identify specific treatments to manage the deficits in lung function and symptoms observed. Future research should focus on the causes and mechanisms of preterm-born wheeze to examine if there are any impaired lung growth or inflammatory processes taking place.
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