Seminars in Fetal & Neonatal Medicine 17 (2012) 73e76

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Long term respiratory outcomes of very premature birth (<32 weeks)

Anne Greenough*
Division of Asthma, Allergy and Lung Biology, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Kings College London School of Medicine at Guys,
Kings College and St Thomas Hospitals, London, UK

s u m m a r y
Keywords:
Bronchopulmonary dysplasia
Prematurity
Respiratory syncytial virus

Many very prematurely born infants develop bronchopulmonary dysplasia (BPD), remaining oxygen
dependent for many months and requiring frequent rehospitalisations. Troublesome, recurrent respiratory symptoms requiring treatment and lung function abnormalities at follow-up are common. The
most severely affected may remain symptomatic with evidence of airways obstruction even as adults.
Data from adolescents and adults on the respiratory outcome of extreme prematurity, however, are
usually from patients who have had classical BPD with severe respiratory failure in the neonatal period.
Nowadays, infants have new BPD developing chronic oxygen dependence despite initially minimal or
even no respiratory distress. Affected patients do suffer chronic respiratory morbidity and their lung
function may deteriorate during the rst year after birth. Infants who suffer respiratory syncytial virus
lower respiratory tract infections are most likely to require rehospitalisation and suffer chronic respiratory morbidity, but this may reect greater abnormal premorbid lung function.
2012 Elsevier Ltd. All rights reserved.

1. Introduction
Chronic respiratory morbidity is the most common adverse
outcome of very premature birth, which occurs prior to 32 weeks
gestation. Bronchopulmonary dysplasia (BPD) is diagnosed in
infants who remain chronically oxygen dependent; there have been
various denitions, including oxygen dependency at 36 weeks
postmenstrual age, but oxygen dependency beyond 28 days is now
the most commonly accepted.1 In one series, 77% of 4866 infants
born prior to 32 weeks gestation with a birth weight of <1 kg
developed BPD.2 This new severity-based denition of BPD1
classied more infants as having BPD in one series than the denition of supplemental oxygen at 36 weeks PMA (68% vs 42%).3
This review describes the long term respiratory outcomes of very
prematurely born infants, particularly those who developed BPD.
The reports of older children and adults include patients who had
classical BPD, who often had had severe respiratory failure in the
neonatal period with pulmonary brosis and airway smooth
muscle hypertrophy. In addition, they were not routinely exposed
to antenatal steroids or postnatal surfactant. Nowadays, infants can
become chronically oxygen dependent despite minimal or even no
initial respiratory distress and are described as suffering from new
BPD.4 Such infants have less inammation and brosis, but at post

mortem have dilation of the distal gas exchange units and reduced
alveolarisation,5 perhaps resulting from interference/interruption
of the normal signalling for terminal maturation of alveolarisation
of the lungs.4
The importance of the outcome of chronic respiratory morbidity
in very prematurely born infants is emphasized by the growing
number of preterm births, with a 36% increase from 1984 to 2006 in
one series.6 That study also highlighted substantial race and ethnic
disparities in preterm birth and fetal and infant neonatal mortality,
with non-Hispanic black women at greatest risk of unfavourable
birth outcomes followed by American Indian and Puerto Rican
women.6 Approximately 45% of preterm births are caused by
spontaneous preterm labour, 25e30% by preterm premature
rupture of the membranes, and 30e35% are due to induction of
labour or caesarean delivery for medical indications in the fetus.7
This review focuses on the present population of very prematurely born infants, including those with new BPD, who suffer
chronic respiratory morbidity and whose lung function may deteriorate during the rst year after birth (Box 1). In addition, the
possible contribution of viral infections to the chronic respiratory
morbidity of very prematurely born infants will be explored, as
such information is necessary to ensure that prophylactic therapy is
optimally directed to the most high risk infants.
1.1. Chronic oxygen dependence

* Address: Neonatal Unit, 4th oor, Golden Jubilee Wing, Kings College Hospital,
London SE5 9PJ, UK. Tel.: 44 02 (0) 3299 3037; fax: 44 (0) 20 3299 8284.
E-mail address: anne.greenough@kcl.ac.uk.
1744-165X/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2012.01.009

Very prematurely born infants with BPD can require supplementary oxygen for many months,8 but few of the present

74

A. Greenough / Seminars in Fetal & Neonatal Medicine 17 (2012) 73e76

Box 1. Long term respiratory outcomes of premature birth

before 32 weeks gestation.
 Bronchopulmonary dysplasia defined as oxygen
dependency >28 days.
 Rehospitalisation, usually only in the first 2 years after
birth.
 Recurrent respiratory symptoms into adolescence;
adolescent females affected more than males.
 Lung function abnormalities, particularly air flow
limitation.
population of prematurely born infants remain oxygen dependent
beyond 2 years of age.9 Provision of supplementary oxygen at home
allows earlier discharge home, particularly if infants are discharged
while still being tube-fed,10 but looking after an infant on home
oxygen can adversely impact on their familys quality of life.11
Infants requiring supplementary oxygen at home have the most
severe lung disease as evidenced by the fact that they have a greater
requirement for hospital readmission in the rst 2 years.8 Even
when they are no longer home oxygen dependent, they have greater
healthcare utilisation between 2 and 5 years9 and at school age.12
1.2. Rehospitalisation
In the rst 2 years after birth, rehospitalisation is common,
particularly in infants who had BPD. In one series, 73% of BPD
infants required at least one readmission and 27% had three or
more readmissions.13 The majority of admissions are for respiratory
disorders, particularly respiratory syncytial virus (RSV) lower
respiratory tract infections (LRTIs).14 The hospitalisation rate
declines after the second year9 and was infrequent in prematurely
born children at 14 years of age, regardless of BPD status.15
1.3. Respiratory symptoms
Recurrent respiratory symptoms requiring treatment are
common in prematurely born children and young adults, particularly if they have had BPD. In a cohort of 7e8-year-olds, whereas
30% of BPD children and 24% of prematurely born children without
BPD were wheezing, only 7% of term controls were so affected.16 In
one series, 23% of young adults who had BPD had respiratory
symptoms, wheeze and need for long term medication.17 In
a nationwide follow-up study, the prevalence of doctor-diagnosed
asthma was signicantly higher in 19-year-olds born prior to 32
weeks gestational age than age-matched controls.18 That adverse
outcome, however, was only seen in the females, which may reect
different patterns of thoracic growth according to gender.
1.4. Lung function abnormalities
Prematurely born infants, particularly those who wheeze at
follow-up, were demonstrated to have airways obstruction (a
raised airways resistance and gas trapping) in the rst 2 years after
birth.19 Lung function improves with increasing age, but even at
school age those with ongoing recurrent respiratory symptoms
have evidence of poor airway growth. At 8e9 years of age, children
born before 28 weeks gestation had evidence of airow abnormalities.20 Those abnormalities are particularly marked in children
who had had BPD; in one series, 83% of those who had BPD and 23%
of those born prematurely without BPD had evidence of bronchial
obstruction at 8e14 years of age; 79% of those with bronchial
obstruction were symptomatic.21 In addition, a strong correlation
was demonstrated between the maximum ow at functional

residual capacity (Vmax FRC) at 2 years of age and forced expiratory

volume in one second (FEV1) at school age, suggesting persistent
airow limitation in some patients with BPD.22 Young children who
had BPD have been demonstrated to have reduced gas transfer
(diffusion capacity of the lung for carbon monoxide (DLCO) and
alveolar volume (VA) at rest and a lack of increase in DLCO/VA during
exercise suggesting reduced alveolar surface area.23 In the EPICURE
study, infants born before 25 completed weeks gestation were
assessed at 11 years of age; 56% were found to have abnormal
baseline spirometry and 27% had a positive bronchodilator
response.24 In adolescents, evidence of airways obstruction and
hyper-reactivity and an increased responsiveness to histamine25,26
have been documented, and apparently asymptomatic BPD
patients have been demonstrated to desaturate on exercise.27 The
exercise capacity of a group of very prematurely born school-aged
children was reported to be <50% of that of a control group born at
term.28 In adulthood,17 52% of a cohort who had severe BPD had
reactive airway disease and 24% had xed airway obstruction.
1.5. New BPD
There is growing evidence that the present population of very
prematurely born infants including those with new BPD also suffer
chronic respiratory morbidity. Examination of 492 infants born
prior to 29 weeks gestational age from the United Kingdom
Oscillation Study (UKOS) revealed that 27% were coughing and 20%
wheezing at both 6 and 12 months, and 6% were coughing and 3%
wheezing more than once a week.29 Fourteen percent had taken
bronchodilators and 8% inhaled steroids.29 BPD was a signicant
risk factor for wheeze (odds ratio: 2.7) and medication requirement
(odds ratio: 2.4). At preschool age, respiratory symptoms remain
common; in one BPD cohort, 28% coughed more than once a week
and 7% wheezed more than once a week.9 Infants who were
symptomatic have the worst lung function, and in one series30 days
of wheeze correlated with the degree of gas trapping. More
worrying is that there are now several reports that the lung function of prematurely born infants may decline over the rst year
after birth.31,32 It is not known whether affected infants experience
catch-up lung growth, but non-randomised evidence suggests
that high frequency oscillation rather than conventional ventilation
may protect small airway function at follow-up.32 As a consequence, infants who were entered into the randomised UKOS study
are now being examined at school age to determine whether high
frequency oscillation or conventional ventilation mode inuences
long term lung function without adversely affecting cardiac or
neurodevelopmental outcomes.
1.6. Respiratory syncytial virus infection
Respiratory syncytial virus LRTI in infants born prematurely,
particularly those who had had BPD, has been associated with
chronic respiratory morbidity resulting in healthcare utilisation13,14,33,34 and lung function abnormalities35 even at school
age.34 It is possible, however, that those adverse outcomes reect
that infants who develop symptomatic LRTIs have diminished
premorbid lung function. Among infants born before 32 weeks
gestation, those who developed an RSV LRTI had a signicantly
higher resistance of the respiratory system at 36 weeks postmenstrual age (PMA) compared with those who did not, and had
greater wheeze at follow-up.36 In a subsequent study37 of 159
infants with a median gestational age of 34 (range: 23e36) weeks,
those who required hospitalisation for an RSV or another viral LRTI
compared with those who were not had signicantly higher
resistance of the respiratory system prior to the LRTI, further suggesting that certain prematurely born infants may have a functional

A. Greenough / Seminars in Fetal & Neonatal Medicine 17 (2012) 73e76

predisposition to severe RSV LRTIs. There is also some evidence to

suggest that prematurely born infants may have a genetic predisposition to RSV infection. In one study, polymorphisms in innate
immunity, innate and adaptive immunity, and in airway remodelling genes affected disease susceptibility differently in prematurely
born infants.38
1.6.1. RSV prophylaxis
If RSV infection does increase the chronic respiratory
morbidity suffered by prematurely born infants then RSV
prophylactic agents should reduce that morbidity, and there is
some evidence that they do so. In a non-randomised comparison
of infants with BPD who had or had not received prophylactic RSV
immunoglobulin, the treated group had fewer RSV infections and
a higher FEV1/FVC ratio than controls at 10 years of age. The
number of acute asthma episodes, upper respiratory tract infections and school days missed were signicantly smaller in the
treated group.39 There are other data highlighting that RSV
prophylaxis might reduce chronic respiratory morbidity following
RSV LRTI. In a prospective, matched, double cohort, multicentre
study of prematurely born infants, later recurrent wheezing was
58% lower and physician-diagnosed recurrent wheezing was 65%
lower in infants who received Palivizumab compared with the
controls.40 It was subsequently highlighted41 that RSV prophylaxis
was associated with an 80% reduction in the relative risk of
recurrent wheezing in non-atopic children, but had no signicant
effect in infants with an atopic family history. However, the study
excluded infants who had received RSV prophylaxis and were
subsequently hospitalised e such infants might have been expected to do worse at follow-up. A randomised controlled trial
with long term respiratory follow-up is required to determine
whether indeed RSV prophylaxis reduces the long term respiratory morbidity suffered by very prematurely born infants.

Practice points
 Chronic respiratory morbidity remains common in the
present population of very prematurely born infants.
 Oxygen dependency beyond 2 years of age is unusual.
 Infants are likely to suffer wheeze at follow-up and
require appropriate investigation and treatment.

Research directions
 The contribution of viral infections to the chronic
respiratory morbidity of extremely prematurely born
infants needs to be determined to ensure that prophylactic therapy is optimally directed to the infants at
highest risk.
 Whether RSV prophylaxis reduces chronic respiratory
morbidity in prematurely born infants should be tested
in a randomised trial with long term follow-up.

Conict of interest statement

None declared.
Funding sources
None.

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