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Seminars in Fetal &Neonatal MedicineAmsterdam Boston London New York Oxford Paris Philadelphia San Diego St. Louis
Aims and ScopeSeminars in Fetal & Neonatal Medicine (formerly Seminars in Neonatology) is a
bi-monthly journal which publishes topic-based issues, including current Hot Topics on the
latest advances in fetal and neonatal medicine. The change in title relates to the growing
interest amongst obstetricians, midwives and fetal medicine specialists.
The Journal commissions review-based content covering current clinical opinion on the
care and treatment of the neonate and draws on the necessary specialist knowledge,
including that of the respiratory physician, the infectious disease physician, the surgeon,as well as the paediatrician and obstetrician.
Each topic-based issue is edited by an authority in their field and contains 810 articles.
Current and forthcoming events can be viewed on the Internet at:
http://www.elsevier.com/locate/siny
Seminars in Fetal & Neonatal Medicine provides:
coverage of major developments in neonatal care;
value to practising neonatologists, consultant and trainee paediatricians,
obstetricians, midwives and fetal medicine specialists wishing to extend their
knowledge in this field;
up-to-date information in an attractive and relevant format.
Editorial BoardEditor-in-Chief
Professor M I LeveneUniversity of Leeds
School of Medicine
D Floor, Clarendon Wing
The General Infirmary at Leeds
Leeds LS2 9NS, UK
Associate EditorsM Blennow, Huddinge, Sweden K Marsa l, Lund, SwedenL Cornette, Brugge, Belgium D Peebles, London, UKD J Field, Leicester, UK S Sinha, Middlesbrough, UKI Laing, Edinburgh, UK A M Weindling, Liverpool, UK
Advisory Board
F A Chervenak, USA P C NG, Hong KongS M Donn, USA J M Perlman, USAN Evans, Australia E Saliba, FranceV Fellman, Sweden M Vento, AlicanteN N Finer, USA L de Vries, The Netherlands
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Editorial
Prologue: Advances in Bronchopulmonary Dysplasia
It has been 42 years since our first published report of broncho-
pulmonary dysplasia (BPD)1; it is still a problem for premature
infants. The original goal of using mechanical ventilation to treat
premature infants with respiratory distress syndrome and respira-
tory failure was to decrease the significant mortality. During the
ensuing decades, a decrease in mortality has indeed occurred.Once recognized, it was hoped that a reduction of supplemental
oxygen concentrations and ventilatory pressure would eliminate
or decrease the incidence of BPD. This has, for the most part,
been achieved in the 33 week gestational age infants originally
described. Advances in neonatal care and respiratory therapy since
1967 have resulted in the successful ventilation of increasingly
more immature infants. As a result the original radiographic picture
and pathology have been modified.
The understanding of the growth and development of the
extremely premature lung and the genetic, intrauterine, biochem-
ical, and infectious factors that influence the susceptibility and
severity of BPD has also advanced. This has led to improvements
in prevention strategies and both ventilatory and non-ventilatory
treatment of BPD. Unfortunately, it has not eliminated BPD or led
to a more precise diagnosis. The chest radiographic changes are
much more subtle and are seldom used in the diagnosis. Infants
are now delivered while their lungs are in the late canalicular to
early saccular stage of development. It has yet to be determined
whether there is an oxygen concentration or ventilator pressure
below which these treatments are non-injurious. Prevention of
premature delivery remains an elusive and persistent problem.
The long-term pulmonary function of premature infants with
or without BPD surviving beyond adolescence to older adulthood
is also unknown. Whereas some of the original premature
infants with BPD displayed persistent pulmonary dysfunction as
adolescents, it is not known if these changes regressed, persisted,
or exacerbated in older adulthood. These original infants were
less premature than todays neonatal intensive care unit popula-
tion. They also were treated with higher concentrations of supple-
mental oxygen, and higher ventilator pressures than are currentlyused, and prior to the widespread use of antenatal corticosteroids
and surfactant therapy. The persistence of BPD in more immature
premature infants indicates the need for long-term clinical and
pulmonary function testing. Physicians who deal with these
patients as adults will need to be aware of their possible
late pulmonary disability. Knowledge of the evolving pulmonary
function of infants born very prematurely might best be obtained
if pediatric and adult oriented pulmonologists combine their
interest and talents.
We should not forget, however, that the continuing morbidity
from BPD is the result of the successful application of modern
neonatal intensive care to very premature infants to improve their
survival.
Reference
1. Northway Jr WH, Rosan RC, Porter DY. Pulmonary disease following respiratortherapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl JMed1967;276:35768.
William H. Northway Jr.
Stanford University, Lucile Packard Childrens Hospital, Palo Alto,
California, USA
E-mail address: [email protected]
Contents lists available atScienceDirect
Seminars in Fetal & Neonatal Medicine
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / s i n y
1744-165X/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2009.08.008
Seminars in Fetal & Neonatal Medicine 14 (2009) 331
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Editorial
Despite the myriad of advances in neonatal intensive care in the
more than 40 years since Prof. Northway and colleagues first coined
the term bronchopulmonary dysplasia to describe the aftermath
of neonatal mechanical ventilation, the incidence of chronic lung
disease has not appreciably changed. Approximately 3040% of
infants weighing less than 1500 g at birth sustain chronic lung
disease, evenwith the advent of antenatal corticosteroid treatment,surfactant replacement therapy, and sophisticated techniques for
both non-invasive and invasive mechanical ventilation. What has
changed, however, is the demographic composition of affected
infants, many of whom received only mild or modest respiratory
support, suggesting that chronic lung disease may now reflect an
alteration in lung development and growth. This issue ofSeminars
in Fetal & Neonatal Medicine examines recent advances in the
understanding and management of bronchopulmonary dysplasia.
We are most grateful to our distinguished group of contribu-
tors, headed by Professor Northway, himself, who kindly wrote
the Prologue for this issue. Our first article was written by
Professor Philip, who puts another historical context to chronic
lung disease. His interest in the subject dates back to his seminal
paper published in 1975. Next, Professor Greenough presentsa novel perspective on the potential prenatal factors which might
predispose an infant to the development of chronic lung disease.
Professor Merritt and colleagues provide an interesting commen-
tary on whether the new BPD is actually different from the
old BPD and examine the challenges that are ahead. Dr. Van
Marter subsequently re-examines the epidemiology of chronic
lung disease and evaluates its multifactorial etiology. Dr. Laughon
and colleagues critically evaluate the evidence for preventive
strategies. Our own chapter on ventilation follows, where we
summarize both lung protective strategies and ventilatory
management of BPD. Professor Wiswell and Dr. Tin examine in
detail many of the medical myths that surround BPD and presentthe evidence to date. Prof. Chiswick has written a thoughtful and
provocative piece on the ethics of managing end-stage BPD.
Finally, Professor Doyle and colleagues examine the long term
outcomes of affected infants.
We hope that the readers will realise that BPD is a multi-faceted
disorder and not merely the effect of ventilator-induced lung injury.
The genetic, cellular, developmental, and nutritional milieu of the
fetus and newborn are all contributing factors and deserve to be
thoroughly investigated. If this issue is a stimulus for such, it will
be an unqualified success.
Steven M. Donn*
C S Mott Childrens Hospital, Div. of Neonatal-Perinatal Medicine,
Dept. of Pediatrics, Ann Arbor, Michigan, USA Corresponding author.
E-mail address: [email protected](S.M. Donn)
Sunil K. Sinha
Middlesbrough, UK
Contents lists available atScienceDirect
Seminars in Fetal & Neonatal Medicine
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / s i n y
1744-165X/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2009.08.006
Seminars in Fetal & Neonatal Medicine 14 (2009) 332
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Chronic lung disease of prematurity: A short history
Alistair G.S. Philip
Stanford University School of Medicine, Division of Neonatal and Developmental Medicine, Suite 315, 750 Welch Road, Palo Alto, CA 94304, USA
Keywords:
Bronchopulmonary dysplasia
Chronic lung disease
Genetic predisposition
Prematurity
WilsonMikity syndrome
s u m m a r y
Chronic lung disease of prematurity (CLD) is commonly considered to be a consequence of assisted
ventilation. However, prior to the description in 1967 of bronchopulmonary dysplasia (BPD), following
ventilator therapy for respiratory distress syndrome, WilsonMikity syndrome (WMS) had beendescribed in very preterm infants on minimal oxygen supplementation. In the 1970s and 1980s, many
infants treated with assisted ventilation required prolonged mechanical ventilation after developing
radiographic features of coarse infiltrates, severe hyperinflation, and microcystic changes, associated
with hypercarbemia and the need for increased inspired oxygen concentrations. Some infants died and
showed evidence of pulmonary fibrosis, obstructive bronchiolitis, and dysplastic change. The role of
supplemental oxygen, positive pressure ventilation, and the immaturity of the lung have long been
considered important in the etiology of CLD/BPD. More recently, the role of inflammation (particularly
antenatal exposure to cytokines) and individual susceptibility (genetic predisposition) have assumed
greater etiologic importance. The historical setting into which corticosteroid treatment for BPD was
introduced is also discussed. After the licensing of exogenous surfactant to treat RDS in the early 1990s
and more widespread use of prenatal corticosteroids in the mid-1990s, severe BPD became an unusual
event. Gradually, the diagnosis of CLD, still often referred to as BPD, was based on an oxygen requirement
at 36 weeks postmenstrual age. However, it is not clear that this new BPD is substantially different from
WMS. It is difficult to make prognostications about long-term lung function of these infants based on
oxygen requirement at 36 weeks, since supplemental oxygen is frequently used unnecessarily.
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Prior to the introduction of assisted (mechanical) ventilation,
comparatively few very low birth weight (VLBW) infants (
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same medical center in 1969,6 and many other cases were reported
from around the world.7 WMS was observed in very preterm
infants approximately two weeks after birth. For the most part,
these were infants who initially had little or no oxygen require-
ment, but later developed the need for increasing supplemental
oxygen concentrations of up to 40% to prevent cyanosis. Radio-
graphically, microcystic changes, with some degree of hyperinfla-
tion and flattening of the diaphragms were seen. Some infants
recovered spontaneously over weeks to months, but others died
and demonstrated hyper-aeration and reduced alveolar septa at
postmortem examination. A few had evidence of pulmonary
fibrosis and obstructive bronchiolitis.
3. Oxygen toxicity in adults, animal models and in vitro
The terms pulmonary oxygen toxicity or pulmonary poisoning
were used at about this time, both in animals and in humans.8
Pathologic findings were described in adult humans treated with
oxygen and artificial (mechanical) ventilation.9 The additive roles of
oxygen and assisted ventilation were noted in lambs10 and
pulmonary oxygen toxicity was reported in monkeys.11 Somewhat
later, findings similar to those in WMS were noted when lunghistology was evaluated in extremely premature baboons exposed
to carefully controlled assisted ventilation and oxygen adminis-
tration.12 Loss of muco-ciliary function was also noted when
cultured human neonatal respiratory epithelium was exposed to
80% oxygen for 4896 h in vitro.13
4. First description of bronchopulmonary dysplasia
Soon after the introduction of mechanical ventilation to manage
RDS in the mid-1960s, reports began to appear of radiographic and
pathologic abnormalities that seemed to result from exposure to
high concentrations of oxygen using mechanical ventilation. The
first description of bronchopulmonary dysplasia (BPD) is generally
attributed to Northway et al. in 1967.14
They used the term bron-chopulmonary dysplasia to describe findings of pulmonary
disease following respirator therapy of hyaline membrane disease.
However, almost identical findingswere described in the same year
by Hawker et al. from London, noting infants who died after
respirator treatment for severe hyaline membrane disease.15
Northway et al. believed that the critical factor appeared to be
exposure to an inspired oxygen concentration>80% for longer than
150 h.14 Hawker et al. linked the lung findings to >60% oxygen for
more than 5 days (120 h).15 In a review of pulmonary oxygen
toxicity in 1969, Nelson stated that there seemed to be general
agreement that oxygen partial pressures of less than 0.6
atmospheres are not toxic, over any time span.16 On the other
hand, Pusey et al. (also in 1969) suggested that neither HMD nor
concentrations of oxygen >80% were needed to produce
pulmonary fibroplasia, the key feature of BPD, and that assisted
ventilation was more important.17
A comparison of the principal features of BPD (in the late 1960s)
and WMS is provided inTable 1.
5. Negative pressure respirators (ventilators)
Although the introduction of mechanical ventilation in the
1960s was predominantly concerned with positive pressure
machines, some investigators, including Stahlman and Stern,
believed that there might be advantages in using negative pressure
devices. They reported that it was unusual to observe pulmonary
oxygen toxicity when negative pressure respirators were used,
even with prolonged exposure to high oxygen concentrations.
18
This apparent advantage of the negative pressure respirator didnot gain general acceptance. The negative pressure device available
at the time looked a little like a modified incubator, based on the
iron lung devices used to manage severe cases of poliomyelitis in
older children and adults (Fig.1). Themost difficult part about using
the machines was to createan adequate seal at the neck to generate
adequate negative pressure around the baby, without disrupting
venous return from the brain. It was also difficult to use in infants
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oxygen toxicity, we attempted to minimize exposure of preterm
infants to high oxygen concentrations. Nevertheless, we encoun-
tered many infants treated with positive pressure who developed
radiographic features of BPD. It seemed that the problem could not
simply be duration of exposure to high oxygen concentrations. Two
other factors seemed to be important: the immaturity of the lung,
and the role of the endotracheal tube. Since negative pressure
ventilation was rarely associated with chronic lung disease, it
seemed possible that the endotracheal tube allowed pressure to be
applied more directly to the immature lung (later referred to as
barotrauma). In a series of ten infants who developed BPD that I
reported in 1975,19 only two required >80% oxygen for more than
24 h, and only one required 60% oxygen for more than 100 h. I
suggested that the etiology of BPD might be a complicated
interaction between oxygen plus pressure plus time and that
immature lungs when exposed to oxygen concentrations>40% for
as little as three days, via positive pressure ventilation, might
develop BPD. It also seemedpossible that WMSmight form one end
of a spectrum, where the very immature lung might react adversely
to even minor increases in oxygen exposure (since they should not
have been exposed to any). I also suggested that there might be
individual susceptibility.19 Much evidence now supports these
hypotheses.
7. National Institutes of Health (NIH) consensus conference
In the late 1970s, there was increasing attention paid to the
development of lung injury in preterm infants, most of whom had
received assisted ventilation. The NIH convened a consensus
conference in late 1978. The results were published in 1979.20
Northway was the opening speaker. Some of those in attendance
were inclined to use the term chronic lung disease of prematurity
(CLD), but the majority favored the term bronchopulmonary
dysplasia (BPD). This seemed somewhat unusual to me, since the
term RDS (a clinical definition) had been favored over HMD (a
pathological definition) at an earlier consensus conference. BPD,
like HMD, suggests knowledge of histopathology, whereas CLDexpresses what is happening clinically.
There was considerable discussion of possible etiologic factors,
the clinical and radiographic findings and diagnostic criteria.20 Key
features of BPD/CLD were prolonged oxygen dependency and
associated radiographic features of hyperinflation, usually
accompanied by increased pCO2. Not infrequently, in the 1970s and
1980s, prolonged assisted ventilation was required and hospital
stays of many months were common. Severe cases of BPD
frequently resulted in death from cor pulmonale.
8. Oxygen radical disease
Although the etiology of BPD is likely multifactorial, the concept
of pulmonary oxygen toxicity received additional support in the1980s. In a series of papers, Saugstad promoted the concept that
oxygen free radicals could result in pulmonary damage.21,22 He had
earlier documented the importance of hypoxanthine and xanthine
oxidase in asphyxial insult.23 He extended these observations and
proposed that several problems frequently encountered in very
preterm infants might be the result of a common pathway. He
proposed that BPD, retinopathy of prematurity (ROP), necrotizing
enterocolitis (NEC), patent ductus arteriosus (PDA), periventricular
leukomalacia (PVL), and possibly intraventricular hemorrhage
(IVH) might all be part of an entity he called oxygen radical disease
of the newborn.22 The initial proposal was that a burst of oxygen
free radicals was generated in the re-oxygenation phase following
an acute hypoxic insult, which could cause widespread injury. This
idea has continued to be supported, rather than refuted, in recent
years. Attempts arenow made to minimize the exposureof preterm
infants to high oxygen saturations.
9. Chorioamnionitis, cytokines and chemokines
Before considering the role that exogenous surfactant has
played in decreasing the severity of BPD, other etiologic factors in
the production of BPD/CLD emerged in the late 1970s and 1980s.
Excessive fluid administration was implicated, although this may
have been because it resulted in exposure to higher oxygen
concentrations.24 Cytomegalovirus (CMV) infection was also
implicated in late-onset chronic lung disease25 in an era before
CMV screening of blood for transfusion became routine.
The possibility that chorioamnionitis might predispose to BPD
seemed unlikely when it was first reported, but the role of
inflammation gained increasing acceptance as a variety of
cytokines and chemokines were reported to be circulating
following chorioamnionitis. One of the first reports came from
Japan in 1983.26 Elevated levels of immunoglobulin M (IgM) were
noted in low birth weight infants with chronic respiratory insuffi-
ciency. Subsequently, the same group reported higher IgM levels in
infants evaluated within 72 h of birth who went on to develop
WMS.27 Somewhat surprisingly, much lower levels were seen inthose who developed BPD or unexplained chronic lung disease.
Over the next decade, lung inflammation was increasingly
recognized, and the role of cytokines was reported in evolving
BPD.28,29 By the turn of the millennium, inflammation was firmly
established in the etiology of BPD30,31 and currently seems to be
even more entrenched as an antenatal precursor to lung injury and
the development of BPD.32,33
10. Status of BPD in the 1980s
During the 1970s, neonatologists became more adept at
managing mechanical ventilation, and survival of VLBW infants
improved. This improvement was partly the result of the learning
curve as increasing numbers of people learned to manage VLBWinfants successfully. This was, in part, attributed to the develop-
ment of ventilators specifically designed to be used in infants, and
partly from other improvements (e.g. parenteral nutrition). The
possibility that undernutrition was a contributing factor in the
pathogenesis of BPD was proposed.34
In 1980, the first report of successful treatment of RDS with
exogenous surfactant came from Fujiwara et al. in Japan.35 Within
a few years, there was an explosion of interest in exogenous
surfactants, which were evaluated at the end of the decade in
multiple randomized controlled studies around the world, with
spectacular success. By 1991, both Exosurf (colfosceril, a synthetic
surfactant) and Survanta (beractant, a bovine-extract surfactant)
had been approved by the Federal Drug Administration. Although
the introduction of exogenous surfactant did not eliminate thedevelopment of BPD, it substantially altered its severity, so that by
1999 Jobe referred to chronic lung disease of preterm infants
observed at that time as the new BPD.36
During the 1980s, our ability to keep babies alive with
successful mechanical ventilation came at considerable expense
(Fig. 2). This was an era of chronic ventilator dependence, with
some infants being ventilated for several months. Whereas many
were eventually ableto be weaned, some were pulmonary cripples
and others died of cor pulmonale after several months in the
neonatal intensive care unit (NICU). We tried to remain optimistic
about the future for these preterm infants by reminding ourselves
(and parents) that lung growth continues for many months after
birth (for as long as three years), and we tried to minimize the
duration of exposure to ventilation as much as possible.
A.G.S. Philip / Seminars in Fetal & Neonatal Medicine 14 (2009) 333338 335
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11. Prevention and therapeutic strategies
Prior to surfactant therapy, therewere few prevention strategies.Antioxidants were promoted, but initial enthusiasm for vitamin E
and superoxide dismutase were tempered by negative results. 37,38
On the other hand, vitamin A was more convincing 39 and seems to
have a place in standard care of most VLBW infants. More recently,
a large, prospective, randomized study of caffeine to prevent apnea
documented a significantreduction in CLD/BPD.40 In 1972,reduction
in the incidence and severity of RDS was reported by Liggins and
Howie using antenatal betamethasone.41 Although used by many,
widespread acceptance of this strategy did not occur for more than
20 years.42 However, maternal antenatal glucocorticoid adminis-
tration was shown to reduce the risk of BPD in 1990.43
Since cor pulmonale was frequently observed, diuretics and
digoxin were often used, but the most impressive improvement was
noted withpostnatal corticosteroids(see below).In order todecreasehospital stay, some infants were discharged home on nasal cannula
oxygen (Fig. 3). Initially, this was facilitated by transcutaneous
oxygen monitoring44 and later by pulse oximetry.45 Another
suggestion was to use early continuous positive airway pressure, as
the incidence of CLD was much lower in one center adopting this
strategy compared with seven that did not.46 This approach has
gained increased support in recent years, although it may be difficult
to separate it from the effects of early surfactant administration.47
12. Introduction of corticosteroids for BPD
There has been increasing concern that using corticosteroids to
prevent BPD may be creating other problems, particularly
neurodevelopmental delay.48 It seems important to establish the
circumstances into which this treatment was introduced. Some
infants who developed CLD/BPD required assisted ventilation for
months. Against this backdrop, it is a little easier to understand why
steroid use had considerable appeal. Steroids certainly seemed to
shorten the duration of mechanical ventilation and the link
between mechanical ventilation and CLD/BPD appeared to be
well-established.
My own experience may have contributed to more widespread
use of corticosteroids. In 1974, I presented a paper at the Western
Society for Pediatric Research documenting pulmonary improve-
ment and rapid weaning from assisted ventilation in ten infants
with severe BPD.49 In the first two patients, steroids had been used
for other reasons (cerebral edema in one and laryngeal edema at
attempted extubation in the other), with serendipitous pulmonary
improvement. Although I prepared a manuscript describing the
results, it was not published because reviewers were concernedabout possible long-term consequences, based on animal data. This
was not something to which I had given much thought. My use of
steroids for CLD/BPD was subsequently limited to late treatment in
severe cases with prolonged requirements of assisted ventilation.
In the ensuing years, there was considerable discussion. We all
wrestled with how to minimize the long-term effects of assisted
ventilation. The first randomized controlled study of corticosteroids
for BPD was published in 1983 by Mammel et al.50 and a second
study appeared in 1985.51 Protocols for both of these studies had
comparatively short courses of steroids.
The most influential study appeared in 1989, with earlier
administration and a prolonged weaning course.52 After this,
corticosteroid use became more popular, until concerns about long-
term sequelae were expressed.48 Exogenous surfactant was beingevaluated at about the same time that this report appeared. 52 Any
decrease in severity of CLD/BPD may have been attributed, by some,
more to steroids than to surfactant, because there was a tendency
to use steroids earlier than before. Even when surfactant was being
used more routinely, it was still difficult to wean VLBW infants from
assisted ventilation and even short courses of steroids (seven days)
seemed to be helpful in facilitating extubation and decreasing the
duration of mechanical ventilation and the incidence of CLD.53
13. Surfactant protein deficiency states
One group of infants who developed CLD that was difficult to
understand was term infants who appeared to have RDS.
Fig. 2. An example of the chest radiograph findings of bronchopulmonary dysplasia
commonly observed in the 1970s and 1980s, demonstrating coarse infiltrates, hyper-
inflation and microcystic changes. (Courtesy of Steven M. Donn, MD.).
Fig. 3. An infant on nasal cannula oxygen supplementation being assessed as an
outpatient with a transcutaneous oxygen monitor placed on the back.
A.G.S. Philip / Seminars in Fetal & Neonatal Medicine 14 (2009) 333338336
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Frequently, it was believed that mistakes had been made in deter-
mining gestational age. In recent years, surfactant proteins have
been categorized, and many of these infants probably had a specific
surfactant protein (SP) deficiency, usually SP-B or SP-C.54 There is
also evidence that there are associations between genetic variants
of surfactant proteins and BPD.55
14. Individual susceptibility
While debate continued about the relative importance of
oxygen or assisted ventilation in the etiology of CLD/BPD, 20 at or
soon after birth, it was difficult to predict which infants would go
on to develop CLD/BPD. Thus, it seemed possible that there might
be some factor or factors that contributed to individual suscepti-
bility. One of the first associations, reported in 1982, was between
CLD and HLA (human lymphocyte antigen) phenotypes.56 In the
ensuing 25 years, the idea that there may be a genetic predispo-
sition to develop CLD/BPD has become generally accepted.57,58
Further details can be found in Chapter 3 of this issue.
15. The new BPD
With the widespread use of surfactant, in conjunction withgreater use of antenatal betamethasone, following another NIH
consensus development conference in 1994,42 the outcome for
most preterm infants was altered substantially. Not only did
survival improve for each gestational age, but the severity of
residual lung damage also decreased.59 Today, we almost never
encounter the severe hyperinflation of the lungs with flattened
diaphragms and associated severe hypercarbemia seen in the 1970s
and 1980s. The concern now is whether or not an infant with
continuing oxygen requirement does or does not have CLD/BPD.
In many NICUs, the nursing staff became very reliant on pulse
oximetery monitors, introduced in the mid to late 1980s.60 They
would frequently adjust inspired oxygen concentration to maintain
SaO2at 98 to 100%, in order to decrease the amount of apnea and
reduce the frequency of alarms. However, early supplementaloxygen may have contributed to the development of chronic lung
disease because of oxygen free radicals. Recent years have seen
changes in delivery room and NICU management to limit exposure
to supplemental oxygen.61 There has been a move away from using
100%oxygenas the standard method of delivery roomresuscitation,
since many infants respond to room air and may even do better.
Oxygen blenders have become more common in delivery rooms.
The radiographic features of old BPD are nowseen infrequently
and rarely do babies die of BPD, so that the pathologic features are
almost never seen. Jobe coined the term the new BPD in 1999. 36 A
second National Institute of Child Health and Human Development
(NICHD) consensus conference followed.62 The new definition of
BPD became a supplemental oxygen need at 36 weeks post-
menstrual age. However, such an oxygen requirement may not bereal. The NICHD neonatal network centers demonstrated that many
babies who required oxygen, according to the nursing staff, were
able to maintain SaO2> 90% on room air.63 Of 1598 infants with
birth weights 5011249 g, 560 (35%) had clinical BPD (oxygen use
at 36 weeks), but only 398 (25%) had physiologic BPD (SaO 2< 90%
in room air).63
16. Final thoughts
The late Joan Hodgman (who collaborated with Mikity in the
1960s) questioned whether or not the new BPD was indeed
another name for WMS.7 Even more recently, Lefkowitz and
Rosenberg pointed out that it is now unfeasible to directly examine
the relationship between the histopathologic disease and its
long-term pulmonary outcome.64 It might be possible if one were
willing to perform lung biopsies on these infants (and some were
done in the past), but few would recommend this now. As they
state, The term bronchopulmonary dysplasia (BPD) is an overused
catchall for all aspects of chronic lung disease in the neonatal
population.64 They noted that the main reason for labeling an
infant as having BPD was to predict long-term pulmonary outcome,
but also observed that Shennan et al.65 had suggested that many
infants with a functional abnormality as neonates had normal
long-term outcomes. They further added . it is important to
recognize that from Shennan et al. forward, the clinical character-
istic of some degree of supplemental oxygen use at 36 weeks
post-menstrual age was considered simply a possible screening test
for abnormal long-term pulmonary outcome, not a marker of
a particular histopathology.64
Because neonatology has changed substantially in the past 40
years, CLD may be one entity (a clinical description) and BPD
another (a histopathologic description). It still seems probable that
WMS and BPD are parts of a continuum of CLD of prematurity.
Conflict of interest statement
None declared.Funding sources
None.
References
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3. Usher R. Reduction of mortality from respiratory distress syndrome ofprematurity with early administration of intravenous glucose and sodiumbicarbonate. Pediatrics 1963;32:96675.
4. Wilson MJ, Mikity VG. A new form of respiratory disease in premature infants.Am J Dis Child1960;99:48999.
5. Sykes MK. Intermittent positive pressure respiration in tetanus neonatorum.Anesthesia1960, Oct;15:40110.
6. Hodgman JE, Mikity VG, Tatter D, Cleland RS. Chronic respiratory distress in thepremature infant: WilsonMikity syndrome.Pediatrics 1969;44:17995.
7. Hodgman JE. Relationship between WilsonMikity syndrome and the newbronchopulmonary dysplasia.Pediatrics 2003;112:14145.
8. Giamonna ST, Kerner D, Bondurant S. Effect of oxygen breathing at atmosphericpressure on pulmonary surfactant. J Appl Physiol 1965;20:8558.
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10. de Lemos R, Wolfsdorf J, Nachman R, et al. Lung injury from oxygen in lambs:the role of artificial ventilation. Anesthesiology 1969;30:60918.
11. Kaplan HP, Robinson FR, Kapanci Y, Weibel ER. Pathogenesis and reversibility ofthe pulmonary lesions of oxygen toxicity in monkeys. 1: clinical and lightmicroscopic studies.Lab Invest1969;20:94100.
12. Coalson JJ, Winter VT, Siler-Khodr T, Yoder BA. Neonatal chronic lung disease inextremely immature baboons. Am J Respir Crit Care Med 1999;160:133346.
13. Boat TF, Kleinerman JI, Fanaroff AA, Matthews LW. Toxic effects of oxygen oncultured human neonatal respiratory epithelium. Pediatr Res 1973;7:60715.
14. Northway Jr WH, Rosan RC, Porter DY. Pulmonary disease following respiratortherapy of hyaline membrane disease: bronchopulmonary dysplasia. N Eng
J Med1967;276:35768.15. Hawker JM, Reynolds EOR, Taghizadeh A. Pulmonary surface tension and
pathological changes in infants dying after respirator treatment for severehyaline membrane disease.Lancet1967;ii:757.
16. Nelson NM. Chronology, morphology and physiology of pulmonary oxygentoxicity. In: Lucey JF, editor. Problems of neonatal intensive care units. Report ofthe 59th Ross Conference on Pediatric Research. Columbus, Ohio: Ross Labora-tories; 1969. p. 44.
17. Pusey VA, MacPherson RI, Chernick V. Pulmonary fibroplasia followingprolonged artificial ventilation of newborn infants. Can Med Assoc J 1969;100:4517.
18. Swyer PR. Symposium on artificial ventilation. Summary of conferenceproceedings. Biol Neonate 1970;16:1915.
19. Philip AGS. Oxygen plus pressure plus time: the etiology of bronchopulmonarydysplasia.Pediatrics1975;55:4550.
20. Workshop on bronchopulmonary dysplasia. J Pediatr 1979;95(5, part 2):
815920.
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21. Saugstad OD. Oxygen radicals and pulmonary damage. Pediatr Pulmonol1985;1:16775.
22. Saugstad OD. Oxygen toxicity in the neonatal period. Acta Pediatr Scand1990;79:88192.
23. Saugstad OD, Gluck L. Plasma hypoxanthine levels in newborn infants:a specific indicator of hypoxia. J Perinat Med 1982;10:26672.
24. Brown ER, Stark A, Sosenko I, Lawson EE, Avery ME. Bronchopulmonarydysplasia: possible relationship to pulmonary edema. J Pediatr1978;92:9824.
25. Ballard RA, Drew WL, Hufnagle KG, Riedel PA. Acquired cytomegalovirusinfection in preterm infants. Am J Dis Child 1979;133:4825.
26. Fujimura M, Takeuchi T, Ando M, et al. Elevated immunoglobulin M levels inlow birth-weight neonates with chronic respiratory insufficiency. Early HumDev1983;9:2733.
27. Fujimura M, Takeuchi T, Kitajima H, Nakajima M. Chorioamnionitis and serumimmunoglobulin M in WilsonMikity syndrome. Arch Dis Child 1989;64:137983.
28. Watterberg KL, Carmichael DF, Gerdes JS, Werner S, Backstrom C, Murphy S.Secretory leukocyte protease inhibitor and lung inflammation in developingBPD. J Pediatr1994;125:2649.
29. Yoon BH, Romero R, Jun JK, et al. Amniotic fluid cytokines (interleukin-6, tumornecrosis factor-alpha, interleukin-1-beta and interleukin-8) and the risk fordevelopment of bronchopulmonary dysplasia. Am J Obstet Gynecol1997;177:82530.
30. Lyon A. Chronic lung disease of prematurity: the role of intra-uterine infection.Eur J Pediatr2000;159:798802.
31. Speer CP. Inflammation and bronchopulmonary dysplasia. Semin Neonatol2003;8:2938.
32. Kramer BW. Antenatal inflammation and lung injury: prenatal origin ofneonatal disease. J Perinatol 2008;28(Suppl. 1):S217.
33. Bose CL, Dammann CF, Laughon MM. Bronchopulmonary dysplasia andinflammatory biomarkers in the premature neonate. Arch Dis Child FetalNeonatal Ed2008;93:F45561.
34. Frank L, Sosenko IR. Undernutrition as a major contributing factor in thepathogenesis of bronchopulmonary dysplasia. Am Rev Respir Dis 1988;138:7259.
35. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactanttherapy in hyaline membrane disease. Lancet1980;i:559.
36. Jobe AH. The new BPD: an arrest of lung development. Pediatr Res1999;66:6413.
37. Saldanha RI, Cepeda EE, Poland RL. The effect of vitamin E prophylaxis on theincidence and severity of bronchopulmonary dysplasia. J Pediatr 1982;101:8993.
38. Thomas W, Speer CP. Non-ventilator strategies for prevention and treatment ofbronchopulmonary dysplasiawhat is the evidence? Neonatology2008;94:1509.
39. Shenai JP, Kennedy KA, Chytil F, Stahlman MT. Clinical trial of vitamin Asupplementation in infants susceptible to bronchopulmonary dysplasia.
J Pediatr1987;111:26977.40. Schmidt B, Roberts R, Miller D, Kirpalani H. Evidence-based neonatal drugtherapy for prevention of bronchopulmonary dysplasia in very low birth-weight infants. Neonatology2008;93:2847.
41. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treat-ment for prevention of the respiratory distress syndrome in premature infants.Pediatrics1972;50:51525.
42. McCarthy MUS. Recommendations for antenatal corticosteroids. Lancet1994;343:726.
43. van Marter LJ, Leviton A, Kuban KCK, et al. Maternal glucocorticoid therapyand reduced risk of bronchopulmonary dysplasia. Peditatrics 1990;86:3316.
44. Philip AGS, Peabody JL, Lucey JF. Transcutaneous pO2 monitoring in the homemanagement of bronchopulmonary dysplasia. Pediatrics 1978;61:6557.
45. Hudak BB, Allen MC, Hudak ML, Loughlin GM. Home oxygen therapy forchronic lung disease in extremely low birth-weight infants. Am J Dis Child1989;143:35760.
46. Avery ME, Tooley WH, Keller JE, et al. Is chronic lung disease in low birthweight infants preventable? A survey of eight centers. Pediatrics 1987;79:
2630.47. Patel D, Greenough A. Does nasal CPAP reduce bronchopulmonary dysplasia
(BPD)? Acta Paediatr2008;97:13147.48. Stark AR. Risks and benefits of post-natal corticosteroids. NeoReviews
2005;6:e99103.49. Philip AGS. Treatment of bronchopulmonary dysplasia with corticosteroids.
Clin Res 1974;22:242A.50. Mammel MC, Green TP, Johnson DE, Thompson TR. Controlled trial of dexa-
methasone therapy in infants with bronchopulmonary dysplasia. Lancet1983;i:13568.
51. Avery GB, Fletcher AB, Kaplan M, Brudno DS. Controlled trial of dexamethasonein respirator-dependent infants with bronchopulmonary dysplasia. Pediatrics1985;75:10611.
52. Cummings JJ, DEugenio DB, Gross SJ. A controlled trial of dexamethasone inpreterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med1989;320:150510.
53. Durand M, Sardesai S, McEvoy C. Effects of early dexamethasone therapy onpulmonary mechanics and chronic lung disease in very low birth weightinfants: a randomized controlled trial. Pediatrics 1995;95:58490.
54. Gower WA, Wert SE, Nogee LM. Inherited surfactant disorders. NeoReviews2008;9:e45867.
55. Pavlovic J, Papagaroufalis C, Xanthou M, et al. Genetic variants of surfactantproteins A, B, C and D in bronchopulmonary dysplasia. Dis Markers2006;22:27791.
56. Clark DA, Pincus LG, Oliphant M, Hubbell C, Oates RP, Davey FR. HLA-A2 andchronic lung disease in neonates. J Am Med Assoc1982;248:18689.
57. Bhandari V, Gruen JR. The genomics of bronchopulmonary dysplasia. NeoRe-views2007;8:e33644.
58. Abman SH, Mourani PM, Sontag M. Bronchopulmonary dysplasia: a geneticdisease.Pediatrics 2008;122:6589.
59. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity forvery low birth weight infants, 19911999. Pediatrics 2002;110:14351.
60. Hay Jr WW, Thilo E, Curlander JB. Pulse oximetry in neonatal medicine. ClinPerinatol1991;18:44172.
61. Saugstad OD. Room air resuscitation two decades of neonatal research.EarlyHum Dev2005;81:1116.
62. Jobe AH, Bancalari E. NICHD/NIH Workshop summary: bronchopulmonary
dysplasia.Am J Respir Crit Care Med2001;163:17239.63. Walsh MC, Yao Q, Gettner P, et al. NICHD Neonatal Research Network: impact ofa physiologic definition on bronchopulmonary dysplasia rates. Pediatrics2004;114:130511.
64. Lefkowitz W, Rosenberg SH. Bronchopulmonary dysplasia: pathway fromdisease to long-term outcome. J Perinatol 2008;28:83740.
65. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonaryoutcomes in premature infants: prediction from oxygen requirement in theneonatal period. Pediatrics 1988;82:52732.
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Prenatal factors in the development of chronic lung disease
Anne Greenough*
Division of Asthma, Allergy and Lung Biology, Kings College London School of Medicine, London, UK
Keywords:
Bronchopulmonary dysplasia
Cytokines
Glucocorticoids
Infection
Prematurity
s u m m a r y
Chronic lung disease (CLD), defined as chronic oxygen dependency, is a common outcome of neonatal
intensive care. It occurs most frequently in infants born very prematurely, but also in infants born at term
who had severe lung disease and those with abnormal antenatal lung growth due particularly toreduction in fetal breathing movements, amniotic fluid volume or intrathoracic space. There are,
however, other causes and the importance of antenatal infection/inflammation regarding impairment of
antenatal lung growth is increasingly recognised. Affected infants can suffer chronic respiratory
morbidity including an excess of respiratory symptoms and lung function abnormalities even in adult-
hood. Antenatal interventions directed at improving lung growth are available, but require testing
inappropriately designed trials with pulmonary function at follow-up as an outcome.
2009 Elsevier Ltd. All rights reserved.
1. Introduction
Chronic lung disease (CLD), defined as chronic oxygen depen-
dency, is a common adverse outcome of neonatal intensive care. It
occurs most frequently in infants born very prematurely; morethan 40% of one series of infants born before 29 weeks of gestation
were affected.1 Such infants are now usually described as having
bronchopulmonary dysplasia (BPD). Infants born at term, however,
can remain chronically oxygen dependent, particularly if they have
had severe lung disease as evidenced by a requirement for extra-
corporeal membrane oxygenation (ECMO).2 The other major group
of infants who can suffer chronic oxygen dependency are those
with abnormal antenatal lung growth (Box 1). The aims of this
review are to emphasise the importance of CLD by briefly
describing the associated chronic respiratory morbidity and then to
discuss the evidence as to whether certain prenatal factors
predispose to the development of CLD and if there are effective
antenatal interventions.
2. Chronic respiratory morbidity
2.1. Respiratory symptoms
Recurrent respiratory symptoms requiring treatment are
common in prematurely born children, particularly those who had
BPD. At preschool age, 28% of a BPD cohort coughed and 7%
wheezed more than once a week.3 Prematurely born infants, even
without BPD, are more at risk of being symptomatic at follow-up
than children born at term. In 78-year-olds, 30% of BPD children
and 24% of prematurely born children without BPD were wheezing,whereas only 7% of term controls were so affected.4 This adverse
respiratory outcome, particularly in those who had BPD, can persist
into adulthood. In a follow-up study in The Netherlands, the
prevalence of doctor-diagnosed asthma was significantly higher in
19-year-olds born prior to 32 weeks of gestational age than in age-
matched controls5; the females not the males had BPD, and
were more likely to wheeze without a cold (35% vs 13%) and be
short of breath on exercise (43% vs 16%).
2.2. Lung function abnormalities
Prematurely born infants, particularly those with wheezing at
follow-up, have evidence of airways obstruction (a raised airways
resistance and gas trapping) in the first 2 years after birth.6 Even atschool age, particularly in those with ongoing recurrent respiratory
symptoms, evidence of poor airway growth persists.7 A strong
correlation was demonstrated between the maximum flow at
functional residual capacity at 2 years of age and forced expiratory
volume in one second at school age, suggesting persistent airflow
limitation at least in some patients with BPD.7 Adolescents who had
BPD have evidence of airways obstruction and hyper-reactivity,
with an increased responsiveness to histamine8 and apparently
asymptomatic BPD patients have been demonstrated to desaturate
on exercise.9 It is important to emphasise, however, that those
adolescents received intensive care many years before and that the
* Newborn Unit, 4th Floor Golden Jubilee Wing, Kings College Hospital, Denmark
Hill, London SE5 9RS, UK. Tel.: 44 20 3299 3037; fax: 44 20 3299 8284.
E-mail address: [email protected]
Contents lists available atScienceDirect
Seminars in Fetal & Neonatal Medicine
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / s i n y
1744-165X/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.siny.2009.08.001
Seminars in Fetal & Neonatal Medicine 14 (2009) 339344
mailto:[email protected]://www.sciencedirect.com/science/journal/1744165Xhttp://www.elsevier.com/locate/sinyhttp://www.elsevier.com/locate/sinyhttp://www.sciencedirect.com/science/journal/1744165Xmailto:[email protected] -
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long-term pulmonary function of those currently receiving inten-
sive care is not known. Such infants are described as suffering from
new BPD and, although they have less inflammation and fibrosis,
they have an arrest in acinar development resulting in fewer and
larger alveoli and reduction in the number of arteries.10 Whether
such patients have appropriate catch-up lung growth requires
careful investigation, particularly in infants with BPD, as there is
evidence that their small airway function can decline over the first
year.11
There is a spectrum of severity in survivors with abnormal lung
growth; some require many months of supplementary oxygen and
recurrent respiratory symptoms are common, whereas those
mildly affected may have only a raised respiratory rate in infancy.12
Those patients who had surgically repaired congenital diaphrag-
matic hernia in infancy have lung function abnormalities in
adolescence, including reduction in forced expiratory volume,
airways obstruction and increased airways hyper-responsiveness.13
In addition, perfusion to the ipsilateral lung is decreased,14
reflecting a persistent reduction in the number of branches or
generations of pulmonary arteries. Some studies have suggested
that these abnormalities are not associated with persisting symp-
toms, but others have reported reduced exercise tolerance, with
only 50% having enough stamina to take part in sport.15
3. Prenatal factors predisposing to CLD
3.1. Immaturity
In the past, prematurely born infants who developed CLD
frequently had had severe respiratory failure requiring high pres-
sure mechanical ventilation with high concentrations of supple-
mentary oxygen. Nowadays, CLD can occur in very prematurely
born infants who initially had minimal or even no signs of lung
disease,16 so-called new BPD. It has been suggested that in such
infants abnormal vascular development may lead to the abnor-
malities of lung growth. It has been proposed that the new BPDmay be a maldevelopment sequence resulting from interference/
interruption of normal development signalling for terminal matu-
ration and alveolarisation of the lungs of very preterm infants.17
3.1.1. Antenatal infection/inflammation
Certain evidence suggests that CLD may be more common if
there has been antenatal infection/inflammation. Chorioamnionitis
reduces the incidence of respiratory distress syndrome (RDS), but
has been shown to be associated with an increase in CLD.18 In
another series,19 however, histological chorioamnionitis was only
associated with an increased risk of BPD if the infant subsequently
developed postnatal infection or required mechanical ventilation
for more than 7 days. It was therefore suggested that antenatal
infection and/or inflammation is protective, unless there is post-natal sepsis or prolonged ventilation, and a multi-hit model for BPD
development was proposed.19 A strong joint effect of prematurity
and chorioamnionitis was demonstrated on early childhood
wheezing in the Boston Birth cohort (n 1096), who were followed
from birth to a mean age of 2.2 years.20
Results from animal models demonstrate mechanisms by which
antenatal infection/inflammation may result in BPD. For example,
in preterm fetal lambs, a single dose of intra-amniotic endotoxin
given before preterm delivery at 125 days of gestation resulted in
an increased expression of mRNA for transforming growth factor
(TGF)-b1 and a reduction in the expression of connective tissue
growth factor (CTGF).21 TGF-b1 is a regulator of lung development,
angiogenesis and airway remodelling22; transfer of TGF-b1 genes
by an adenovirus vector to newborn rat pups resulted in enlarged
alveolar airspaces.23 Decreased CTGF expression inhibits vascular
development.
3.1.2. Antenatal glucocorticoids
It has been suggested that antenatal glucocorticoids are the first
hit taken by the fetal lung, which primes the lung for more venti-
lation-induced injury.24 The impact of antenatal endotoxin and
betamethasone on the structure and function of preterm sheep
lungs has been compared.25 Both treatments led to thinning of the
alveolar walls, but the average alveolar volume increased by about
20% and the total alveolar number decreased by almost 30%. The
impact of antenatal betamethasone on fetal inflammation has been
investigated in a sheep model.26 Ewes were treated at 108110 days
of gestation (term being 150 days) with intra-amniotic endotoxin,
intramuscular betamethasone, both or saline (control). At five days,
the lambs who had received the combined intervention had
increased alveolar neutrophils and proinflammatory cytokine
mRNA expression, hence it was hypothesised that glucocorticoids
impair the ability of the preterm lung to downregulate endotoxin-
induced inflammation.26
3.2. Reduction in amniotic fluid volume
3.2.1. Renal abnormalities
Reduction in amniotic fluid is associated with bladder outlet
obstruction, bilateral renal dysplasia/hypoplasia and multicystic
kidneys.27 Affected infants may be further predisposed to pulmo-
nary hypoplasia by reduced renal proline production or thoracic
compression.
3.2.1.1. Antenatal interventions. Antenatal interventions to try to
prevent pulmonary hypoplasia in infants with renal anomalies
include relieving the oligohydramnios by amnioinfusion or by
bypassing the urinary tract obstruction. A review of 169 cases of
vesico-amniotic shunting (placing a pigtail shunt between the fetal
bladder and amniotic cavity under ultrasound guidance) demon-
strated only 47% perinatal survival and 45% shunt-related compli-cations.28 Oligohydramnios present before shunt replacement (56%
mortality) and failure to restore amniotic fluid volume (100%
mortality) were signs of a poor prognosis.28 An alternative
approach has been to undertake laser therapy during fetal cystos-
copy to disrupt posterior urethral valves, but this may result in
damage to the nearby bowel. The impact of neither intervention on
pulmonary development has been determined.
3.2.2. Oligohydramnios
The timing of onset of oligohydramnios in pregnancies
complicated by premature, prelabour rupture of the membranes
(PPROM) is critical; pulmonary hypoplasia only occurs if membrane
rupture is prior to 26 weeks of gestation.29 Abnormal lung devel-
opment, however, is not an invariable consequence of early-onsetoligohydramnios; 23% of one cohort with membrane rupture prior
to 20 weeks of gestation had no signs of pulmonary hypoplasia.30
3.2.2.1. Antenatal interventions. Serial amnio-infusion has been
studied in pregnancies complicated by oligohydramnios resulting
from PPROM. Unfortunately, the infused fluid was retained only in
30% of one series of patients and in the remaining 70% oligohy-
dramnios recurred within at least 48 h of the procedure.31
3.2.3. Invasive antenatal diagnostic procedures
Several groups have reported an excess of lung function
abnormalities in the neonatal period and early infancy following
first32 or second33 trimester amniocentesis. In addition, in a rand-
omised trial the occurrence of neonatal RDS and pneumonia was
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doubled in infants whose mother had undergone amniocentesis at
a mean gestation of 16 weeks.34 Infants whose mothers who had
undergone first trimester amniocentesis had more neonatal unit
admissions35 and were more likely to be symptomatic at follow-
up36 compared not only with controls, but also with infants whose
mothers had had first trimester chorion villous sampling. Those
data36 suggest that removal of even a small amount of amniotic
fluid at a critical stage during pregnancy can adversely affect lung
growth.
3.3. Reduction in fetal breathing movements
Selective destruction of the upper cervical cord between the
lower medulla and the level of the phrenic nucleus results in
cessation of fetal breathing movements and arrested lung growth
and development.37 Cessation or reduction of fetal breathing
movements may be responsible for the abnormal lung growth seen
in such conditions as WerdigHoffman Disease and myotonic
dystrophy. It has been suggested that the persistent absence of fetal
breathing movements in pregnancies complicated by oligohy-
dramnios due to premature and prolonged rupture of the
membranes is a poor prognostic sign.38 Infants with anterior
abdominal wall defects (AWD) can have abnormal lung growth.Stillbirths with exomphalos have been demonstrated to have small
chests and infants with giant exomphalos reduced chest wall
widths and lung areas on chest radiography. At follow-up, infants
with either gastroschisis or exomphalos had significantly lower
lung volumes than controls and five of the 13 had lung volumes
below the normal range.39 Fetuses with AWD have a reduction in
viscera in the upper part of the abdominal cavity and hence an
inadequate framework for chest wall development. The low intra-
abdominal pressure experienced by such patients could result in
impaired diaphragmatic development. Indeed, in the neonatal
period, the trans-diaphragmatic pressure generated by magnetic
stimulation of the phrenic nerves has been demonstrated to be
significantly lower in infants with gastroschisis than controls.40
Those data40 suggest that the abnormal lung growth seen in certainAWD infants may be a reduction in fetal breathing activity.
3.4. Reduction in intrathoracic space
This can occur because of a small chest, particularly asphyxi-
ating thoracic dystrophy, malformations of the lung [e.g. cystic
adenomatoid malformation (CCAM) or lung cysts], pleural effusions
and congenital diaphragmatic hernia (CDH). Fetal pleural effusions
which spontaneously resolve have a good prognosis, but they can
progress to non-immune hydrops because of impaired venous
return and congestive cardiac failure due to compression. Fatal
pulmonary hypoplasia also occurs in fetuses with rhesus iso-
immunisation and results from chronic compression of the lungs by
fetal ascites and pleural effusions. There may also be a directimmune-mediated injury affecting lung growth.41 Follow-up
infants who had rhesus isoimmunisation demonstrated that those
who had lower lung volumes had the first fetal blood sampling and
intrauterine transfusion at a significantly earlier gestation.42
3.4.1. Antenatal interventions
3.4.1.1. Thoraco-amniotic shunting. Thoraco-amniotic shunting was
initially used to decompress a large cyst in a fetus with a CCAM;
subsequently further affected fetuses have been so treated, with
70% survival in fetuses with macrocystic CCAM in one series.43 This
intervention, however, is inappropriate for fetuses with solid or
multicystic CCAMs. Pleural effusions can also be treated by thoraco-
amniotic shunting with a pigtail catheter being placed under local
anaesthetic into the effusion, which is then drained into the
amniotic cavity. This can achieve reversal of the associated hydrops
and chronic drainage with fetal lung expansion facilitating resus-
citation at birth. Placement of thoraco-amniotic shunts was asso-
ciatedwith 57% survival in fetuses with hydrops in one series; all 31
survivors of 54 treated fetuses had chylothorax.44 Follow-up lung
function studies45 demonstrated that the majority of infants who
had had thoraco-amniotic shunting had lung volumes within the
normal range,but the procedure was usuallyperformed in the third
trimesterand hence probably toolate to influence lung growth. The
UK National Institute for Health and Clinical Excellence (NICE) 46
supports insertion of pleura-amniotic shunts with appropriate
patient selection and counselling. An alternative strategy to
manage fetal pleural effusions is to cause pleurodesis by an intra-
pleural injection of OK-432. OK-432 is derived from a low virulence
Su strain of type 3 Group A Streptococcus pyrogens. There are case
reports of successful treatment.47 Rusticos review of the literature
suggests that in-utero intervention (repeated thoracocentesis,
intrauterine shunting or pleurodesis) improves the chances of
survival in fetuses with persistent effusions48; nevertheless, rand-
omised trials are required to determine if long-term respiratory
outcome is improved.
3.4.1.2. In-utero surgery. Open resection via maternal hysterotomyhas been associated with 5060% survival rates for fetuses with
CCAM and associated hydrops.49 In animal models of CDH,
pulmonary hypoplasia was reversed following repair of surgically
created diaphragmatic defects; direct repair was performed by
maternal hysterotomy and subsequent fetal thoracotomy.50 In
a prospective trial in infants, however, no benefit over standard
postnatal therapy was demonstrated51; fetal surgery was particu-
larly inappropriate if there was liver herniation, as liver reduction
resulted in kinking of the umbilical vein compromising venous
return.51 Clinical observations of distended, hyperplastic lungs in
cases of congenital high airway obstruction syndrome (CHAOS)
prompted investigation of temporary tracheal occlusion in animal
models as a potential method of preventing lung hypoplasia.
Prevention of lung fluid egress causes lung tissue stretch,promoting airway and pulmonary vessel growth.52 Initial attempts
at tracheal occlusion were via hysterotomy, but with poor survival
rates; the limited data available demonstrated that, although open
fetal tracheal occlusion was associated with increased lung growth
as evidenced by an increase in lung weight, there was no
improvement in the lung parenchymal lung structure or reduction
in muscularisation of the pulmonary arteries.53 Fetoscopic inter-
vention was then used which involved fetal neck dissection and
temporary occlusive titanium clips; unfortunately this was associ-
ated with complications including vocal cord paresis.54 As
a consequence, the technique has now been modified such that the
endoscopic placement of a balloon is used to temporarily obstruct
the trachea (FETO). The balloon is retrieved by fetal tracheoscopy at
34 weeks or is punctured during ultrasound guidance. Ultrasoundexaminations after FETO have demonstrated an increase in the
echogenicity of the lungs within 48 h.55 Survival to discharge was
50% following FETO in a multicentre study compared to 8% in
eligible contemporary controls,56 but the cases were not rando-
mised. Lung function of infants entered into a randomised trial of
tracheal occlusion by an external clip or a balloon demonstrated
only modest improvements in neonatal pulmonary function, but
only 20 infants were studied.57 Complications of FETO include
PPROM. The efficacy of FETO needs to be studied in a randomised
trial including long term pulmonary outcomes.
3.4.2. Prediction of pulmonary hypoplasia
Antenatal lung:head circumference ratio (LHR) has been used as
a prognostic indicator for CDH outcome. In a retrospective
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multicentre review, LHR measurements and position of the liver
were obtained in 134cases of left-sided CDH between 24 and 28
weeks of gestation.
58
When the LHR was 52 mmHg (minimal ventilation) or
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infants
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treatment with systemic corticosteroids, have proven efficacy
based on RCTs. Although not used specifically for the prevention
of BPD, the treatment of apnea of prematurity with caffeine and
the use of aggressive phototherapy in ELBW infants are also
associated with reductions in BPD. Individually, these treatments
reduce risk by 711%. Unfortunately, treatment with systemic
corticosteroids (particularly dexamethasone), although effective
in reducing the risk of BPD, is associated with an increased rate
of neurodevelopmental impairment. The benefits of treatment
with systemic corticosteroids may outweigh the risks in infants
with high baseline risk of BPD. The use of CPAP in selected
populations of infants, in lieu of mechanical ventilation, may also
decrease the incidence of BPD, but further data are needed to
define this population. The use of quality improvement meth-
odologies has potential for reducing BPD, but will rely upon
high quality evidence from RCTs that support bundles of
best practices.
Because of the economic impact and long-term consequences of
BPD, new preventive therapies are desirable. Future trials that test
these therapies should incorporate strategies to systematically
quantify the risk of BPD prior to enrollment. To date, a method for
predicting BPD with sufficiently high sensitivity and specificity has
not been available. A new tool using clinical and demographicvariables appears promising.103 Because of the heterogeneity of the
causal pathways that lead to the development of BPD, it is unlikely
that a single preventive strategy will have a major impact on its
reduction. Rather, several strategies, with the expectation that each
will contribute to a modest reduction in BPD, will need to be tested
in RCTs.
Conflict of interest statement
None declared.
Funding sources
None.
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Practice points
BPD is an important morbidity associated with prema-
ture birth.
The prevention strategies with the highest qualityevidence with most favorable benefit/risk ratio include
vitamin A and caffeine.
Corticosteroids reduce the incidence of BPD, butincrease the risk of abnormal neurologic examination.
Research directions
A simple, clinically relevant, predictive model that
objectively assesses the risk of BPD needs to be
developed.
Well-powered trials of surfactant therapy with briefventilation, and later surfactant therapy with the primary
endpoint of CLD, are needed.
An RCT of systemic corticosteroids versus placeboamong patients at high risk of bronchopulmonary
dysplasia, with appropriate neurodevelopmental follow-
up, is needed.
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