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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
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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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





doi:10.1016/j.siny.2009.08.006



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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.

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8. Giamonna ST, Kerner D, Bondurant S. Effect of oxygen breathing at atmosphericpressure on pulmonary surfactant. J Appl Physiol 1965;20:8558.

9. Nash G, Blennerhassett JB, Pontoppidan H. Pulmonary lesions associated withoxygen therapy and artificial ventilation. N Eng J Med 1967;276:36874.

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]





doi:10.1016/j.siny.2009.08.001



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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

A. Greenough / Seminars in Fetal & Neonatal Medicine 14 (2009) 339344340


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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

A. Greenough / Seminars in Fetal & Neonatal Medicine 14 (2009) 339344 341


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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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11. Stevens TP, Blennow M, Soll RF. Early surfactant administration with briefventilation vs selective surfactant and continued mechanical ventilation forpreterm infants with or at risk for RDS. Cochrane Database Syst Rev; 2002.CD003063.

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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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