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Antenatal and postnatal lung and vascular anatomic and functional studies in congenital diaphragmatic hernia Implications for clinical management.

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American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 145C:184– 200 (2007)
A R T I C L E
Antenatal and Postnatal Lung and Vascular
Anatomic and Functional Studies in Congenital
Diaphragmatic Hernia: Implications for
Clinical Management
ROBERTA
L. KELLER
*
Congenital diaphragmatic hernia is characterized by fetal and neonatal lung hypoplasia as well as vascular
hypoplasia. Antenatal imaging studies have been performed that attempt to quantify the degree of hypoplasia
and its impact on infant prognosis. Prenatal and perinatal growth of the lung and vasculature are interdependent
and their continued coordinated growth is critical for survival after birth in this patient population. Lung
protection strategies appear to improve survival in newborns with diaphragmatic hernia, but a subset of infants
remain who demonstrate sufficiently severe lung hypoplasia that we are unable to provide support long-term
after birth. Fetal intervention is a strategy designed to enhance fetal lung growth towards improving survival in
this most severely affected group, though other therapies to enhance postnatal lung and vascular growth should
be concurrently investigated. However, any of these interventions will require careful selection of those infants at
risk for poor outcome and thorough follow up, since long-term morbidity is significant in children with
diaphragmatic hernia. ß 2007 Wiley-Liss, Inc.
KEY WORDS: lung hypoplasia; persistent pulmonary hypertension of the newborn; pulmonary function; tracheal occlusion
How to cite this article: Keller RL. 2007. Antenatal and postnatal lung and vascular anatomic and
functional studies in congenital diaphragmatic hernia: Implications for clinical management.
Am J Med Genet Part C Semin Med Genet 145C:184–200.
INTRODUCTION
Congenital diaphragmatic hernia (CDH)
is a condition characterized by fetal and
neonatal pulmonary parenchymal and
vascular hypoplasia. Pre-acinar airway
and vascular structures develop together
through the pseudoglandular stage of
development (6–16 weeks’ gestational
age, GA) [Bucher and Reid, 1961; Hall
et al., 2000], while more peripheral
intra-acinar airway and vessel develop-
ment are also inter-dependent (reviewed
by Hislop [2002]). Respiratory surface
area and the extent of the vascular bed,
therefore, are closely related. Due to an
early arrest of pre-acinar lung development, newborns with symptomatic
CDH have respiratory failure with a
delayed transition to postnatal circulation. Survival is limited by lung hypoplasia and postnatal lung injury. The use
of gentle ventilation techniques has
resulted in improved survival for new-
Abbreviations: AP, anterior–posterior; CDH, congenital diaphragmatic hernia; ECMO,
extracorporeal membrane oxygenation; EXIT procedure, ex utero intrapartum procedure; FTO,
fetal tracheal occlusion; FRC, functional residual capacity; GA, gestational age; LD, lung diameter;
LHR, lung-to-head ratio; L/T ratio, lung-to-thorax ratio; MRI, magnetic resonance imaging PA,
pulmonary artery; PVR, pulmonary vascular resistance; ROC curve, receiver operator characteristic
curve; SBP, systemic blood pressure; TC, thoracic circumference; 3D ultrasound, threedimensional ultrasound; 2D ultrasound, two-dimensional ultrasound.
Roberta L. Keller, M.D. is an Assistant Professor of Clinical Pediatrics at the University of
California San Francisco, an attending neonatologist in the William H. Tooley Intensive Care
Nursery and the Medical Director of the neonatal Extracorporeal Membrane Oxygenation
program at the UCSF Children’s Hospital in San Francisco, CA. Dr. Keller’s interests include lung
and vascular growth and remodeling in congenital diaphragmatic hernia and other developmental disorders of the newborn lung.
*Correspondence to: Roberta L. Keller, M.D., UCSF Box 0748, San Francisco, CA 94143.
E-mail: kellerr@peds.ucsf.edu
DOI 10.1002/ajmg.c.30130
ß 2007 Wiley-Liss, Inc.
borns with symptomatic CDH in individual institutions, but overall mortality
remains at 45–50% in population-based
studies [Dott et al., 2003; Stege et al.,
2003; Colvin et al., 2005]. This review
will discuss the development of the
lung in CDH, focusing on Bochdalek
(posterolateral) hernias, and how
antenatal and postnatal anatomical and
physiological measurements of the lung
and vasculature are related to morphometric observations.
CDH AND PULMONARY
HYPOPLASIA
Lung Airway and Parenchymal
Development
Diaphragmatic defects in humans are
associated with bilateral pulmonary
hypoplasia. This pulmonary hypoplasia
develops, in part, secondary to abdominal contents occupying the thoracic
space with shift of mediastinal tissues
into the contralateral hemithorax. Pul-
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
185
monary hypoplasia may also have a
primary developmental component, as
animal models have confirmed that
developmental regulation of the lung
and diaphragm is controlled by some of
the same genes [Guilbert et al., 2000;
Diaphragmatic defects
in humans are associated
with bilateral pulmonary
hypoplasia. This pulmonary
hypoplasia develops, in part,
secondary to abdominal
contents occupying the thoracic
space with shift of mediastinal
tissues into the contralateral
hemithorax. Pulmonary
hypoplasia may also have a
primary developmental
component, as animal
models have confirmed that
developmental regulation
of the lung and diaphragm
is controlled by some
of the same genes.
Keijzer et al., 2000; Ackerman et al.,
2005; You et al., 2005]. A typical severe
diaphragmatic defect with herniation of
bowel into the left chest is shown in
Figure 1.
This hypoplasia is an early fetal
event occurring during the pseudoglandular stage of lung development in
some cases, as evidenced by the arrest of
pre-acinar airway branching at 10–
14 weeks’ GA. Pre-acinar airway
branches are decreased in number to
1/3–2/3 of normal values, with the
greatest reductions in the ipsilateral lung.
Similarly, even the main stem bronchi
are severely reduced in diameter, particularly in the ipsilateral lung [Areechon
and Reid, 1963; Kitigawa et al., 1971;
Thurlbeck et al., 1979; Geggel et al.,
1985]. Although airway muscle is not
significantly increased in those infants
Figure 1. Infant with unrepaired left congenital diaphragmatic hernia. Note the
presence of liver and intestines in the left thoracic cavity (white arrows). The heart and
mediastinal structures are shifted to the right (H, heart). The stomach is usually intrathoracic and posterior in fetuses and infants with left diaphragmatic hernia and liver
herniated into the thorax. The diaphragm under the heart is intact (marked with black
arrow). Courtesy of KK Nobuhara.
that die at less than 24 hr of age
(compared to controls), increased musculature is demonstrated in infants that
die later, and it is greatly increased in
infants that die after receiving high
ventilator assistance [Broughton et al.,
1998]. Overall lung volume is reduced to
10–30% of normal volumes in those
infants that die at less than 24 hr of age
[Kitigawa et al., 1971; Thibeault and
Haney, 1998]. Alveolar counts are relatively normal per acinus, but overall
numbers of alveoli are severely reduced
(6.6 106 compared to the normal
average of approximately 50 106) and
alveoli are generally smaller than those
present in control lungs [Areechon and
Reid, 1963; Kitigawa et al., 1971;
Langston et al., 1984; Geggel et al.,
1985]. The surface area available for gas
exchange in these infants, therefore, is
substantially decreased. However, the
lung does have capacity for compensatory growth. One child with left CDH
that later died from trauma at 64 months
of age had 107 106 alveoli on the left
side and 242 106 alveoli on the right
side. Thus, the total alveolar numbers
were normal for age, but the right lung
demonstrated compensatory growth and
had twice the number of alveoli
expected [Thurlbeck et al., 1979].
Pulmonary Vascular Development
The pulmonary vascular tree also
demonstrates a developmental arrest of
arterial branching at 12–14 weeks’ GA.
Similarly, the diameter of the vessels is
decreased, and related to lung volume
[Kitigawa et al., 1971]. This results in a
decreased cross-sectional area of the
vascular bed, with a requisite increase
in pulmonary vascular resistance (PVR).
Pre-acinar and intra-acinar arteries are
decreased in size in infants that die in the
first week of life. In some infants, intraacinar arteries have a muscular wall,
whereas other infants have no distal
muscularization [Kitigawa et al., 1971;
Geggel et al., 1985]. Muscular wall
thickness and muscle mass are increased
in arteries bilaterally, compared to normal controls, and this increase in muscle
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
mass is inversely proportional to the
degree of lung hypoplasia [Kitigawa
et al., 1971; Naeye et al., 1976].
influencing survival (e.g., ventilation
strategy, GA at delivery and associated
anomalies).
ANTENATAL
MEASUREMENTS OF
PULMONARY HYPOPLASIA
Measurement of Lung Hypoplasia
to Predict Prognosis
Pulmonary hypoplasia is a pathological
diagnosis. Several anatomical measures
of lung and vascular hypoplasia by fetal
ultrasound have been proposed. In
fetal CDH, these measurements have
included thoracic, lung, and pulmonary
artery (PA) sizes, as well as proxies for the
mass of the herniated abdominal viscera
(degree of mediastinal shift to the
contralateral hemithorax, liver herniation into the hemithorax, decreased
abdominal circumference and decreased
left ventricular mass). However, most of
these studies do not have pathological
correlation to verify the accuracy of the
diagnosis of lung hypoplasia. Instead,
these measures have been evaluated as
antenatal predictors of survival and other
outcomes in CDH, to allow for counseling of families and to assess criteria for
fetal intervention. Results from these
prognostic studies have been inconsistent, which may be due to variability in
the technique and gestational timing of
measurement, the range of severity
of lung hypoplasia in the population of
fetuses and newborns being studied or
the confounding effects of other factors
There are various methods now available
for quantification of in utero lung size.
These include two-dimensional (2D)
ultrasound to measure lung size in
relation to transverse thoracic area
(L/T ratio) or head circumference
(LHR) and measurement of lung
volume by magnetic resonance imaging (MRI) or three-dimensional (3D)
ultrasound.
Measurement of bilateral lung area
by two-dimensional ultrasound (2D
ultrasound), normalized to the transverse thoracic area (L/T ratio), was
described in 1990 [Hasegawa et al.,
1990]. This measurement was found to
be decreased in CDH, with no differences in measurements between survivors and non-survivors with CDH in a
small series; however, a lower L/T ratio
was associated with worse indices of
neonatal gas exchange and increased
need for ECMO support [Kamata
et al., 1992]. In subsequent publications
from other centers, lung area measurements in CDH were confined to the
contralateral lung, as the ipsilateral lung
can often not be appreciated (Fig. 2A,B)
[Guibaud et al., 1996; Lipshutz et al.,
ARTICLE
1997; Jani et al., 2006b]. In a recent
study, the contralateral (right) lung area
divided by the total thoracic area in seven
fetuses with left CDH showed findings
similar to Kamata and colleagues; specifically, the authors could not demonstrate a relationship of the ratio to
survival in CDH, but they did demonstrate that lower ratios were associated
with poorer initial oxygenation and
need for ECMO support [Nakata et al.,
2003]. Variations on these measurements have included the fetal right lung
diameter (LD) at the level of the cardiac
atria divide by the thoracic circumference (TC). In seven fetuses with CDH,
when the LD/TC was less than 5th
centile, lung hypoplasia was confirmed
by pathological examination in all cases
Variations on these
measurements have included
the fetal right LD at the level
of the cardiac atria divide by the
TC. In seven fetuses with
CDH, when the LD/TC was
less than 5th centile, lung
hypoplasia was confirmed by
pathological examination
in all cases.
Figure 2. Fetal ultrasound (A) and chest radiograph (B) from patients with severe left congenital diaphragmatic hernia. Ultrasound (A)
is used to measure the right (contralateral) lung area (RL) using a cross-sectional view of the thorax at the level of the 4-chamber view of the
heart (H). This fetus had liver herniated into the left hemithorax and the hypoplastic left lung cannot be appreciated (Ao, aorta and S,
stomach). The chest radiograph (B) demonstrates findings in a newborn with severe left diaphragmatic hernia who is intubated and on
mechanical ventilation. The extremely hypoplastic left lung is actually well-expanded (arrow).
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
[Merz et al., 1999]. A follow up study
from this group demonstrated that 11/
14 fetuses with ultrasound measurements <5th centile died (the nine infants
with post-mortem examinations met
pathological criteria for lung hypoplasia), whereas three fetuses with measures
>5th centile survived. In 6/7 fetuses
who had repeated fetal LD measures <5th centile, all infants expired
[Bahlmann et al., 1999]. The one fetus
with increasing LD centiles survived. A
separate study, measuring contralateral
lung area divided by hemithoracic area,
demonstrated that a ratio less than 50%
predicted was significantly associated
with death (5/20 survivors vs. 6/7
survivors, P ¼ 0.009). There was excellent agreement between these measurements obtained by two different
observers (kappa ¼ 0.87) [Guibaud
et al., 1996].
The lung-to-head ratio (LHR),
developed by our group at the University of California San Francisco
(UCSF), is calculated by measuring the
area of the contralateral lung at the level
of the cardiac atria (obtained on a
transverse section of the thorax
(Fig. 2A)) divided by the biparietal head
circumference.
The lung-to-head ratio (LHR),
developed by our group at the
University of California
San Francisco (UCSF), is
calculated by measuring the
area of the contralateral lung at
the level of the cardiac atria
(obtained on a transverse section
of the thorax) divided by the
biparietal head circumference.
In a series of 55 fetuses with left CDH,
the LHR was identified as the only
independent predictor of survival (LHR
1.33 0.50 for survivors vs. 0.87 0.32
for non-survivors, P < 0.001). There
were no survivors with LHR <0.6
(n ¼ 5) and 100% survival with LHR >
1.35 (n ¼ 14). The presence of liver
herniated into the left hemithorax was
also significantly associated with death
(not independent of the LHR), and the
severity of liver herniation was inversely
proportional to the LHR [Metkus et al.,
1996]. A subsequent small (n ¼ 15)
UCSF series confined the analysis to
fetuses with left CDH, liver herniated
into the hemithorax and LHR measurement at 24–26 weeks’ GA. Again, the
LHR was higher in survivors than in
non-survivors; there were no survivors
with LHR < 1.0 (n ¼ 3) and 100%
survival with an LHR > 1.4 (n ¼ 4).
We subsequently demonstrated that the
LHR had good inter-observer agreement (among four blinded sonologists)
with an intraclass correlation coefficient
of 0.70 and excellent intra-observer
agreement with an intraclass correlation
coefficient of 0.80 [Keller et al., 2003].
However, the LHR was not found
to be predictive of survival in fetuses
with left CDH when the liver was not
herniated on ultrasound at 26 weeks’
GA. Eight of nine fetuses with
LHR 1.4 survived and 8/11 with
LHR > 1.4 survived. In our experience,
fetal liver herniation in left CDH is a
significant predictor of neonatal morbidity [need for extracorporeal membrane oxygenation support (ECMO):
17/30 (57%) with liver herniation vs. 3/
15 (20%) without liver herniation,
P ¼ 0.04] and mortality [17/30 (57%)
vs. 1/15 (7%), P ¼ 0.001] [Albanese
et al., 1998]. Similar findings have
been demonstrated in left CDH with
fetal liver herniation detected by MRI
(at 20–39 weeks’ GA); mortality was
60–70% with liver herniated versus 10–
20% without liver herniated [Walsh
et al., 2000; Kitano et al., 2005].
Interestingly, the ultrasound LHR was
significantly lower in fetuses with
herniated liver (by MRI), compared
to those without herniated liver
(1.4 0.6 vs. 2.0 0.3, P ¼ 0.01)
[Kitano et al., 2005].
Other single center studies reporting on the prognostic value of the LHR
have had results that are not always
consistent with ours. Flake et al. [2000]
reported that all fetuses with left CDH
and LHR 1.0 (n ¼ 7) expired when
187
liver was herniated, and 20/24 fetuses
with LHR > 1.4 survived. LHR (measured at 28–37 weeks’ GA) was higher
in survivors than non-survivors in
another series of 21 fetuses with left
CDH. All fetuses with LHR < 1.1
expired, while all fetuses with
LHR > 1.4 survived (n ¼ 8); the presence of liver herniation was not determined in this study [Laudy et al., 2003].
Heling et al. [2005], however, did not
find a relationship between LHR and
survival, when fetuses with liver herniated and not herniated were included,
as were fetuses with both left and right
CDH. Similarly, in a series of 28 fetuses
reported by Arkovitz et al., no relationship between LHR and survival was
seen. However, only four infants subsequently died among this group of fetuses
with both left and right CDH and with
and without liver herniation [Arkovitz
et al., 2007]. We participated in a recent
large multicenter evaluation of LHR in
fetal left CDH and liver herniation
ascertained at 22–27 weeks’ GA. In this
report of neonatal survival in 184 fetuses,
the presence of liver herniation was
associated with decreased odds of survival in a multivariate analysis (OR 0.48,
P ¼ 0.035), as was a lower LHR. When
confining the analyses to fetuses with or
without liver herniation, the LHR
relationship to mortality was stronger
in those fetuses with liver herniation
(OR 26.6 vs. OR 3.3). There were no
survivors in this large group with liver
herniation and LHR < 0.8, and only
3/27 infants (11%) with LHR < 1.0
survived [Jani et al., 2006a]. In comparison, 11/19 fetuses (58%) with
LHR < 1.0 and without liver herniation
survived.
There are additional concerns
regarding the interpretation of the
LHR measurement, which may make
extrapolation of studies from one center
difficult to apply to findings at another
center. One issue is the methodology of
obtaining the measurement. Although
all centers describe their measurement at
the level of the cardiac atria obtained on
a transverse section of the thorax, the
lung area measurement can be obtained
in two ways. One technique employs the
aorta and lateral rib as landmarks for the
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lateral measurement, with the orthogonal diameter the anterior–posterior
(AP) measurement from the cardiac atria
to the posterior rib (AP measurement,
consistently performed and reported at
UCSF, RA Filly, personal communication). Alternatively, the largest diameter of visible lung can be measured
from a site lateral to the atria to the
posterior rib with the resulting orthogonal measurement used to calculate the
lung area (Long measurement) [Deprest
et al., 2006]. As anticipated, LHR
measures obtained by the Long technique are consistently higher. A blinded
test series of 25 cases of left CDH with
herniated liver yielded a mean LHR of
1.29 by AP measure compared to the
LHR of 1.55 by Long measure, with
excellent correlation (R2 ¼ 0.98) between the two measures [Keller et al.,
2003; RA Filly, unpublished work]. A
recent study of these two measurement
techniques, which compared the resulting lung areas in control and CDH
fetuses to lung volumes obtained by 3dimensional (3D) ultrasound, found that
right lung areas measured by both
techniques correlated equally well with
lung volumes in control fetuses
(R ¼ 0.95 for both methods). In CDH,
lung area and LHR measures obtained
by the AP method were consistently
lower than those obtained by the Long
method [Jani et al., 2006b]. Therefore,
the measurement technique and its
prognostic thresholds should be accounted for when counseling families
with respect to prognosis.
A second issue, regardless of technique, is which LHR measure is
reported and used for counseling. There
is variability in the measurement for any
individual fetus. We previously reported
the prognostic value for survival of the
minimum, average, and maximum LHR
measures. The minimum LHR measure
demonstrated slightly better prognostication than the average LHR, based on
the receiver operator characteristic
curves (ROC curves) (area under the
curve 0.73, 0.72, and 0.59 for minimum,
average, and maximum LHR, respectively) [Keller et al., 2003]. All LHR
reports from UCSF had used the minimum LHR, so we have continued to use
the minimum LHR for counseling and
reporting (RA Filly, personal communication). However, if maximum LHR
is reported, the prognosis should be
based on different thresholds. A third
issue has to do with the timing of LHR
measurement. The LHR was developed
in an attempt to normalize the lung area
to the size of the fetus, using the head
circumference as a proxy for fetal size. In
normal controls, the LHR increases over
gestation (from 12 to 32 weeks’) when
using measurements of either the right
or left lung. The measurements have
different quadratic relationships with
respect to GA, with the head circumference increasing 4-fold and the lung area
increasing 16-fold over the measurement period [Peralta et al., 2005]. Thus,
timing of the LHR measurement may
also have some relevance in prenatal
counseling, and the implication of the
timing of the measurement may be even
greater since the rate of lung growth in
severe CDH at 29–38 weeks’ GA may
be decreased compared to lung growth
in normal controls [Bahlmann et al.,
1999]. The fourth issue is the site of
delivery and neonatal care after a fetal
diagnosis of severe CDH. From our fetal
database, we have found that in the most
severe CDH group (liver herniated with
LHR 1.0), when LHR was measured
at 20–29 weeks’ GA, infants were more
likely to survive if their care was at UCSF
compared to care given at a broad group
of other institutions [17/30 (57%) vs. 8/
37 (22%), P ¼ 0.01, unpublished work].
Therefore, prenatal counseling regarding prognosis in severe CDH should
incorporate the planned site of delivery
and postnatal care, with specific data as to
survival in different fetal risk groups.
Finally, data on LHR and other
measures in right CDH is scarce. Right
CDH is less frequent, and may be more
difficult to diagnose antenatally, since
mediastinal shift may not be appreciated.
A single series of fetuses and newborns
with right CDH demonstrated 3/4
fetuses with LHR 1.0 survived
[Hedrick et al., 2004]. The right lung
is consistently larger than the left lung in
fetuses without lung hypoplasia [Peralta
et al., 2005], although it is not clear how
this differential would affect prognosti-
ARTICLE
cation in CDH where the problem is
bilateral lung hypoplasia. Criteria for
fetal intervention (such as fetal tracheal
occlusion [FTO]) for severe right CDH
at our center and others, however, are
the same as those for severe left fetal
CDH: the presence of liver herniated
into the chest and LHR 1.0 [Deprest
et al., 2006].
MRI and three-dimensional ultrasound (3D ultrasound) (which compare
observed to predicted lung volume
ratios) may be more promising tools
to prognosticate survival throughout
gestation. In unaffected fetuses, MRI
lung volumes correlate well with
standard biometric data obtained by
fetal ultrasound [Coakley et al., 2000;
MRI and 3D ultrasound
(which compare observed to
predicted lung volume ratios)
may be more promising tools
to prognosticate survival
throughout gestation. In
unaffected fetuses, MRI
lung volumes correlate well
with standard biometric
data obtained by
fetal ultrasound.
Rypens et al., 2001]. Further, MRI lung
volumes from control fetuses correlated
well with autopsy lung volumes [Rypens
et al., 2001]. A potential advantage of
MRI and 3D ultrasound is that these
techniques allow for quantification of
bilateral lung volume in less severe CDH
(compared to the unilateral measurements quantified by some 2D ratios).
However, in more severe cases (where
prognostication is most important), the
ipsilateral lung can be difficult to measure or visualize by either of these newer
techniques [Ruano et al., 2004b]. In one
series, fetuses in whom the ipsilateral
lung on MRI could not be identified had
significantly higher mortality than those
in whom the ipsilateral lung was visualized [Gorincour et al., 2005]. Other
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
limitations of these volumetric measurements include difficulties with reproducibility; studies have found both good
agreement [Ruano et al., 2004b] and
poor agreement [Peralta et al., 2006c]
between MRI and 3D ultrasound lung
volume measurements. Further, centers
use different predictive equations for
expected lung volume measurements,
and prognostic ability within a center
may be impacted by the relatively
narrow ranges of normal lung volume
predicted during mid-gestation, and
the wide ranges of normal lung
volume predicted later in gestation
[Mahieu-Caputo et al., 2001; Rypens
et al., 2001; Kasprian et al., 2006; Peralta
et al., 2006a].
Walsh et al. [2000] published a series
of 41 fetuses with CDH and MRI lung
volume measurements at 20–39 weeks’
GA. Seventeen infants expired, but there
were no differences in lung volume
between survivors and non-survivors,
and also no differences in lung volume
indexed for GA (ml/week GA). In a
smaller series, the ratio of observed to
expected lung volumes by MRI was
evaluated in 13 fetuses with CDH at 28–
37 weeks’ GA. These ratios were
significantly lower in fetuses with
CDH than in controls, despite considerable variability in the measured lung
volume of unaffected fetuses. Further,
observed to expected lung volume ratios
were lower among the nine CDH fetuses
that expired as newborns, compared to
the four that survived (median 0.26 vs.
0.46, P ¼ 0.03). In 5/6 infants undergoing autopsy, lung hypoplasia was
confirmed by low lung to body weight
ratios; all of these infants had an observed
to expected lung volume ratio 0.35
[Mahieu-Caputo et al., 2001]. A series
of 26 fetuses (20–28 weeks’ GA) from
our center (using a different algorithm
for predicting expected lung volume)
demonstrated a strong correlation
between observed to expected fetal lung
volumes by MRI and LHR. Also, lower
observed to expected fetal lung volumes
correlated with worsening outcomes
(e.g., death, need for ECMO support,
prolonged duration of mechanical ventilation) in 11 infants with left CDH.
This study further demonstrated excel-
lent agreement in estimation of MR
lung volume between two independent
observers [Paek et al., 2001]. An additional recent series of 77 fetuses studied
at 24–37 weeks’ GA (which again used a
different predictive equation for
expected lung volume) demonstrated
lower ratios of observed to expected
lung volume in non-survivors versus
survivors (0.24 0.12 vs. 0.36 0.13,
P < 0.001). Fetuses with a ratio below
0.25 had a survival rate lower than the
40% observed in the entire cohort, and
those with a ratio above 0.25 had a
survival rate greater than 40% (sensitivity
79%, specificity 64%) [Gorincour et al.,
2005]. In a smaller study of 22 fetuses at
30–32 weeks’ GA using the same
predictive equation, a threshold of 0.30
was the best fit for predicting mortality
(sensitivity 83%, specificity 100%) [Bonfils et al., 2006] and in a study of 14
fetuses with CDH, all three infants that
subsequently expired had an observed to
expected lung volume ratio of 0.15
[Barnewolt et al., 2007]. Unfortunately,
no reference is reported for the generation of the predictive algorithm in this
study. Thus, there remains uncertainty in
the prognostic ability of MRI measures
in lung hypoplasia, similar to the concerns with 2D ultrasound measures.
Three-dimensional ultrasound is
proving useful for predicting lung
size. Ipsilateral and contralateral lung
volumes measured by 3D ultrasound
are decreased in fetuses with CDH,
although in some cases the contralateral
lung is still within the normal range [Jani
et al., 2006b; Peralta et al., 2006b].
Observed to expected lung volume
ratios were found to be decreased in
fetuses with CDH (compared to controls), and infants with CDH that
expired had lower ratios than those that
survived (median 0.16 vs. median 0.44,
P ¼ 0.04). All infants with a ratio 0.32
expired and lung hypoplasia was confirmed on three of those infants that
underwent post-mortem examination
[Ruano et al., 2004a]. A subsequent
study wherein absolute lung volumes
ascertained by 3D ultrasound in CDH
and controls were compared to postmortem lung volumes demonstrated
85% accuracy in measurements in fetuses
189
with CDH and 91% accuracy in controls
[Ruano et al., 2005].
Fetal Measurement of Vascular
Hypoplasia and Prognosis
The data describing the impact of
abnormal antenatal pulmonary vascular
development on prognosis in CDH are
limited. Main and branch PA diameter
can be measured by fetal echocardiogram on a cross-section of the fetal
thorax at the level of the main PA,
ascending aorta and superior vena cava.
In one series of fetuses with CDH, these
branch PA measurements correlated
well with individual lung weights
obtained at autopsy. In both retrospective and prospective studies of these
measurements (a total of 43 fetuses with
left CDH), ipsilateral PA diameter was
consistently smaller than contralateral
PA diameter. On initial echocardiogram
obtained during mid-gestation, ipsilateral PA diameter was at the low end of
the normal range of values (usually
<25th centile). Serial measures, however, demonstrated progressive hypoplasia of the ipsilateral PA, with the PA
diameter percentile (corrected for GA)
usually decreasing in studies after
30 weeks’ GA (consistent with the lack
of lung growth observed by ultrasound
in CDH [Bahlmann et al., 1999]). Fetal
left PA measures were inversely correlated with the duration of mechanical
ventilation, oxygen supplementation
and length of hospital stay, and they
were predictive of prolonged duration
(>28 days) for all of these outcomes
[Sokol et al., 2002, 2006]. Another
method of quantification of the pulmonary vasculature in CDH is visualization of PA branches by Doppler in the
contralateral lung on a cross-section of
the thorax at the level of the largest
image of the lung. In one study, the
ability to visualize three branches of the
PA was considered a normal vascular
tree, two branches was considered a
poor vascular tree, and one branch was
considered an absent vascular tree. In
this series of 42 fetuses with CDH,
mortality was 25% (5/20) with normal
vascular tree and 82% (18/22) with an
abnormal vascular tree (P ¼ 0.0002)
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[Mahieu-Caputo et al., 2004]. Finally, a
more recent study proposed the use of
power Doppler imaging by 3D ultrasound to ascertain vascularization index
(percent of color signal in the lung
volume as a measure of number of vessels
detected), flow index (amplitude of
color signal as a measure of pulmonary
blood flow) and vascularization-flow
index (a combination of vascularity and
flow). These indices were all significantly correlated with the ratio of
observed to expected lung volume.
Among 21 fetuses with CDH, a lower
vascularization index for either both
lungs or the contralateral lung only was
significantly associated with mortality.
Lower pulmonary blood flow, however,
was less strongly associated with mortality and there was no association if the
contralateral lung alone was considered
[Ruano et al., 2006]. These measures of
pulmonary vascular development may
enhance the prognostic abilities of the
measures of fetal lung development
described previously.
There are also very limited data
regarding fetal pulmonary vascular function in lung hypoplasia. In two fetuses
with CDH and autopsy-proven pulmonary hypoplasia, pulsatility index
(a Doppler measure of pulmonary
vascular impedance) in the branch PA
was elevated in utero [Chaoui et al.,
1999]. A subsequent study evaluated
reactivity of the pulmonary vasculature
in response to maternal hyperoxygenation. A reactive test was defined as a
decrease in branch PA pulsatility index of
20% (indicating a decrease in vascular
impedance and an increase in pulmonary
blood flow). Ten of the 29 fetuses
evaluated in this study had a diagnosis
of CDH. Eleven of 14 fetuses with a
non-reactive test died from lung hypoplasia, while only 1/15 fetuses with a
reactive test died from lung hypoplasia
[Broth et al., 2002]. Another measurement that has been studied is the branch
PA acceleration time/ejection time
ratio. This parameter is low in adults
with pulmonary arterial hypertension.
In a series of fetuses with suspected lung
hypoplasia, ten had CDH and four of
these had low acceleration time/ejection
time ratios in the contralateral branch
PA. These fetuses either expired, or had
lung hypoplasia confirmed by postmortem evaluation. The surviving newborns all had ratios that were within the
normal range [Fuke et al., 2003].
EFFECTS OF FETAL
TRACHEAL OCCLUSION
(FTO)
FTO was developed as a strategy to
enhance fetal lung growth in CDH.
Animal models of tracheal occlusion
have provided an opportunity to start to
understand the effects of stretch and
distension on lung growth and maturation. These models of tracheal occlusion
are discussed in detail in the review by
Dr. Khan, Dr. Cloutier, and Dr. Piedboeuf. Tracheal occlusion was first
performed on human fetuses only with
severe CDH and was reported from our
center in 1996 [Harrison et al., 1996].
The occlusion technique has evolved
from the placement of an internal
tracheal plug, to an external clip,
and then to an endotracheal balloon
[Harrison et al., 1996, 2001]. The
surgical approach has also evolved from
an open fetal surgical procedure with a
maternal hysterotomy [Harrison et al.,
1996], to an endoscopic procedure via
maternal laparotomy [Harrison et al.,
1998], and subsequently to a completely
endoscopic procedure, with occlusion
placed at 26–28 weeks’ GA and released
prior to delivery at 33–36 weeks’ GA.
The release prior to delivery has abrogated the need for a specialized Cesarean
section delivery wherein the occlusion
was released at delivery (ex utero
intrapartum procedure [EXIT procedure]) [Deprest et al., 2004].
FTO and Survival in Severe CDH
As FTO and predictive diagnostic techniques have evolved, so has the approach
to FTO in humans. Initially, fetuses with
CDH meeting inclusion criteria for
FTO had to demonstrate herniated liver
with an LHR 1.4 measured during
mid-gestation. Fetuses also had to have a
normal karyotype with no additional
anomalies detected by ultrasound or
echocardiography. The open procedure
ARTICLE
led to substantial fetal and neonatal
morbidity [Harrison et al., 1996]. Once
the endoscopic technique was accomplished, the early experience in this
severely affected group was promising,
with survival 75% (6/8) following FTO
compared to survival of 38% (5/13) in a
contemporary comparison group without FTO [Harrison et al., 1998]. These
initial results led to our single-center
randomized controlled trial of FTO for
severe left CDH, with the procedure
accomplished at 24–28 weeks’ GA.
Interim analysis by the data safety
monitoring board resulted in early trial
termination due to the fact that we
would be unlikely to detect a survival
difference with completion of the study.
These initial results led to
our single-center randomized
controlled trial of FTO for
severe left CDH, with the
procedure accomplished at
24–28 weeks’ GA. Interim
analysis by the data safety
monitoring board resulted in
early trial termination due to
the fact that we would be
unlikely to detect a survival
difference with completion
of the study.
We found survival at 90 days in both
groups to be similar to the historical
survival in the FTO group [10/13 (77%)
vs. 8/11 (73%), control vs. FTO group,
P ¼ 1.0]. Pre-term delivery remained a
problem in the FTO group, with mean
GA at delivery significantly higher in
the control group (30.8 2.0 vs. 37.0 1.5 weeks, P < 0.001) [Harrison et al.,
2003].
The data from this trial also suggested that an LHR threshold of 1.0
rather than 1.4 could be used for
selection of candidates for FTO. Mortality was significantly increased when
LHR was 0.90 (Hazard ratio 0.13, 95%
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
confidence interval 0.03, 0.64), with
long-term survival 3/9 if LHR 0.90
and 13/15 if LHR > 0.90 [Harrison
et al., 2003]. This was similar to the
inclusion criteria for FTO previously
used by Flake et al. [2000] (liver
herniated and LHR 1.0), and these
criteria that have subsequently been
adopted at our center and in Europe
[Deprest et al., 2004]. Flake et al. [2000]
presented a survival of 33% (5/15) in a
mixed group of left and right CDH
following open FTO and the European
FETO Task Group presented a survival
of 48% in their first 21 endoscopic fetal
procedures with both left and right
CDH. Survival among fetuses that were
evaluated by the same group but did not
undergo FTO was 8% (1/12) [Deprest
et al., 2004]. Contrary to the promising
FTO data from Europe, a recent retrospective evaluation of the UCSF Fetal
Treatment Center database, demonstrated that among fetuses with liver
herniated and LHR 1.0 who were
subsequently cared for in the neonatal
period at UCSF, survival was comparable whether or not endoscopic FTO
was performed [16/29 (55%) vs. 14/26
(54%), P ¼ 0.92, standard care vs. FTO,
unpublished work].
Lung Growth After FTO
Early data from our center on 16 infants
undergoing endoscopic FTO with left
CDH suggested that an initial LHR of
1.0 was a significant predictor of
survival [Keller et al., 2003]. Similarly,
the FETO Task Group has recently
reported that initial LHR remains a
significant predictor of survival [which
was 57% (16/28) in this series for an
LHR < 1.0 in left CDH] following
FTO [Jani et al., 2006c]. Lung growth
as assessed by ultrasound following FTO
appears to be variable. It was thought to
be occurring in the initial experience
with FTO, with shift of the mediastinum
back toward the midline beginning at
1 week following the procedure in 5/7
fetuses that survived FTO. Yet, only one
of these fetuses (that had exhibited lung
growth) ultimately survived the newborn period. In the remaining six
infants, autopsy evidence of pulmonary
hypoplasia was consistent with fetal
ultrasound evidence of fetal lung growth
[Harrison et al., 1996]. Flake et al. [2000]
demonstrated increasing LHR on serial
ultrasounds in 8 of 13 fetuses and the
FETO Task Group has also documented
increased LHR after FTO, wherein the
median LHR increased from 0.7 to 1.7
within 2 weeks of the procedure [Jani
et al., 2005]. Data are not yet available
investigating whether the appearance of
lung growth is related to survival
following FTO, and it may be that
other imaging modalities (or functional
studies) are needed to evaluate the intrauterine effects of FTO in humans. An
autopsy series from UCSF demonstrated
a mean lung-to-body weight ratio of
0.021 0.011 in fetuses and infants with
fetal intervention (n ¼ 11) compared to a
mean ratio of 0.011 0.004 in those
without intervention (n ¼ 8, all subjects
at 29 weeks post-conceptual age). A
lung-to-body weight ratio less than or
equal to 0.012 is considered to be
evidence of lung hypoplasia [Askenazi
and Perlman, 1979]. However, there was
a tendency toward larger alveoli in the
group of subjects with fetal intervention
[Heerema et al., 2003]. In addition, four
of 16 subjects with GAs of 29–30 weeks
were classified in the alveolar stage of
development following FTO, whereas
no subjects without fetal intervention
were in the alveolar stage prior to
34 weeks’ gestation (alveoli may be
present as early as 32 weeks’ gestation
in fetuses without CDH) [Langston
et al., 1984; Heerema et al., 2003].
Morphometric data from the lungs of
animals with CDH and FTO are discussed in the article by Dr. Khan et al.
PULMONARY GROWTH
AND FUNCTION IN CDH
Short-Term Pulmonary
Function Measurements
A number of different investigators have
studied lung function during the newborn hospitalization in CDH. Measurements include lung compliance, lung
volume, and pulmonary resistance.
Although timing of measurements and
inclusion criteria for studies differ, some
191
general conclusions can be made. First,
dynamic compliance of the respiratory
system and/or the lung is decreased in
CDH in this short-term period,
although it tends to normalize over the
first 6 months of life [Landau et al., 1977;
Nakayama et al., 1991a; Koumbourlis
et al., 2006]. Compliance usually
improves (increases) over the first several
days of life [Sakai et al., 1987; Nakayama
et al., 1991a; Moffitt et al., 1995]
although it transiently worsens
(decreases) acutely in the post-operative
period (Table I) [Sakai et al., 1987].
Thus, the delay of CDH repair until the
patient is medically stabilized has most
likely contributed to improved outcomes, as this delay allows for the development of improved lung and vascular
function. Some studies have shown
that higher lung compliance is observed
in survivors versus non-survivors
[Nakayama et al., 1991a; Tracy et al.,
1994; Antunes et al., 1995], although
results may depend on study selection
criteria and timing of compliance measurements. Second, lung volume is
decreased in the acute period in most
infants with CDH, indicative of restrictive lung disease (Table II) [Landau et al.,
1977; Nakayama et al., 1991b; Antunes
et al., 1995; Kavvadia et al., 1997;
Dinger et al., 2000]. However, over a
varying time course (up to several
months), it tends to normalize [Landau
et al., 1977; Koumbourlis et al., 2006].
This time course may depend on the
severity of the lung hypoplasia, as some
infants have rapid increases in lung
volume after surgery (with expansion
of compressed lung) and others have no
change for a period of weeks [Antunes
et al., 1995; Kavvadia et al., 1997;
Dinger et al., 2000]. In one series, all
ten non-survivors had a pre-operative
functional residual capacity (FRC) of
<9 ml/kg (normal infant FRC 26–
31 ml/kg) [Chu et al., 1967; Schwartz
et al., 1978], whereas among survivors,
only 2/15 had FRC < 9 ml/kg [Antunes
et al., 1995]. In some infants lung
volumes are increased over normal
values, indicating some degree of hyperinflation or emphysema [Landau et al.,
1977; Koumbourlis et al., 2006]. Finally,
many infants with CDH demonstrate
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ARTICLE
TABLE I. Respiratory System Compliance (Crs) in Infants With CDH at Various Time Points During
Neonatal Hospitalization
Respiratory system compliance (mL/cmH2O/kg)
Study
Sakai et al. [1987]
Nakayama et al. [1991a]
Inclusion
Respiratory distress
<6 hr (n ¼ 9)
Respiratory distress
<24 hr (n ¼ 22)
Respiratory distress
<6 hr (n ¼ 8)
Kavvadia et al. [1997]c
Dinger et al. [2000]d
Keller et al. [2004]
Post-op
8–92 hr (median 20 hr)
1.69 0.68
1.20 0.77a
Immediate repair
(10.6 1.5 hr)
Survivors: 0.37 0.04
non-survivors:
0.18 0.04
Initial: 0.23 0.04
pre-op (137 29 hr):
0.46 0.04
7 days of age: Survivors:
0.38 0.03 nonsurvivors: 0.20 0.04
7 days of age:
0.37 0.03
Delayed repair
(not stated)
Nakayama et al. [1991b]b
Pre-op
Age at initial study
0.98 0.22
<30 days
1–9 days (median 2 days)
0.20 (range: 0.16–0.39)
Prenatal diagnosis
or present at birth
(n ¼ 5)
Severe fetal left CDH
Standard care (n ¼ 9)
6–10 hr
0.25 0.10
<24 hr
Initial: 0.20 0.06
pre-op (6.4 1.8 days):
0.17 0.04
Fetal tracheal occlusion
(n ¼ 11)
<24 hr
Initial: 0.22 0.18
pre-op: (5.5 2.5 days):
0.28 0.12
1 day: 0.19 (0.13–0.40)
4 days: 0.27
(0.15–0.46)
24 hr: 0.34 0.13
7–9 days: 0.54 0.13
24 hr: 0.24 0.19
pre-extubation
(30 10 days of age):
0.51 0.16
24 hr: 0.36 0.25
pre-extubation
(34 20 days of age):
0.93 0.45
Pre-op indicates prior to CDH repair; post-op, following CDH repair (timing refers to post-operative day unless otherwise indicated).
7/9 subjects decreased Crs after surgery.
b
Data are mean SEM.
c
Subjects not studied if on high frequency ventilation. Data are median and range.
d
All measures fell immediately post-op, but improved by 24 hr.
a
some degree of increased expiratory
airway resistance [Nakayama et al.,
1991b; Boas et al., 1996; Koumbourlis
et al., 2006]. There is variable response
to bronchodilator challenge, but this
may become more consistent over time,
with studies at a later time point
demonstrating some degree of airway
reactivity [Boas et al., 1996]. This
obstructive lung disease may be a reflection of the small caliber airways demonstrated in CDH, differences in airway
muscle function and/or airway remodeling with increases in airway smooth
muscle [Broughton et al., 1998] and/or
increasing functional abnormalities fol-
lowing periods of prolonged mechanical
ventilation.
Pulmonary Function After
Tracheal Occlusion
We have previously presented data on
acute lung function following FTO,
from the subjects enrolled in our randomized, controlled clinical trial [Keller
et al., 2004]. Table I shows the differences in respiratory system compliance
between the control group (n ¼ 9) and
the FTO group (n ¼ 11) at four important time points in the neonatal course.
Over the newborn hospitalization,
compliance improved in all surviving
infants, however, it improved more
rapidly in the FTO group than in the
control group. Peak expiratory flows
were consistently higher in the TO
group at all time points, possibly reflecting decreased airway muscle under the
influence of FTO. However, there were
no differences in indices of ventilation
through the peri-operative period (with
PaCO2 tightly controlled) and there
were no differences in minute ventilation between the groups. Oxygenation
from birth through the peri-operative
period was also modestly better in the
FTO group [Keller et al., 2004].
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193
TABLE II. Lung Volume Measurements in Infants With CDH at Various Time Points During Neonatal Hospitalization
Lung volume (ml/kg)
Study
Nakayama et al. [1991b]
Antunes et al. [1995]b
Kavvadia et al. [1997]c
Dinger et al. [2000]
Thibeault et al. [2002]
Inclusion
a
Age at initial study
Pre-op
FVC: 20.8 3.3
Respiratory distress
<6 hr (n ¼ 8)
All admitted (n ¼ 25)
<30 days
All delivered at center
(n ¼ 16)
Prenatal diagnosis or
distress at birth (n ¼ 5)
Requiring ECMO
support (n ¼ 6)
1–9 days (median 2 days)
FRC: All CDH:
10.0 6.0 survivors:
14.0 2.0 nonsurvivors: 4.5 1.0
FRC: 9.4 (3.6–14.7)
6–10 hr
FRC: 10.6 1.7
Not stated
FRC: 13.3 3.3
2.3 1.5 days
(8 hr–8 days)
Post-op
3 and 7 days: survivors:
increased nonsurvivors: no change
1 day: 8.4 (5.9–13.3)
4 days: 8.3 (6.9–19.1)
24 hr: 13.0 3.5
7–9 days: 22.7 3.5
22.4 5.6d
Pre-op indicates prior to CDH repair; post-op, following CDH repair (timing refers to post-operative day), FVC, forced vital capacity;
FRC, functional residual capacity.
a
Data are mean SEM. Control FVC was 39.8 3.3 ml/kg.
b
Normal infant FRC is 26–31 ml/kg [Chu et al., 1967; Schwartz et al., 1978].
c
Subjects not studied if on high frequency ventilation. Data are median and range.
d
One infant expired prior to repeat measurement. This subject had the lowest pre-op lung volume of 8.5 ml/kg.
We also performed pulmonary
function measurements during spontaneous sleep at one year follow up visits.
Thirteen children were studied (seven
standard perinatal care, six FTO). There
were no significant differences between
groups in any of the parameters: respiratory rate, tidal volume, minute ventilation, or peak expiratory flow. In both
groups, respiratory rates were elevated
(42.7 11.4 breaths/min, normal
26 breaths/min) and tidal volumes were
decreased (4.2 2.0 ml/kg, normal 8.9
ml/kg) [American Thoracic Society/
European Respiratory Society, 1993;
Cortes et al., 2005]. Oxygen saturation
on room air by pulse oximetry was not
different between groups; the range for
control subjects was 90–100% and for
FTO subjects it was 86–99%. All
subjects from this trial required a prosthetic patch or muscle flap repair due to
severe hemidiaphragm hypoplasia. The
findings from our 1 year evaluation are
consistent with a number of possible
explanations related to lung function,
but ipsilateral diaphragmatic function is
likely also an issue. At long-term follow
up (5–26 years), diaphragmatic function
is impaired even in subjects that underwent primary closure of the diaphragmatic defect [Wohl et al., 1977; Arena
et al., 2005b].
Long-Term Pulmonary
Function Measurements
Pulmonary function studies in the CDH
population have been performed in
older children and adults. There is quite
a bit of range in the age of these subjects
(6–49 years), reflecting survivors over
many years of neonatal intensive care
with probable variability of diaphragmatic defect severity. In early childhood,
chronic medications for respiratory
indications are used by 35–50% of
children with CDH [Muratore et al.,
2001; Cortes et al., 2005]. Further,
children and adults with CDH report
respiratory symptoms more frequently
than in age-matched control subjects
[Falconer et al., 1990; Trachsel et al.,
2005]. As previously noted, lung volume
measurements normalize in the first
weeks of life and most measurements of
lung volume are normal at later follow
up [Wohl et al., 1977; Trachsel et al.,
2005]. However, a subset of subjects has
increased residual volume, and this
finding has been associated with prolonged mechanical ventilation in the
newborn period and persistent chest
wall deformity [Wohl et al., 1977;
Ijsselstijn et al., 1997; Trachsel et al.,
2005]. Morphometric evaluation of the
lungs of two children with CDH dying
of unrelated causes (8 and 64 months of
age) revealed enlarged and emphysematous alveoli with alveolar destruction
bilaterally (affecting the ipsilateral lung
to a greater extent than the contralateral
lung) [Thurlbeck et al., 1979]. These
studies likely explain the functional
findings, and they are consistent with
hyperlucencies appreciated on follow up
chest radiographs [Wohl et al., 1977;
Arena et al., 2005a] and gas trapping
noted on ventilation scans [Jeandot et al.,
1989].
The most common lung function
abnormality in survivors of CDH is
expiratory obstruction, with up to 50%
of these subjects demonstrating a pattern
consistent with obstructive lung disease
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The most common lung
function abnormality in
survivors of CDH is expiratory
obstruction, with up to 50%
of these subjects demonstrating
a pattern consistent with
obstructive lung disease.
[Falconer et al., 1990; Vanamo et al.,
1996; Ijsselstijn et al., 1997; Marven
et al., 1998; Trachsel et al., 2005].
Further, the airways are hyperresponsive, with an abnormal response to
methacholine challenge in 38% of children [Ijsselstijn et al., 1997]. Restrictive
lung disease has also been appreciated in
the minority of subjects (approximately
30%) in some series [Vanamo et al.,
Restrictive lung disease has
also been appreciated in
the minority of subjects
(approximately 30%) in
some series.
1996; Stefanutti et al., 2004]. However,
diffusion capacity appears to be normal
in other studies [Ijsselstijn et al., 1997;
Trachsel et al., 2005]. Exercise capacity
in children with CDH (measured by
exercise stress testing) is impaired, compared to age-matched controls [Zaccara
et al., 1996; Marven et al., 1998; Trachsel
et al., 2006]. These children demonstrate shorter duration of exercise and
decreased maximal oxygen consumption. In less active children with CDH,
these abnormalities are more pronounced [Zaccara et al., 1996]. In one
series, children with CDH had
decreased tidal volumes and increased
respiratory rates when exercising at
maximal capacity [Marven et al., 1998].
In another series, children with CDH
and decreased exercise capacity (<80%
predicted) had previous evidence of
obstructive lung disease on pulmonary
function testing, whereas children with
normal exercise capacity did not have
obstructive lung disease [Trachsel et al.,
2006]. However, since children with
CDH also have abnormalities of the
pulmonary vascular bed, impaired exercise capability may reflect abnormal
vascular function, which cannot be
independently studied by non-invasive
means.
VASCULAR GROWTH AND
FUNCTION IN NEWBORNS
WITH CDH
Evaluation of the pulmonary circulation
has been an important part of neonatal
management of infants with CDH in
recent years. Several studies have evaluated neonatal branch PA dimensions
and related them to survival. In nine
infants with left CDH, an analysis of the
ratio of the left PA/right PA diameter at
admission revealed that in the six infants
with a ratio <0.80, four expired. Five
of the six infants had evidence of
persistent pulmonary hypertension of
the newborn (i.e., failure to transition to
postnatal circulation, evidenced by
right-to-left or bidirectional shunting
at the ductus arteriosus). Three of these
infants expired and all had met criteria
for lung hypoplasia on post-mortem
examination [Hasegawa et al., 1994].
The modified McGoon index is the sum
of the left PA and the right PA dimensions, divided by the size of the descending aorta. In a retrospective series of 40
subjects with CDH with an echocardiogram at admission, survivors had a larger
McGoon index than non-survivors
(1.7 0.2 vs. 1.2 0.2, P < 0.05) [Suda
et al., 2000]. A subsequent series
(n ¼ 34) found a significantly higher
mortality with higher McGoon index;
a cut-off of 1.25 had a sensitivity of 73%
and specificity of 78% for survival
[Casaccia et al., 2006]. Interestingly,
another approach has evaluated the ratio
between left and right heart cardiac
output in CDH by measuring the area
of the pulmonic valve divided by the area
of the aortic valve. While healthy
controls had a flow ratio centered at
1.0, newborns with CDH that subsequently required ECMO support had
evidence of increased right heart output
ARTICLE
compared to left with a mean ratio of
approximately 3.0 [Baumgart et al.,
1998]. These findings are consistent
with studies documenting decreased
fetal left ventricular size (in comparison
to right ventricular size) in CDH,
potentially due to a compression effect
of the hernia mass, or reflecting antenatal
hemodynamic alterations in pulmonary
hypoplasia [Thebaud et al., 1997]. These
findings likely also reflect right-to-left
shunting via the patent ductus arteriosus,
with blood bypassing the pulmonary
circulation and the left heart. The
findings are not inconsistent with a
higher McGoon index among survivors,
since in that case it is the descending
aorta dimension that is considered.
Persistent pulmonary hypertension
of the newborn is a common problem in
newborns with CDH, contributing to
their acute cardiopulmonary instability.
Persistent pulmonary
hypertension of the newborn
is a common problem in
newborns with CDH,
contributing to their acute
cardiopulmonary instability.
Persistent supra systemic elevation of
PVR frequently after delivery compromises systemic oxygenation and oxygen
delivery due to extra-pulmonary shunting and impaired myocardial function.
This high resistance may persist due to
the anatomical problem of a small
vascular bed with abnormal arterial
muscular structure, but there also may
be functional abnormalities of the pulmonary vasculature. A single center
study of echocardiographic diagnosis of
persistent pulmonary hypertension in
newborns with CDH described an
incidence of 46% (21/46) [Bos et al.,
1993]. Serial measures of pulmonary
arterial pressure by echocardiogram have
also been proposed as a parameter to
evaluate for stabilization prior to CDH
repair. In a small series of eight subjects,
either a fall in PA pressure or a reversal of
ductus arteriosus blood flow were taken
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as evidence of fall in PVR, which
occurred at 3–20 days of age [Haugen
et al., 1991]. Other investigators have
attempted to quantify the ratio of right
ventricular systolic pressure or PA pressure to systemic blood pressure (SBP),
with decreases in this ratio reflecting
decreases in PVR. In 34 infants with
CDH that required ECMO support,
pulmonary or right ventricular pressures
equaled SBP (ratio of PA pressure to
SBP ¼ 1.0) while in 16 of 20 survivors,
there was a fall in the right-sided
pressures to 50% SBP within 11 days
of instituting ECMO support. The
additional infants had intermediate
ranges of pulmonary hypertension (PA
pressure to SBP ratios between 0.50 and
0.69) when they were taken off of
ECMO support. Among non-survivors,
the right ventricle to systemic pressure
ratio decreased to 0.50 after 14 days of
ECMO support in 8/14 infants. In the
remainder, the ratio remained >0.50
when they were removed from ECMO
support. On autopsy, infants with CDH
had increased thickness of the intraacinar arterial walls compared to controls, with the ipsilateral lung more
affected than the contralateral lung. This
pattern persisted even in infants that
expired with a right ventricle to systemic
pressure ratio of 0.50 [Thibeault and
Haney, 1998]. Iocono et al., used the
same definition of elevated PA pressure:
a right ventricle to systemic ratio 0.50.
At the time of hospital discharge (mean
71 days), 7/40 infants had persistent
elevations in their estimated PA pressure
despite the prolonged hospitalization
in this group of infants. One infant
subsequently died at 13 months with
pulmonary hypertension and cor pulmonale [Iocono et al., 1999]. Later data
from this center suggested a stratification
of prognosis based on the timing of
resolution of the pulmonary hypertension. Twenty-three of 47 infants
resolved their pulmonary hypertension
by 3 weeks of age and all survived.
Sixteen of the 47 infants had persistently
elevated estimates of PA pressure
(a 0.50 but less than 1.0 ratio of PA
to systemic pressure) and 12 survived.
Median time to resolution of pulmonary
hypertension in this group was 49 days.
Eight infants had persistent elevations of
PA pressure estimated at greater than or
equal to systemic pressure; there were no
survivors among this group despite
ECMO therapy [Dillon et al., 2004].
Kinsella et al. [2003] defined late
pulmonary hypertension in CDH based
on a threshold of estimated PA pressure
2/3 systemic pressure at the time of
elective tracheal extubation (26 3
days); 10/42 infants met these criteria.
These studies do not reveal information about pulmonary vascular function or pulmonary vascular tone. That is,
does the vasculature have the ability to
dilate to accommodate increases in
cardiac output and does the vasculature
respond to pulmonary vasodilator challenge? In patients who cannot cooperate
with testing (or those with both cardiovascular and pulmonary disease) there is
no definitive methodology for evaluating function. Therefore, we can only test
the response to pulmonary vasodilator
challenge. Early experiences with PA
catheterization in the management of
newborns with CDH demonstrated
that, in some patients, the pulmonary
circulation could vasodilate in response
to sedation, high-inspired oxygen concentration and vasodilators. In these
situations, pulmonary blood flow increased and oxygenation improved,
although pulmonary arterial pressure
did not always fall [German et al.,
1977; Vacanti et al., 1984]. Bos et al.,
challenged newborns with CDH and
persistent pulmonary hypertension of
the newborn with two vasodilators:
tolazoline and prostacyclin. There were
no improvements in oxygenation with
tolazoline (which, as a non-specific
vasodilator also resulted in lower SBP).
After prostacyclin challenge, oxygenation did improve and SBP was
unchanged [Bos et al., 1993]. Subsequent studies of inhaled nitric oxide (a
specific pulmonary vasodilator) during
the acute management of newborns
with CDH, have demonstrated sustained improvements in oxygenation in
only 10–15% of subjects [Kinsella et al.,
1997; The Neonatal Inhaled Nitric
Oxide Study Group, 1997]. In using
the change in PVR as the measure of
response to inhaled nitric oxide, we
195
have documented significant pulmonary
vasodilation during cardiac catheterization in three children with CDH at later
time points (9 weeks to 11 years of age)
[Keller et al., 2006]. Therefore, we
suspect that abnormal pulmonary vascular tone is a component of pulmonary
hypertension in a subset of patients with
CDH and vascular hypoplasia. But, we
do not know if and when specific
treatment for pulmonary hypertension
is beneficial in this patient population.
Long-term follow up studies of
abnormal vascular function in this
patient population are difficult, due to
compromise of both cardiovascular and
pulmonary function. Schwartz et al.,
evaluated pulmonary hypertension in
21 children (3.2 1.4 years) that survived CDH and neonatal ECMO. They
measured right ventricle systolic time
intervals by echocardiogram and performed exercise testing in the children
with abnormal echocardiograms. Eight
children (38%) met criteria for pulmonary hypertension. Five of these children
had abnormal exercise tests and seven
were under treatment for chronic respiratory disease [Schwartz et al., 1999].
There is additional information
available, however, as to the long-term
development of the pulmonary vascular
tree. Multiple groups of investigators
have evaluated differential lung perfusion (ipsilateral vs. contralateral lung) or
ventilation or volume to perfusion ratios
in CDH. In late studies (6–18 years of
age), the proportion of ventilation to the
ipsilateral lung normalizes, whereas perfusion remains decreased, indicating
failure of full development of the
pulmonary vascular tree. Ipsilateral perfusion in these subjects was reduced,
averaging 39% and 42% (with normal
left lung perfusion approximately 46%)
[Wohl et al., 1977; Falconer et al., 1990].
Children with CDH that were followed
serially from the first several months of
life to 6 years of age showed initial low
perfusion and ventilation (or volume) in
the ipsilateral lung. Although lung
ventilation/volume tended to improve
at follow up studies at age 1–6 years,
perfusion remained low (or decreased),
resulting in low perfusion to ventilation
ratios. These findings were particularly
196
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
pronounced when the neonatal course
and/or the anatomic findings were more
severe (worse indices of oxygenation,
prolonged mechanical ventilation and
need for ECMO support or prosthetic
patch repair of CDH) [Jeandot et al.,
1989; Nagaya et al., 1996; Okuyama
et al., 2006; Hayward et al., 2007].
Further, Okuyama and colleagues found
an association between worse growth
indices at one and two years of age and
more asymmetric perfusion at initial and
follow up studies [Okuyama et al.,
2006]. We studied five children with
severe left CDH (liver herniated into the
chest and prosthetic patch repair of
diaphragmatic defect). The mean perfusion to the left lung was 28% (22–37%,
normal is approximately 46%) at 21–
38 days of age (unpublished work).
Follow up studies in two children at 13
and 20 months showed no change (left
lung perfusion 20% and 34%). This lack
of growth of the pulmonary vascular tree
may be more pronounced in severe
CDH, consistent with a ‘‘pruning’’ of
the pulmonary vascular tree and loss of
microvasculature development seen by
post-mortem angiogram in infants that
die late in infancy, which does not appear
in infants dying early in their course
(Fig. 3).
IMPLICATIONS OF
ANATOMICAL AND
FUNCTIONAL STUDIES
OF THE LUNGS IN
HUMAN CDH
It is now clear that abnormal development of the diaphragm and lung in utero
leads to chronic cardiopulmonary morbidity. In the acute neonatal period,
there is a major focus on maintaining
sufficient cardiopulmonary function for
adequate oxygen delivery and survival,
yet aggressive neonatal management
practices that lead to lung injury have
not served this group of patients well.
Survival has increased with more gentle
and permissive standards for both ventilation and oxygenation [Kays et al.,
1999; Bohn, 2002]. It is likely longterm cardiopulmonary function in survivors also benefits from these practices,
since later abnormalities in lung and
vascular structure and function often
follow a more severe neonatal clinical
course, and reflect lung injury, airway
and alveolar remodeling and impaired
vascular growth. The implementation of
these management standards is a challenge, as they require understanding and
commitment from all intensive care staff
members.
ARTICLE
It is still not clear if the potential
lung growth effects of FTO will benefit
the most severely affected fetuses.
It is still not clear if the
potential lung growth effects
of FTO will benefit the most
severely affected fetuses.
The completion of our randomized trial
[Harrison et al., 2003] was limited by at
least two factors. First, survival in the
control group was twice what was
expected from our historical experience.
This may have been the result of the
consistent care delivered at our high
volume center. Second, significant premature delivery likely affected the outcomes in the FTO group. Pre-term
delivery has recently become less significant with less invasive complete
endoscopic techniques enabled by the
development of newer instruments
[Deprest et al., 2004]. Thus, further
studies employing these techniques in
high volume experienced centers may
be warranted, since survival in the
highest risk fetal groups (based on liver
herniation and LHR) remains below
Figure 3. Post-mortem angiograms from infants with severe left diaphragmatic hernia obtained by perfusing the branch pulmonary
arteries with barium gelatin under 100 cmH2O pressure. A: Demonstrates the right (R) lung of an infant dying at 15 days of age from
hemorrhagic complications while receiving ECMO support. Note the well-developed peripheral pulmonary vasculature. B: Demonstrates
the right (R) and left (L) lungs of an infant dying at 79 days of age with chronic lung disease, pulmonary hypertension, and cor pulmonale.
Note severe ‘‘pruning’’ of the distal pulmonary vascular tree.
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
60%. Additional fetal anatomical and
functional studies may also be able to
better define this high-risk group
(enhancing selection criteria for fetal
intervention) and long-term evaluation
of survivors must occur. Alternatively,
postnatal strategies to enhance lung
growth should be studied in a controlled manner in severely affected
infants. These may include trophic or
anti-inflammatory agents administered directly to the lung (e.g., inhaled
nitric oxide or perfluourocarbon
[Hirschl et al., 2003]) or systemically
(phosphodiesterase inhibitors or endothelin receptor antagonists). Again,
timing of the intervention and appropriate selection criteria will be important, as many therapies also have the
potential for harm in this vulnerable
patient population.
ACKNOWLEDGMENTS
Roberta Keller is supported by K23 HL079922 (Keller).
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