Fetal Surgery For Congenital Diaphragmatic Hernia Is Back From Never Gone
Fetal Surgery For Congenital Diaphragmatic Hernia Is Back From Never Gone
Fetal Surgery For Congenital Diaphragmatic Hernia Is Back From Never Gone
a
Division Woman and Child, University Hospitals KU Leuven, Leuven, Belgium; b Kings College Hospital,
Harris Birthright Centre for Fetal Medicine, London, UK; c Hospital Clinic-Idibaps, University of Barcelona and
CIBER-ER, Barcelona, Spain
Key Words
Congenital diaphragmatic hernia Fetal intervention
Endoscopic tracheal occlusion, fetal Fetoscopy
Pulmonary hypoplasia
Abstract
Over half of the cases of congenital diaphragmatic hernia are
picked up prenatally. Prenatal assessment aims to rule out
associated anomalies and to make an individual prognosis.
Prediction of outcome is based on measurements of lung
size and vasculature as well as on liver herniation. A subset
of fetuses likely to die in the postnatal period is eligible for a
fetal intervention that can promote lung growth. Two randomized trials have shown that fetal surgery using open anatomical repair or tracheal occlusion via hysterostomy has
no benefit. Since then, a percutaneous fetoscopic technique
has been introduced, which has been shown to be safe and
seems to improve survival when compared to historical controls. Rupture of the fetal membranes and early delivery, nevertheless, remain an issue, but are less likely as compared to
earlier experience. Improved outcomes are confirmed in two
other studies published in this issue of Fetal Diagnosis and
Therapy. This paper summarizes the experimental and clinical history of fetal surgery for congenital diaphragmatic hernia. It stresses the need for another randomized trial. This
trial started in Europe and patients should be asked whether
they would like to participate.
Copyright 2011 S. Karger AG, Basel
Introduction
Congenital diaphragmatic hernia (CDH) is a congenital birth defect which occurs in 1/3,000 to 1/5,000 live
births [1]. This number includes what has been called the
hidden mortality, such as stillbirths or neonatal death
before transfer to a tertiary care centre, so that a more accurately estimated incidence of CDH is believed to be 1
in 2,200 live births [2, 3]. Eurostat counted 5,420,900 live
births in the European Union (EU-27) in 2008. As a consequence, this means that in absolute numbers at least
every 4 h one new case is born alive [4]! According to a
meta-analysis, up to 40% of cases have associated problems [5]. These can occur in the absence or presence of
identified syndromes or other genetic problems. Their
presence is an independent predictor of neonatal death.
The majority thus are apparently isolated. The surgical
defect is typically left sided, but 10% are right sided and
2% are bilateral. Though CDH is a surgically correctable
defect, neonates may not make it to the operation because
of the pulmonary underdevelopment that is invariably
present. It affects both airways and vessels, leading to
variable degrees of ventilatory insufficiency and/or pulmonary hypertension (PHT). Pulmonary hypoplasia is
more prominent on the side of the lesion, but both lungs
are affected.
The authors founded the FETO Task Force.
In case of prenatal diagnosis, in utero transfer is therefore recommended to ensure optimal neonatal management. Since the 1990s postnatal management has shifted
from emergency repair, aggressive ventilation and hyperoxygenation to gentle ventilation followed by delayed surgery, together with measures for control of PHT [6]. Gentilation with permissive hypercapnia and minimal sedation must avoid baro- and volutrauma of the lung. Over
the course of years other novel neonatal strategies, such as
the use of inhaled nitric oxide and prostaglandins (for
PHT), high-frequency oscillatory ventilation, extracorporeal membrane oxygenation and even liquid ventilation
(for ventilator insufficiency) have been embraced, with
the hope to improve survival; however, this was in vain [7].
It is extremely difficult to compare results from different
centres, as case load, case mix and neonatal management
may be significantly different. It seems, however, fair to
say that mortality rates for prenatally diagnosed, isolated
left-sided CDH are still as high as 30% in tertiary centres
[8]. As postnatal strategies may fall short, prenatal therapy
has been suggested as early as 1963 to treat (nearly) lethal
pulmonary hypoplasia [9]. CDH has always been high on
the fetal surgery agenda, but its story followed certainly
cycles of hope and despair. Over the last decade, we have
seen a renewed interest because of a coinciding improvement in prenatal diagnostic tools, as well as the introduction of (yet another) prenatal intervention.
Different experimental models were designed to reproduce the pathophysiology of CDH. In rodents, the diaphragmatic defect and pulmonary hypoplasia are typically induced by a teratogen or dietary changes [20]. The literature on nitrofen-exposed rodents is huge, and several
Fetal Diagn Ther 2011;29:617
Extreme
Severe
Moderate
Mild
100
90
80
70
60
50
40
30
20
10
0
Fig. 1. Survival rates of fetuses with isolated left-sided CDH, depending on measurement of the observed/expected (O/E)
LHR and position of the liver as in the antenatal CDH registry [adapted from 124].
<15
1525
2635
3645
46 and higher
c
Sonogram
T-bar
Chin suture
Trocar
Tracheal screw
Fig. 2. Clinical TO techniques using a foam plug (a), an external clip (b) [44], and the same but applied by fetoscopy (c) [101]. Reproduced with permission.
tion ultrasound and increasing access to prenatal screening have made it possible in western countries to diagnose
2 cases out of 3 antenatally [77]. Following diagnosis, additional imaging methods and genetic studies allow to rule
out the vast majority of associated anomalies, which have
a proven negative effect on postnatal outcome. Karyotyping is an essential step in the work-up of the fetus with
CDH, but its resolution may fall short of excluding underlying genetic problems. Modern techniques are, therefore,
increasingly being used, also to better understand the aetiopathogenesis of CDH [78, 79]. In this issue, Brady et al.
[80] review these new approaches that are slowly introduced into the clinic. They recently designed a purposedesigned array, targeting genes previously linked to CDH,
and applied it to fetuses with apparently isolated CDH [81].
They hypothesized that even in those isolated cases, there
might be underlying genetic causes resulting from copy
number variants. Indeed, in nearly 4% of the samples a genomic imbalance was detected, and 2 out of 3 located on
genes earlier tied to CDH. This underscores the need for
further investigation of the genetic basis of this condition,
including in cases phenotypically presenting as isolated
CDH. Today, genome-wide comparative hybridization is
technically feasible and we are integrating it into our assessment of anomalies like CDH [82]. However, the interpretation of the detected copy number variations (particularly those that exhibit reduced penetrance or with variable
expression), incidental findings not clearly related to the
anomaly involved or unclassified variants remains difficult. Therefore, these novel techniques have to be used
with caution within research protocols [83].
10
(fig.1) [86]. This is also the sole method tested for prediction of (early neonatal) morbidity [87].
Bilateral lung volumetry, as compared to 2-dimensional measurement of the contralateral lung area, certainly has the potential to improve prediction, but this
remains to be demonstrated [8890]. Again, here volumes also need to be expressed as a function of what is
expected in a normal control. The most accurate method
is to match cases with normal lung development and with
equal estimated fetal weight, though gestational age also
works fairly well [91]. There is a debate on whether lung
volumetry should be done by 3-dimensional ultrasound
or fetal magnetic resonance. In our own experience, the
latter seemed superior because of its higher resolution allowing more often a reliable measurement of the ipsilateral (smaller) lung [92]. Liver-up has already early on
been recognized as a poor prognostic factor, and this has
been confirmed in two meta-analyses [93, 94]. Herniation of the liver into the thorax is observed in about 50%
of left-sided cases, whereas it is nearly a constant in the
right-sided cases. Logically, the predictive value could be
improved if the amount of liver herniation is quantified
more precisely. This was already done by several groups,
but standardization is lacking [95]. Also, it remains to be
demonstrated whether lung volume and (amount of) liver hernation are independent predictors, as suggested in
our recent study [96]. From a pragmatic viewpoint, in Europe we currently use a combination of both variables for
prenatal counselling.
Another tool is the assessment of the pulmonary circulation, which one might hope may be predictive of
PHT. This is the second most important cause of death
in CDH. Over the course of time, measurements of the
number of branches, vessel diameters, flow velocimetry
or volume, and reactivity to maternal oxygen inhalation
have been made. This is described in detail in the contribution of Cruz-Martinez et al. [97]. Vascular and airway
development are interconnected so that there is certainly
a relationship between vascular assessment and measurements of lung size [98100]. However, several studies
have already pointed to the independent nature of these
measurements.
The tale of clinical TO started, as for most fetal surgical procedures, at the University of California, San Francisco (UCSF). Following the failure of foam plugs to occlude the trachea, TO was achieved by laparotomy, hysFetal Surgery for CDH
11
Perfusion scope
Ultrasound
Balloon
inflated
Balloon
detached
Fig. 3. Clinical TO techniques using a balloon. a Via laparotomy and hysterostomy [49]. b Percutaneous [122].
Reproduced with permission.
Anaesthesia
general
locoregional or local
locoregional
laparotomy
percutaneous
percutaneous
Access diameter
5-mm cannula
3.3-mm cannula
2.7-mm trocar
3.3-mm trocar
Occlusive device
clip or balloon
balloon
balloon
NR
10 (393)
27.688.3
NR2
Reversal of occlusion
EXIT delivery
in utero reversal
EXIT delivery
in utero reversal
100
25
NR
100
47
35
603
30.8 (2834)
35.3 (25.741.0)
35.6 (2838)
37 (3537)
not eligible
not eligible
1/3 (33%)
86/175 (49%)
12/34 (35%)
2/5 (40%)
1/1
The data in the last column are deducted from the original studies in this issue and take into account all described cases.
The upper line is from Ruano et al. and the lower line is from Peralta et al. NR = Not rated; EXIT = ex utero intrapartum treatment;
PPROM = preterm prelabour rupture of membranes.
1
A contemporary control group was reported with a survival rate of 5.6%.
2
Median of 11 min is quoted, but excludes 12 patients, including 2 failures. Preterm delivery <34 weeks: 35.7%.
3 Preterm PROM rate 35.3%, but exact definition not quoted.
13
The fact that the FETO procedure, just as laser photocoagulation for transfusion syndrome is increasingly being used, underscores the acceptability of a minimally
invasive fetal surgical procedure, both by physicians and
patients. This success may also become the Achilles heel
of the procedure. The above history of fetal surgery for
this condition has demonstrated that things are not always what they seem. Therefore, it is more than time to
conduct, in controlled circumstances, this randomized
trial comparing expectant management during pregnancy and fetal intervention, followed by standardized neonatal care. Controlled means that there is rigorous adherence to selection criteria, surgical technique and skills,
availability of emergency airway management, postnatal
management, follow-up of patients and precise as well
as comprehensive reporting. We may be the first to be
blamed for not having started a randomized trial earlier,
which was for a variety of reasons [19]. Meanwhile, in Europe, we finally moved to a randomized trial comparing
expectant management during pregnancy to late (30
32 weeks) FETO in cases of moderate hypoplasia
(NCT00763737), and more recently, FETO at 2730
weeks for severe cases (NCT01240057).
Soon we will be joining centres in London, Paris and
Toronto which have a considerable fetoscopic turnover as
well as a case load of CDH fetuses, and also have training
for the FETO procedure. Though difficult, it is hoped that
other North American centres will also join the list of
several European centres endorsing this trial. We decided
to adopt a pragmatic approach, with few centres doing
FETO, yet with more tertiary care centres offering standardized postnatal care, either in expectantly managed
cases or after balloon removal. The balloon is removed at
34 weeks. Postnatal management of this multicentre trial
is standardized by a consensus protocol made up by leading European neonatal centres directed by Tibboel and
Schaible [118, 119]. The same neonatal experts report in
this issue on their outcomes using a nearly identical protocol [120]. Given different background survival rates (in
expectantly managed cases) in some areas, there might be
room for additional trials. We would, however, plead for
agreement between investigators to have at least comparable study designs and outcome measures to allow future comparison.
14
Conclusion
Currently, the diagnosis of CDH should prompt referral of the patient to a tertiary care centre used to manage
this condition. There a comprehensive evaluation, including imaging and (high-resolution) genetic studies,
should be carried out. The primary purpose of this evaluation is to rule out associated anomalies and to assess
the severity of pulmonary hypoplasia in order to offer
parents an individualized prognosis. The latter can be
done on the basis of the dimensions of the lung, its vascularization and liver position. Further multidisciplinary
consultation should address the neonatal issues as well as
later morbidities. Based on this complete evaluation and
after extensive counselling, patients should make an informed choice out of the available management options
which also include fetal therapy for more severe cases and
in a number of centres spread over the world. In Europe,
all elements are available to formally evaluate FETO for
severe and moderate CDH. Over the last 5 years, we have
built up sufficient experience to consider FETO as a safe
and clinically acceptable procedure. What needs to be
done now is to assess whether the procedure is truly beneficial, and therefore we have designed 2 randomized trials. Fetal medicine specialists have earlier shown (in
twin-to-twin transfusion syndrome) that RCTs can work
in fetal surgery [121]. These trials are the only way to control the history of FETO, which in the absence of level I
evidence of superiority will start to live its own life with
ever-ongoing debates between advocates and opponents.
We, therefore, strongly urge that patients who are open to
trial participation should be referred to FETO centres for
additional evaluation and counselling about the logistics
of fetal surgery and eventually trial participation.
Acknowledgments
The European Commission funded the EuroSTEC programme (LSHC-CT-2006-037409) which includes the organization of a randomized trial for this condition. The Fonds voor
Wetenschappelijk Onderzoek Vlaanderen (FWO; 1.8.012.07.N.02)
and the Instituut voor Wetenschap en Technologie (IWT/070715)
fund the fetal therapy programme in Leuven (Belgium). We thank
the centres and colleagues of the antenatal CDH registry and the
FETO consortium for making this story happen.
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