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Jornal de Pediatria - Vol. 79, Nº1, 2003 81
0021-7557/03/79-01/81
Jornal de Pediatria
Copyright © 2003 by Sociedade Brasileira de Pediatria
ORIGINAL ARTICLE
Prognostic factors and survival in neonates
with congenital diaphragmatic hernia
Luis R. Longo dos Santos,1 João G. Maksoud-Filho,2
Uenis Tannuri,3 Wagner C. Andrade,4 João G. Maksoud5
Abstract
Objective: to evaluate the prognostic factors importance to survival in neonatal period of newborns
with congenital diaphragmatic hernia treated at Hospital das Clínicas, School of Medicine of Universidade
de São Paulo, and to compare the outcome with data published in medical literature. So that the results of
this study might allow updating family counseling and guiding changes in clinical management of our
department.
Methods: retrospective study of 27 consecutive newborns with congenital diaphragmatic hernia
admitted to the Pediatric Surgery Department of Instituto da Criança, School of Medicine of Universidade
de São Paulo, from April 1991 to January 2002, and statistical comparison with medical literature
metanalysis data.
Results: of 27 patients, 15 were born at our institution and 12 were admitted by transference after birth.
Twelve (44%) have had congenital diaphragmatic hernia diagnosed prenatally and 23 (85%) were full-term
newborns. Most patients presented early respiratory distress and needed intubation at delivery room. Six
newborns presented criteria for indication of extracorporeal membrane oxygenation. Twenty patients
(74%) were submitted to operative repair and seven (26%) died without the minimal clinical stabilization
necessary for surgical procedure (five of these patients reached criteria for indication of extracorporeal
membrane oxygenation). The postoperative mortality was 25% (5/20). The overall survival of neonatal
period was 56% (15/27). The survival of patients that were born at our hospital was 33% (4/12), and the
survival of the newborns admitted by transference was 73% (11/15). Severe respiratory distress, early
indication to mechanical ventilation and severe hypoxemia (post-ductal pO2 < 100 mmHg despite all
efforts) were identified as predictors of bad outcome with statistical significance.
Conclusion: our high mortality rate of newborns with congenital diaphragmatic hernia is statistically
similar to that described in international publications. In the group of non-responsive patients to standard
treatment available, the use of extracorporeal membrane oxygenation should be able to reduce mortality.
The impact of this therapeutical strategy in the overall survival depends on other factors that were not
analyzed in the present study. Family counseling of patients’ parents on congenital diaphragmatic hernia
in our department may follow the same patterns referred in world medical literature.
J Pediatr (Rio J) 2003;79(1):81-6: congenital diaphragmatic hernia, extracorporeal membrane
oxygenation, newborn respiratory failure.
Introduction
The treatment of newborns with congenital
diaphragmatic hernia (CDH) is still a challenge for pediatric
surgeons and neonatologists.
In the last decades, advances in the therapy of primary
pulmonary hypertension (PPH) in newborns, such as mild
1. Professor, Hospital das Clínicas, School of Medicine, Universidade de
São Paulo.
2. PhD, School of Medicine, Universidade de São Paulo.
3. Associate Professor, School of Medicine, Universidade de São Paulo.
4. Resident of Pediatric Surgery, Instituto da Criança, School of Medicine,
Universidade de São Paulo.
5. Professor, School of Medicine, Universidade de São Paulo.
Manuscript received Sept 03 2002. Accepted for publication Nov 06 2002.
81
82 Jornal de Pediatria - Vol. 79, Nº1, 2003
ventilation with permissive hypercapnia,1,2 high-frequency
oscillatory ventilation (HFOV),3 use of nitric oxide (NO) as
selective pulmonary vasodilator4 and extracorporeal
membrane oxygenation (ECMO)5,6 were incorporated into
the treatment of newborns with CDH.
Similarly, the possibility of diagnosis by means of
prenatal ultrasonography and the attempts of intrauterine
intervention have opened up new possibilities of success.7-9
In spite of the initial reports indicating a reduction in
mortality, some retrospective analyses did not confirm a
significant impact on overall survival rate.10-12
The hypoplasia/pulmonary hypertension binomial
remains as the principal mortality factor.13 Several prenatal
and postnatal prognostic factors were described in order to
define the severity of the disease and the individual chances
of survival with the purpose of guiding medical conducts
and family counseling approaches.14-20 Even though none
of these parameters can be separately considered, a few of
them are still accepted all over the world and are used for the
comparative assessment of healthcare quality offered to
these newborns.21
Recently, Beresford and Shaw presented a meta-analysis
based on 35 publications related to the evolution of newborns
or fetuses with diagnosis of CDH.22 In this assessment, they
compared mortality data, relating them to the diagnosis and
treatment developed. The summary of the results is shown
in Table 1.
The purpose of our study was to analyze the importance
of prognostic factors to the survival of patients with CDH in
the neonatal period treated at the Hospital das Clínicas da
Faculdade de Medicina da USP (HCFMUSP), and compare
the results with the ones found in literature, allowing the
collection of updated data that allow guiding family members
and changing the conduct at our service.
Method
Retrospective analysis of medical records of 27 newborns
with CDH treated by the Service of Pediatric Surgery of the
ICr-HCFMUSP between April 1991 and January 2002.
The treatment used in each case, according to the
severity, included:
1) parenteral hydroelectrolytic and nutritional support;
2) hemodynamic and blood gas control through the
catheterization of the umbilical, tibial or radial artery;
3) respiratory support through supplementary oxygen
therapy, conventional mechanical ventilation with
permissive hypercapnia, or high-frequency oscillatory
ventilation;
4) use of exogenous surfactant, sedation, vasoactive drugs
and inhaled nitric oxide;
5) surgical indication after clinical stabilization (delayed
surgery).23-26
Prognostic factors and survival in neonates... - dos Santos LRL et alii
The prognostic factors analyzed were the following:
respiratory distress at birth (Apgar score < 6 in the fifth
minute of life), need of early intubation (< 6 hours of life),
persistent severe hypoxemia (postductal pO 2 lower than
100 mmHg in spite of maximum therapy), association of
severe somatic malformations, severe pulmonary
hypertension (echocardiogram with gradient > 40 mmHg or
repercussion on RV) and potential indication of ECMO
(defined as pO2 < 50 mmHg for over four hours and absence
of response to the conventional therapy available for
newborns with weight over 2,000g without CNS hemorrhage
and cardiac malformations or other malformations
incompatible with life).27
The data referring to mortality and prognostic factors
were analyzed and compared with the ones presented by
Berersford et al., using the Yates-corrected chi square test
or one-tailed or two-tailed Fisher’s exact test, in which a p
values of 0.05 were significant.
This study was approved by the local Ethics and Research
Committee.
Results
Twelve out of the 27 patients were born at our hospital,
and 15 were transferred with an average interval of 3.2 days
of life (15 hours - nine days). Twelve (44%) had a prenatal
diagnosis, and 11 of them were born at the HCFMUSP. The
average birthweight was 2,805 g (1,107 - 4,420 g), and 85%
(23/27) of the babies were full term.
Complex congenital malformations were diagnosed in
eight cases (30%), three (11%) of which involved cardiac
malformations.
In relation to prognostic factors, 56% (15/27) presented
Apgar score < 6 in the fifth minute of life, and 59% (16/27)
were early intubated (most of them in the delivery room).
Pulmonary hypertension (PH) was assessed in the
postoperative period through echocardiogram in 70% (19/
27) of the patients. Among these, 50% presented severe PH.
Six children presented indication for ECMO, and seven
(26%) died without reaching minimum clinical conditions
for surgery. Among the patients who died in the preoperative
phase, five would have been ECMO candidates, and the
method would have been contraindicated in two due to low
weight and severe cardiopathy. Postoperative mortality was
25% (5/20). No intraoperative deaths occurred.
The overall mortality rate in the neonatal period was
44% (12/27). The mortality rate of outpatient newborns was
27% (4/15) and among the ones who were born at the
HCFMUSP, it was 67% (8/12).
The mortality rate in different subgroups - compared to
the one described by Berersford and Shaw - is presented in
Table 2. The analysis of prognostic factors in our patient
population is shown in Table 3.
Prognostic factors and survival in neonates... - dos Santos LRL et alii
Table 1 -
Jornal de Pediatria - Vol. 79, Nº1, 2003 83
Mortality calculated according to the stage reached by patients with CDH diagnosis, meta-analysis by
Beresford et al.
Data/
statistical study
Prenatal
diagnosis
Live-born
infants
NB submited
to surgery
Fetal
death
Preoperative
death
Median mortality (IQR) *
58% (43-65)
48% (35-55)
33% (18-54)
10% (7-25)
27% (14-43)
Mean mortality (95% CI) †
56% (46-66)
47% (40-54)
36% (27-45)
14% (4-24)
30% (20-40)
9
20
27
6
15
n. of studies analyzed
n. of patients
285
844
794
212
538
n. of deaths
164
372
269
29
139
* interquartile range
†
95% confidence interval
Discussion
The group of newborns with CDH treated at our
institution in the study period is quite heterogeneous,
including a wide range of patients, from children with mild
respiratory distress and without other anomalies to patients
with severe pulmonary hypoplasia and associated complex
malformations. These differences partially explain the
discrepancy between the mortality in the cases followed up
from the prenatal period and born at our institution and the
cases diagnosed and transferred after birth. The first group
concentrates most newborns in serious conditions and with
the worst prognosis. The lower mortality rate that occurred
in the cases transferred after birth and without prenatal
diagnosis may be attributed to selection bias, because many
of the severe cases initially assisted at neonatology services
with fewer therapeutic resources die before they can be
Table 2 -
transferred to specialized services and they are not, therefore,
included in the statistics.28
Boloker et al. analyzed 120 consecutive cases of CDH
treated at one single center with standardized therapy, and
also found differences between the group of infants born at
the institution and the babies transferred after birth, observing
a lower incidence of severe malformations and lower
mortality in the second group.29 They concluded that these
differences would be related to preselection and that,
excluding the cases with somatic and/or pulmonary
malformations incompatible with life and the cases with
neurological complications, it is possible to reach a survival
rate greater than 80% through mild ventilation and delayed
surgery, avoiding the mortality related to iatrogenic
disorders.
Comparison of the mortality in each subgroup between patients from ICr-HCFMUSP
and meta-analysis by Beresford et al.
Mortality
ICr-HCFMUSP
Beresford et al.
1. Live-born children
44% (12/27)
48%
p = 0.87
2. Prenatal diagnosis
67% (8/12)
58%
p = 0.74
3. NB with ECMO
83% (5/6)
44%
p = 0.06 one tail
4. Children being prepared for surgery
26% (7/27)
27%
p = 0.82
5. Children submitted to surgery
25% (5/20)
33%
p = 0.55
84 Jornal de Pediatria - Vol. 79, Nº1, 2003
Table 3 -
Prognostic factors and survival in neonates... - dos Santos LRL et alii
Correlation between analyzed prognostic factors and mortality
Prognostic factor
Mortality
with factor
Mortality
without factor
1. Intubation < 6 hours of life
69%
9%
p = 0.005*
2. Impossibility of pO2 > 100
100%
32%
p = 0.01*
3. 5th minute Apgar > 6
67%
17%
p = 0.02*
4. Severe PH on echocardiogram
67%
35%
p = 0.12
5. Prenatal diagnosis
67%
27%
p = 0.09
6. Associated severe malformation
62%
39%
p = 0.40
* Statistically significant values.
By comparing the mortality in our patient population
and the one in the meta-analysis published by Berersford
and Shaw, we did not find any statistically significant
difference in any of the subgroups analyzed. The mortality
in our institution is, indeed, in most of the subgroups,
numerically similar to the average described in literature.
Nevertheless, among the children with indication for
ECMO, our mortality rate was almost twice as high as the
one referred to in literature (83% versus 44%, one-tailed
test p = 0.06). Depending on the sample size, it was not
possible to establish statistical significance in this patient
population. However, the confidence interval (95%CI)
established for the mean mortality rate of the patients with
indication for ECMO in the meta-analysis made by
Berersford (34-50%) is quite distant from our mortality rate
in this subgroup. Out of the seven children who died before
reaching minimum clinical conditions for surgery, five
presented indication for ECMO. These data suggest that the
effective use of ECMO at our service could reduce mortality
in the subgroups. The repercussion on the overall mortality
rate depends, however, on the number of children admitted
with indication for ECMO and of our effective results with
the method.
The definition of reliable prognostic factors is a constant
concern of the centers that treat patients with CDH. Based
on these factors, it is possible to distinguish the children
who effectively benefited from aggressive and costly
therapies from the children to whom this treatment would
only serve to prolong their suffering and their family’s as
well.
Several prognostic factors were described by several
centers, such as perinatal anoxia and early onset of symptoms,
ventilation scores, lung compliance measurements,
occurrence of pneumothorax as a consequence of aggressive
ventilation, capability of reaching pO2 > 100 mmHg, level
of pulmonary hypertension, early antenatal diagnosis, size
of the diaphragmatic defect, herniation of the liver into the
thorax, association of cardiopathy and other complex
malformations.30 These parameters relate to the severity of
pulmonary hypoplasia and pulmonary hypertension.
Therefore, the newborns with early and intense symptoms
who were non-responsive to the therapy would present
severe pulmonary malformations and other malformations
of acutely difficult reversion, while in others pulmonary
hypertension could be handled with different strategies,
breaking the vicious cycle of aggravated PH - hypercapnia
and hypoxemia - acidosis - PH.
Separately, no factor turned out to be ideal to predict
survival in all institutions. This is a consequence of both the
variability of the treatment employed at each center and the
extreme clinical instability of these newborns, who may
present sudden clinical deterioration due to the worsening
of pulmonary hypertension.
Among the unfavorable prognostic factors classically
referred to, statistical correlation was obtained, in our
patient population, for the need of early intubation, Apgar
score < 6 in the fifth minute of life, and impossibility of
reaching pO2 higher than 100mmHg in spite of maximum
therapy. The other factors that were analyzed, even though
they were numerically relevant, were not statistically
significant due to the size of the analyzed sample.
We concluded that the mortality of newborns diagnosed
with CDH remains high in our service, but at levels that are
similar to the average published in international literature.
Prognostic factors and survival in neonates... - dos Santos LRL et alii
In the group of patients that did not respond to standard
treatment, the introduction of ECMO could reduce mortality.
The repercussion of this measure on overall survival depends
on other factors that were not analyzed in this study. The
guidance of family members of patients with CDH in our
service could follow the same standard referred to in the
international literature.
Jornal de Pediatria - Vol. 79, Nº1, 2003 85
12. West KW, Bengston K, Rescorla FJ. Delayed repair and ECMO
improves survival in congenital diaphragmatic hernia. Ann Surg
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13. Bohn D, Tamura M, Perrin D. Ventilatory predictors of pulmonary
hypoplasia in congenital diaphragmatic hernia confirmed by
morphometry. J Pediatr 1987;111:423-31.
14. Sreenan C, Etches P, Osiovich H. The western Canadian
experience with congenital diaphragmatic hernia: perinatal factors
predictive of extracorporeal membrane oxygenation and death.
Pediatr Surg Int 2001;17:196-200.
15. Wilson JM, Lund DP, Lillehei CW, Vacanti JP. Congenital
diaphragmatic hernia: predictors of severity in the ECMO era. J
Pediatr Surg 1991;26:1028-33.
16. Suda K, Bigras JL, Bohn D, Hornberger LK, McCrindle BW.
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17. Kaiser JR, Rosenfeld CR. A population-based study of congenital
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Prognostic factors and survival in neonates... - dos Santos LRL et alii
Corresponding author:
Dr. Luis Ricardo Longo dos Santos
Rua Artur Bernardes, 256 – Centro
CEP 07013-030 – Guarulhos, SP, Brazil
Fax: + 55 11 3069.8668
E-mail: [email protected]