Congenital Diaphragmatic Hernia: A Meta-Analysis

of Mortality Factors
By Hans Skari, Kristin Bjornland, Guttorm Haugen, Thore Egeland, and Ragnhild Emblem
Oslo, Norway

Purpose: The aim of this study was to review all available

studies reported in the English-language literature from 1975
through 1998, and by meta-analysis assess the importance of
prenatal diagnosis, associated malformations, side of hernia,
timing of surgery, and study population on mortality rates in
patients with congenital diaphragmatic hernia (CDH).

among CDH infants with associated major malformations

compared with isolated CDH in all 3 categories. An increased
mortality rate in right-sided CDH was found in category II and
III.

Methods: One-hundred-two studies were identified, and 51

studies (2,980 patients) fulfilled the prespecified inclusion
criteria. Studies were grouped according to study population
into: (I) fetuses diagnosed prenatally; (II) neonates admitted
to a treatment center; and (III) population-based studies.

Conclusions: Prenatal diagnosis of CDH, presence of associated major malformations, and the study population have a
major influence on mortality rate. The very high mortality
rate in studies of fetuses with a prenatal diagnosis of CDH
should be taken into account in prenatal counselling.
J Pediatr Surg 35:1187-1197. Copyright r 2000 by W.B.
Saunders Company.

Results: Pooled total mortality rate was significantly higher in

category I than in category III (75.6% v 58.2%, P .001).
Pooled hidden postnatal mortality rate (deaths before admittance to a treatment center) in population-based studies was
34.9%. Prenatally diagnosed patients in both category II and
III had significantly higher mortality rates than those diagnosed postnatally. Mortality rates were significantly higher

INDEX WORDS: Congenital diaphragmatic hernia, metaanalysis, selection bias, systematic review, associated anomalies, associated major malformations, prenatal diagnosis,
side of hernia, timing of surgery, prenatal ultrasound, termination of pregnancy, intrauterine fetal demise, hidden mortality, neonatal mortality, perinatal outcome.

ECENT REPORTS on congenital diaphragmatic

hernia (CDH) show a variation in mortality rate
from 8% to 79%.1-5 In large series, mortality rates remain
high, although new treatment modalities have been
introduced.6,7 The prognostic value of prenatal diagnosis
versus postnatal diagnosis in predicting prognosis of
CDH has been controversial.7-14 Hidden mortality
(deaths before admittance to a treatment center) has been
shown to influence mortality rates in CDH,2,11,15 but its
importance has been questioned recently.13 The presence
of associated major malformations generally is reported
as a negative prognostic factor,16 but the size of this effect
on mortality rate has not been settled. An increased
mortality rate in right-sided CDH (RCDH) compared
with left-sided CDH (LCDH) has been reported,7,11,15,17,18
but others have found no such influence on mortality
rate2,6 or the opposite effect.19 Since the late 1980s
delayed surgery after preoperative stabilization has been
advocated by most investigators,20-22 but a convincing
improvement in survival following this strategy has not
been documented.23-25
Birth prevalence of CDH recently has been reported in
the range of 0.17 of 1,000 to 0.57 of 1,000.26,27 Geographical differences have been reported, which is suggested to
be caused by differences in ascertainment of cases.28
The aim of the current study was to perform a critical
appraisal of studies on the prognosis of CDH with
Journal of Pediatric Surgery, Vol 35, No 8 (August), 2000: pp 1187-1197

particular emphasis on prenatal diagnosis and associated

major malformations to arrive at estimates of prenatal
and postnatal mortality rates for different CDH populations. Secondarily, we assessed the influence of sidedness
of the hernia and timing of surgery on mortality rate.
Furthermore, we wanted to estimate the pooled birth
prevalence of CDH based on population-based studies.
MATERIALS AND METHODS
A Medline, Embase, and Cochrane search for the period January
1975 through December 1998 was performed. Studies were identified
using the terms prenatal diagnosis, antenatal diagnosis, congenital
diaphragmatic hernia, associated anomalies, associated malformations, pregnancy outcome, survival, and mortality. Each term was
entered as both keyword and textword. The terms were combined in the
following manner: search 1, prenatal diagnosis or antenatal diagnosis, and congenital diaphragmatic hernia, and associated anoma-

From the Department of Surgery and the Department of Obstetrics

and Gynecology, Center for Epidemiology and Hospital Statistics, The
National Hospital, Oslo, Norway.
Supported by The Norwegian Research Council and Dr Alexander
Malthes Foundation.
Address reprint requests to Hans Skari, MD, MPH, Section of
Pediatric Surgery, Surgical Department, The National Hospital, N-0027
Oslo, Norway.
Copyright r 2000 by W.B. Saunders Company
0022-3468/00/3508-0009$03.00/0
doi:10.1053/jpsu.2000.8725
1187

1188

lies or associated malformations, and pregnancy outcome or survival

or mortality; search 2, prenatal diagnosis or antenatal diagnosis, and
congenital diaphragmatic hernia, and pregnancy outcome or survival or mortality; search 3, congenital diaphragmatic hernia, and
associated anomalies or associated malformations, and pregnancy
outcome or survival or mortality. Searches 1, 2, and 3 were combined.
The references of the selected articles were checked further for
completeness.
All English-language, full-length reports concerning CDH and
prenatal diagnosis or associated major malformations or both, were
eligible for inclusion. The following prespecified inclusion criteria were
required for inclusion in the meta-analysis: (1) a detailed description of
study population; (2) results reported on all CDH patients; (3) the report
contained data on prenatal diagnosis, associated major malformations,
or both; (4) postnatal mortality was reported as either neonatal mortality
or deaths before discharge from hospital. Duplications, abstracts, data
on eventration, and case reports were excluded from the study. In the
case of duplication of results from one institution or a region, the largest
series was included in the meta-analysis.
The studies included in the meta-analysis were grouped into 3
categories according to study population: (I) fetuses diagnosed prenatally, (II) neonates admitted to a treatment center, and (III) populationbased studies. Population-based studies were defined as studies based
on registry data or studies intended to cover all cases in a defined
geographical area and time span by use of vitality and hospital records.
In category II we only included studies on CDH patients symptomatic
within the first 24 hours of life. In category I and III this information
generally was not available.
Data were extracted on prenatal diagnosis, presence of associated
major malformations, side of hernia, timing of surgery, termination of
pregnancy (TOP), intrauterine fetal demise (IUFD), and postnatal
deaths. The definitions of the mortality variables are shown in Fig 1.
The primary outcome variable was total mortality defined as any
death in utero or postnatally. Total mortality excluding termination of
pregnancy (TOP) was used as the outcome measure comparing the
effect of prenatal diagnosis and associated major malformations on
CDH mortality rate in study category I and III. In study category II
visible postnatal mortality was used for this purpose.

SKARI ET AL

Odds ratio was used as a measure of magnitude of effect. Odds was

defined as the ratio of the probability of occurrence (death) of an event
to that of nonoccurrence (survival), and odds ratio was defined as the
ratio of 2 odds.29
The inclusion criteria for the analysis of birth prevalence of CDH
were (1) an English-language population-based study of CDH, (2) a
report presenting both the number of CDH patients and the number of
births within a defined region and time period, and (3) all subtypes of
CDH patients reported. Duplicate publications, reports with incomplete
data, and data on eventration were excluded.
Statistical analyses were performed with Excel version 7.0 (Microsoft Corp), SPSS version 8.0 (SPSS Inc, Chicago, IL), and S-Plus
version 4.5 (W.N. Venables and B.D. Ripley, Seatle, WA). Weighted
pooled birth prevalence and pooled proportions were calculated using
the actual numbers from each study reporting on that variable. Pooled
estimates of mortality rate and pooled odds ratios with 95% confidence
intervals (95% CI) were calculated according to Normand.30 When
encountering studies with a cell value of 0 in a 2 2 table, 0.5 was
added to cells containing 0 to calculate the pooled odds ratio. We
checked the results concerning pooled odds ratio using the alternative
Mantel-Haenszel approach; this method is applicable if odds ratios
cannot be calculated for some studies.31 Chi-square test was used as a
test for heterogeneity and for comparison of proportions. P value of less
than .05 was considered significant.

RESULTS

One-hundred-two publications published between 1975

and 1998 were retrieved. Thirty-one of these were
ineligible for analysis because of incomplete report of
outcome,2,4,24,26-28,32-56 15 were duplicate publications,14,20,57-69 4 reported mortality rates incompatible
with the definitions in the meta-analysis,70-73 and 1 study
was an abstract.74 Seventeen of the remaining 51 articles
were considered category I,9,10,16,19,75-87 24 category II,1,58,19,23,55,56,88-102 and 10 category III.11-13,15,103-108

Fig 1. Congenital diaphragmatic hernia: mortality definitions.

CDH: A META-ANALYSIS OF MORTALITY FACTORS

1189

Fetuses With Prenatally Diagnosed CDH

(Category I Studies)
Of 676 fetuses, 142 (21.0%) were terminated, 36
(5.3%) died in utero, 333 (49.3%) died postnatally, and
only 165 (24.4%) survived. Cumulative mortality rates,
combining only the studies reporting on the respective
events, are presented in Table 1. The pooled prevalence of
associated major malformations was 33.7% (range, 15.8%
to 72.7%). TOP was opted for in 46.9% of cases of
associated major malformations compared with 10.3% in
isolated CDH (P .001). Fourteen studies in category I
related associated major malformations to mortality.10,16,7580,82,83,85-87,109 Chi-square test for heterogeneity of these
studies showed a P value of .74, ie, the assumption of
homogeneity among studies was fulfilled. Total mortality
rate excluding TOP was increased significantly in patients with associated major malformations compared
with cases of isolated CDH (89.0% v 57.1%, P .001).
The pooled odds ratio of 4.0 (95% CI 2.1 to 7.7) means
that the probability of death to survival among patients
with associated major malformations was 4 times higher
than the probability of death to survival among patients
with isolated CDH in the 14 included studies. Only 2
studies in category I reported on deaths before admittance
to a treatment center,9,109 and pooled hidden postnatal
mortality rate and pooled visible postnatal mortality rate,
were 12.9% and 61.3%, respectively.
Twelve studies reported on sidedness of CDH,9,75-78,7883,85,109 and the pooled frequencies were LCDH, 90.0%;
RCDH, 8.0%; and other, 2.0% (ie, Morgagni hernia or

bilateral CDH). Six studies reported on the mortality rate

in LCDH and RCDH,9,75-78,82 and we found no significant
difference in pooled total mortality rate excluding TOP
(68.7% v 75.0%, P .59). Four studies provided data on
the influence of sidedness on mortality rate for the
subgroups with isolated CDH and associated major
malformations.75-78 Stratified analyses of total mortality
rate excluding TOP comparing LCDH and RCDH showed
no significant differences (the group with associated
major malformations: 92.9% versus 100%, P .49; and
isolated CDH: 61.2% versus 75.0%, P .36). Four
studies described the occurrence of associated major
malformations in relation to side of hernia,75-78 and no
significant differences were found (LCDH, 28.5% associated major malformations; RCDH, 42.8% associated
major malformations, P .18).
The effect of timing of surgery on mortality rate was
not reported in any of the studies in category I.
Neonates With CDH Referred to a Treatment Center
(Category II Studies)
The pooled visible postnatal mortality rate was 44.6%
with a range from 9.3% to 79.0% in CDH patients
admitted to a center for neonatal treatment (Table 2).
Thirteen studies reported on mortality related to prenatal
diagnosis (Fig 2).3,5-8,19,23,93,95,97,99,100,110 Chi-square test
for heterogeneity showed no significant differences between these 13 studies (P .77). The pooled postnatal
visible mortality rate was significantly higher among
prenatally diagnosed patients compared with postnatally

Table 1. Frequency of Associated Major Malformations and Mortality Rates in Fetuses With Prenatally Diagnosed CDH

Proportion
IUFD
(%)

True
Postnatal
Mortality
Rate
(%)

Total
Mortality
Rate Excl.
TOP
(%)

Total
Mortality
Rate
(%)

Study

No.

Associated
Major
Malformations
(%)

al9

Adzick et
Adzick et al10
Bollmann et al16
Bronshtein et al75
Calisti et al76
Crawford et al77
Dommergues et al78
Fox et al79
Geary et al80
Germain et al81
Guibaud et al82
Howe et al109
Manni et al83
Meizner and Levy84
Sharland et al85
Teixeira et al86
Thorpe-Beeston et al87

94
38
33
15
6
19
135
24
34
32
40
48
28
11
28
36
36

16.0
28.9
72.7
33.3
16.7
15.8
32.6
16.7
47.1
43.8
35.0
43.8
53.6
NA
23.6
25.0
47.2

1.1
10.5
21.2
46.7
0.0
5.3
28.2
NA
44.1
NA
30.0
20.8
7.1
45.5
20.0
50.0
41.7

3.2
20.6
26.9
0.0
0.0
0.0
4.1
8.3
5.3
NA
3.6
10.5
11.5
0.0
6.8
0.0
4.8

78.9
66.7
73.7
25.0
83.0
50.0
71.0
31.8
66.7
81.3
55.5
61.7
82.6
100.0
56.1
64.3
50.0

79.6
73.5
80.8
25.0
83.3
50.0
72.2
37.5
68.4
81.3
57.1
65.8
84.6
100.0
59.1
64.3
52.4

79.8
76.3
84.5
60.0
83.3
52.6
80.0
37.5
82.4
81.3
70.0
72.9
85.7
100.0
67.3
82.1
72.2

Pooled

676

33.7

22.9

7.2

66.9

69.1

75.6

Proportion
TOP
(%)

NOTE. The summary calculations only include the studies providing data on the respective variables.
Abbreviation: NA, not available.

1190

SKARI ET AL

Table 2. Frequency of Prenatal Diagnosis, Frequency of Associated

Major Malformations, and Postnatal Visible Mortality in CDH
Neonates Admitted to a Treatment Center

Study

al88

Adolph et
Al-Hathal et al89
Azarow et al7
Benjamin et al90
Butt et al91
Chan et al5
Cuniff et al92
de la Hunt et al23
Finer et al93
Frenckner et al1
Hansen et al94
Haugen et al95
Lessin et al96
Macken and Thompson19
Miguet et al110
Nakayama et al8
Pfleghaar et al97
Reyes et al3
Ruff et al98
Skari et al99
Steimle et al100
Thibeualt and
Haney101
West et al102
Wilson et al6
Pooled

Prenatal
Diagnosis
(%)

Associated
Major
Malformations
(%)

Visible
Postnatal
Mortality
Rate
(%)

18
21
223
108
90
19
92
54
65
43
75
10
123

NA
52.3
15.2
NA
NA
78.9
NA
59.3
63.1
23.3
NA
50.0
NA

11.1
9.5
15.7
39.8
12.2
52.6
39.1
1.9
NA
2.3
25.3
10.0
0.8

16.7
19.1
45.3
61.1
43.3
79.0
47.8
48.2
21.5
9.3
46.7
20.0
59.4

11
18
20
55
22
26
8
111

63.6
61.1
45.0
42.0
40.9
NA
25.0
34.2

9.1
22.2
40.0
9.1
18.2
61.5
12.5
25.2

36.4
27.8
75.0
50.9
18.2
61.5
37.5
36.0

90
111
196

NA
NA
44.9

8.9
33.3
48.0

36.7
46.9
46.9

1,609

38.2

23.3

44.6

No.

NOTE. The summary calculations only include the studies providing

data on the respective variables.
Abbreviation: NA, not available.

diagnosed patients (51.0% v 37.2%, P .001; pooled

odds ratio, 1.9; 95% CI 1.4 to 2.8). Sixteen studies
reported on mortality rate related to associated major
malformations.3,5-8,19,23,88-90,94,97-99,101,110 Chi-square results for heterogeneity showed a significant difference
between studies (P .001). The large series by Azarow
et al,7 which showed no effect of associated major
malformations on visible postnatal mortality rate, contributed to the above finding of heterogeneity. Pooled
postnatal visible mortality rate was significantly higher
among neonates with associated major malformations
than neonates with isolated CDH (77.0% v 36.3%,
P .001; pooled odds ratio, 5.8, 95% CI 4.0 to 8.4).
Fifteen studies reported on the sidedness of CDH.3,58,19,59,89,90,92,94,95,98,100,102,110 The pooled frequency distribution was LCDH, 82.9%; RCDH, 15.9%; and other, 1.2%.
Seven studies presented data on the relationship of
sidedness to mortality rate.6-8,19,90,95,98 Pooled postnatal
mortality rate was significantly lower in LCDH (47.1%)
compared with RCDH (65.2%), P .006. The corresponding pooled odds ratio was 0.51, 95% CI 0.31 to
0.82. Stratified analysis on the subgroups with associated
major malformations and isolated CDH was based on 3
studies only,8,19,90 and no significant differences in pooled
postnatal mortality rate between LCDH and RCDH were
found (associated major malformation, 93.5% v 100%,
P .49; isolated CDH, 47.5% v 60.0%, P .31). Based
on 4 studies,8,19,90,95 the frequency of associated major
malformations in the subgroups with LCDH and RCDH
were 26.4% and 16.7%, respectively (P .45). Seven
studies compared mortality in patients operated on within
the first 24 hours of life with delayed surgery6,7,23,93,96,100,102
and all but 1 prospective, randomized study23 were
historical comparisons. Pooled postnatal mortality rate in
the groups with delayed surgery and early surgery were
42.9% and 47.7%, respectively, but the difference was

Fig 2. The effect of prenatal diagnosis on visible postnatal mortality. Study

category II.

CDH: A META-ANALYSIS OF MORTALITY FACTORS

1191

Table 3. Population-Based Studies on CDH: Frequency of Prenatal Diagnosis, Frequency of Associated Major Malformations
and Mortality Rates
Associated
Major
Malformations
(%)

Proportion
TOP
(%)

Proportion
IUFD
(%)

Hidden
Postnatal
Mortality
Rate
(%)

Visible
Postnatal
Mortality
Rate
(%)

True
Postnatal
Mortality
Rate
(%)

Total
Mortality
Rate
(%)

Study

No.

Prenatal
Diagnosis
(%)

Cannon et al12
Forrester and Merz104
Harrison et al15
Jaffray and Makinlay11
Moore et al105
Puri and Gorman103
Scott and Renwick106
Steinhorn et al13
Torfs et al107
Wenstrom et al108

96
51
70
44
39
36
9
48
237
65

53.1
23.5
NA
23.5
87.2
NA
0.0
31.3
NA
18.5

46.9
41.2
NA
NA
25.6
58.3
NA
25.0
41.7
27.7

5.2
9.8
NA
NA
20.5
NA
NA
NA
0.8
NA

2.2
2.2
NA
NA
9.7
30.6
11.1
NA
4.3
21.5

NA
NA
52.9
36.4
10.7
60.0
NA
8.3
NA
NA

NA
NA
30.3
46.4
32.0
40.0
NA
34.1
NA
NA

40.4
51.1
67.1
65.9
39.3
76.0
50.0
39.6
58.2
47.1

44.8
56.9
NA
NA
56.4
83.3
55.6
NA
60.3
58.5

Pooled

695

37.2

39.3

4.7

8.2

34.9

35.7

54.2

58.2

NOTE. The summary calculations only include the studies providing data on the respective variables.
Abbreviation: NA, not available.

not statistically significant (pooled odds ratio, 0.84; 95%

CI 0.62 to 1.14). The prospective study by de la Hunt et
al23 reported 43% mortality rate in the delayed surgery
group and 54% mortality rate in the early surgery group
(P .05).
Population-Based Studies (Category III Studies)
The main results are presented in Table 3. Only one
study reported on all prenatal and postnatal events
outlined in Fig 1.105 Seven of 10 studies reported on both
prenatal and postnatal events,12,103-108 and the pooled
outcome for these 533 patients was 20 (3.8%) TOP, 42
(7.9%) deaths in utero, 248 (46.5%) postnatal deaths, and
223 (41.8%) survivors. Only 4 of these studies reported
on termination of pregnancy,12,104,105,107 and the pooled
proportion of TOP in these studies was 4.7%. Five of 10
reports specified whether postnatal deaths occurred at a
treatment center or before admittance to a treatment
center.11,13,15,103,105 In this subset of 215 liveborn, 75 died
before arrival at a treatment center (hidden postnatal
mortality rate, 34.9%), 50 died at a treatment center, and
90 survived. Pooled hidden postnatal mortality rate in the
2 earliest studies15,103 was 54.7% compared with 19.2% in
the 3 most recent studies11,13,105 (P .001).
Five studies reported on prenatal diagnosis in relation
to total mortality rate excluding TOP (Fig 3),11-13,104,105
and Chi-square test for heterogeneity showed no significant differences (P .17). Total mortality rate excluding
TOP was significantly higher among prenatally diagnosed malformations than those diagnosed postnatally
(60.4% and 39.6%, P .002; pooled odds ratio, 3.6, 95%
CI 1.9 to 7.1). Six studies related associated major
malformations to total mortality rate excluding TOP,13,103105,107,108 and no significant differences between studies
were seen (P .16). Total mortality rate excluding TOP
was significantly higher in patients with associated major

malformations compared with isolated CDH (81.4% and

43.2%, P .001; pooled odds ratio, 4.9, 95% CI 3.0 to
7.9).
Eight studies reported on the sidedness of
CDH.11,13,15,103-105,107,108 The pooled frequency distribution was LCDH, 80.8%; RCDH, 14.6%; and other, 4.6%.
Only two studies presented data on sidedness related to
mortality rate,11,15 and the pooled total mortality rate
excluding TOP in LCDH (23.1%) was significantly lower
than in RCDH (66.7%), P .002. The corresponding
pooled odds ratio was 0.12, 95% CI 0.03 to 0.47.
No studies in this category reported on the effect of
timing of surgery on mortality rate.
Comparison of Study Categories
A comparison of prenatal and postnatal mortality rates
across study categories is presented in Table 4. Pooled
proportion of TOP was significantly higher in category I
compared with III (22.9% v 4.7%, P .001). No difference was found in the pooled proportion IUFD (category

Fig 3. The effect of prenatal diagnosis on total mortality excluding

TOP. Study category III.

1192

SKARI ET AL

Table 4. Comparison of Reported Mortality Rates in Different CDH Study Populations

Study
Category

Proportion
TOP (%)

Proportion
IUFD (%)

Hidden
Postnatal
Mortality
Rate (%)

I. Prenatally diagnosed CDH

II. Neonates referred to center
III. Population-based studies

22.9
NA
4.7

7.2
NA
8.2

12.9
NA
34.9

Visible
Postnatal
Mortality
Rate (%)

True
Postnatal
Mortality
Rate (%)

Total
Mortality
Rate Excl.
TOP (%)

Total
Mortality
Rate (%)

61.3
44.6
35.7

66.9
NA
54.2

69.1
NA
56.5

75.6
NA
58.2

Abbreviation: NA, not available.

I, 7.2% v category III, 8.2%, P .54). Pooled true

postnatal mortality rate was significantly higher in category I than in category III, (66.9% v 54.2%, P .001).
The pooled frequencies of prenatal diagnosis in category II and III were similar: 38.2% and 37.2%, respectively (P .74). The frequencies of associated major
malformations were 33.7%, 23.3%, 39.5%, for category
I, II, and III, respectively. All differences in frequencies
were significant (category I v category II, P .001;
category II v category III, P .001; and category I v
category III, P .0035).
Birth Prevalence of CDH in Population-Based Studies
Fifteen studies were included.12,13,15,26-28,32,44,70-72,104,
106-108 Four studies were excluded: 2 because of missing
data on births11,105; 1 because of exclusion of patients
with chromosomal anomalies,45 and 1 because of duplication.103 In addition, the data from California in the
multinational study by Robert et al28 was excluded
because of duplication with the report by Torfs et al.107
The results are presented in Table 5. The birth prevalences ranged from 0.17 in 1,000 to 0.57 in 1,000 with a
pooled estimate of 0.25 in 1,000. Even higher birth
prevalence (0.66 in 1,000) was reported by De Vigan et
al45 in a French study which excluded patients with
chromosomal anomalies. Regional differences are seen in
both the studies from France27,28,71 and the United
States.12,13,26,28,107
DISCUSSION

The current study shows that mortality rate is increased

among prenatally diagnosed CDH patients compared
with postnatally diagnosed patients. The highest pooled
mortality rates were found in the group with fetuses
diagnosed prenatally, and these findings support the
conclusions from other reports,2,12,76 but this is in contrast
to other reports.6,7,13,14,68 The magnitude of the effect of
prenatal diagnosis on pooled mortality rate is relatively
strong with an odds ratio between 2.0 and 4.0 depending
on the study population.
We confirmed quantitatively the role of associated
major malformations as an important predictor of mortality rate, which is in accordance with recent reports.12,16,105,108,111 The pooled odds ratio relating associated major malformations to mortality rate ranged from

4.0 to 5.8 in the different study populations, indicating a

strong statistical association. The finding of associated
major malformations in 33.7%, 23.3%, and 39.5% in
category I, II, and III, respectively, should be taken into
account both during prenatal ultrasound examination of
CDH patients and when undertaking prenatal counselling
of the parents. Only a few of the included studies
subdivided associated malformations into major or miTable 5. Birth Prevalence of CDH in Population-Based Studies
Study

Place and
Period (Births)

Langham et al26

Florida 1988-92 (962,516 livebirths)

Norway 1969-75 (383,000 liveHarrison et al15
births)
Hawaii 1975-82 (107,967 liveBoychuk et al32
births)
Central-East France 1976-93
Robert et al28
(1,558,000 live and stillbirths)
Northern Region, England
Scott and Ren1987 (40,603 live and stillwick106
births)
Sweden 1973-92 (2,191,790
Robert et al28
live and stillbirths)
Hawaii 1987-96 (208,163 live
Forrester and
and stillbirths)
Merz104
Wenstrom et al108 Iowa 1983-88 (241,473 live and
stillbirths)
Julian-Reynier et Marseille, France 1984-90
(164,509 live and stillbirths)
al70
David and Illing- South-west England 1943-74
(433,333 livebirths)
worth44
Sweed and Puri72 Dublin, Ireland 1973-90
(368,772 livebirths)
California 1983-87 (718,208
Torfs et al107
live and stillbirths)
Utah 1988-94 (260,176 liveCannon et al12
births)
Steinhorn et al13 Minnesota 1988-90 (133,162
livebirths)
Languedoc-Roussillon, France
Sarda et al71
1989-91 (49,350 live and stillbirths)
Bouches-du-Rhone, France
Philip et al27
1982-88 (136,161 live and
stillbirths)
Pooled

15 studies (7,957,183 births)

NOTE. Prevalence per 1,000 births.

No.

Birth
Prevalence

166

0.17

70

0.18

21

0.19

310

0.20

0.22

498

0.23

51

0.25

65

0.27

45

0.27

136

0.31

116

0.31

237

0.33

91

0.35

48

0.36

20

0.41

77

0.57

1,950

0.25

CDH: A META-ANALYSIS OF MORTALITY FACTORS

nor; hence, we limited the current study to associated

major malformations. We believe that prospective studies
have to be conducted to assess the prognostic value of
major and minor associated malformations in relation to
mortality rate to avoid misclassification bias.
In accordance with previous reports, we found higher
mortality rates in RCDH than in LCDH.7,11,15,17,18 The
relatively few studies exploring this relationship in the
subgroups with associated major malformations and
isolated CDH resulted in a limited pooled sample size
with loss of statistical power. We did not find a clear
association between sidedness and presence of associated
major malformations, which suggests that other differences between LCDH and RCDH probably exist contributing to the differences in pooled mortality rates.
Our analysis of timing of surgery is limited to studies
of neonates admitted for surgery. Furthermore, our data
are limited by the small samples and weakness in study
design of most studies (historical comparisons). We
found no significant differences in pooled postnatal
mortality rate between neonates with early and delayed
repair, respectively, which is in accordance with the
findings of 2 prospective studies exploring the effect of
early versus delayed repair.23,24 De la Hunt et al23
concluded that further studies have to be conducted to
compare the effect of timing of surgery on outcome.
Among neonates admitted to a treatment center there is
a wide range in visible postnatal mortality rate. Differences in selection of patients in terms of proportion with
associated major malformations and prenatal diagnosis
probably are important. Hospital selection bias may
further complicate the interpretation of results. Hospitals
may select a higher proportion of some categories of
patients (for instance, extracorporeal membrane oxygenation patients) or may serve all patient categories in a
defined geographical region. Different management protocols may cause a difference, and there are observational
studies using historical comparisons showing significant
improvement over time.1,3,4,6,93 However, an evaluation of
various treatment regimes was beyond the scope of this
study. The contribution of hidden postnatal mortality rate
appears to be important as can be extrapolated from the
data reported from population-based studies.
Despite the heterogeneity among category II studies
because of different degrees of selection bias, we chose to
include this category in the meta-analysis. The included
studies in category II appear to represent the main body
of available evidence for the pediatric surgeon and seem
to present the most detailed data concerning postnatal
management.
In the era of prenatal ultrasound diagnosis of fetal
malformations it often has been stated that in utero
transport as a consequence of prenatal diagnosis, and a
planned delivery at a tertiary center is an advantage for

1193

mother and baby.112,113 For CDH we have not been able to

show this in our meta-analysis. However, it seems that
prenatal ultrasound diagnosis is more likely in the most
severely affected cases. Prenatal diagnosis might imply a
more severe degree of malformation, ie, the likelihood of
prenatal detection increases with a larger hernia with a
considerable mediastinal shift and resulting lung hypoplasia.2,114
The concept hidden mortality introduced by Harrison et al15 represents the group of fetuses not eligible to
study at the center of surgical treatment. To investigate
hidden mortality is difficult and requires a populationbased fetal and birth monitoring program or another
access to prenatal and postnatal clinical data. In addition,
autopsy of stillborn and newborn babies who die of
unknown cause must be performed to diagnose this
condition. We identified only 7 studies dealing with these
aspects to a greater or lesser extent.9,11,13,15,103,105,109
Hidden postnatal mortality rate was 34.9% in 5 populationbased studies, and was reduced to 19.2% when including
only the 3 most recent studies. In 1978 Harrison et al15
reported a hidden mortality rate of 53% among CDH
patients in Norway, and the decrease found in the current
study may be caused by several changes. Prenatal detection may result in termination of some of the pregnancies
with a special impact on the frequency of CDH patients
with associated major malformations as shown by different termination rates. For the patients identified prenatally, the current practice of planned in utero transport to a
center reduces the number dying at general hospitals or
during transport. This is in accordance with a recent
publication reporting a higher proportion of very affected
infants in recent years.53 Only 2 of 17 studies on fetuses
with a prenatal diagnosis of CDH reported on deaths
before admittance to a treatment center. From these data,
one might speculate that prenatal diagnosis to a large
extent ensures birth at a treatment center and in this way
eliminates postnatal hidden mortality rate in this group.
The detection rate by prenatal ultrasound scan varies
from 15.2% to 78.9% in category II studies, but has been
reported to increase over time.100
Associated lethal nonpulmonary malformations have
been found in 95% of the stillborn with CDH and in up to
60% of those who die within 24 hours of delivery.115 The
lower reported prevalence of associated major malformations in the population of neonates admitted to a center
than in the fetal population may be caused by a higher
proportion of hidden mortality among patients with
associated major malformations or differences in referral
practice. In the current study, the frequency of associated
major malformations was highest in category III, followed by category I, and category II.
TOP occured in 22.9% (range, 0% to 50%) of patients
in category I studies. The majority of terminations were

1194

SKARI ET AL

undertaken if both CDH and an associated malformation

were diagnosed. A higher termination rate in the group
with associated major malformations changes the spectrum of CDH patients, and this introduces a selection bias
that will tend to improve survival rate in the group
continuing the pregnancy. Furthermore, the effect of
prenatal detection of CDH or associated major malformations on the termination rate is dependent on the legislation and the attitudes of doctors and parents, respectively.
This is seen in the great variation in frequency of TOP
among the studies.
Because of the rarity of CDH and the resulting low
statistical power of most studies, meta-analysis represents a valuable research tool complimentary to the
narrative review by increasing statistical power.110 Given
the incidence of CDH in the order of 1:4,000, the current
meta-analysis of approximately 3,000 CDH patients
represents about 12 million pregnancies.
We limited the current study to reports published in the
English language based on the fact that the majority of
eligible studies were in this category. On this basis, the
results of the current study are generalizable to a lesser
extent to countries where the majority of studies are not
published in the English language.
The current meta-analysis is based on tabulated data
and not on individual data provided by the respective
investigators. The latter would enable a more efficient
analysis of the relative importance of prognostic factors,
but requires a collaborative effort of many researchers to
obtain reliable results.
One of the major methodological problems using
meta-analysis is publication bias. The probability of
having a scientific work published increases if significant
differences are shown.110 This biases the narrative review
to the same extent, but rather, in a qualitatively manner.
In addition, we speculate that series with low mortality
rates are more likely to be published than series with
poorer results. According to Altman,116 however, it is
better to use the available information in a systematic

way than to rely on subjective assessment of the various

trials. To reduce publication bias, the inclusion of unpublished data has been recommended.117 However, we did
not consider this a feasible option for the current study.
In the current study we have expressed the effect of
prenatal diagnosis and associated major malformations
on mortality rate by means of odds ratios and 95% CI.
This is recommended as a measure of the statistical
association.118 We calculated pooled odds ratios using
both the methods described by Normand30 and Mantel
and Haenszel,31 and negligible differences were found.
The heterogeneity of CDH as a disease entity has been
documented in population-based studies,107 and the pooling of all subtypes of CDH represents a limitation in our
study. However, to reduce bias we only have included
studies reporting on all kinds of CDH.
Langham et al,26 in a review article, reported an
unweighted mean birth prevalence of CDH of 0.285 in
1,000. In the current investigation, which, in contrast, did
not include studies published before 1975, a comparable
birth prevalence and range was found, and the differences
between pooled weighted and unweighted estimates were
negligible.
The most striking finding in our study is the increased
mortality rate found across study categories in patients
with prenatal diagnosis. This knowledge should be taken
into consideration when prenatal counselling is undertaken, and the relative high prevalence of associated
major malformations should be considered both during
prenatal examination of these fetuses and when counselling the parents. There still is a considerable hidden
mortality of CDH that must be taken into account when
comparing results, but the magnitude of hidden mortality
declined significantly in recent as compared with earlier
studies.
ACKNOWLEDGMENT
The authors thank Professor Per Magnus at The National Institute of
Public Health for helpful advice.

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