PEDIATRICS Vol. 100 No. 1 July 1997,
p. e4
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Mortality, Severe Respiratory Distress Syndrome, and Chronic Lung
Disease of the Newborn Are Reduced More After Prophylactic Than After
Therapeutic Administration of the Surfactant Curosurf
Johannes Egberts*,
Roland Brand
,
Hervé Walti§,
Giulio Bevilacqua
,
Gérard Bréart MD¶, and
Fabrizio Gardini#
From the Departments of * Obstetrics and Gynecology and
Medical Statistics, University of Leiden, The Netherlands; § Service
de Médicine Néonatale, CHU Cochin Port Royal, Paris and
¶ Unité de Recherche Épidémiologique sur la
Santé des Femmes et des Enfants INSERM U-149, Paris, France; and
the Institute of Child Health and Neonatal Medicine, University of
Parma and # Division of Statistics, Chiesi Farmaceutici SPA, Parma,
Italy.
ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- ACKNOWLEDGMENTS
- ABBREVIATIONS
- REFERENCES
ABSTRACT 
Objective. To test the hypothesis that
prophylactic treatment with the surfactant Curosurf (Chiesi
Farmaceutici SPA, Parma, Italy) improves survival and respiratory
problems more than rescue treatment.
Design. Meta-analysis of three prophylaxis versus rescue
treatment trials, conducted in four countries.
Methods. A meta-analysis was performed with the original,
individual data of mortality, severe respiratory distress syndrome, and
chronic lung disease of 671 newborns as outcomes. The random-effects logistic model (accounting for the trial-within-country structure) was
applied and adjusted for imbalances in covariates.
Results. The probability of each outcome differed between
the countries, but the actual treatment effect itself did not. The adjusted odds ratios (ORs) and confidence intervals (CIs) for prophylaxis versus rescue were as follows: mortality: OR, .47; 95% CI,
.30 to .73; severe RDS: OR, .50; 95% CI, .33 to .74; and chronic lung
disease of the newborn in the survivors at day 28 after birth: OR, .54;
95% CI, .34 to .86. Gender, birth weight, gestational age, and
prenatal administration of glucocorticosteroids were significant
confounding covariates.
Conclusion. The analysis shows that for the porcine
surfactant Curosurf, prophylactic administration of surfactant has
significant advantages over rescue therapy.
Key words:
mortality,
respiratory distress syndrome,
chronic lung disease of the newborn,
surfactant,
prophylaxis,
meta-analysis.
INTRODUCTION
Meta-analyses have shown that prophylactic and rescue
treatment with surfactant reduce mortality rate, severity of acute
respiratory problems, and the incidence of chronic lung disease in
preterm newborns.1 After performing a meta-analysis
of seven randomized trials comparing prophylaxis with rescue
treatment,4 we found that prophylactic treatment
reduced the mortality rate more than rescue treatment [odds ratio
(OR), .65; 95% confidence interval (CI), .50 to .84]. Mortality rate
is likely to be reduced because of less severe acute respiratory
problems such as respiratory distress syndrome (RDS), pneumothorax and
pulmonary interstitial emphysema. Furthermore, one might expect that if
the acute respiratory problems are reduced, and if the number of
patients per randomized group is large enough, the incidence of chronic
lung disease of the newborn (CLDN) would also be lowered significantly.
Even within these seven trials including more than 2700 preterm
newborns this was not so (OR, .85; 95% CI, .67 to 1.06). Four
different natural surfactants, and seven different protocols for
treatment in at least eight different countries were used in these
trials.4
In any meta-analysis of published results, heterogeneity among trials,
possibly induced by differences among centers, populations, treatment
protocols, surfactants, and so forth, can lead to both under- and
overestimation of the magnitude of treatment effects as well as their
statistical significance.11 However, when individual data
instead of general effect measures are available, the application of
multivariate random-effect regression models can adjust for some
variations in treatment effect that might have resulted from interstudy
differences. In this study, using the data on the individual infants,
we calculated the average effect among these trials (condensed in the
term country) with respect to the outcomes: mortality, severe RDS, and
CLDN, after different prophylactic or rescue treatment protocols with
Curosurf in 34 neonatal intensive care units.
MATERIALS AND METHODS
Curosurf (Chiesi Farmaceutici SPA, Parma, Italy) is isolated
from porcine lungs and its characteristics, clinical efficacy, and how
and when it was given and tolerated have been described extensively.12 The trials were performed during 1989 to 1991 in two Dutch and two Swedish neonatal intensive care units,
during 1990 and 1991 in 12 French units, and during 1991 to 1992 in 18 Italian hospitals. The protocols of these trials have been described elsewhere8; the treatment schedules are summarized in
Table 1. Different patient data books and databases were
used in the three trials. Fields of interest for this study were merged
from each database and edited, if necessary. The data of each trial within the new database were checked for errors by the respective trial
coordinators.
|
Table 1.
Summarized Treatment Protocols per Trial
[View Table]
|
Patients
The combined trials included 345 prophylactically
treated infants and 326 enrolled infants, who were eligible for rescue
therapy if they fulfilled the entry criteria for surfactant
administration. A total of 57 infants were excluded from the trials
because of violation of the entry criteria or withdrawal of parental
consent (32 in France, 19 in Italy, 1 in The Netherlands, and 1 in
Sweden). Table 2 shows the baseline characteristics of
the treatment groups by country.
|
Table 2.
Perinatal Baseline Characteristics per Country and per Treatment Group
[View Table]
|
The Outcome Variables
In this study, analyses were performed to determine whether or
not prophylaxis when compared with rescue treatment would result in
lower incidence of the outcome variables. 1) Severe RDS was defined as
grade 3 to 4 according to Giedion et al13 or Bomsel (see footnote at the bottom of this page)14; 2) Neonatal
mortality, without a differentiation between respiratory and
nonrespiratory causes; and 3) CLDN at 28 days after birth in the
surviving infants. CLDN was defined as requirement for respiratory
support (need for supplementary oxygen and/or ventilatory support).
These outcome variables differ slightly from the primary endpoints of
the three trials: 1) an improvement of the
PaO2/FIO2
ratio8; a reduction of (severe) RDS8,10; and 3)
an increase of survival without BPD at 28 days after
birth.9 In the three trials more infants were included than
needed to detect assumed differences between the treatment protocols at
an 
error of 5% and a power (1-
) of 80 or 90%.
Statistical Methodology
Because for this meta-analysis we had access to the individual
data rather than the overall effect estimates, the analyses amount to
the usual multivariate regression models in which the probability of a
specific outcome is modeled as a function of the treatment (randomly
allocated) and several covariates. However, the usual logistic
regression model is not applicable because the different trials were
carried out in different countries under different circumstances. This
stratification induces a correlation structure on the individual data
and thus a random effects model was chosen in which all observations
were stratified by country. We included the variable country in our
models to account for additional variation attributable to country
beyond, and not instead of that induced by the centers themselves. All
P values are based on the appropriate likelihood ratio tests
comparing a model with and without the treatment factor, but
incorporating the random effect term and the covariates of importance:
birth weight (BW), gestational age, gender, and prenatal administration
of glucocorticosteroids.
As an initial analysis and for display purposes, we used a
Mantel-Haenszel approach, showing the relation between treatment and
outcome in a series of 2 × 2 tables, stratified by country. For a
series of randomized trials the ORs obtained in this way will be very
close to those obtained by logistic regression; the P
values, however, are solely based on the logistic random-effects models. For the calculation of the adjusted ORs, the significant covariates were included in this model as regression terms. The software used was EGRET ("Epidemiological Graphics, Estimation, and
Testing package, Analysis Module: PECAN"; SERC, Seattle, WA).
RESULTS
Baseline Characteristics
Table 2 shows the perinatal baseline characteristics of each
trial. Treatment arms are well balanced in all but two cases: BW for
the Dutch trial and gestational age for the French one. In view of the
number of covariates and trials, this is well within bounds induced by
chance fluctuations. Although both gestational age and BW in themselves
are predictors for the outcomes under study, there was no measurable
confounding effect attributable to these imbalances.
The necessity of stratification is clear from the differences among the
trials with respect to the criteria of surfactant treatment and
retreatment (Tables 1 and 3). The prophylactic administration of Curosurf occurred in all cases within 15 minutes. Rescue treatment was given independently of postnatal age in the French
and Italian trials, whereas in the Dutch-Swedish trial it was postponed
for 6 hours postnatally. Rescue treatment was given after a median
period of 6 hours in the Dutch and Swedish subgroups, and after 4 hours
in the French study and 7 hours in the Italian study. Retreatment after
prophylaxis occurred in 12% (Dutch), 9% (Swedish), 4% (Italian), and
in 45% of the (French) infants. Rescue treatment was given to 31%
(Dutch), 30% (Swedish), 40% (Italian), and to 55% (French),
respectively, of the infants. Retreatment of rescue-treated infants was
also allowed in the French study and it was done in 70% of these
infants.
|
Table 3.
Treatment of the Randomized Groups per Country
[View Table]
|
The Outcomes
The different trials, carried out in different countries under
different circumstances and different groups of patients showed correlations between the individual observations attributable to the
patient-within-country structure. This random effects term in the
models for the three outcomes was highly significant (mortality, P = .005; severe RDS, P = .05; and
CLDN, P = .001). Thus, the ORs for the outcomes of the
combined results were corrected for the random effects term although
this had virtually no effect on the estimates of the ORs. Table
4 summarizes in a series of 2 × 2 tables the
relation of treatment and outcomes by country and for the combined
trials, after correction for the random effects term.
|
Table 4.
Outcomes per Country and Odds Ratio for Severe RDS, Mortality, and CLDN
[View Table]
|
Outcome 1: Reduction of RDS at Six Hours After Birth
The incidence of radiologically and/or clinically diagnosed very
mild to severe RDS was 70.2% (grade 1 to 4) in the rescue-eligible groups and 64.2% in the prophylactically treated infants (relative reduction or risk ratio (RRR) 8.5%, not significant). For severe RDS
(grade 3 to 4), it was 29.7% in the rescue-eligible group and 18.9%
in the prophylactically treated infants (RRR, 36.4%; OR, .55; 95% CI,
.38 to .79; P = .001). The incidence of the respiratory complications pneumothorax plus pulmonary interstitial emphysema was
20.6% in the rescue-eligible group and 12.2% in the prophylactically treated infants (RRR, 40.8%; OR, .54; 95 %CI, .35 to .82).
The test for homogeneity of the four ORs for severe RDS was not
significant suggesting that the differences in treatment effect between
the trials (countries) can be explained by chance fluctuations.
Outcome 2: Reduction of Neonatal Mortality
Mortality was reduced in all three trials (resulting in an
increased percentage of survivors) when comparing prophylaxis (84.9%) with rescue treatment (74.5%) (RRR on mortality, 40.7%; OR, .52; 95%
CI, .35 to .76; P < .001). Again differences in
estimated ORs can be attributed to chance fluctuations.
Outcome 3: Reduction of the Incidence of CLDN in Survivors at 28 Days After Birth
The incidence of CLDN at 28 days after birth was not reduced if
all randomized infants were included in the calculation
(P = .15). In the group of prophylactically
treated survivors the incidence of CLDN at day 28 (24.4%) was reduced
significantly when compared with the survivors of the rescue-eligible
group (31.7%) (RRR, 23%; OR, .67; 95% CI, .45 to 1.00;
P = .05). Although significant changes were not found
between the separate trials and differences in estimated ORs are most
likely the result of chance fluctuations, heterogeneity might be
present.
Evaluation of Possible Confounding Covariates
The usual logistic model probably yields P values that
are too optimistic because that model assumes all individual
observations to be independent, which is not true. The variable
country, which includes differences in rescue and normal-procedure
protocols and also in populations, was a significant random effects
term that therefore needs to be taken into account when calculating the
significance (P value) of any treatment effect. This
was done by incorporating it as a stratification variable in a random
effects logistic model.
Independent of the effect of prophylaxis, we found that male neonates
were more likely to develop severe RDS than female neonates (P < .001), that the rate of severe RDS
decreased significantly in neonates with higher BWs or gestational
ages, and if corticosteroids were given prenatally. The same variables
as for RDS will change the OR values of mortality, and except for an
effect of corticosteroids, also those of CLDN. Multiple birth,
preeclampsia, and caesarean section were insignificant covariates. The
ORs for these outcomes, and adjusted confounding covariates are shown
in Table 4.
DISCUSSION
The mortality rate and the incidence of RDS and CLDN in survivors
decrease after the prophylactic and therapeutic administration of
surfactant,1 but lower odds for CLDN were only
observed if the meta-analyses were limited to surviving
infants.4 Both strategies for surfactant therapy have their
advantages and disadvantages and trials were started, comparing the
effects of the prophylactic and therapeutic approach. Meta-analysis of
the seven studies,4 comparing prophylaxis with rescue
therapy in very premature neonates shows that prophylaxis reduced the
mortality rate more than rescue therapy (OR, .65; CI, .50 to .84) but
the incidence of CLDN in the groups of survivors had not changed
significantly (OR, .85; CI, .69 to 1.06). Only some of the natural
surfactants of human,4 bovine,5 or
porcine8 origin were used in these comparative studies
and not the synthetic surfactants ALEC and EXOSURF and the natural
bovine surfactants Survanta and Alv(e)ofact. The two trials,4,5 that included relatively small groups of infants did not show any benefit for using surfactant prophylactically instead
of therapeutically. A meta-analysis of the surfactants that included
more than 600 infants in their studies and without any correction or
adjustment showed similar outcomes for the two Infasurf
(=CLSE)6,7 and three Curosurf trials.8 The
odds for mortality reduced significantly after prophylaxis (Infasurf: OR, .50; CI, .31 to .80; and Curosurf: OR, .52; CI, .36 to .76) and
were lower for CLDN, but not statistically significant (Infasurf: OR,
.76; CI, .56 to 1.03; and Curosurf: OR, .70; CI, .47 to 1.03). However,
the impression that the incidence of CLDN has declined could change
into rejection or acceptance of such an effect when ORs are adjusted
for confounders.
Curosurf has, as other surfactants, proven its clinical efficacy by
reducing the mortality rate and the incidence of severe RDS in rescue
and multiple dose trials15 and also in prophylaxis versus rescue trials.8 In this study, individual data
instead of general effect measures were available and the effect of
adjustment of ORs for covariates within a meta-analysis for this
surfactant could be shown. The important intertrial differences may be
considered to be the weakness of this study. Rescue treatment was
started at different stages of RDS in the three trials. The
Dutch-Swedish trial had a 6 hours postpartum plus fraction of inspired
oxygen 
.6 entry-criterion and only neonates suffering from
severe RDS were given surfactant. For the Italian and French trials the
entry criteria for rescue treatment (a mildly or moderately reduced respiratory condition of the neonate, and independent of postnatal age)
were similar to those of the other prophylaxis versus rescue studies.4 The entry criteria for rescue treatment of the
latter two trials are close to the criteria that neonatologists
currently use. One might expect that because of the late treatment in
the Dutch-Swedish trial, this trial has resulted in the largest
differences in outcomes between the prophylactic and rescue treatment
arms. Then the mean ORs for the three trials (as shown above) may
differ more from one than without the Dutch-Swedish results. However, the opposite was true: after exclusion of the Dutch-Swedish results the
difference from one became larger. We have kept the Dutch-Swedish results within this meta-analysis because the meta-analysis is then as
inclusive as possible and gives real estimates of the effect which one
might anticipate for this surfactant.
Adjusting the ORs of the Curosurf studies for the significant
differences that were present for the probability of mortality, severe
RDS, and CLDN between the countries did not change these ratios
substantially. Furthermore, the effect on the outcomes could not be
attributed to the length of time after birth before rescue treatment
was started (that is for most of the infants when RDS was still mild or
moderate), or to the number of doses used for prophylaxis or for rescue
treatment. This means that, independent of all differences, the actual
treatment effect does not differ between the countries. A test to
detect heterogeneity of ORs after stratification by country, was
nonsignificant for each of the outcomes. Although the power to
discriminate true differences is weak for tests of homogeneity, the
result of this analysis suggests that the assumption of a common OR
(treatment effect) over all trials is warranted. The results do not,
however, show what is the best protocol for (multiple) prophylactic or rescue treatment.
All data stem from randomized trials and, after merging the four
databases, there is strictly speaking, no need to incorporate the
covariates in the model except to increase the power of the analysis or
to correct for imbalances. There should not exist any confounding
because treatments were randomly allocated. That this was indeed the
case, was verified for all analyses by comparing the unadjusted OR
(measuring the treatment effect on the outcome) with the adjusted one
after incorporating gestational age, BW, gender, antenatal
administration of corticosteroids, multiple pregnancy, and the method
of delivery in the random-effects logistic model. After adjustment the
power of the analysis increased but the differences between the
adjusted and unadjusted ORs were not significant. Adjustment of the
CLDN OR for confounders as BW, gestational age, gender, and
corticosteroids demonstrates that the incidence of CLDN was
significantly lower after prophylactic administration than after rescue
treatment. The number of infants with CLDN has not decreased, but its
incidence has. This is the result of larger number of survivors after
prophylaxis and most likely also of less severe RDS after this type of
intervention. In many randomized surfactant trials the ORs for the
outcome, death plus BPD, is given. We believe that it is wrong to group the infants who died with those who will often survive without serious
problems. (eg, the OR = 1 for the outcomes 7% mortality plus 3%
CLDN in group A and 3% mortality plus 7% CLDN in group B). Therefore
we have intentionally excluded this finding, although the odds for
death plus BPD were lower after prophylaxis than after rescue
treatment.
Independent of surfactant therapy, the prenatal administration of
glucocorticosteroids resulted in the well-known effect of lowering the
odds for mortality and RDS. There was no effect on the incidence of
CLDN, probably because of the relatively low percentage of prenatally
treated newborns (19%). The odds for CLDN on day 28 of neonates
without RDS are significantly lower than for those suffering from
severe RDS (RRR, 46%; OR, .36; CI, .22 to .59). It is therefore better
to prevent than to cure RDS because the absence of RDS will result in
reduced risks for developing CLDN,18 even at 36 weeks'
postconceptional age.19
The prophylactic administration of surfactant is a significant factor
(P < .01) in reducing the odds for mortality
and severe RDS, and therefore also for CLDN. BW, gestational age,
gender, and the prenatal administration of glucocorticosteroids are
important confounders. Thus, prophylaxis should be considered as the
best therapeutic approach for those newborns, who have increased risks for developing RDS and CLDN. We hypothesize that similar effects can
also be obtained with natural surfactants other than Curosurf.
FOOTNOTES
(Definition of the radiological stages of RDS according to
Giedion et al13 and Bomsel14 are comparable:
Stage I: very fine reticulo-granular pattern, normal lucency, air
bronchogram within cardiac border. Stage II: generalized typical
reticulo-granular pattern, slightly diminished lucency, air bronchogram
extending the cardiac border. Stage III: confluent reticulo-granular
densities, marked reduction of lucency with indistinct cardiac border.
Stage IV: total opacification, white lungs).
Received for publication Jun 26, 1996; accepted Nov 17, 1996.
Reprint requests to (J.E.) Department of Obstetrics and
Gynecology, Leiden University Hospital, Building 1; P3-P, PO Box 9600, 2300 RC Leiden, The Netherlands.
ACKNOWLEDGMENTS
We acknowledge the contribution of all neonatologists, fellows,
residents, and nurses during the course of the three trials. We thank
especially Dr Oliver Gebhardt for this constructive advice during the
preparation of the manuscript.
Conflict of interest: The three trials in this meta-analysis were
originally supported by Chiesi Farmaceutici SPA, Parma, Italy. The
company allowed us to use the individual data of the Italian trial. The
design and analysis of the present study is independent of the company
and it was not supported by grants.
ABBREVIATIONS
OR, odds ratio.
CI, confidence interval.
RDS, respiratory distress syndrome.
CLDN, chronic lung disease of the
newborn.
BPD, bronchopulmonary dysplasia.
RRR, relative reduction of
the risk ratio.
BW, birth weight.
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