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
,
,
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
|
Table 1. Summarized Treatment Protocols per Trial |
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 |
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.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.
Table 3.
Treatment of the Randomized Groups per Country
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 |
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.DISCUSSION
.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.
FOOTNOTES
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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Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
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