Chronic Oxygen Dependency in Infants Born at Less Than 32 Weeks' Gestation: Incidence and Risk Factors

DISCUSSION

To our knowledge, this is the first prospective, multicenter study to describe incidence and risk factors of COD in a cohort of very premature survivors in the surfactant era. The mortality rate of 14% is consistent with other published data.^11,,12

COD incidence varies widely in the published data.^2,,313–15 Some of this difference can be explained by the various combinations of numerators and denominators used to compute this incidence. The denominator may be based on figures from the hospital,¹³ multiple center,¹⁴ or the general population.¹⁵ Unlike population-based data, our denominator does not include infants who were recorded as liveborn but who died before reaching the nursery. In the population-based study by Darlow et al,¹⁴ these newborns represented 12.5% of the very low birth weight population. As we expressed COD incidence among survivors, this difference does not affect the interpretation of our results.

The standard for oxygen was the same in all 8 centers: an oxygen saturation between 92% and 96% during quiet sleep, with the same precalibrated oximeter. Differences in management (eg, fluid intake, ventilation settings, postnatal corticosteroids) might explain variations in the incidence of COD among centers. In an 8-center survey about BPD, Avery et al¹⁶ pointed out a similar degree of variability in nursery policies among centers, especially for respiratory care.

After multiple regression analysis that adjusted for center, other risk factors remained important. The most significant was GA.

Few studies have focused on populations defined by GA; they most often reported data stratified by birth weight. Fenton et al¹⁵reported BPD rates in a population-based study of 2 regions, Trent and British Columbia, in 1990 and 1991. BPD incidence in survivors of 32 weeks or less or of 750 to 1500 g was 16.3% and 24.5%, respectively. The CLD rate was 6.4% and 18.5%.

Lenoir et al¹⁷ described the short- and mid-term outcome of 1157 neonates with respiratory distress syndrome (RDS), born during a 15-month period in 1990 to 1991. BPD occurred in 72% of the infants who were born before 26 weeks' GA, 50% at 26 to 27 weeks' GA, 28% at 28 to 29 weeks' GA, and 13% at 30 to 31 weeks' GA.

In a recent 1-year prospective multicenter study, Rubaltelli et al¹⁸ enrolled 1048 infants who were born before 32 weeks' gestation. The infants were treated with surfactant and managed with oxygen, continuous positive airway pressure, and conventional ventilation. Incidence of BPD was low in every GA group: 10% for infants born at 23 to 25 weeks, 13% for those born at 26 to 27 weeks, 9% for those born at 28 to 29 weeks, and 2% for those born at 30 to 31 weeks. The author explained this lower incidence of BPD by a high rate of antenatal steroid treatment (71% of infants with respiratory disorders vs 51% in our study). This difference also might be explained by mortality: mortality data were not provided, and the BPD incidence was calculated with the entire population, rather than simply survivors, as the denominator.

It seems to us that GA is a reliable predictor of COD. It is related to the morphologic and functional immaturity of the respiratory system, and this immaturity is one of the major determinants of COD in very preterm infants.

We also found the CRIB score to be related to COD. As others have reported,^7,,19 CRIB was correlated with the risk of death in our population, a finding indicating that the score was valid. Our results show that CRIB also is an accurate index of initial neonatal risk of COD at 28 days of life and at 36 and 42 weeks' PCA.

CRIB initially was defined as “a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units” for infants with a birth weight of 1500 g or less or a GA younger than 31 weeks.¹⁹ In 1996, Fowlie et al²⁰ reported that this scoring system also could contribute to more comprehensive predictive models of death and nosocomial bacteremia. More recently, these authors²¹ showed that throughout the first week of life, CRIB score was correlated with the risk of death, disability, and prolonged treatment with oxygen at 28 days and 36 weeks' PCA. Only 1% of the high-risk neonates included in Fowlie's study, however, were treated with surfactant replacement. Accordingly, it has been suggested that “this relationship may not be present in the surfactant era” and that “surfactant use has aged the CRIB score faster than other scores.”²² As surfactant replacement therapy has a minimal impact on BPD,²³ we do not think that this conclusion necessarily follows. It certainly is not confirmed by the results of our multicenter prospective study in which 76% of the ventilated infants received surfactant.

Moreover, our results are logically consistent, because 4 of the 6 variables considered in CRIB are confirmed BPD risk factors (low GA, birth weight, and minimum and maximum inspired fraction of oxygen in the first 12 hours of life, which can be considered as markers of severe RDS). Our findings thus demonstrate that CRIB is not yet at risk of being “washed away by clinical advance.”²² It remains an early and reliable score that helps to predict the occurrence and severity of COD in infants who are born at less than 32 weeks' gestation.

IUGR, present in 25% of our population, also was a risk factor for COD. Distribution of IUGR was homogeneous among the 8 centers. Conflicting results in the early 1990s reported that IUGR was a protective factor²⁴ or a risk factor for COD.¹⁷ More recently, Todd et al,¹³ using multivariate analysis, also reported a strong correlation between IUGR and COD at 36 weeks' PCA in a cohort of 1454 infants who were born at 24 to 32 weeks' gestation. These clinical results are supported by experimental data about malnutrition-induced adverse pulmonary effects during the perinatal period.^25,,26

Antenatal steroid therapy was not correlated with a lower incidence of COD in univariate analysis. We believe that the beneficial effects of antenatal steroid therapy on COD would have been demonstrated if the rate of treatment has been clearly higher.

Incidence of surfactant therapy was 57% in the overall population but 76% of ventilated infants. This indicates an early therapeutic approach to RDS management and not a rescue strategy, which would have selected the most severe patients. The correlation between surfactant replacement and COD in our population suggests that surfactant therapy could not prevent RDS from developing into BPD. Two meta-analyses^1,,27 failed to find that surfactant treatment, regardless of its type or mode, has any direct preventive effect on BPD that seems to be determined multifactorially and is not linked to RDS alone.

It is unexpected that although inflammation is thought to be associated closely with CLD,^28,,29 none of the relevant factors recorded in our study (premature rupture of membranes, neonatal or nosocomial sepsis, corticosteroid therapy) was found to be a significant risk factor. Because no data were available concerning chorioamnionitis, we could not test its relation with CLD.