Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants

Abstract

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Keywords: bronchopulmonary dysplasia; extremely preterm infant; intermittent hypoxemia; pulse oximetry.

Figure 1.

Association between exposure to prolonged hypoxemia and the probability of developing severe bronchopulmonary dysplasia (BPD). The left panel shows the relationship between the median number of hypoxemic episodes lasting six or more consecutive 10-second readings or approximately 1 minute or longer and the probability of developing severe BPD. The right panel shows the relationship between the median proportion of time per day with the amount of oxygen saturation as measured by pulse oximetry (Sp_O2) <80%. Both measures of hypoxemia are summarized for the period of time beginning within the first 24 hours after birth and ending at 36 weeks’ postmenstrual age or at discharge to home if it occurred earlier. The solid curves and shaded areas display the probabilities and 95% confidence intervals derived from an adjusted logistic regression model fitted with severe BPD as the dependent variable and the square root–transformed hypoxemia data as the continuous independent variable. The dashed curves display the probabilities obtained from the unadjusted logistic regression model. To enable clinical interpretation, the scales of the x-axes quantify the untransformed rates of hypoxemia. To visualize model fit, the study cohort was subdivided into deciles according to the amount of exposure to each measure of hypoxemia. The observed (unadjusted) rates of severe BPD for each decile, plotted against the mean, square root–transformed rates of hypoxemia in each decile, are superimposed on the graphical displays. The C statistic values for the adjusted logistic regression models were 0.861 for prolonged hypoxemic episodes per day and 0.844 for the proportion of time per day with Sp_O2 <80%, indicating strong model fit.

Figure 2.

Exposure to prolonged hypoxemia by postnatal age stratified by severe bronchopulmonary dysplasia (BPD) status. (A) The top panels show the association between the median number of prolonged hypoxemic episodes per day by postnatal age in weeks for infants who did and those who did not develop severe BPD. (B) The bottom panels show the corresponding results for the median proportion of time per day with an oxygen saturation as measured by pulse oximetry (Sp_O2) <80%. The plots on the left depict the rates of hypoxemia over the first 8 postnatal weeks, and the plots on the right depict the rates of hypoxemia over the first 4 weeks. The solid curves and shaded areas display the estimated rates of hypoxemia and 95% confidence intervals derived from the adjusted mixed-effects models. The dashed curves display rates from the unadjusted models. To visualize model fit, the average observed (unadjusted) rates of hypoxemia at each weekly time point are plotted. The P values reported in the plots correspond to the severe BPD × (week)² (plots on the left) and the severe BPD × week (plots on the right) interaction terms included in the mixed-effects models using the square root–transformed hypoxemia rate data. These P values of <0.001 indicate significant differences in Sp_O2 trajectories between infants who developed severe BPD and those who did not. The model-derived rates of prolonged intermittent hypoxemia and the proportion of time per day with Sp_O2 <80% differed significantly (P < 0.001) at each weekly time point over the first 4 postnatal weeks between infants who developed severe BPD and those who did not. Tables E2 and E3 show the model-estimated weekly rates of hypoxemia for the first 4 postnatal weeks. The observed weekly rates of hypoxemia for the first 8 postnatal weeks are reported in Tables E4 and E5. CI = confidence interval.