OBJECTIVE: To assess dexamethasone (DEX) and hydrocortisone (HC) use in premature infants over time and the association of steroid use with the incidence of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age.
METHODS: We analyzed data from the Pediatrix database for neonates of 23 to 32 weeks' gestation managed during 1997–2006 (N = 77520). We compared the use of DEX, HC and BPD (defined by oxygen use at 36 weeks' postmenstrual age) according to year and estimated gestational age. Mantel-Haenszel χ2 was used to compare the trends in steroid use and BPD rates according to year.
RESULTS: There were no differences by year in the proportion of births at each gestation or in early or late neonatal death. DEX use decreased from a peak of 25.0% in 1998 to 6.8% in 2006, but HC use increased from 1.1% in 1997 to a peak of 6.5% in 2006. The median age at initiation of DEX use increased >2 weeks from 1997 to 2006. BPD rates increased from 19% in 1997 to 25% by 2006. Rates for severe BPD (defined by positive pressure support) also increased significantly over time. Between 23 and 28 weeks, there was a significant increase in BPD rates associated with the decrease in DEX over time.
CONCLUSIONS: Steroid use and preference have changed significantly over the past decade. Decreased use of DEX was associated with increased rates of BPD, any or severe, among very preterm infants. Well-designed, randomized, noncrossover trials with long-term outcome analysis of high-risk infants are needed.
Postnatal steroids for prevention and/or treatment of bronchopulmonary dysplasia (BPD) have been used for many years, with increasing use noted during the 1990s.1 Dexamethasone, the most commonly used drug, was often administered in very high doses over several weeks. Several meta-analyses suggested decreased rates of BPD with dexamethasone use, with greater effect at earlier ages of therapeutic intervention.2–4 Subsequent concerns over adverse effects on later neurodevelopmental outcome contributed to the recommendation in 2002 by the American Academy of Pediatrics and the Canadian Paediatric Society against routine systemic dexamethasone use for the prevention or treatment of BPD in preterm infants.5,6
Two follow-up reports noted a significant reduction in the use of postnatal steroids after the consensus statements.1,7 More recently, a report from Israel noted that decreased use of postnatal steroids was temporally associated with a significant increase in the rate of BPD at 36 weeks' corrected age.8 The data reported to date are not clear on the type of steroid used, the pattern of use of different steroids by gestational and postnatal age, and the association of steroid use on subsequent BPD rates in the larger clinical community. We conducted a retrospective review of postnatal steroid use, including dexamethasone and hydrocortisone, over a 10-year period among preterm infants ≤32 weeks' gestation from a large clinical practice group and examined the association of postnatal steroid use and BPD rates over time.
Data for this retrospective study were obtained in a deidentified manner from the Pediatrix Medical Group electronic data warehouse. Data within this warehouse are generated from each practice NICU using admission, discharge, and daily progress notes created by patient providers. Each day's progress note includes information on a number of variables, including the patient's examination, nutrition, respiratory support, medications, and diagnoses. This data warehouse is managed compliant with regulations of the Health Insurance and Portability Accountability Act of 1996.
We queried the Pediatrix Medical Group data warehouse for all of the infants with a gestational age of 23 to 32 weeks and admitted between January 1, 1997, and December 31, 2006. Data for the following variables were extracted from the warehouse: year of birth, gestation, birth weight, gender, maternal race, use of antenatal steroids, delivery mode, Apgar scores, discharge status, date of discharge, initial ventilator support, surfactant therapy, respiratory support at discharge, any use of dexamethasone or hydrocortisone during hospitalization, and the postnatal age first treated. Because of the method for recording medications in the warehouse database, the dose and duration of each medication were not available. We excluded all of the infants with major congenital malformations (neurologic, pulmonary, cardiac, abdominal, or chromosomal) and analyzed outcomes on the basis of survival to ≥28 days of age. The definition of BPD varies between units and can be altered by the application of a specific approach to diagnosis.9 In the Pediatrix Medical Group deidentified data set, the degree of support and fractional inspired oxygen levels are collected daily while the patient remains in the hospital. For this article, we defined BPD as the use of supplemental oxygen at 36 weeks' postmenstrual age in hospitalized infants or discharge to home on use of supplemental oxygen before 36 weeks. In addition, we defined severe BPD by the use of any form of positive pressure respiratory support (including ventilator, continuous positive airway pressure, or high-flow nasal cannula) at 36 weeks' postmenstrual age or on discharge to the home.8
We compared the use of dexamethasone and hydrocortisone, as well as the diagnosis of BPD and severe BPD, according to birth year and gestational age. By Mantel-Haenszel χ2 test, we analyzed the association of BPD and severe BPD with use of either of the 2 steroids by birth epoch, with the epochs defined as follows: era 1 was 1997–1999, era 2 was 2000–2003, and era 3 was 2004–2006. These time epochs were derived based around the development and dissemination in 2001–2002 of the combined statement on postnatal corticosteroid use in preterm infants by the American Academy of Pediatrics and the Canadian Paediatric Society.5,6 To facilitate analysis, infants born at 23 and 24 weeks' gestation were combined into a single group. Continuous data are presented as mean with SD unless otherwise noted. Continuous variables were analyzed by 1-way analysis of variance or Kruskal-Wallis test to look for differences between groups and over time. Categorical variables were analyzed by 2-tailed χ2 and Fisher's exact tests. Data were analyzed by using SPSS 14.0 (SPSS Inc, Chicago, IL). Given the very large data set and the performance of multiple analyses, a P value of <.01 was required for significance. Before analysis, approval was granted by the institutional review boards of the University of Utah and the Pediatrix Medical Group.
In the data warehouse, we identified 96813 infants from 243 NICUs during the 10-year study period. There was a significant increase in the number of infants in the data set over time, but the relative proportion of births, the overall mortality rate, and the mortality rate according to gestation remained unchanged over the same time period. (Fig 1) We subsequently excluded 19392 infants from analysis as follows: 4043 for major anomalies, 6040 for death before 28 days, and 9209 for missing data at 36 weeks' postmenstrual age. Demographic features of the final study population (N = 77520) according to year-group intervals are shown in Table 1. There were no differences over time in gestation, birth weight, or male gender, but a significant increase was found for the percentage treated with antenatal steroids and surfactant, born by cesarean delivery, and with maternal black race. The percentage of infants with ventilator support on day 1 of life significantly decreased over time, and this pattern was consistently found at each gestational age (data not shown according to gestation).
As seen in Fig 2, at each gestational age, dexamethasone use significantly decreased and hydrocortisone use significantly increased over time. Overall, dexamethasone use decreased nearly fourfold from a peak of 25.0% in 1998 to a minimum of 6.8% in 2005 and 2006. Among infants <27 weeks' gestation, dexamethasone use decreased from 74.0% in 1997–1999 to 30.0% in 2004–2006. Overall, hydrocortisone use increased more than sixfold from a low of 1.0% in 1997 to a peak of 6.5% in 2005. Among infants <27 weeks' gestation, hydrocortisone use increased from 13.0% in 1997–1999 to 29.0% in 2004–2006. Combined use of both steroids in the same infant was relatively stable over the years, ranging between 2.0% and 3.0%.
Table 2 shows the rates for BPD and severe BPD according to gestation at birth and the birth-year time epoch. The rates of BPD and severe BPD significantly increased over time. Significant differences in BPD were noted for infants born at ≤28 weeks' gestation and for severe BPD within all of the gestational groups. Multivariable logistic regression analysis (adjusted for maternal race, antenatal steroid therapy, multiple gestation, mode of delivery, and male gender) revealed a significantly increased risk for BPD and severe BPD in the birth years 2000–2003 and 2004–2006 compared with 1997–1999 (for BPD, odds ratio [OR]: 1.25 [95% confidence interval (CI): 1.18–1.32] and 1.34 [95% CI: 1.27–1.42], respectively; for severe BPD, OR: 1.45 [95% CI: 1.29–1.63] and 2.76 [95% CI: 2.47–3.00], respectively).
The changes over time in dexamethasone administration and BPD rates for infants born at 24 to 28 weeks' gestation are shown in Fig 3. At each gestational age, the time-related increase in BPD is inversely related to the decreasing dexamethasone use. In comparing 1997–1999 with 2004–2006, the overall effect of this association was to increase BPD rates in the latter time period by the equivalent of 1 full week younger gestation (Table 2).
The pattern of postnatal steroid administration also significantly changed over time. The median age at initiation of dexamethasone in 1997–1999 was 13 days compared with 22 days in 2000–2003 and 33 days in 2004–2006 (P < .001). The median age at initiation of hydrocortisone also increased significantly over time (P < .005). Table 3 compares the median (25%–75%) age at initiation of dexamethasone and hydrocortisone according to gestational age and birth-year epoch.
In this retrospective analysis of a large national neonatal database, we found a significant change in the pattern of postnatal steroid use over a 10-year period centered around joint consensus statements recommending against the use of dexamethasone for prevention or treatment of BPD.5,6 Similar to the report by Walsh et al,1 we found that postnatal steroid use peaked 3 to 4 years before publication of the consensus statements. The decline in dexamethasone use was greatest in the years before publication of the consensus statements and has decreased little since then. Unlike the data available to Walsh et al,1 we were able to differentiate the specific steroid given. Although dexamethasone use declined, there was a concomitant increase in the use of hydrocortisone over the same time period, with hydrocortisone use exceeding dexamethasone by 2004. The increasing use of hydrocortisone in contrast to dexamethasone is similar to the data reported from the California Perinatal Quality Care Collaborative by Finer et al.7
It is important to note that, although overall steroid use in this population decreased from ∼25% in 1998 to <7% in 2006, there was still frequent use of postnatal steroids among infants at the lowest gestational ages. Thus, >40% of infants born at 24 weeks and ∼30% of infants born at 25 weeks continued to receive dexamethasone in 2004–2006; if the use of either dexamethasone or hydrocortisone was considered, the rates were 65% and 31%, respectively. Thus, infants at the highest risk for adverse pulmonary and neurodevelopmental outcomes continue to have relatively high exposure to postnatal steroids.
We did not have data on the duration of or the indications for steroid use, but our finding that hydrocortisone was primarily used early in life and dexamethasone later in life was similar to that noted by Finer et al.7 In addition, we noted a significant shift over time in the pattern of steroid use, with the median age at initiation of dexamethasone therapy increasing by ∼3 weeks. This shift is in line with the suggestion by meta-analyses that delayed steroid therapy may have equivalent pulmonary benefit but lower neurologic risk than very early treatment.2,3,10 Because of the limited data or time span involved with each study, neither Walsh et al1 nor Finer et al7 could analyze the relationship between steroid use and BPD rates over time.
Authors of a recent report from Israel analyzed this relationship.8 Similar to our findings, they reported a significant decrease in the overall use of postnatal steroids from 1997 through 2004. Despite some differences in study population design, the reported rates of steroid use in their study were very similar to those that we found, although they did not differentiate the type or age at initiation of steroid therapy. Also similar to our findings, Shinwell et al8 found an association between decreasing steroid use and increasing BPD rates over time. Our finding of increased BPD rates occurred despite some time-related differences in demographics or treatment that might favor lower BPD rates. These included increased antenatal steroid use, increased surfactant administration, and decreased use of mechanical ventilation on the first day of life. As expected, the risk for BPD increased markedly as gestation decreased. An important finding of this study, compared with previous reports, is the differentiation of steroid use and the subsequent associated effect on BPD rates (any and severe) according to gestational age at birth. The rates for any BPD and for severe BPD were much higher in the last time epoch when postnatal steroid therapy was lowest. When closely analyzed, these data suggest that the potential impact of reduced postnatal steroid use on BPD may be greater as gestational age decreases. For example, among infants born at <27 weeks' gestation, at each week of gestation, the rate of BPD in time epoch 3 approximated that in time epoch 1 of an infant 2 weeks younger. That is, the rate for BPD of a 26-week infant in 2004–2006 was equivalent to that of a 24-week infant in 1997–1999. The effect was even greater for severe BPD, with an approximated shift of 3 weeks. As gestational age increased above 26 weeks, the shift in BPD rates between time epochs diminished to the point that, above 29 weeks, the rate for severe BPD resulted in only a 1-week difference in gestation, and the rate for any BPD equated to an increase <1 week.
There are important limitations to this study. Similar to previous such reports, this was a retrospective observational study. Although the data set is very large, national in distribution, and linked to daily clinical progress notes, the reported associations cannot determine causation. In addition, ∼10% of the patients from this very large data set were excluded from analysis because of missing data, which introduces a potential selection bias. Because of the nature of the available database, we were unable to determine indications for postnatal steroid use, the initial or total dose of steroid provided, the duration of treatment, or any associated short-term effects. Rates of BPD were determined by the continued use of oxygen supplementation at 36 weeks' corrected age, but there was no systematic approach to determine the absolute need for oxygen supplements. Such an approach can alter the rate for diagnosis of BPD.9 This limitation is diminished by defining severe BPD with the more objective end point of positive pressure support. Finally, our report does not address the important issues related to long-term neurologic function.
Postnatal steroids have been used in the management of BPD for at least the past 25 years.11 A variety of approaches and steroids have been used, with a general consensus that they are associated with a short-term pulmonary benefit.2,3,10 The effect of postnatal steroids on long-term outcome, especially neurodevelopmental, remains a major concern.5,6,12–14 The majority of studies involving postnatal steroid use are scientifically flawed by the presence of crossover drug use. This flaw does not preclude the importance of this concern in the meta-analyses that have been performed, as evidenced by the consensus statements against routine postnatal steroid use from all of the major pediatric organizations. This concern is emphasized by the recent report from Yeh et al,14 finding significantly increased adverse neurodevelopmental outcomes among infants exposed to high-dose early dexamethasone therapy. Although there was some crossover steroid use in their placebo group, it was low and short-term. In contrast are the findings by O'Shea et al,15 who performed the only recent large trial (and large is relative, with a total enrollment of 118 infants) with adequate long-term follow-up and without crossover drug contamination. In long-term follow-up, they have reported improved pulmonary function with dexamethasone therapy of ventilator-dependent preterm infants initiated between 15 and 25 days age, with no difference in later growth or blood pressure and with similar composite outcome of death or major neurodevelopmental impairment.16–18 Other recent reports suggest that there may be a benefit to postnatal steroid use depending on the type of steroid, the dosing algorithm, and the target population.10,19–22 Although the use of postnatal steroids has dramatically decreased over the past 10 years and despite admonitions against their routine use in preterm infants, the highest-risk infants continue to receive postnatal steroids frequently.
The American Academy of Pediatrics and the Canadian Paediatric Society consensus statements recommended the development of well-designed randomized, placebo-controlled trials to further evaluate the long-term pulmonary and neurologic benefits and risks of postnatal steroid use in high-risk infants.5,6 Since the publication of the consensus statements, only 1 single-center trial involving postnatal steroid use in very preterm infants has been registered on clinicaltrials.gov. Additional trials are needed, with careful thought to the type of steroid, the dose and duration, the timing of intervention, the specific population with the greatest potential benefit/risk ratio, and with a prohibition of crossover drug use.23 Failure to do so will only continue to contribute to the ongoing use of these potent and potentially harmful drugs in an uncontrolled manner.24
Steroid use and preference have dramatically changed over the past decade. Decreased use of dexamethasone was associated with increased rates of BPD among very preterm infants, without an effect on overall mortality. Despite recommendations to the contrary, significant numbers of immature infants continue to be treated with postnatal steroids, and the treatment algorithm seems to be changing. We wish to emphasize that our study does not support an increased use of postnatal steroids but rather the development of well-designed, randomized, controlled noncrossover trials to better define the potential benefits and risks of these potent drugs in this vulnerable population.
- Accepted December 11, 2008.
- Address correspondence to Bradley A. Yoder, MD, University of Utah School of Medicine, Department of Pediatrics, PO Box 581289, Salt Lake City, UT 84158-1289. E-mail:
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject:
Postnatal steroids decrease BPD rates but have been associated with increased adverse neurological outcome. American Academy of Pediatrics and Canadian Paediatric Society consensus statements have led to decreased use of postnatal steroids, but the effect on BPD rates is unclear.
What This Study Adds:
Overall postnatal steroid use has fallen, but relatively high use continues among the most immature infants. Decreased steroid use was associated with increased BPD rates among infants <29 weeks' gestation.
- ↵Walsh MC, Yao Q, Horbar JD, Carpenter JH, Lee SK, Ohlsson A. Changes in the use of postnatal steroids for bronchopulmonary dysplasia in 3 large neonatal networks. Pediatrics.2006;118 (5). Available at: www.pediatrics.org/cgi/content/full/118/5/e1328
- ↵Halliday H, Ehrenkranz R, Doyle L. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev.2003;(1):CD001146
- ↵Halliday H, Ehrenkranz R, Doyle L. Delayed (> 3 weeks) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev.2003;(1):CD001145
- ↵Halliday H, Ehrenkranz R, Doyle L. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev.2003;(1):CD001144
- ↵American Academy of Pediatrics, Committee on Fetus and Newborn. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics.2002;109 (2):330– 338
- ↵Finer NN, Powers RJ, Ou CS, et al. Prospective evaluation of postnatal steroid administration: a 1-year experience from the California Perinatal Quality Care Collaborative. Pediatrics.2006;117 (3):704– 713
- ↵Shinwell E, Lerner-Geva L, Lusky A, Reichman B. Less postnatal steroids, more bronchopulmonary dysplasia: a population-based study in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed.2007;92 (1):F30– F33
- ↵Walsh MC, Yao Q, Gettner P, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics.2004;114 (5):1305– s1311
- Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC. Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics.2005;115 (3):655– 661
- ↵O'Shea TM, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics.1999;104 (1 pt 1):15– 21
- O'Shea TM, Washburn LK, Nixon PA, Goldstein DJ. Follow-up of a randomized, placebo-controlled trial of dexamethasone to decrease the duration of ventilator dependency in very low birth weight infants: neurodevelopmental outcomes at 4 to 11 years of age. Pediatrics.2007;120 (3):594– 602
- ↵Washburn LK, Nixon PA, O'Shea TM. Follow-up of a randomized, placebo-controlled trial of postnatal dexamethasone: blood pressure and anthropometric measurements at school age. Pediatrics.2006;118 (4):1592– 1599
- ↵Doyle LW, Davis PG, Morley CJ, McPhee A, Carlin JB; DART Study Investigators. Outcome at 2 years of age of infants from the DART Study: a multicenter, international, randomized, controlled trial of low-dose dexamethasone. Pediatrics.2007;119 (4):716– 721
- Watterberg KL, Shaffer ML, Mishefske MJ, et al. Growth and neurodevelopmental outcomes after early low-dose hydrocortisone treatment in extremely low birth weight infants. Pediatrics.2007;120 (1):40– 48
- ↵McEvoy C, Bowling S, Williamson K, McGaw P, Durand M. Randomized, double-blinded trial of low-dose dexamethasone: II. Functional residual capacity and pulmonary outcome in very low birth weight infants at risk for bronchopulmonary dysplasia. Pediatr Pulmonol.2004;38 (1):55– 63
- ↵Bose CL, Laughon MM. Corticosteroids and chronic lung disease: time for another randomized, controlled trial? Pediatrics.2005;115 (3):794
- ↵Bhandari A, Schramm CM, Kimble C, Pappagallo M, Hussain N. Effect of a short course of prednisolone in infants with oxygen-dependent bronchopulmonary dysplasia. Pediatrics.2008;121 (2). Available at: www.pediatrics.org/cgi/content/full/121/2/e344
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