PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1032-e1038 (doi:10.1542/peds.2007-2608)
ARTICLE |
Decreased Respiratory Compliance in Infants Less Than or Equal to 32 Weeks' Gestation, Delivered More Than 7 Days After Antenatal Steroid Therapy
a Division of Neonatology, Department of Pediatrics
b Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon
c Division of Neonatal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Our objective was to compare the pulmonary function (respiratory compliance) of infants who were
32 weeks' gestation and delivered >7 days after a single course of antenatal steroids versus infants who were delivered 1 to 7 days after a single course of antenatal steroids.
METHODS. A prospective cohort study of respiratory system compliance was conducted of infants 32 weeks' gestation within 72 hours of life and before surfactant therapy if needed. The study (remote) group was composed of infants who were treated with antenatal steroids >7 days before delivery and the comparison group (ideal group) of matched infants who were treated with antenatal steroids 1 to 7 days before delivery. Respiratory system compliance was measured with the single-breath occlusion technique.
RESULTS. Twenty-eight remotely treated infants and 28 ideally treated infants were studied. The remote group had a significantly lower respiratory system compliance per kilogram and total respiratory system compliance when compared with the ideal antenatal steroids group. Within the remote group, infants who received antenatal steroids 8 to 14 days (n = 10) before delivery had a significantly higher respiratory system compliance and a trend to less surfactant need (10% vs 33%) as compared with infants who received antenatal steroids >14 days (n = 18) before delivery.
CONCLUSIONS. Infants who were 32 weeks' gestation and remotely treated with antenatal steroids (average 21 days) had a significantly lower respiratory compliance compared with matched infants who were ideally treated with antenatal steroids. We speculate that the lower respiratory system compliance may reflect the dissipation of beneficial effects of antenatal steroids on pulmonary function when delivery occurs >7 days after therapy and particularly when therapy is >14 days before delivery.
Key Words: antenatal corticosteroids • betamethasone • premature infants • pulmonary function • respiratory compliance
Abbreviations: AS—antenatal steroids • RDS—respiratory distress syndrome • Crs—passive respiratory system compliance • CPAP—continuous positive airway pressure • PFT—pulmonary function test • CI—confidence interval
A single course of antenatal steroids (AS) remains the standard of care for the pregnant woman who is at risk for preterm delivery between 24 and 34 weeks' gestation.1,2 AS therapy accelerates the structural and biochemical maturation of the fetal lung, thereby decreasing the incidence of respiratory distress syndrome (RDS) in treated preterm infants.1–3 Studies in humans and animal models have shown significant improvements in measurements of pulmonary function (respiratory compliance and lung volumes) after dosing with AS.4–6
Despite its long history of use, the duration of the clinical and/or pulmonary benefit of a single course of AS is unknown and central to the question of a repeat course of AS during pregnancy. There is evidence that the optimal response to AS occurs when dosing is at least 24 hours and <7 days before delivery.1,2 Unfortunately, many preterm deliveries occur outside this "ideal treatment window." Recent randomized clinical data suggested that repeat treatment with AS for infants (<32 weeks' gestation) who are at continued risk for preterm delivery and >7 days from initial treatment may reduce the severity of neonatal lung disease7; however, there are insufficient data on the relative risks and benefits of repeated courses of AS.8,9
We have used pulmonary function testing as an objective and reproducible way of quantifying the effect of AS on passive respiratory system compliance (Crs).4,10 We previously reported a 50% increase in Crs in preterm infants who were treated with a single course of AS, 1 to 7 days before delivery, versus matched untreated infants.4 The objective of this study was to quantify and compare the Crs of infants who were 32 weeks' gestation and delivered >7 days after a single course of AS versus matched infants who were delivering "ideally" (ie, 1–7 days after a single course of AS). We hypothesized that infants who were delivered >7 days after treatment would have a significantly decreased Crs when compared with infants who had received a single course of AS within 7 days of delivery.
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METHODS |
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Eligibility Criteria
This prospective trial was conducted at the NICU at Oregon Health and Science University (Portland, OR). The study was reviewed and approved by the institutional review board at our institution, and informed consent was obtained for each enrolled patient. We prospectively studied infants who met the following inclusion criteria: (1) gestational age of 25 to 32 weeks, (2) birth weight of
2000 g, (3) appropriate for gestational age, (4) pulmonary function tests (PFTs) performed within 72 hours of age but before surfactant therapy if required, and (5) informed consent from parents. The study group, labeled as the remote AS group, was defined as infants who met these criteria and received a course of AS (two 12-mg doses of betamethasone intramuscularly every 24 hours) >7 days before delivery. The comparison group, labeled as the ideal AS group, were infants who were matched to the remote group for gestational age, birth weight, race, and gender but who received a course of AS 1 to 7 days before delivery. We excluded infants who were delivered to mothers with insulin-dependent diabetes, mothers with clinical chorioamnionitis, or drug-addicted mothers and infants with multiple congenital anomalies or chromosomal abnormalities. Infants who were delivered after incomplete or multiple courses of betamethasone were also excluded.
Study Design
A prospective cohort study design was used. Infants were studied in the supine position while quietly asleep. Pulmonary function was measured within 72 hours of age and before surfactant (rescue) administration when it was needed. Surfactant was given when the infant required >30% oxygen when ventilated with pressures giving tidal volumes of 5 to 7 mL/kg. Comparison of Crs between the 2 groups was our primary end point. Other pertinent clinical outcome measures between the 2 groups were also monitored. Neither muscle relaxants nor sedation was used during the study period.
Measurements
Respiratory mechanics were measured with a computerized infant pulmonary function cart (SensorMedics 2600; SensorMedics Inc, Yorba Linda, CA). Crs was obtained with the single-breath occlusion technique.4,11–13 These measurements can be performed on intubated and nonintubated infants, as previously reported.4,10 In ventilated patients, testing was performed by connecting the infant's endotracheal tube into the system via a 3-way valve that also connected to the ventilator. In nonintubated patients, the infants breathed through a face mask that was connected to the 3-way valve.
For the single-breath occlusion technique,4,11–13 the airway was briefly occluded at end inspiration until an airway pressure plateau was observed and the Hering Breuer reflex was invoked. The linear portion of the passive flow-volume curve was identified, and a regression line was drawn to obtain the best fit. From the intercepts on the flow and volume axes, Crs and resistance were calculated. Acceptance criteria included (1) stable end expiratory baseline; (2) plateau pressure lasting >100 milliseconds; (3) plateau pressure varying by ± 0.125 cmH2O or less; (4) acceptable flow-volume curve by visual inspection, with linear data segment identified; and (5) at least 10 breaths accepted with a coefficient of variation of <20%.14 Clinical outcome parameters including surfactant administration, days on mechanical ventilation, days on continuous positive airway pressure (CPAP), and days on supplemental oxygen, were also monitored.
Statistical Methods
We have reported a 50% increase in Crs in preterm infants who were treated with a single course of AS 1 to 7 days before delivery when compared with matched untreated infants.4 We have also conducted a prospective, randomized trial in which larger preterm infants who had not been delivered 1 week after their initial course of AS were randomly assigned to either weekly courses of AS or weekly courses of placebo until delivery or 34 weeks' gestation.10 The infants who were randomly assigned to placebo were delivered an average of 24 days after AS dosing (range: 7.5–55.0 days) and had Crs measurements that were on average 20% lower than those for infants who were randomly assigned to weekly courses of AS; however, these measurements were not significantly different, perhaps as a result of small sample size, because the study was stopped early because of concerns of possible adverse effects of weekly AS therapy.
For this study, we hypothesized that matched preterm infants (32 weeks' gestational age) who were treated with AS >7 days before delivery would have a significantly lower Crs than those who were treated with a course of AS 1 to 7 days before delivery. We estimated that to show at least a 30% difference in Crs between the groups, we would need to study 
25 patients in each group to reject the null hypothesis with a type I error of .05 and a power of 80%.
Differences in continuous variables including respiratory compliance between the 2 groups were analyzed by 2-tailed, Student's t tests, Mann-Whitney U test, and Wilcoxon signed ranks test were used where appropriate (for data not normally distributed).15 Categorical variables were evaluated with 
2 tests for paired and unpaired data and Fisher's exact test where appropriate. Data are expressed as means ± SD, unless otherwise indicated.
Mixed linear modeling16 was used to compare respiratory compliance per kilogram in the remote and ideally treated groups. This approach incorporates the matched design of the study, allowing for correlation between observations on the matched infants. It also allows for adjustment for additional covariates. We matched 28 infants in the remote AS group as closely as possible to 28 infants in the ideal AS group on the basis of gestational age at delivery, birth weight, race, and gender. Potential confounders included in the analyses were multiple gestation, mode of delivery, maternal age, maternal smoking history, mechanical ventilation at the time of PFT, and CPAP history for the infant. We used SPSS 15 for Windows (Chicago, IL) and SAS 9.1.3 (SAS Institute Inc, Cary, NC) for analyses.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients for this study were recruited from July 2004 through October 2005. We studied a total of 56 infants, 28 in the remote group and 28 matched infants in the ideally treated AS group. Maternal and infant characteristics were comparable between the 2 groups (Table 1). Both study groups were
1500 g and 30.5 weeks' gestation at birth, with a similar percentage of girls and white infants in each group. There was no significant difference in fraction of inspired oxygen, need for mechanical ventilation, or postnatal age at time of PFT between the 2 groups (Table 2). PFTs were performed at a median age of 28 hours in the remote group and 33.5 hours in the ideal AS group (not significant). The infants in the remote AS group were delivered an average of 21 ± 10 days (range: 8–37 days) after dosing with AS.
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The infants who were delivered >7 days after AS therapy had significantly lower measurements of total Crs and Crs normalized per weight than infants who were delivered 1 to 7 days after AS therapy: 1.52 mL/cmH2O versus 2.12 mL/cmH2O (95% confidence interval [CI]: 0.20–0.99; P = .005) and 0.98 mL/cmH2O per kg versus 1.41 mL/cmH2O per kg (95% CI: 0.19–0.67; P = .001; Figs 1 and 2).
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Although not 1 of the primary outcome variables of our study, there was no significant difference in surfactant administration between the groups; however, the infants who were remotely treated with AS did spend significantly more days on mechanical ventilation and on oxygen supplementation than those in the ideal AS group (P < .05; Table 2). From the total study population, only 1 patient in the remotely treated group died.
To evaluate further the relationship of the interval between dosing with AS and delivery and subsequent Crs, we then did a posthoc analysis of the infants in the remote AS group. We compared those who were delivered 8 to 14 days (n = 10) after AS therapy with those who were delivered >14 days after AS therapy (n = 18). There were no significant differences in birth weight, gestational age, race, gender, or fraction of inspired oxygen at the time of pulmonary function testing (Table 3). Although there was no significant difference in surfactant therapy between these 2 groups, 1 of 10 of the infants who were delivered 8 to 14 days after AS therapy required surfactant versus 6 of 18 infants who were delivered >14 days after AS therapy (Table 3). The infants who were delivered >14 days after AS therapy had a significantly lower Crs than those who were delivered 8 to 14 days after AS therapy (0.82 mL/cmH2O per kg vs 1.29 mL/cmH2O per kg; P < .05; Fig 3).
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As expected, mixed linear modeling showed that variables used in matching, gestational age, birth weight, race, or gender were not statistically significant when added to the model that contained only treatment group. Similarly, multiple gestation, mode of delivery, maternal age, maternal smoking, mechanical ventilation (intermittent mandatory ventilation), and CPAP were not statistically significant when added to the model, and the addition of these covariates had no significant effect on the effect size of AS treatment timing on respiratory compliance (Table 4). The estimated difference in Crs between the ideal and remotely treated groups ranged from 0.41 to 0.44 when adjusting for multiple gestation, mode of delivery, maternal age and CPAP. Adjusting for maternal smoking, although itself nonsignificant, resulted in a larger estimate of the mean Crs difference (from 0.43 to 0.49) between the treatments groups, whereas adjusting for intermittent mandatory ventilation, again nonsignificant, resulted in a somewhat smaller estimate of the mean Crs difference (from 0.43 to 0.36; Table 4). There was also a significant difference in the Crs measurements between infants who were treated with AS 1 to 7 days, 8 to 14 days, and >14 days before delivery, when analyzed by mixed linear models (P = .001; P < .001 for infants who were treated 1 to 7 days versus >14 days, and P < .05 for infants treated 8 to 14 days versus >14 days before delivery, respectively); however, there was no significant difference in Crs for infants who were treated 1 to 7 days versus 8 to 14 days before delivery.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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With the 2000 National Institutes of Health recommendation that repeat courses of AS be given only within a research protocol,8 an increasing number of preterm infants are being delivered >7 days after AS therapy. In this study, we showed that infants who were
32 weeks' gestation and treated with a course of AS >7 days before delivery (remotely treated, mean of 21 days before delivery) had a significantly lower Crs than matched infants who were delivered within 7 days of AS treatment. In addition, within the remotely treated group of infants, those who were delivered >14 days after AS therapy demonstrated an even lower Crs than infants who were ideally treated with AS or those who were treated with AS 8 to 14 days before delivery.
Our findings are consistent with our previous study of larger preterm infants, 35 weeks' gestation at birth, that showed that infants who were treated with multiple courses of AS (with delivery within 7 days of therapy) had improved respiratory compliance compared with untreated as well as remotely treated infants,11 suggesting that the enzyme system responsible for surfactant production can be repetitively induced despite previous treatment with AS. Measurements of pulmonary function have been used to quantify the newborn infant's response to various therapeutic interventions,17,18 including surfactant administration13,19 and antenatal corticosteroid therapy4,10,11 in preterm infants. A single course of AS significantly improved respiratory mechanics, and these changes correlated well with improved clinical outcome in preterm infants1,4; however, the duration of the clinical effect of a single course of betamethasone (given within 7 days versus >7 days before delivery) on respiratory mechanics in very preterm infants (32 weeks' gestation) has not been evaluated in previous studies.
Two large, randomized, controlled trials of repeat weekly courses of AS versus a single course of AS followed by placebo7,20 showed repeat courses of AS (24 mg of betamethasone) to have pulmonary benefits, particularly in very preterm infants (<32 weeks and <28 weeks' gestation, respectively). The trial by Guinn et al20 randomly assigned a total of 502 patients and found no significant difference in the primary outcome of composite morbidity; however, it did demonstrate a significant decrease in severe RDS at 15.3% in the repeat group versus 24.1% in the remote group (P = .01).20 Infants who were born at <28 weeks' gestation also had a significant decrease in composite morbidity after repetitive therapy (P = .03).
The National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network recently reported a randomized trial in which women who were at risk for preterm delivery and had not delivered 1 week after an initial course of AS were randomly assigned to weekly courses of betamethasone (n = 252) or placebo (n = 243).7 There was no difference in the primary outcome (composite morbidity) between the 2 groups, but of the infants who were delivered at <32 weeks, there was a trend for reduction in the primary outcome, which was a composite of perinatal death, severe RDS, grades 3 to 4 intraventricular hemorrhage, periventricular leukomalacia, or chronic lung disease after repeat steroids versus placebo (23.3% vs 38.5%; P = .08). In the entire cohort, there was also a significant difference in a number of the pulmonary outcomes between the 2 groups, with the repeat AS group needing less surfactant therapy (11.6% vs 19.0%; P = .02) and less mechanical ventilation (14.4% vs 24.8%; P = .004). These differences in pulmonary outcomes were even more significant for infants who were delivered at <32 weeks' gestation. There was no significant difference in average birth weight or head circumference overall, but infants who received 
4 courses of AS had a significantly lower birth weight (P = .01).7 This study concluded that routine weekly courses of AS to all women who are at high risk for preterm birth cannot be justified (77% of the pregnancies eligible for repetitive AS delivered at 32 weeks). This study also concluded that additional investigation of limited repeated steroid therapy for women who are at high risk for early preterm birth is warranted.7
Two recent studies using 11.4 mg21 and 12 mg22 of betamethasone (instead of 24 mg) after an initial course of AS reported conflicting results. Peltoniemi et al22 showed no difference in the primary outcome (survival without RDS or severe intraventricular hemorrhage) between patients who received a single dose of betamethasone (12 mg) versus placebo. Posthoc analysis showed a tendency for increased risk for RDS and decreased intact survival rates for infants who were delivered within 1 to 24 hours in the AS group, whereas the opposite trend was observed for infants who were delivered at 24 hours after AS. In that study, 79% of the population was born within 24 hours after the intervention.22 In the other randomized, multicenter trial, 982 women who were at risk for preterm birth 7 or more days after an initial course of AS were randomly assigned to receive weekly doses of betamethasone (11.4 mg) or placebo.21 That study documented that exposure to repeat doses of AS decreased the primary outcomes of the study, including neonatal RDS (P = .01) and severe lung disease (P = .0003), when compared with the placebo group. Mean weight, length, and head circumference at birth and hospital discharge did not differ between the groups. Z scores for weight (P = .04) and head circumference (P = .03) at birth were lower for infants who received repeat AS, but at hospital discharge, z scores were not different between both groups.21 Consistent with other studies,7,20 35% of infants in the 2 groups were delivered at 34 weeks. The authors concluded that there is evidence of short-term benefit of repeat doses of AS in reducing neonatal lung disease and had planned a follow-up of the infants at 2 years of corrected age21; however, at present, the appropriate number and timing of repeat courses, the clinical balance between risks and benefits, and the ideal gestational age for therapy are still uncertain and are being investigated in randomized trials in the United States and Canada.23,24
Our study was not randomized; therefore, a causal relationship between the timing of AS administration and changes in Crs cannot be established. Maternal factors and events surrounding delivery can stimulate the secretion of endogenous steroids and affect the measurement of pulmonary function in newborns. We limited potential confounding factors by matching the patients by gestational age, birth weight, gender, and race. In addition, our pulmonary function findings were adjusted for possible confounding by multiple gestation, mode of delivery, maternal age, maternal smoking, mechanical ventilation, and CPAP. Infants who were delivered >7 days after AS therapy may have had different underlying mechanisms of preterm birth than those of infants who were delivered within 7 days of therapy.25 These underlying mechanisms may also affect their lung maturation and therefore subsequent pulmonary function. Because our patients were 1500 g and 30.5 weeks' gestation at birth, our findings may not apply to an exclusive population of extremely low birth weight (<1000 g) infants. Our sample size did not have the power to detect differences in clinical outcome measures because it was based on changes in respiratory compliance as the primary end point. Finally, for infants who require mechanical ventilation the level of positive end-expiratory pressure can affect measurements of Crs; however, all of our patients were studied on a physiologic positive end-expiratory pressure of 4 cmH2O.
We found that infants who were remotely treated with AS demonstrated a lower Crs, particularly when therapy was >14 days before delivery. This could be attributable to decreased responsiveness of the fetal lung at this early gestational age. A randomized trial by Garite et al26 of a single course of AS versus placebo showed no significant pulmonary benefit (but a significant reduction in severe intraventricular hemorrhage) for infants 24 to 28 weeks' gestation; however, Crowley's2 meta-analysis demonstrated that AS therapy was effective in reducing pulmonary morbidity down to gestations as low as 24 weeks. We speculate that the lower Crs demonstrated by the remotely treated group in our study may reflect the dissipation of the beneficial effects of AS on pulmonary function, if delivery occurs >7 days after therapy and particularly if therapy is >14 days before delivery. This is supported by in vitro studies with human lung explants showing that the biochemical effects of AS begin to decrease after 7 days if AS is removed.27
It has been difficult to define the duration of the clinical/pulmonary effect of a single course of AS, but data from randomized trials seem to indicate that it may decrease after 7 to 14 days.1,2 A recent meta-analysis examined 7 trials involving 862 infants, 434 who were born to women who were treated with AS >7 days before delivery versus 428 who were born to control (untreated) women.25 The infants who were treated >7 days before delivery had no reduction in the risk for RDS (relative risk: 0.72; 95% CI: 0.49–1.07).25 In the last trial to randomly assign patients to a single course of AS versus placebo, the investigators did not find a significant difference in pulmonary outcomes for infants who received AS 7 days or 14 days before delivery.28 The posthoc analysis of the thyrotropin-releasing hormone trial also did not find a decrease in the pulmonary benefits of a course of AS when given up to 14 days before delivery.9 Our study supports an evidence-based decision analysis evaluating a number of dosing regimens of AS, as described by Caughey and Parer.29 In that study, the benefits from AS were maximized in terms of decreasing cases of RDS and risks minimized with a single repeat course of AS at a 2-week interval after the first course of therapy with AS.29
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Infants who were
32 weeks' gestation and remotely treated with a course of AS had a significantly lower Crs when compared with matched infants who were "ideally" treated with a course of AS (betamethasone). We speculate that if treatment with a course of AS has occurred >14 days before delivery in selected infants who are <32 weeks' gestation, then a second course (24-mg rescue course) may improve pulmonary function. This should be studied in a randomized, controlled trial in a selected group of patients at highest risk, and the risks and benefits including long-term pulmonary, growth, and neurodevelopmental outcomes must be closely monitored.
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ACKNOWLEDGMENTS |
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This study was supported in part by Oregon Health and Science University, General Clinical Research Center/Public Health Service grant 5 M01 RR000334 and by the American Lung Association.
We thank the neonatologists, obstetricians, neonatal fellows, and the staff of our NICU for cooperation with the study.
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FOOTNOTES |
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Accepted Nov 1, 2007.
Address correspondence to Cindy McEvoy, MD, Department of Pediatrics, Oregon Health & Science University, 707 SW Gaines Rd (CDRC-P), Portland, OR 97239. E-mail: mcevoyc{at}ohsu.edu
This work was presented in part at the annual meeting of the Pediatric Academic Societies/Society for Pediatric Research; April 29 to May 4, 2006; San Francisco, CA.
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject A single course of AS is the standard of care for pregnant women who are at risk for preterm delivery between 24 and 34 weeks' gestation.
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| What This Study Adds Preterm infants who are delivered >7 days after AS therapy have a significantly lower Crs than those who are delivered within 7 days of therapy.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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