ARTICLE
Decreased Respiratory Compliance in Infants Less
Than or Equal to 32 Weeks’ Gestation, Delivered
More Than 7 Days After Antenatal Steroid Therapy
Cindy McEvoy, MDa, Diane Schilling, RRTa, Patricia Spitale, MDa, Dawn Peters, PhDb, Jean O’Malley, MPHb, Manuel Durand, MDc
aDivision of Neonatology, Department of Pediatrics andbDepartment of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon; cDivision of Neonatal Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
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.
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.
ABSTRACT
OBJECTIVES.Our objective was to compare the pulmonary function (respiratory com-pliance) of infants who were ⱕ32 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 infantsⱕ32 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 tech-nique.
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 wereⱕ32 weeks’ gestation and remotely treated with an-tenatal 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.
A
SINGLE COURSEof antenatal steroids (AS) remains the standard of care for the pregnant woman who is at riskfor preterm delivery between 24 and 34 weeks’ gestation.1,2AS therapy accelerates the structural and
biochem-ical maturation of the fetal lung, thereby decreasing the incidence of respiratory distress syndrome (RDS) in treated preterm infants.1–3Studies 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.1,2Unfortunately, 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).4,10We previously reported a 50% increase in Crs in preterm infants who
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-2608
doi:10.1542/peds.2007-2608
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.
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
Accepted for publication 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@ohsu.edu
were treated with a single course of AS, 1 to 7 days before delivery, versus matched untreated infants.4The
objective of this study was to quantify and compare the Crs of infants who wereⱕ32 weeks’ gestation and de-livered ⬎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 com-pared with infants who had received a single course of AS within 7 days of delivery.
METHODS
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 institu-tional review board at our institution, and informed consent was obtained for each enrolled patient. We pro-spectively studied infants who met the following inclu-sion criteria: (1) gestational age of 25 to 32 weeks, (2) birth weight ofⱕ2000 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 de-fined as infants who met these criteria and received a course of AS (two 12-mg doses of betamethasone intra-muscularly 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 ges-tational 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 ab-normalities. Infants who were delivered after incomplete or multiple courses of betamethasone were also ex-cluded.
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 comput-erized infant pulmonary function cart (SensorMedics 2600; SensorMedics Inc, Yorba Linda, CA). Crs was ob-tained with the single-breath occlusion technique.4,11–13
These measurements can be performed on intubated and
nonintubated infants, as previously reported.4,10In
ven-tilated 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 nonintu-bated 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 regres-sion line was drawn to obtain the best fit. From the intercepts on the flow and volume axes, Crs and resis-tance were calculated. Accepresis-tance criteria included (1) stable end expiratory baseline; (2) plateau pressure last-ing ⬎100 milliseconds; (3) plateau pressure varying by⫾0.125 cm H2O 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%.14Clinical outcome
pa-rameters including surfactant administration, days on mechanical ventilation, days on continuous positive air-way pressure (CPAP), and days on supplemental oxy-gen, 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.4We have also conducted a
prospec-tive, 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
ran-domly 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 pre-term infants (ⱕ32 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 respira-tory 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
vari-ables were evaluated with 2 tests for paired and
Data are expressed as means ⫾ SD, unless otherwise indicated.
Mixed linear modeling16was used to compare
respi-ratory compliance per kilogram in the remote and ide-ally 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.
RESULTS
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 character-istics were comparable between the 2 groups (Table 1). Both study groups were⬃1500 g and 30.5 weeks’ ges-tation 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 me-chanical 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.
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/ cm H2O versus 2.12 mL/cm H2O (95% confidence
inter-val [CI]: 0.20 – 0.99;P⫽.005) and 0.98 mL/cm H2O per
kg versus 1.41 mL/cm H2O per kg (95% CI: 0.19 – 0.67;
P⫽.001; Figs 1 and 2).
TABLE 1 Maternal and Infant Demographics
Demographic Ideal AS (n⫽28) Remote AS (n⫽28) P
Maternal age, mean⫾SD, y 25.1⫾5.8 26.0⫾6.0 NS
Preterm labor,n(%) 25/28 (89) 24/28 (86) NS
Preeclampsia,n(%) 6/28 (21) 1/28 (4) NS
Antepartum hemorrhage,n(%) 5/28 (18) 1/28 (4) NS
Maternal smoking,n(%) 8/28 (29) 3/28 (11) NS
Rupture of membranes, median (25th–75th percentiles), h 0.25 (0.0–67.5) 0.0 (0.0–133.0) NS
Rupture of membranes⬎24 h,n(%) 9/28 (32) 8/28 (29) NS
NSVD,n(%) 12/28 (43) 9/28 (32) NS
Multiple gestation,n(%) 8/28 (29) 14/28 (50) NS
Gestational age at AS therapy, mean⫾SD, wk 30.0⫾1.9 27.5⫾2.0 .001 Gestational age at birth, mean⫾SD, wk 30.5⫾1.9 30.5⫾1.6 NS
Birth weight, mean⫾SD, g 1485⫾322 1517⫾302 NS
White,n(%) 16/28 (57) 19/28 (68) NS
Female,n(%) 16/28 (57) 17/28 (61) NS
1-min Apgar, median (25th–75th percentiles) 8 (5–8) 7 (5–8) NS 5-min Apgar, median (25th–75th percentiles) 8 (7–9) 8 (7–9) NS
NS indicates not significant; NSVD, normal spontaneous vaginal delivery.
TABLE 2 Clinical Respiratory Outcomes in the 2 Groups of Infants
Parameter Ideal AS (n⫽28) Remote AS (n⫽28) P
FIO2⬎0.21 at time of PFT,n(%) 3/28 (11) 8/28 (29) NS
Surfactant,n(%) 4/28 (14) 7/28 (25) NS
Mechanical ventilation,n(%) 5/28 (18) 11/28 (39) NS
RDS,n(%) 5/28 (18) 11/28 (39) NS
Days of mechanical ventilation ⬍.05
Mean⫾SD 0.10⫾0.30 1.30⫾2.20a
Median (25th–75th percentiles) 0.00 (0.00–0.00) 0.00 (0.00–2.80) Days of CPAP
Mean⫾SD 0.50⫾1.00 1.60⫾2.60a NS
Median (25th–75th percentiles) 0.00 (0.00–0.90) 0.00 (0.00–2.00) Days on oxygen
Mean⫾SD 1.00⫾1.70 4.50⫾6.60a ⬍.05
Median (25th–75th percentiles) 0.00 (0.00–1.60) 1.00 (0.00–9.00)
Survival at discharge,n(%) 28/28 (100) 27/28 (96) NS
Although not 1 of the primary outcome variables of our study, there was no significant difference in surfac-tant 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 popula-tion, 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 deliv-ered 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 ox-ygen at the time of pulmonary function testing (Table 3). Although there was no significant difference in surfac-tant 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 in-fants 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/cm H2O per kg vs
1.29 mL/cm H2O per kg;P⬍.05; Fig 3).
As expected, mixed linear modeling showed that vari-ables 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, re-sulted in a larger estimate of the mean Crs difference (from 0.43 to 0.49) between the treatments groups, whereas adjusting for intermittent mandatory ventila-tion, 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, andP⬍.05 for infants treated 8 to 14 days versus ⬎14 days before delivery, respec-tively); however, there was no significant difference in Crs for infants who were treated 1 to 7 days versus 8 to 14 days before delivery.
DISCUSSION
With the 2000 National Institutes of Health recommen-dation that repeat courses of AS be given only within a
FIGURE 1
Mean⫾SEM values of total respiratory compliance (Crs) in mL/cm H2O in 56 infants at
ⱕ32 weeks’ gestation; 28 in the ideal AS group versus 28 in the remote AS group. Respiratory compliance was significantly decreased in the remote AS group compared with the ideal AS group.
FIGURE 2
Measurements of respiratory compliance normalized for weight (Crs/kg) in mL/cm H2O per kg in 56 infants atⱕ32 weeks’ gestation (Mean⫾SEM). The remote AS group had a significantly decreased Crs/kg compared with the ideal AS group.
FIGURE 3
Mean⫾SEM values of respiratory compliance normalized for weight (Crs/kg) in mL/cm H2O per kg in 28 infants of the remote AS group. Crs/kg was significantly lower in infants treated with AS⬎14 days before delivery (n⫽18) versus infants treated with AS 8 to 14 days before delivery (n⫽10).
TABLE 3 Analysis of Subgroups of Infants Treated With Remote AS
Parameter No. of Days AS Given
Before Delivery
P
8–14 (n⫽10) ⬎14 (n⫽18)
Gestational age at birth, mean⫾SD, wk
30.30⫾2.10 30.60⫾1.30 .63
Birth weight, mean⫾SD, g 1552⫾328 1498⫾296 .66
Female,n(%) 6/10 (60) 11/18 (61) .95
White,n(%) 5/10 (50) 14/18 (78) .21
FIO2⬎0.21,n(%) 2/10 (20) 6/18 (33) .67 Surfactant,n(%) 1/10 (10) 6/18 (33) .36
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 ⱕ32 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, ⱕ35 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
suggest-ing that the enzyme system responsible for surfactant production can be repetitively induced despite previous treatment with AS. Measurements of pulmonary func-tion have been used to quantify the newborn infant’s response to various therapeutic interventions,17,18
in-cluding surfactant administration13,19and antenatal
cor-ticosteroid therapy4,10,11 in preterm infants. A single
course of AS significantly improved respiratory mechan-ics, and these changes correlated well with improved clinical outcome in preterm infants1,4; however, the
du-ration of the clinical effect of a single course of beta-methasone (given within 7 days versus⬎7 days before delivery) on respiratory mechanics in very preterm in-fants (ⱕ32 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 fol-lowed by placebo7,20showed repeat courses of AS (24 mg
of betamethasone) to have pulmonary benefits, particu-larly 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 com-posite morbidity; however, it did demonstrate a signifi-cant 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 repet-itive 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 de-livered 1 week after an initial course of AS were ran-domly assigned to weekly courses of betamethasone (n⫽252) or placebo (n⫽243).7There 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 pri-mary outcome, which was a composite of perinatal death, severe RDS, grades 3 to 4 intraventricular hem-orrhage, 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 out-comes were even more significant for infants who were delivered at⬍32 weeks’ gestation. There was no signif-icant difference in average birth weight or head circum-ference overall, but infants who receivedⱖ4 courses of AS had a significantly lower birth weight (P⫽.01).7This
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 atⱖ32 weeks). This study also concluded that additional investigation of limited repeated steroid therapy for women who are at high risk for early pre-term 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) be-tween patients who received a single dose of betametha-sone (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 ⱖ24 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, includ-ing 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,zscores were not different between both groups.21Consistent with other studies,7,20 TABLE 4 Effect of Individual Covariates on Crs
Model Estimated Difference in Crs (Between 2-Covariate
Group)
AS Timing Effect
(Ideal-Remote) Estimate (95% CI) P Effect P
AS timing only 0.43 .0012
AS⫹multiple gestation ⫺0.09 (⫺0.47 to 0.29) .62 0.41 .0031 AS⫹mode of delivery ⫺0.08 (⫺0.46 to 0.31) .66 0.44 .0013 AS⫹maternal agea ⫺0.01 (⫺0.04 to 0.02) .42 0.42 .0017
AS⫹maternal smoking 0.31 (⫺0.17 to 0.81) .17 0.49 .0005 AS⫹IMV ⫺0.33 (⫺0.80 to 0.13) .14 0.36 .0073 AS⫹CPAP 0.03 (⫺0.37 to 0.44) .87 0.43 .0015 aThis is the estimated difference in Crs corresponding to a 1-year increase in maternal age. IMV
⬃35% of infants in the 2 groups were delivered atⱖ34 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 uncer-tain 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 fac-tors and events surrounding delivery can stimulate the secretion of endogenous steroids and affect the measure-ment 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 ad-justed for possible confounding by multiple gestation, mode of delivery, maternal age, maternal smoking, me-chanical ventilation, and CPAP. Infants who were deliv-ered⬎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 func-tion. 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 compli-ance 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 physio-logic positive end-expiratory pressure of 4 cm H2O.
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 al26of a single course of AS versus placebo showed no
significant pulmonary benefit (but a significant reduc-tion 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 dem-onstrated 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 hu-man 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.25The 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).25In the last trial
to randomly assign patients to a single course of AS versus placebo, the investigators did not find a signifi-cant 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 ben-efits of a course of AS when given up to 14 days before delivery.9 Our study supports an evidence-based
deci-sion analysis evaluating a number of dosing regimens of AS, as described by Caughey and Parer.29In 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
CONCLUSIONS
Infants who were ⱕ32 weeks’ gestation and remotely treated with a course of AS had a significantly lower Crs when compared with matched infants who were “ide-ally” 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 func-tion. 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.
ACKNOWLEDGMENTS
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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DOI: 10.1542/peds.2007-2608
2008;121;e1032
Pediatrics
Manuel Durand
Cindy McEvoy, Diane Schilling, Patricia Spitale, Dawn Peters, Jean O'Malley and
Gestation, Delivered More Than 7 Days After Antenatal Steroid Therapy
Decreased Respiratory Compliance in Infants Less Than or Equal to 32 Weeks'
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DOI: 10.1542/peds.2007-2608
2008;121;e1032
Pediatrics
Manuel Durand
Cindy McEvoy, Diane Schilling, Patricia Spitale, Dawn Peters, Jean O'Malley and
Gestation, Delivered More Than 7 Days After Antenatal Steroid Therapy
Decreased Respiratory Compliance in Infants Less Than or Equal to 32 Weeks'
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