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Respiratory compliance in preterm infants after a single rescue course of antenatal steroids: a randomized controlled trial

Published:March 15, 2010DOI:https://doi.org/10.1016/j.ajog.2010.01.038

      Objective

      To compare respiratory compliance and functional residual capacity in infants randomized to a rescue course of antenatal steroids vs placebo.

      Study Design

      Randomized, double-blinded trial. Pregnant women ≥14 days after initial antenatal steroids were randomized to rescue antenatal steroids or placebo. The primary outcomes were measurements of respiratory compliance and functional residual capacity. This study is registered with clinicaltrials.gov (NCT00669383).

      Results

      Forty-four mothers (56 infants) received rescue antenatal steroids and 41 mothers (57 infants) received placebo. There was no significant difference in birthweight, or head circumference. Infants in the rescue group had an increased respiratory compliance (1.21 vs 1.01 mL/cm H2O/kg; adjusted 95% confidence interval, 0.01-0.49; P = .0433) compared with placebo. 13% in the rescue vs 29% in the placebo group required ≥30% oxygen (P < .05). Patients delivered at ≤34 weeks had greater pulmonary benefits.

      Conclusion

      Infants randomized to rescue antenatal steroids have a significantly increased respiratory compliance compared with placebo.

      Key words

      Respiratory distress syndrome (RDS) is a common complication of preterm delivery and increases neonatal mortality and morbidity.
      • Jobe A.H.
      • Bancalari E.
      NICHD/NHLBI/ORD Workshop Summary Bronchopulmonary dysplasia.
      A single course of antenatal steroids (AS) remains the standard of care for women at risk for preterm delivery between 24 and 34 weeks of gestation,
      National Institutes of Health Consensus Development Conference Statement Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994.
      • Crowley P.A.
      Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.
      and significantly decreases mortality and RDS. The optimal response to a course of AS occurs if it is given at least 24 hours before but within 7 days of delivery.
      National Institutes of Health Consensus Development Conference Statement Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994.
      • Crowley P.A.
      Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.
      The duration of the clinical effect of a course of AS remains uncertain, and the efficacy and safety of repeat courses of AS remains a topic of continuing debate and study.
      National Institutes of Health Consensus Development Panel
      Antenatal corticosteroids revisited: Repeat courses-NIH Consensus Development Conference Statement, August 17-18, 2000.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      • Stiles A.D.
      Prenatal corticosteroids: early gain, long-term questions.
      For Editors' Commentary, see Table of Contents
      Recent randomized data show weekly courses of AS in preterm infants may improve lung function outcomes.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      Crowther et al randomized 982 women at <32 weeks of gestation to weekly AS vs placebo.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      They demonstrated a significant decrease in RDS and severe lung disease in the AS group.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      The Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network also reported improved pulmonary outcomes in preterm infants randomized to weekly courses of AS vs placebo.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      Despite the suggestion of pulmonary benefits after repeat courses of AS, concern remains of possible harm after weekly AS therapy, particularly in terms of reduced in utero growth and long-term neurodevelopmental outcome.
      • Stiles A.D.
      Prenatal corticosteroids: early gain, long-term questions.
      However, a recent trial by Garite et al of 1 rescue course of AS vs placebo showed improved neonatal outcome without apparent increased short-term risk.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      We have used measurements of pulmonary function, specifically passive respiratory compliance (Crs) and functional residual capacity (FRC), as an objective and reproducible way of quantifying the effects of AS on pulmonary function.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Collins J.
      • Tolaymat L.
      • Maher J.
      Timing of antenatal corticosteroids and neonatal pulmonary mechanics.
      These physiologic measurements correlate with clinical respiratory outcomes.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      We recently reported that infants ≤32 weeks of gestation treated with a single course of AS >7 days before delivery had a significantly lower Crs compared with matched infants treated with a course of AS 1-7 days before delivery.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      The difference in Crs was more striking if the infants received AS >14 days before delivery.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      Our objective was to compare pulmonary function (Crs and FRC) in infants who received a course of AS, remained undelivered for at least 14 days, and were randomized to a single rescue course of AS vs placebo. We hypothesized that infants who received a rescue course of AS would have a significantly increased Crs compared with those who received placebo.

      Materials and Methods

      Eligibility criteria

      This prospective randomized trial was conducted at the Neonatal Intensive Care Unit at Oregon Health and Science University (Portland, OR) and at Sacred Heart Hospital (Pensacola, FL). The study was approved by the institutional review boards at each institution and informed consent obtained for each enrolled patient. This study is registered with clinicaltrials.gov (registration no. NCT00669383). Inclusion criteria included: (1) pregnant women 26 to <34 weeks of gestation; (2) at least 14 days after first course of AS (93% received betamethasone); (3) continued risk of preterm delivery as determined by their care provider; and (4) informed consent.
      We excluded patients with: (1) multiple gestations greater than twins; (2) insulin dependent diabetes; (3) clinical chorioamnionitis; (4) major documented fetal or chromosomal abnormalities; (5) first course of AS given at <24 weeks of gestation; and (6) chronic steroid use during pregnancy for clinical care.

      Study design

      This was a prospective, randomized, double-blinded trial stratified by gestational age (≤28 vs >28 weeks' gestation) and multiple gestation (twins vs singletons). After obtaining informed consent, patients were randomized to rescue AS or placebo only if there were recurrent signs of preterm delivery as determined by the mother's clinician. Patients assigned to the “rescue AS” group received a course of AS (two 12 mg intramuscular injections of betamethasone [Celestone Soluspan; Schering-Plough Corporation, Kenilworth, NJ] 24 hours apart). Those assigned to the “placebo” group received 2 doses of placebo that were identical in appearance to the betamethasone and consisted of 25 mg cortisone acetate, an inactive steroid.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      Group assignment was performed using a randomization table. A staff pharmacist performed randomization and study drug preparation at each institution, and all patients, investigators, and care providers were unaware of treatment allocation. Pulmonary function was measured within 72 hours of birth and before surfactant therapy, when required. Infants were studied in the supine position while quietly asleep; no sedation was used.
      Comparisons of Crs and FRC between groups were our primary endpoints. Other pertinent clinical outcome measures between groups were also monitored. All outcomes were assessed blinded to treatment group allocation.

      Measurements

      Respiratory mechanics and lung volume 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 and FRC with the nitrogen washout method.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Collins J.
      • Tolaymat L.
      • Maher J.
      Timing of antenatal corticosteroids and neonatal pulmonary mechanics.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      In intubated patients, including those requiring surfactant, 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, a face mask was used.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Collins J.
      • Tolaymat L.
      • Maher J.
      Timing of antenatal corticosteroids and neonatal pulmonary mechanics.
      For the single-breath occlusion technique,
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      • Haland G.
      • Lodrup Carlsen K.C.
      • Sandvik L.
      • et al.
      Reduced lung function at birth and the risk of asthma at 10 years of age.
      • LeSouef P.N.
      • England S.J.
      • Bryan A.C.
      Passive respiratory mechanics in newborns and children.
      • Kelly E.
      • Bryan H.
      • Possmayer F.
      • Frndova H.
      • Bryan C.
      Compliance of the respiratory system in newborn infants pre- and postsurfactant replacement therapy.
      the airway was briefly occluded at end inspiration until an airway pressure plateau was observed and the Hering Breuer reflex invoked. The linear portion of the passive flow-volume curve was identified, and a regression line drawn to obtain the best fit. From the intercepts on the flow and volume axes, respiratory system compliance and resistance were calculated. Acceptance criteria included: (1) stable end expiratory baseline; (2) plateau pressure lasting >100 msec; (3) plateau pressure varying by < ± 0.125 cm H2O; (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%.
      American Thoracic Society/European Respiratory Society
      Respiratory mechanics in infants: physiologic evaluation in health and disease.
      For the nitrogen washout technique,
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Collins J.
      • Tolaymat L.
      • Maher J.
      Timing of antenatal corticosteroids and neonatal pulmonary mechanics.
      • Yuksel B.
      • Greenough A.
      • Chan V.
      • Russell R.R.
      Comparison of helium dilution and nitrogen washout measurements of functional residual capacity in premature infants.
      • Cotton R.B.
      • Olsson T.
      • Law A.B.
      • et al.
      The physiologic effects of surfactant treatment on gas exchange in newborn premature infants with hyaline membrane disease.
      calibration was performed with 2 known volumes, and a calibration line was constructed for the system at the specific flow rate. The calibration curve was then used to correlate the nitrogen washed out to the infant's FRC. The system corrected for dead space present and corrected the FRC to body temperature, pressure, and water-saturated conditions. Total FRC was related to body weight. Acceptance criteria included: (1) infant supine and quietly asleep; (2) test initiated at end expiration; (3) no evidence of leak on tracing of the washout; (4) consistent tracings; and (5) at least 3 measurements with a coefficient of variation of <10%.
      American Thoracic Society/European Respiratory Society
      Respiratory mechanics in infants: physiologic evaluation in health and disease.
      Growth measurements (weight, head circumference, and length) at birth and hospital discharge were compared between groups, and corresponding Z-scores for these measurements were calculated.
      • Fenton T.R.
      • Sauve R.S.
      Using the LMS method to calculate z-scores for the Fenton preterm infant growth chart.
      National Center for Health Statistics, Centers for Disease Control and Prevention, US Department of Health and Human Services.
      Other clinical outcome parameters, including surfactant administration, diagnosis of RDS (defined as clinical signs of respiratory distress with radiographic appearance and needing supplemental oxygen with FiO2 >0.21), respiratory distress with FiO2 requirement ≥0.30 and ≥0.40 at 24 hours of age, days on mechanical ventilation, and days on supplemental oxygen were monitored.

      Statistical methods

      Differences in continuous variables between the 2 groups were first analyzed by 2-tailed, independent samples Student t tests or the Mann-Whitney U test where appropriate (for data not normally distributed). Categorical variables were evaluated with χ
      National Institutes of Health Consensus Development Conference Statement Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994.
      tests and Fisher's exact test where appropriate. Data are presented as mean ± standard deviation (SD), unless otherwise indicated.
      The statistical analyses were on intention-to-treat. Comparisons of the primary outcomes between groups were performed using linear mixed modeling.
      • Brown H.
      • Prescott R.
      Applied mixed models in medicine.
      • Chow S.C.
      • Liu J.P.
      Design and analysis of clinical trials: concepts and methodologies.
      This approach accounts for the correlation (nonindependence) between twins, and allows for adjustment of additional covariates and potential confounders.
      • Brown H.
      • Prescott R.
      Applied mixed models in medicine.
      • Chow S.C.
      • Liu J.P.
      Design and analysis of clinical trials: concepts and methodologies.
      We began with a model, including rescue dose, gestational age (GA) at birth, multiple gestations, maternal smoking history, rupture of membranes, and gestational diabetes, as these were the initial predictors of interest. The remaining covariates: GA at first AS dosing, GA at study dosing, race, gender, and mode of delivery were introduced to the model 1 at a time, and examined for their statistical significance and/or their effect on the relationship between rescue dose and each outcome. We also planned a subgroup analysis for infants who delivered at ≤34 weeks of gestation. We used SPSS for Windows, Version 15 (SPSS, Inc, Chicago, IL) and SAS 9.1.3 (SAS Institute Inc, Cary, NC) for analyses.
      Power calculations were based on previous studies. We reported a 50% increase in Crs in preterm infants treated with a single course of AS 1-7 days before delivery when compared with matched untreated infants.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      We also conducted a randomized trial, in which infants undelivered 1 week after their initial AS course were randomized to weekly AS versus placebo.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      Infants randomized to placebo delivered an average of 24 days after AS dosing and had Crs measurements that were on average 20% lower than in infants randomized to weekly AS. These findings were not significantly different perhaps due to small sample size, as the study was stopped early due to concerns of possible adverse effects of weekly AS therapy.
      For our current study, we hypothesized that infants in the rescue AS group would have significantly increased Crs than those in the placebo group. We estimated that to show about a 30% difference in Crs between the groups, we would need to study approximately 40 pregnancies in each group to reject the null hypothesis with a type I error of 0.05 and a power of 80%. Data were reviewed once by the independent, data safety monitoring committee, who were not aware of treatment-group allocation. An interim analysis was conducted when 49.6% (56/113) of the infants were delivered.

      Results

      Patients were recruited from June 2001 to May 2007. The study profile is shown in the Figure. A total of 44 mothers with 56 infants were randomly assigned to a rescue course of AS and 41 mothers with 57 infants to placebo. The first 8 patients were recruited at Sacred Heart Hospital, with the remaining patients recruited at Oregon Health and Science University. Eighty-six percent of the rescue and 90% of the placebo group received a full course of the study medication. Neonatal data were not available for 1 infant in the placebo group, resulting in 56 vs 56 infants available for analysis (Figure).
      Figure thumbnail gr1
      FIGUREOutline of enrollment and randomization of the study participants
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      Maternal and infant characteristics were comparable between the groups (TABLE 1, TABLE 2), except for significantly more smokers by history in the rescue group. Both groups of mothers received their first course of AS at about 27 weeks; and received their study dose at about 30 weeks of gestation (Table 1). Patients in the rescue AS group delivered 8 (2-24) days after receiving rescue/study dosing vs 11 (3-20) days in the placebo group (median, 25th-75th percentiles; P = .66). Eighty-three of a total of 113 infants (73.5%) were delivered at ≤34 weeks. There were no significant differences in birthweight, GA at birth, admission head circumference, birth length, or incidence of small for GA infants (birthweight <10th percentile) between groups. There was no difference in Z-scores for birthweight, head circumference, or length between groups (Table 2).
      TABLE 1Baseline characteristics of the randomized mothers
      CharacteristicRescue AS (n = 44)Placebo (n = 41)P
      Maternal age, y
      Mean ± SD;
      26.9 ± 7.528.6 ± 6.4NS
      White, n (%)30 (68)27 (66)NS
      Maternal smoking, n (%)11 (25)2 (5)< .05
      Twin gestation, n (%)12 (27)16 (39)NS
      Rupture of membranes, h
      Median (25th-75th percentiles).
      0.5 (0-9)0 (0-8)NS
      Rupture of membranes >24 h, n (%)9 (20)6 (15)NS
      Gestational diabetes, n (%)2 (5)5 (12)NS
      Cesarean section, n (%)24 (55)24 (59)NS
      GA at 1st AS dosing, wk
      Mean ± SD;
      26.6 ± 1.927.1 ± 2.2NS
      GA at study dosing, wk
      Mean ± SD;
      29.8 ± 1.930.3 ± 2.1NS
      Preterm labor, n (%)35 (80)29 (71)NS
      Preeclampsia, n (%)3 (7)2 (5)NS
      Antepartum hemorrhage, n (%)7 (16)11 (27)NS
      AS, antenatal steroids; GA, gestational age; NS, not significant.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Mean ± SD;
      b Median (25th-75th percentiles).
      TABLE 2Demographic characteristics of the 2 groups of infants
      CharacteristicRescue AS (n = 56)Placebo (n = 56)P
      GA at birth, wk
      Mean ± SD;
      31.9 ± 3.332.3 ± 2.9NS
      White, n (%)39 (70)38 (68)NS
      Female, n (%)28 (50)29 (52)NS
      Apgar score 1, 5 min
      Median values;
      7, 88, 9NS
      Birthweight, g
      Mean ± SD;
      1806 ± 7781830 ± 657NS
      Birthweight Z score
      Mean ± SD;
      −0.14 ± 0.86−0.14 ± 0.98NS
      Small for gestational age, n (%)6 (11)8 (14)NS
      Birth head circumference, cm
      Mean ± SD;
      Data available for 53 vs 54 patients.
      28.7 ± 3.029.2 ± 2.9NS
      Birth head circumference Z score
      Mean ± SD;
      −0.19 ± 0.90−0.18 ± 0.93NS
      Birth length, cm
      Mean ± SD;
      41.9 ± 4.742.4 ± 4.4NS
      Birth length Z score
      Mean ± SD;
      −0.11 ± 0.99−0.06 ± 0.96NS
      AS, antenatal steroids; GA, gestational age; NS, not significant.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Mean ± SD;
      b Median values;
      c Data available for 53 vs 54 patients.
      Pulmonary function tests were performed at a median postnatal age of 22 hours in the rescue AS and 21 hours in the placebo group. Successful measurements of Crs were obtained in 49 rescue and 49 placebo patients. Accounting for the correlation between twins and using linear mixed modeling, there was a significant difference in Crs with the rescue AS group having a mean Crs of 1.21 mL/cm H2O/kg vs 1.01 mL/cm H2O/kg in the placebo group, adjusted 95% confidence interval (CI) for difference (0.01-0.49), P = .0433 (Table 3). We did not demonstrate a significant difference in FRC between groups: 24.8 mL/kg in the rescue vs 22.0 mL/kg in the placebo group, adjusted 95% CI for difference (−1.40 to 6.62), P = .19 (Table 3).
      TABLE 3Primary outcomes: measurements of pulmonary function
      OutcomeRescue ASPlacebo95% CI
      Adjusted for gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes (linear mixed modeling);
      P value
      Adjusted for gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes (linear mixed modeling);
      All infants(n = 49)(n = 49)
      Crs (mL/cm H2O/kg)1.21 ± 0.531.01 ± 0.51(0.01–0.49).0433
      FRC (mL/kg)
      FRC obtained in 46 and 47 patients;
      24.8 ± 8.822.0 ± 7.9(−1.40 to 6.62)NS
      Infants ≤34 weeks' gestation(n = 40)(n = 34)
      Crs (mL/cm H2O/kg)1.17 ± 0.550.90 ± 0.52(0.02–0.60).0395
      FRC (mL/kg)
      FRC obtained in 38 and 33 patients, respectively.
      24.3 ± 9.321.1 ± 8.5(−0.13 to 8.53)NS
      AS, antenatal steroids; CI, confidence interval; Crs, respiratory compliance; FRC, functional residual capacity; NS, not significant.
      Values are mean ± SD and (95% confidence intervals).
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Adjusted for gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes (linear mixed modeling);
      b FRC obtained in 46 and 47 patients;
      c FRC obtained in 38 and 33 patients, respectively.
      Although not 1 of the primary outcome variables of our study, fewer patients in the rescue group required surfactant or had RDS compared with the placebo group, but this was not significantly different. However, significantly fewer patients in the rescue group required ≥30% oxygen (13% vs 29%) or ≥40% oxygen (9% vs 23%) than those in the placebo group (P < .05; Table 4). There was no significant difference in discharge weight, head circumference, or length; or in Z-scores for these growth measurements between groups (Table 4). From the total study population, there was 1 neonatal death caused by sepsis in the rescue group.
      TABLE 4Secondary outcomes in the 2 groups of infants
      OutcomeRescue AS (n = 56)Placebo (n = 56)P value
      Surfactant, n (%)15 (27)22 (39)NS
      Mechanical ventilation, n (%)15 (27)18 (32)NS
      RDS, n (%)15 (27)23 (41)NS
      FiO2 ≥0.30, n (%)7 (13)16 (29)< .05
      FiO2 ≥0.40, n (%)5 (9)13 (23)< .05
      Days of mechanical ventilation
      Median (25th-75th percentiles) in survivors;
      0 (0-0.4)0 (0-1)NS
      Days on oxygen
      Median (25th-75th percentiles) in survivors;
      0 (0-13.9)1.7 (0-25)NS
      Length of stay, d
      Median (25th-75th percentiles) in survivors;
      51 vs 55 patients;
      27.0 (15-55)25.0 (11-49)NS
      Neonatal survival, n (%)55 (98)56 (100)NS
      Discharge weight, g
      Median (25th-75th percentiles) in survivors;
      50 vs 55 patients;
      2474 (2196-2856)2380 (2092-2675)NS
      Discharge weight Z score
      Mean ± SD;
      −0.80 ± 0.88−0.77 ± 1.03NS
      Discharge OFC, cm
      Mean ± SD;
      50 vs 55 patients;
      32.6 ± 1.732.3 ± 1.6NS
      Discharge OFC Z score
      Mean ± SD;
      −0.26 ± 0.90−0.34 ± 0.94NS
      Discharge length, cm
      Mean ± SD;
      49 vs 50 patients.
      46.5 ± 2.946.4 ± 2.8NS
      Discharge length Z score
      Mean ± SD;
      −0.63 ± 1.14−0.37 ± 1.09NS
      AS, antenatal steroids; NS, not significant; OFC, head circumference; RDS, respiratory distress syndrome.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Median (25th-75th percentiles) in survivors;
      b 51 vs 55 patients;
      c 50 vs 55 patients;
      d Mean ± SD;
      e 49 vs 50 patients.
      In the planned subgroup analysis of infants born at ≤34 weeks (44 rescue and 39 placebo patients), there were no significant differences in growth measurements or corresponding Z-scores at birth (Table 5). This subgroup demonstrated more pronounced pulmonary benefits: Crs in the rescue group was 1.17 mL/cm H2O/kg vs 0.90 mL/cm H2O/kg in the placebo group, adjusted 95% CI for difference (0.02-0.60), P = .0395. There was no significant difference in FRC measurements (Table 3). Fewer patients in the rescue group had any RDS, required ≥30% oxygen, or ≥40% oxygen than patients in the placebo group (P < .05), suggesting an enhanced benefit of rescue AS in those at highest risk for respiratory distress. There were no significant differences in discharge growth measurements or corresponding Z-scores (Table 6).
      TABLE 5Demographics of subgroup of infants ≤34 weeks of gestation
      DemographicRescue AS (n = 44)Placebo (n = 39)P
      GA at birth, wk
      Mean ± SD;
      30.5 ± 2.030.8 ± 2.0NS
      White, n (%)30 (68)25 (64)NS
      Female, n (%)26 (59)19 (49)NS
      Apgar score 1, 5 min
      Median (25th-75th percentiles).
      7, 87, 8NS
      Birthweight, g
      Mean ± SD;
      1467 ± 3981541 ± 476NS
      Birthweight, g
      Median (25th-75th percentiles).
      1416 (1170-1848)1460 (1185-1865)NS
      Birthweight Z score
      Mean ± SD;
      −0.15 ± 0.840.01 ± 0.89NS
      Small for gestational age, n (%)6 (14)5 (13)NS
      Birth head circumference, cm
      Mean ± SD;
      27.8 ± 2.328.0 ± 2.3NS
      Birth head circumference Z score
      Mean ± SD;
      −0.19 ± 0.94−0.17 ± 0.90NS
      Birth length, cm
      Mean ± SD;
      40.0 ± 3.040.3 ± 3.3NS
      Birth length Z score
      Mean ± SD;
      −0.20 ± 0.97−0.15 ± 1.01NS
      AS, antenatal steroids; GA, gestational age; NS, not significant.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Mean ± SD;
      b Median (25th-75th percentiles).
      TABLE 6Secondary outcomes for subgroup of infants ≤34 weeks of gestation
      OutcomeRescue AS (n = 44)Placebo (n = 39)P value
      Surfactant, n (%)15 (34)21 (54)NS
      Mechanical ventilation, n (%)15 (34)18 (46)NS
      RDS, n (%)15 (34)22 (56)< .05
      FiO2 ≥0.30, n (%)7 (16)16 (41)< .05
      FiO2 ≥0.40, n (%)5 (11)13 (33)< .05
      Days of mechanical ventilation
      Median (25th-75th percentiles) in survivors;
      0 (0-1)0.1 (0-5)NS
      Days on oxygen
      Median (25th-75th percentiles) in survivors;
      1.7 (0-18)4.7 (0-32)NS
      Neonatal survival, n (%)43 (98)39 (100)NS
      Discharge weight, g
      Mean ± SD;
      38 vs 38 patients;
      2424 ± 4672376 ± 427NS
      Discharge weight Z score
      Mean ± SD;
      −0.90 ± 0.81−0.68 ± 1.04NS
      Discharge OFC, cm
      Mean ± SD;
      38 vs 38 patients;
      32.4 ± 1.731.9 ± 1.6NS
      Discharge OFC Z score
      Mean ± SD;
      −0.29 ± 0.93−0.39 ± 1.01NS
      Discharge length, cm
      Mean ± SD;
      37 vs 34 patients.
      45.7 ± 2.545.5 ± 2.7NS
      Discharge length Z score
      Mean ± SD;
      −0.84 ± 1.09−0.55 ± 1.11NS
      AS, antenatal steroids; NS, not significant; OFC, head circumference; RDS, respiratory distress syndrome.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Median (25th-75th percentiles) in survivors;
      b Mean ± SD;
      c 38 vs 38 patients;
      d 37 vs 34 patients.
      Results using linear mixed models for multivariable modeling are shown in TABLE 7, TABLE 8. For the entire study population, when adding GA at first AS therapy, GA at study dosing, race, gender, or mode of delivery to the model, the relationship between rescue AS dose and Crs was relatively unaffected. In addition, none of these variables were statistically significant (Table 7). Similarly, when adding these 5 covariates to the model, the relationship between rescue dose and FRC was relatively unaffected. For the subgroup of patients who were delivered at ≤34 weeks of gestation, when adding the same 5 covariates to the model, the relationship between rescue dose and Crs (Table 8) or rescue dose and FRC was also relatively unaffected.
      TABLE 7Effect of individual covariates on respiratory compliance (all patients)
      Model
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      Estimated difference in CrsRescue AS effect
      (Between 2 covariate group)(Rescue-placebo)
      Estimate (95% CI)P valueEffectP value
      Rescue AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      0.25.0433
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + GA at 1st AS dosing
      This is the estimated difference in Crs corresponding to a 1-wk increase in gestational age.
      0.00 (−0.07 to 0.07).920.25.0452
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + GA at study dosing
      This is the estimated difference in Crs corresponding to a 1-wk increase in gestational age.
      0.00 (−0.07 to 0.07).930.25.0448
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + race
      0.16 (−0.11 to 0.42).230.25.0453
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + gender
      0.04 (−0.17 to 0.24).710.25.0422
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + mode of delivery
      −0.08 (−0.31 to 0.16).520.25.0417
      AS, antenatal steroids; CI, confidence interval; Crs, respiratory compliance; GA, gestational age.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      b This is the estimated difference in Crs corresponding to a 1-wk increase in gestational age.
      TABLE 8Effect of individual covariates on respiratory compliance (infants ≤34 weeks of gestation)
      Model
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      Estimated difference in CrsRescue AS effect
      (Between 2 covariate group)(Rescue-placebo)
      Estimate (95% CI)P valueEffectP value
      Rescue AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      0.31.0395
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + GA at 1st AS dosing
      This is the estimated difference in Crs corresponding to a 1-wk increase in gestational age.
      0.05 (−0.06 to 0.15).370.28.0605
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + GA at study dosing
      This is the estimated difference in Crs corresponding to a 1-wk increase in gestational age.
      0.13 (−0.02 to 0.28).080.30.0408
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + race
      0.13 (−0.19 to 0.45).420.30.0448
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + gender
      0.04 (−0.22 to 0.29).760.30.0424
      AS
      Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      + mode of delivery
      −0.14 (−0.43 to 0.15).320.32.0354
      AS, antenatal steroids; CI, confidence interval; Crs, respiratory compliance; GA, gestational age.
      McEvoy. Newborn pulmonary function and rescue antenatal steroids. Am J Obstet Gynecol 2010.
      a Indicates block of covariates included in all models, including: gestational age at birth, twin gestation, maternal smoking, rupture of membranes, and gestational diabetes;
      b This is the estimated difference in Crs corresponding to a 1-wk increase in gestational age.

      Comment

      Infants randomly assigned to a rescue course of AS have a significantly increased respiratory compliance (about a 20% increase) than patients randomly assigned to placebo. The subgroup of infants who delivered at ≤34 weeks of gestation demonstrates greater pulmonary function benefits (about 30% increase in Crs). Our findings suggest that improvement in Crs translates into improved clinical respiratory outcomes, with less oxygen requirements, and a trend toward less RDS.
      Although our study was a randomized, double-blind, placebo-controlled trial, we acknowledge some limitations. Preterm delivery is difficult to predict and therefore treatment with a rescue course of AS may be difficult to time. However, 73.5% of our patients delivered at ≤34 weeks and about 90% received the full course of study medication. Our study was powered to detect differences in pulmonary function tests (Crs), thus assessment of other clinical outcomes will need a larger sample size. Maternal and delivery factors can stimulate endogenous steroid secretion and impact the measurement of newborn pulmonary function. We limited potential confounding factors by using a randomized, placebo-controlled study design. All outcomes were assessed blinded to treatment group assignment, eliminating any possibility of expectation bias. Also, our pulmonary function findings were adjusted for correlation between twins and possible confounding by GA at birth, multiple gestations, maternal smoking, rupture of membranes, and gestational diabetes.
      • Brown H.
      • Prescott R.
      Applied mixed models in medicine.
      • Chow S.C.
      • Liu J.P.
      Design and analysis of clinical trials: concepts and methodologies.
      Finally, our patients were about 32 weeks of gestation at birth; therefore, our findings may not apply to an exclusive population of infants delivered at <28 weeks.
      Our findings are consistent with our previous study, demonstrating that infants ≤32 weeks of gestation treated with a single course of AS 1-7 days before delivery had improved Crs compared with infants treated >7 days before delivery.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      Our findings of increased Crs in the rescue AS group also are consistent with a multicenter study,
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      reporting a decrease in RDS and severe lung disease in patients randomly assigned to weekly AS vs placebo. This suggests that the enzyme system responsible for surfactant production can be repetitively induced, despite prior treatment with AS. Measurements of pulmonary function have been used to quantify the newborn infant's response to different treatments,
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      • Kelly E.
      • Bryan H.
      • Possmayer F.
      • Frndova H.
      • Bryan C.
      Compliance of the respiratory system in newborn infants pre- and postsurfactant replacement therapy.
      • McEvoy C.
      • Sardesai S.
      • Macri C.
      • Paul R.
      • Durand M.
      Neonatal pulmonary mechanics and oxygenation after prophylactic amnioinfusion in labor: a randomized clinical trial.
      • Durand M.
      • Mendoza M.E.
      • Tantivit P.
      • Kugelman A.
      • McEvoy C.
      A randomized trial of moderately early low-dose dexamethasone therapy in very low birth weight infants: dynamic pulmonary mechanics, oxygenation, and ventilation.
      including surfactant and AS therapy.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      • Kelly E.
      • Bryan H.
      • Possmayer F.
      • Frndova H.
      • Bryan C.
      Compliance of the respiratory system in newborn infants pre- and postsurfactant replacement therapy.
      Studies in humans and animal models demonstrated significant improvements in respiratory compliance and lung volumes after dosing with AS.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      • Ikegami M.
      • Polk D.H.
      • Jobe A.H.
      • et al.
      Effect of interval from fetal corticosteroid treatment to delivery on postnatal lung function of preterm lambs.
      • Ikegami M.
      • Polk D.
      • Jobe A.
      Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs.
      A single course of AS is 1 of the most effective therapies available to improve the outcome of infants born prematurely, and when given within 1 week of delivery significantly increases Crs and FRC about 50%.
      National Institutes of Health Consensus Development Conference Statement Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • Stewart M.
      • Durand M.
      Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      This is the context for the significant increase in Crs of 20-30% that we are demonstrating in this study. However, there are insufficient data on the risks and benefits of repeat/weekly courses of AS,
      National Institutes of Health Consensus Development Panel
      Antenatal corticosteroids revisited: Repeat courses-NIH Consensus Development Conference Statement, August 17-18, 2000.
      • Stiles A.D.
      Prenatal corticosteroids: early gain, long-term questions.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      • Banks B.A.
      • Cnaan A.
      • Morgan M.A.
      • et al.
      Multiple courses of antenatal corticosteroids and outcome of premature neonates.
      and there are no randomized trials examining the effects of a single repeat course of AS on Crs and FRC in preterm infants.
      Several large randomized trials of weekly betamethasone vs placebo,
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      • Guinn D.A.
      • Atkinson M.W.
      • Sullivan L.
      • et al.
      Single versus weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial.
      have shown repeat courses of AS have pulmonary benefits. Wapner et al
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      reported no difference in the primary outcome (composite morbidity) between groups. In the entire cohort, and particularly in infants <32 weeks, there was a significant difference in a number of pulmonary outcomes, with the weekly AS group (24 mg betamethasone) requiring less surfactant and less mechanical ventilation. There was no significant difference in birthweight or head circumference overall, but infants receiving ≥4 courses of AS had decreased birthweight.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      In addition, 2 studies using lower doses of betamethasone after an initial course of AS have reported conflicting results.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Peltoniemi O.M.
      • Kari M.A.
      • Tammela O.
      • et al.
      Repeat Antenatal Betamethasone Study Group
      Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.
      In a large study, 982 women were randomly assigned to weekly betamethasone (11.4 mg) vs placebo.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      Repeat doses of AS significantly decreased the primary outcomes of the study (RDS and severe lung disease) compared with placebo.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      The second study reported no difference in the primary outcome (survival without RDS or severe intraventricular hemorrhage) between patients randomly assigned to a single dose of betamethasone (12 mg) vs placebo.
      • Peltoniemi O.M.
      • Kari M.A.
      • Tammela O.
      • et al.
      Repeat Antenatal Betamethasone Study Group
      Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.
      However, 79% of the study population was born within 24 hours of dosing.
      • Peltoniemi O.M.
      • Kari M.A.
      • Tammela O.
      • et al.
      Repeat Antenatal Betamethasone Study Group
      Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth.
      The 2 most recently published studies used different regimens of repeat AS.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      MACS Collaborative Group
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      Murphy et al
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      MACS Collaborative Group
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      reported no difference in the primary outcome (composite morbidity and mortality) between 1858 patients receiving multiple courses of AS (24 mg of betamethasone, every 14 days) or placebo, but documented significant decreases in birthweight, length, and head circumference in the repeat AS group. The mean GA at birth were 34.5 and 34.9 weeks, with 35% of pregnancies delivering at 33-36 weeks and 32% at ≥37 weeks.
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      MACS Collaborative Group
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      In contrast, Garite et al
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      recently reported the first large study (n = 437) evaluating a single rescue course of AS on neonatal outcome. They documented a significant reduction in the primary outcome, composite neonatal morbidity at <34 weeks, in patients randomly assigned to a rescue course of AS (24 mg of betamethasone) vs placebo (43.9% vs 63.6%; P = .002). There was also a significant decrease in RDS, ventilator support, and surfactant use in the rescue AS group; but there were no differences in perinatal mortality or other morbidities, birthweight, and head circumference.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      A reduction of composite morbidity in the rescue group was still observed (32.1% vs 42.6%; P = .034) as well as decreased respiratory morbidities, when all 558 newborns were included, regardless of GA at delivery. In this study, 55% of patients in each group delivered at <34 weeks and the mean GA at birth was 33.0 weeks for all patients.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      Our study design of dosing with a rescue course of AS was very similar to the design of the trial by Garite et al.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      Our findings of improved respiratory compliance in the rescue AS group (about 20% increase in the total population and 30% in patients ≤34 weeks) are consistent with the latter study, and provide a physiologic basis for the improved respiratory outcomes observed after a rescue course of AS in the trial by Garite et al.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.
      A recent metaanalysis confirmed the pulmonary benefits of repeat/weekly AS,
      • Crowther C.A.
      • Harding J.E.
      Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease.
      but concern remains of possible adverse effects.
      National Institutes of Health Consensus Development Panel
      Antenatal corticosteroids revisited: Repeat courses-NIH Consensus Development Conference Statement, August 17-18, 2000.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      • Stiles A.D.
      Prenatal corticosteroids: early gain, long-term questions.
      Crowther et al
      • Crowther C.A.
      • Doyle L.W.
      • Haslam R.R.
      • Hiller J.E.
      • Harding J.E.
      • Robinson J.S.
      Outcome at 2 years of age after repeat doses of antenatal corticosteroids.
      and Wapner et al
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      reported neurodevelopmental and growth outcomes at 24-36 months of age in infants randomly assigned to weekly AS vs placebo.
      • Crowther C.A.
      • Haslam R.R.
      • Hiller J.E.
      • Doyle L.W.
      • Robinson J.S.
      Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group
      Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.
      • Wapner R.J.
      • Sorokin Y.
      • Thom E.A.
      • et al.
      NICHD Maternal Fetal Medicine Units Network
      Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
      These studies offer some reassurance that limited weekly AS do not significantly increase major adverse neurodevelopmental outcomes or growth delay,
      • Stiles A.D.
      Prenatal corticosteroids: early gain, long-term questions.
      • Crowther C.A.
      • Doyle L.W.
      • Haslam R.R.
      • Hiller J.E.
      • Harding J.E.
      • Robinson J.S.
      Outcome at 2 years of age after repeat doses of antenatal corticosteroids.
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      although 1 of the studies reported a nonsignificant trend for increased cerebral palsy after weekly AS.
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      Therefore, additional studies of neurodevelopmental performance and growth are warranted.
      • Stiles A.D.
      Prenatal corticosteroids: early gain, long-term questions.
      These studies
      • Crowther C.A.
      • Doyle L.W.
      • Haslam R.R.
      • Hiller J.E.
      • Harding J.E.
      • Robinson J.S.
      Outcome at 2 years of age after repeat doses of antenatal corticosteroids.
      • Wapner R.J.
      • Sorokin Y.
      • Mele L.
      • et al.
      Long-term outcomes after repeat doses of antenatal corticosteroids.
      also raise questions about AS dosing and whether higher doses of prenatal corticosteroids (weekly doses of 24 mg vs 11.4 mg) may increase adverse outcomes.
      AS therapy accelerates the structural and biochemical maturation of the fetal lung, reducing the incidence of RDS in preterm infants.
      National Institutes of Health Consensus Development Conference Statement Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994.
      • Crowley P.A.
      Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.
      As described by Caughey and Parer,
      • Caughey A.B.
      • Parer J.T.
      Recommendations for repeat courses of antenatal corticosteroids: a decision analysis.
      to maximize the benefits while minimizing fetal exposure to AS, we randomly assigned patients to a single rescue course of AS vs placebo. Although it has been difficult to define the duration of the pulmonary effects of a single course of AS, data from randomized trials,
      National Institutes of Health Consensus Development Conference Statement Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994.
      • Crowley P.A.
      Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994.
      our recent prospective cohort study,
      • McEvoy C.
      • Schilling D.
      • Spitale P.
      • Peters D.
      • O'Malley J.
      • Durand M.
      Decreased respiratory compliance in infants less than or equal to 32 weeks' gestation, delivered more than 7 days after antenatal steroid therapy.
      and a retrospective study evaluating a rescue dose of AS
      • Vermillion S.T.
      • Bland M.L.
      • Soper D.E.
      Effectiveness of a rescue dose of antenatal betamethasone after an initial single dose.
      indicate that it may decrease after 7-14 days. We found an increased Crs in infants assigned to the rescue AS group, with greater changes in infants who delivered at ≤34 weeks. In vitro studies with human lung explants have shown that the biochemical effects of AS begin to decrease after 7 days if AS is removed,
      • Ballard P.L.
      • Ballard R.A.
      Scientific basis and therapeutic regimens for use of antenatal glucocorticoids.
      although the corresponding structural changes persist. We speculate that the lower Crs in the placebo group in our study may reflect the dissipation of the beneficial effects of AS on induction of the surfactant system. FRC was only slightly increased in the rescue AS group, although not significantly different, suggesting that the structural changes after a course of AS persist longer than the biochemical changes.
      • McEvoy C.
      • Bowling S.
      • Williamson K.
      • et al.
      The effect of a single remote course versus weekly courses of antenatal corticosteroids on functional residual capacity in preterm infants: a randomized trial.
      • Ballard P.L.
      • Ballard R.A.
      Scientific basis and therapeutic regimens for use of antenatal glucocorticoids.

      Conclusions

      Infants randomly assigned to a single rescue course of AS have a significantly increased Crs compared with those randomly assigned to placebo. The subgroup of patients who delivered at ≤34 weeks demonstrates greater pulmonary function benefits. Our findings suggest that improvement in Crs translates into improved clinical respiratory outcomes. Long-term follow-up of our patients is underway. We speculate that if treatment with a course of AS has occurred >14 days before delivery, a rescue course of AS may decrease pulmonary morbidity. This should be studied in a large placebo-controlled trial of high-risk patients, and risks and benefits, including long-term pulmonary, growth, and neurodevelopmental outcomes should be monitored. The recent study by Garite et al is an important step toward this goal.
      • Garite T.J.
      • Kurtzman J.
      • Maurel K.
      • Clark R.
      Obstetrix Collaborative Research Network
      Impact of a rescue course of antenatal corticosteroids: a multicenter randomized placebo-controlled trial.

      Acknowledgments

      Data Safety Monitoring Board members: Robert Steiner, MD and Melanie Gillingham, PhD.
      We thank the neonatologists, obstetricians, neonatal fellows, and the staff of our Newborn Intensive Care Units for their cooperation with the study. We also thank the parents and infants who participated in this study.

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