The Effect of a Single Remote Course Versus Weekly Courses of Antenatal Corticosteroids on Functional Residual Capacity in Preterm Infants: A Randomized Trial
* Department of Pediatrics, Division of Neonatology
Department of Obstetrics and Gynecology, Sacred Heart Hospital, University of Florida, Pensacola, Florida
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Objective. There are no randomized data on the effect of repeat courses of corticosteroids during pregnancy on newborn pulmonary function. Our objective was to compare the effect of a single remote course of antenatal steroids (AS) with weekly courses of AS on functional residual capacity (FRC) and respiratory compliance in preterm infants.
Study Design/Methods. Pregnant women 25 to 33 weeks’ gestation, who remained undelivered 1 week after their first course of antenatal corticosteroids (two 12-mg doses of betamethasone) were randomized to weekly courses of corticosteroids versus weekly placebo until delivery or 34 weeks’ gestation. FRC was measured with the nitrogen washout technique and respiratory compliance with the single breath occlusion technique within 48 hours of life.
Results. Thirty-seven infants (mean gestational age at delivery 
32.5 weeks) were studied. Maternal and infant demographics were similar. There was no significant difference in FRC (28.5 vs 27.5 mL/kg) or respiratory compliance between the infants who received a single remote course of antenatal corticosteroids and those who received weekly courses of corticosteroids until delivery. There was no significant difference in admission head circumference or birth weights between the groups.
Conclusions. Our results demonstrate that weekly repetitive courses of AS do not significantly increase FRC or respiratory compliance in preterm infants when compared with a single remote course of steroids given at a mean gestational age of 29 weeks.
Key Words: functional residual capacity • antenatal corticosteroids • respiratory compliance • respiratory distress syndrome • preterm infants
Abbreviations: AS, antenatal steroids • RDS, respiratory distress syndrome • NIH, National Institutes of Health • FRC, functional residual capacity • Crs, passive respiratory compliance • ACTH, adrenocorticotrophic hormone
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INTRODUCTION |
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Antenatal steroids (AS) decrease neonatal mortality and respiratory distress syndrome (RDS) in treated preterm infants.1,2 The use of AS therapy has increased1,2 since the 1994 National Institutes of Health (NIH) Consensus Conference, which recommended that a single course of AS should be given to women between 24 and 34 weeks’ gestation at significant risk of preterm delivery. This conference identified investigation of the potential risks and benefits of repeated courses of AS during pregnancy as a priority for future research.2
Pulmonary function testing has been used to quantify the newborn infant’s physiologic response to therapeutic interventions.3,4 We have used pulmonary function testing as an objective way of quantifying the effect of different permutations of AS on functional residual capacity (FRC, or lung volume at the end of expiration) and passive respiratory compliance (Crs), 5,6 and have correlated these measurements with clinical outcomes. There are no randomized data on the effect of repetitive dosing of AS on pulmonary function in preterm infants.
The objective of our study was to quantify and compare the effect of weekly courses of AS versus a single remote course of AS, ie, an initial course of AS followed by weekly courses of placebo, on lung volume (FRC) and Crs in preterm infants. Based on our previous data, we hypothesized that these 2 groups of preterm infants would have comparable FRC measurements.
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METHODS |
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Eligibility Criteria
Thirty-seven infants were prospectively studied in the intensive care nursery at Sacred Heart Hospital in Pensacola, Florida, over a 3-year period ending in December 1999. The hospital’s institutional review board approved the study, and informed consent was obtained from the parents. Eligibility criteria included the following: 1) pregnant women at 25 to 33 weeks’ gestation; 2) singleton gestation; 3) undelivered 1 week after an initial course of AS (defined as two 12-mg doses of betamethasone, intramuscularly) given because of increased risk of preterm delivery; and 4) informed consent obtained. The gestational age was calculated from the last normal menstrual period and confirmed by Ballard examination. We excluded infants delivered to insulin-dependent diabetic mothers, drug-addicted mothers, and infants with multiple congenital anomalies. Once eligibility criteria were met and consent obtained, the mothers were randomized in a double-blinded fashion to weekly courses of AS (two 12-mg doses of betamethasone [Celestone Soluspan, Schering Corporation, Kenilworth, NJ] intramuscularly) or weekly courses of placebo until delivery or 34 weeks’ gestation. The placebo was identical in appearance to the betamethasone and consisted of 25 mg of cortisone acetate, an inactive steroid.7 We defined the infants who received an initial course of AS followed by weekly courses of placebo as the single course remote group, and those who received weekly courses of AS as the repetitive group.
Study Design/Methods
A randomized, double-blinded study design was used, with group assignment done through the pharmacy using a randomization table. The study medication was prepared by the pharmacy, and the investigators and clinical care providers were unaware of the treatment allocation. Pulmonary function including FRC and Crs were measured within 48 hours of age. Comparison of the FRC measurements between the 2 groups of infants was our primary endpoint. Clinical outcome measures between the groups were monitored, and a subset of patients had an adrenocorticotrophic hormone (ACTH) stimulation test performed. Infants were studied supine while quietly asleep. Infants who required surfactant had to be studied before its administration (rescue therapy).
Measurements
FRC and respiratory mechanics were measured with a computerized infant pulmonary function cart (SensorMedics 2600, SensorMedics, Inc, Yorba Linda, CA). FRC was measured with the nitrogen washout method8–10 and respiratory mechanics with the single-breath occlusion technique.11,12 Both measurements can be performed in intubated and extubated infants, as previously reported.5,6
For the nitrogen washout technique,5,6,8–10 calibration was done with 2 known volumes, and a calibration line was constructed for the system at the specific flow rate. The infant was switched in at end expiration from his/her baseline fraction of inspired oxygen to 100% oxygen at the flow rate used for calibration. 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 the following: 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) a coefficient of variation <10%.13
Passive respiratory mechanics were measured with the single-breath occlusion technique.5,6,11,12 The airway was occluded at end inspiration until an airway pressure plateau was observed and the Hering Breuer reflex invoked. From the passive flow-volume curve, respiratory system compliance and resistance were calculated. Acceptance criteria included the following: 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%.13
Clinical outcome parameters including admission head circumference, surfactant administration, days on oxygen, and mechanical ventilation were monitored. A subset of patients had an ACTH stimulation test14 performed on day 5 of life using the chemiluminescence method (Access Cortisol, Beckman Instruments, Inc, Fullerton, CA). For this test, Cortrosyn (Organen Inc, West Orange, NJ) (ACTH) 36 µg/kg was given intravenously, and cortisol levels were drawn before and 30 minutes after Cortrosyn administration.
Statistical Analysis
We have reported a 50% increase in FRC in preterm infants treated with a single course of AS when compared with untreated infants.5 For this study, we hypothesized that the FRC of the single course remote group would be no >10% smaller than the FRC measured in the repetitive AS group. If the 2 treatment groups are equivalent in terms of FRC changes, we estimated we would need to study 25 patients in each group to reject the null hypothesis with an 
of 0.05 and a power of 80%. An interim analysis was performed after the enrollment of 40 patients. At that time there was no trend toward a difference in FRC between the groups, and because of increasing data of possible adverse effects of repetitive AS therapy we believed it was ethically appropriate to stop enrollment of patients. Our current sample size allows us to say that the average FRC in the single course remote group is no >12% smaller than the average FRC in the repetitive group with an of 0.05 and a power of 80%.
An intention-to-treat analysis was performed. Differences in FRC and respiratory mechanics were evaluated using the Student t test for independent samples (2-tailed). Student t test or Mann-Whitney U test were used to compare continuous variables, and categorical variables were analyzed with Pearson 
2 or Fisher exact test as appropriate (SPSS for Windows, version 7.5, SPSS, Chicago, IL). Statistical significance was set at P < .05 for all tests.
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RESULTS |
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Fifty-eight patients were potentially eligible for enrollment during the study period, and 37 were enrolled. The other 21 eligible patients were not enrolled because informed consent was not obtained because of family refusal to participate, unavailability of the principal investigator, or the refusal of the attending physician to enroll the patient. There was no difference in birth weight, race, or gender between infants enrolled and those who were not enrolled. Of the 37 patients enrolled, 19 were randomized to the single course remote group and 18 to the weekly repetitive group. Infants in both groups received their initial course of AS at an average of 29 weeks and were consented and randomized at 30 weeks’ gestation when they remained undelivered. The infants randomized to the single course remote group delivered at a mean gestational age of 32.8 weeks versus 32.2 weeks for the infants who received weekly repetitive courses (Table 1). The mean birth weight in the single course remote group was 1975 g versus 1767 g in the weekly repetitive group (median birth weights: 1805 g vs 1740 g). One infant in each group delivered at >36 weeks’ gestation. Maternal and infant characteristics were comparable between the 2 groups (Table 1).
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Women treated with weekly courses of AS received 2 to 5 courses with a mean of 2.8 courses (8 mothers received 2 courses; 5 received 3 courses; 4 received 4 courses; 1 received 5 courses). The infants in the single course remote group delivered an average of 24 days after dosing with AS (range: 7.5–55 days). The pulmonary function tests were performed at a median age of 24 hours in both groups; 37 infants had successful FRC studies, and 31 had successful Crs measurements. Crs failures were attributable to inadequate relaxation of the infant. There was no significant difference in the measurements of FRC (28.5 vs 27.5 mL/kg; P = .68) or Crs (1.09 vs 1.32 mL/cm H2O/kg; P = .37; Figs 1 and 2) in the single course remote group versus the repetitive group, respectively. More infants in the repetitive group were on mechanical ventilation at the time of study, but all were ventilated with a physiologic positive end expiratory pressure of 4 cm H2O. If only extubated patients were examined, the pulmonary function test results remained the same between the 2 groups. Of the 19 infants in the single course remote group, 7 delivered <14 days after dosing and 12 infants delivered
14 days after dosing with AS. There was no significant difference in FRC or Crs between these infants.
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Although not the primary outcome variables of our study, there was no significant difference in any of the important clinical outcome parameters including admission head circumference or birth weight between the 2 groups (Tables 1 and 2). A comparable number of infants in each group received surfactant, and there was no significant difference in days on mechanical ventilation or on oxygen supplementation. Of the subset of infants who had an ACTH stimulation test performed (n = 11), there was no significant difference in the baseline serum cortisol levels, but the repetitive weekly group had a significantly decreased level of cortisol at 30 minutes after Cortrosyn when compared with the single course remote group (20.1 vs 33.5 µg/dL; P <.05; Table 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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In 1994, the NIH Consensus Conference recommended the use of a single course of AS for threatened deliveries between 24 and 34 weeks’ gestation, but cautioned that repeat AS administration during pregnancy required additional study.2 Subsequently, the use of a single course of AS significantly increased, but widespread use of repeat courses of AS also evolved. There are growing animal data and retrospective clinical data indicating that multiple courses of AS may not be clinically beneficial, and may have adverse effects on the ultimate growth of the lung and brain of preterm infants.15–18 A more recent NIH Consensus Conference recommended that repeat courses of AS during pregnancy should not be given outside of a study protocol.19 There are currently no published randomized trials regarding the effect of repeat courses of AS on newborn lung function, specifically FRC. Our randomized, controlled trial demonstrates no significant difference in FRC or Crs between infants who received a single remote course of AS at an average gestational age of 29 weeks compared with infants who received weekly courses of AS started at the same average gestational age.
Studies of pulmonary mechanics after repetitive AS therapy in preterm lamb models have had different results. One study16 using the maternal route of administration demonstrated incremental increases in lung volume and compliance with additional doses of betamethasone, whereas a separate study20 using fetal administration showed no significant improvement in lung function after retreatment. The difference in the conclusions of these studies may be attributable to differences in the route of administration of AS, gestational age at the initiation of treatment, or interval between doses required to achieve the cumulative effect. Jobe et al21 examined the effect of fetal and maternal administration of repetitive antenatal corticosteroids given at 7-day intervals in preterm lambs. In this study, both modes of therapy significantly increased lung function, but the maternal route of administration was the more potent, implicating the probable induction of a maturational agent through the placenta.
Similar to animals studies, we have reported a 50% increase in both FRC and Crs in 20 preterm infants (mean gestational age: 28.8 weeks) who received a single course of AS when compared with 20 matched infants who did not receive AS therapy.5 The FRC values of the single course remote group and of the weekly repetitive group in our present study are very consistent with our previously published FRC values in the group treated with a single course of AS.5 Our present randomized trial does not demonstrate incremental increases in FRC with repetitive dosing of AS. The remote single course group continued to have a comparable FRC to the repetitive group regardless of dosing to delivery interval. These results seem to support the premise of a long-lasting structural effect of AS on lung volume (FRC). Unlike our previous nonrandomized study,6 which demonstrated the repetitively treated infants to have a significantly higher Crs compared with the single course group, we demonstrated only a trend for a difference in Crs between the 2 groups of infants in our present study. The difference in the Crs measurements between the 2 studies may have been attributable to the following: differences in study design (nonrandomized vs randomized); different total AS dosages given to the repetitive groups; and different mean time intervals from dosing of AS until delivery between the 2 study’s single course remote groups.
The consistent measurement of FRC is important in that it reflects the growth and development of the lung, can be used to quantify treatment responses, to predict the disease course, and is an important reference value for other measurements of pulmonary mechanics. Increases in FRC after AS therapy can be secondary to structural changes in the lungs, increased surfactant production, and/or secondary to increased distension of patent alveoli, decreased atelectasis, and decreased pulmonary edema.10,22 Our findings of an increased FRC after a single course of AS therapy are consistent with the improved clinical outcomes in treated preterm infants including decreased RDS.1,2 Of interest, the infants in the present study without RDS had a significantly higher FRC than those who had RDS.
A recently published randomized study23 evaluating the effect of repetitive courses of AS versus a single course of AS demonstrated no differences in composite morbidity (including severe RDS and bronchopulmonary dysplasia), birth weight, or admission head circumference between the 2 groups of infants. There was a reduced risk of severe RDS in infants <28 weeks’ gestation in the repetitive group. Previous retrospective studies have had varying results, but have raised concern regarding repetitive AS therapy and possible fetal growth retardation. French et al18 reported no decrease in RDS after multiple courses of antenatal steroids, but did report a decrease in birth weight and head circumference with increasing courses of AS. Banks et al17 found that infants exposed to >2 courses of AS had a lower birth weight, those exposed to >3 courses had an increased risk of death, and found no relationship between the incidence of RDS and the number of courses of steroids. Although not the primary endpoints of our study, we found no significant difference in the clinical outcome measures between the 2 groups of infants.
Our study was randomized and double-blinded, but it still had some limitations. We did not see a difference in clinical outcome measures between the 2 groups of infants, but our sample size did not have the power to address these issues as it was based on changes in FRC as the primary endpoint. Only 14% of our study population delivered at <28 weeks’ gestation, thus more information is needed in these very low birth weight infants. Our study involved a relatively small number of patients so we cannot rule out a ß error completely, but it is unlikely that there would be a significant difference in FRC between the 2 groups because no trend was detected. Our current sample size allows us to say that the FRC in the single course remote group is no >12% smaller than the FRC in the repetitive group with an of 0.05 and a power of 80%. Several maternal factors and events surrounding delivery can stimulate the secretion of endogenous steroids and impact the subsequent measurement of lung function. With randomization, there was no significant difference between the 2 groups in terms of important maternal or infant risk factors. In addition, all pulmonary function tests were performed at a median age of 24 hours in both groups, or before surfactant therapy if clinically indicated.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This randomized, placebo-controlled trial demonstrates no significant difference in FRC or Crs in preterm infants who received a single remote course of AS therapy (initiated at a mean gestational age of 29 weeks) versus infants who received weekly courses of AS until delivery or 34 weeks’ gestation. In view of the possible serious adverse effects of repetitive AS therapy on growth and the lack of demonstrated additional benefit on pulmonary function, this preliminary trial does not support the administration of weekly courses of AS in pregnant women.
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ACKNOWLEDGMENTS |
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This study was supported, in part, by the American Lung Association.
We thank the neonatologists, obstetricians, intensive care nurses, and respiratory therapists at Sacred Heart Hospital who helped facilitate this study. We also thank Dr Manuel Durand and Dr James Padbury for critical review of the manuscript.
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FOOTNOTES |
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Received for publication Oct 15, 2002; Accepted Mar 6, 2002.
Reprint requests to (C.M.) Pediatrics Department (CDRC-P), Oregon Health and Science University, 707 SW Gaines Rd, Portland, OR 97201-2998. E-mail: mcevoyc{at}ohsu.edu
This study was presented, in part, at the Society for Pediatric Research Annual Meeting, Baltimore, MD, May 1, 2001.
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REFERENCES |
|---|
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
- Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol.1995; 173 :322 –334[CrossRef][Web of Science][Medline]
- National Institutes of Health Consensus Development Conference Statement. Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28-March 2, 1994. Am J Obstet Gynecol.1995; 173 :246 –252[CrossRef][Web of Science]
- Kugelman A, Durand M, Garg M. Pulmonary effect of inhaled furosemide in ventilated infants with severe bronchopulmonary dysplasia.
Pediatrics.1997; 99
:71
–75
[Abstract/Free Full Text] - Durand M, Sardesai S, McEvoy C. Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial.
Pediatrics.1995; 95
:584
–590
[Abstract/Free Full Text] - McEvoy C, Bowling S, Williamson K, Stewart M, Durand M. Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants. Pediatr Pulmonol.2001; 31 :425 –430[CrossRef][Web of Science][Medline]
- McEvoy C, Bowling S, Williamson K, Collins J, Tolaymat L, Maher J. Timing of antenatal corticosteroids and neonatal pulmonary mechanics. Am J Obstet Gynecol.2000; 183 :895 –899[CrossRef][Web of Science][Medline]
- Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
Pediatrics.1972; 50
:515
–523
[Abstract/Free Full Text] - Gerhardt T, Hehre D, Bancalari E, Watson H. A simple method for measuring functional residual capacity by N2 washout in small animals and newborn infants. Pediatr Res.1985; 19 :1165 –1169[Web of Science][Medline]
- Yuksel B, Greenough A, Chan V, Russell RR. Comparison of helium dilution and nitrogen washout measurements of functional residual capacity in premature infants. Pediatr Pulmonol.1993; 16 :197 –200[Web of Science][Medline]
- Cotton RB, Olsson T, Law AB, et al. The physiologic effects of surfactant treatment on gas exchange in newborn premature infants with hyaline membrane disease. Pediatr Res.1993; 34 :495 –501[Web of Science][Medline]
- LeSouef PN, England SJ, Bryan AC. Passive respiratory mechanics in newborns and children. Am Rev Respir Dis.1984; 129 :552 –556[Web of Science][Medline]
- Kelly E, Bryan H, Possmayer F, Frndova H, Bryan C. Compliance of the respiratory system in newborn infants pre- and post surfactant replacement therapy. Pediatr Pulmonol.1993; 15 :225 –230[Web of Science][Medline]
- American Thoracic Society/European Respiratory Society. Respiratory mechanics in infants: physiologic evaluation in health and disease. Am Rev Respir Dis.1993; 147 :474 –496[Web of Science][Medline]
- Hanna CE, Keith LD, Colasurdo MA, et al. Hypothalamic pituitary adrenal function in the extremely low birth weight infant. J Clin Endocrinol Metab.1993; 76 :384 –387[Abstract]
- Gumbinas M, Oda M, Huttenlocher P. The effects of corticosteroids on myelination of the developing rat brain. Biol Neonate.1973; 22 :355 –366[CrossRef][Web of Science][Medline]
- Ikegami M, Jobe AH, Newnham J, Polk DL, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.
Am J Respir Crit Care Med.1997; 156
:178
–184
[Abstract/Free Full Text] - Banks BA, Canaan A, Morgan MA, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. Am J Obstet Gynecol.1999; 181 :709 –717[CrossRef][Web of Science][Medline]
- French NP, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol.1999; 180 :114 –121[CrossRef][Web of Science][Medline]
- National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: repeat courses—NIH Consensus Development Conference Statement, August 17–18, 2000. Obstet Gynecol.2001; 98 :144 –150[CrossRef][Web of Science][Medline]
- Polk DH, Ikegami M, Jobe AH, Sly P, Kohan R, Newnham J. Preterm lung function after retreatment with antenatal betamethasone in preterm lambs. Am J Obstet Gynecol.1997; 176 :308 –315[CrossRef][Web of Science][Medline]
- Jobe AH, Newnham J, Willet K, Sly P, Ikegami M. Fetal versus maternal and gestational age effects of repetitive antenatal glucocorticoids.
Pediatrics.1998; 102
:1116
–1125
[Abstract/Free Full Text] - Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol.1995; 173 :254 –262[CrossRef][Web of Science][Medline]
- Guinn DA, Atkinson MW, Sullivan L, et al. Single versus weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized trial.
JAMA.2001; 286
:1581
–1587
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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