Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial

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OBSTETRICS

Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial Thomas J. Garite, MD; James Kurtzman, MD; Kimberly Maurel, MSN; Reese Clark, MD; for the Obstetrix Collaborative Research Network OBJECTIVE: Previous studies using repetitive courses of antenatal corti-

costeroids (ACS) have demonstrated marginal or no benefit and concern over potential risk. No prior prospective or randomized studies have evaluated the option of a single rescue course of ACS on neonatal outcome. STUDY DESIGN: A multicenter randomized double-blind placebo-controlled trial was performed from May 2003 through February 2008 in 18 private (15) and university (3) medical centers. Patients with singletons or twins ⬍ 33 weeks who had completed a single course of ACS before 30 weeks and at least 14 days before inclusion, and were judged to have a recurring threat of preterm delivery in the coming week, were included. Patients were randomized to receive a single rescue course of betamethasone, 2 12-mg doses 24 hours apart, or placebo. Exclusion criteria included: premature rupture of membranes, advanced dilation (⬎ 5 cm), chorioamnionitis, and other steroid use. RESULTS: In all, 437 patients were randomized (223 rescue steroid group and

214 placebo group). A total of 55% of patients in each group delivered at ⬍ 34

weeks. There was a significant reduction in the primary outcome of composite neonatal morbidity ⬍ 34 weeks in the rescue steroid group vs placebo (43.9% vs 63.6%; odds ratio, 0.45; 95% confidence interval, 0.27-0.75; P ⫽ .002) and significantly decreased respiratory distress syndrome, ventilator support, and surfactant use. Perinatal mortality and other morbidities were similar in each group. Including all neonates in the analysis (regardless of gestational age at delivery) still demonstrated a significant reduction in composite morbidity in the rescue course group (32.1% vs 42.6%, odds ratio, 0.65; 95% confidence interval, 0.44-0.97; P ⫽ .0034) and improvement in respiratory morbidities. CONCLUSION: Administration of a single rescue course of ACS before

33 weeks improves neonatal outcome without apparent increased short-term risk. Key words: antenatal corticosteroids, neonatal respiratory morbidity, prematurity

Cite this article as: Garite TJ, Kurtzman J, Maurel K, et al. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009;200:248.e1-248.e9.

T

he administration of antenatal corticosteroids (ACS) to mothers who subsequently deliver prematurely is one of the few obstetric interventions that

unequivocally improves outcome in premature babies.1,2 Benefits to the new-

From the Pediatrix Medical Group, Sunrise, FL (all authors), and the Department of Obstetrics and Gynecology, University of California, Irvine, College of Medicine, Irvine, CA (Drs Garite and Kurtzman). This research was presented at the 29th Annual Meeting of the Society for Maternal–Fetal Medicine, San Diego, CA, Jan. 26-31, 2009. Received Oct. 27, 2008; accepted Jan. 20, 2009. Reprints not available from the authors. The research was completely funded by the Maternal–Fetal Medicine practices of Pediatrix Medical Group, which has no financial interest in the outcome of the study. No authors have known conflicts of interest. Although the majority of authors are employed by Pediatrix Medical Group, which is a physician practice management group, Pediatrix Medical Group has no stake or interest in the outcome of the study so no conflict of interest is perceived by the authors for this relationship. However, in the interest of completeness we include this statement. Study registered with www.clinicaltrials.gov. Registration No. NCT00201643. Registered Sept. 12, 2005. 0002-9378/free • © 2009 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2009.01.021

For Editors’ Commentary, see Table of Contents See related editorial, page 217

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American Journal of Obstetrics & Gynecology MARCH 2009

born include reductions in mortality, respiratory distress syndrome (RDS), and intraventricular hemorrhage (IVH). One of the questions raised by the original randomized trials is the risk and benefit of repeating courses of ACS in patients who do not deliver in the week or 2 after the original course but who remain at risk of premature delivery. This question arose because of information suggesting that the beneficial effects of ACS were no longer apparent beyond a week after receiving the original ACS course.3 Subsequently a number of randomized controlled trials (RCTs) of multiple courses of ACS4-6 were performed as well as neonatal follow-up studies to address this question.7-9 Although showing a modest reduction in RDS, concerns have been raised including the unnecessary treatment of many patients who did not deliver prematurely. In addition, decreased fetal growth and reduction in fetal head circumference in those babies receiving multiple doses of steroids has been shown in a number of studies eval-

Obstetrics

www.AJOG.org uating repeated courses of ACS.5-8 The National Institutes of Health (NIH), in its second consensus conference regarding ACS, and the opinion of the American College of Obstetricians and Gynecologists, concluded that “repetitive doses of ACS could not be recommended outside of clinical trials including so-called rescue doses.”10,11 The concept of a rescue course of ACS basically involves administering a second course to patients whose pregnancies continue more than a week or 2 from their original course and only in whom, in the judgment of the clinician, delivery has again become likely. This is the 1 approach that has not yet been evaluated in any of the prospective randomized trials of ACS. We, therefore, chose to perform a multicenter trial to evaluate the potential benefit of a single rescue course of ACS to answer this last major unanswered question regarding the optimal method of ACS administration.

M ATERIALS AND M ETHODS We performed a multicenter randomized double-blind placebo-controlled trial to evaluate the impact of a rescue course of antenatal steroids on the incidence of neonatal morbidity and mortality. Study approval was obtained from every participating hospital’s institutional review board and all women signed written informed consent. Eligible women with singleton or twin pregnancies with intact membranes at 25-32 6/7 weeks, judged to have a recurrent or continued threat of preterm delivery within the next 7 days, and who initiated their first course of betamethasone at least 14 days before enrollment and before 30 weeks’ gestation, were consented and enrolled. Consenting patients were randomized to either a repeated course of betamethasone 12 mg intramuscularly, 2 doses given 24 hours apart, or placebo. The research pharmacist (unblinded) at each site prepared the medication based on a blocked randomization sequence that was prepared centrally. The syringes were completely covered by a label to conceal the contents. As betamethasone had become unavailable in many US

hospitals, in such a situation the protocol allowed for the alternative of dexamethasone to be used in a dose of 6 mg intramuscularly every 12 hours ⫻ 4 doses total, with the placebo group receiving the same volume and frequency of normal saline. Patients excluded were those with known major fetal anomalies, with highorder multiple gestation (ⱖ triplets), with cervical dilation ⱖ 5 cm, with ruptured membranes, with clinical chorioamnionitis, with documented lung maturity, receiving corticosteroids for other maternal indications, and with human immunodeficiency virus or active tuberculosis. The remainder of clinical care remained at the discretion of the clinician. The primary outcome measure, as specified by the protocol, was composite neonatal morbidity in babies delivering ⬍ 34 weeks. Composite morbidity was defined as ⱖ 1 of the following: RDS (oxygen requirement, clinical diagnosis, and consistent chest radiograph), bronchopulmonary dysplasia (requirement for oxygen support at 30 days of life), severe IVH (grades III or IV), periventricular leukomalacia, blood culture-proven sepsis, necrotizing enterocolitis, or perinatal death (stillbirth or death before neonatal hospital discharge). Secondary outcome measures included: preterm delivery before 34 weeks, RDS alone, gestational age at delivery, birth weight, intrauterine growth restriction (IUGR), head circumference, need for surfactant therapy, pneumothorax, and maternal infectious morbidity.

Statistical Tests and Analyses We hypothesized that administration of a second rescue course of ACS, compared with 1 course, would show a 40% reduction in the incidence of composite neonatal outcome in patients delivering before 34 weeks’ gestation. The sample size was estimated based on a composite morbidity of 28%.4 Each arm required at least 217 subjects to have 80% power to detect a 40% reduction to 16.8% (2tailed, alpha ⫽ .05) using a comparison for proportions between groups (Fisher exact test). Although the prespecified primary outcome was composite neonatal morbidity/mortality in patients delivering

Research

before 34 weeks’ gestation, analyses were also conducted in all randomized women with a known outcome and in the treatment group to which they were randomized (modified intent to treat). Analysis of the primary outcome used a repeated measures approach (generalized estimating equations with an exchangeable correlation structure12 where each baby was considered the repeated measure). Odds ratios, 95% confidence intervals, and P values were determined from the repeated measures model. Differences between treatment groups in baseline maternal characteristics and maternal delivery characteristics were determined using a 2-tailed ␹2 test and Fisher exact test for dichotomous variables and a Wilcoxon rank sum test for continuous or ordinal variables. Differences between the treatment groups in neonatal characteristics and secondary outcome measures were determined from a repeated measures model where each baby was considered the repeated measure (generalized estimating equations for dichotomous variables and a mixed linear model for continuous variables). All analyses were performed using software (SAS 9.1.3; SAS Institute Inc, Cary, NC). An internal safety monitoring committee, which included 3 individuals not participating in the study, reviewed safety and efficacy data twice while the study was ongoing and reviewed all serious adverse events. Two interim analyses of the primary efficacy outcome were conducted when 24.3% (140/577) and 52.3% (302/577) of babies were delivered. Thus, based on the O’Brien-Fleming spending function, the adjusted alpha level for the primary outcome is 0.049. For all other analyses, no adjustments are made and an alpha level of 0.05 is used. All statistical tests appear as 2-sided P values.

R ESULTS This multicenter study was performed from May 2003 through February 2008 in 18 private (15) and university (3) medical centers and conducted by investigators from 10 Obstetrix/Pediatrix Medical Group (Sunrise, FL) maternal-

MARCH 2009 American Journal of Obstetrics & Gynecology

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FIGURE

Consort Flow Diagram

Assessed for eligibility = 2122

Excluded = 1685 • Not meeting inclusion criteria=1209 • Refused to participate = 324 • Met criteria but discharged from hospital prior to enrollment = 112 • Other reasons = 40

Enrollment

Randomized = 437

Allocated to ACS Group = 223 pregnancies Received allocated intervention • Full course of study drug = 196 • Partial course/delivered before full course = 17 • Delivered before 1st dose = 5 • Discontinued intervention/Withdrew = 5

Allocation

Babies Delivered = 289 • 156 = Singleton pregnancies • 67 = Twin pregnancies (1 fetal death prior to randomization)

Allocated to Placebo Group = 214 pregnancies Received allocated intervention • Full course placebo drug = 184 • Partial course/delivered before full course = 21 • Delivered before 1st dose = 5 • Discontinued intervention/Withdrew = 4

Follow-up

Neonatal Data Unavailable = 13

Babies Delivered = 288 • 140 = Singleton pregnancies • 74 = Twin pregnancies

Neonatal Data Unavailable = 6

Babies with Known Outcome n = 276

Analysis

All Randomized 88/276 (32.1%) OR, 0.65; (95% CI, 0.44-0.97); P = .034

Outcomes Composite Morbidity

Babies with Known Outcome n = 282

Delivery < 34 weeks 71/163 (43.9%) OR, 0.45; (95% CI, 0.27-0.45); P = .002

Overview of clinical trail enrollment. ACS, antenatal corticosteroids; OR, odds ratio. Garite. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009.

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All Randomized 120/282 (42.6%)

Delivery < 34 weeks 105/165 (63.6%)

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TABLE 1

Baseline characteristics All patients

GA at delivery < 34 wk

Variables

ACS

Placebo

ACS

Placebo

No. in each group

223

214

124

119

................................................................................................................................................................................................................................................................................................................................................................................

Maternal age (y), mean ⫾ std

29 ⫾ 6

29 ⫾ 6

29 ⫾ 6

28 ⫾ 5

Maternal height (in), mean ⫾ std

64 ⫾ 3

64 ⫾ 3

64 ⫾ 3

64 ⫾ 3

Maternal weight (lb), mean ⫾ std

157 ⫾ 43

160 ⫾ 47

158 ⫾ 46.

160 ⫾ 42

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

GA (wk) at randomization, mean ⫾ SD

29.5 ⫾ 2.2

29.4 ⫾ 1.9

29.1 ⫾ 2.3

29.1 ⫾ 1.9

................................................................................................................................................................................................................................................................................................................................................................................

Parity, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

0

96 (43)

84 (39.3)

56 (45.1)

49 (41.1)

1

65 (29.1)

76 (35.5)

34 (27.4)

41 (34.5)

ⱖ2

62 (27.8)

54 (25.2)

34 (27.4)

29 (24.4)

141 (63.2)

142 (66.4)

78 (62.9)

77 (64.7)

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Married, n (%)

................................................................................................................................................................................................................................................................................................................................................................................

Ethnicity, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

African American

12 (5.4)

21 (9.8)

9 (7.3)

12 (10.1)

Asian or Pacific Islander

14 (6.3)

12 (5.6)

10 (8.1)

10 (8.4)

133 (59.6)

114 (53.3)

71 (57.3)

53 (44.5)

51 (22.9)

57 (26.6)

29 (23.4)

40 (33.6)

Native American

6 (2.7)

4 (1.9)

2 (1.6)

2 (1.7)

Other

7 (3.1)

6 (2.8)

3 (2.4)

2 (1.7)

Maternal GBS, n (%)

28 (12.6)

28 (13.1)

16 (12.9)

16 (13.5)

Smoker, n (%)

36 (16.1)

38 (17.8)

24 (19.4)

19 (16.0)

4 (1.9)

3 (2.4)

1 (0.8)

7 (5.7)

7 (5.9)

44 (35.5)

47 (39.5)

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Caucasian

.......................................................................................................................................................................................................................................................................................................................................................................

Hispanic

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

ETOH abuse, n (%)

3 (1.3)

................................................................................................................................................................................................................................................................................................................................................................................

Report of drug abuse, n (%)

10 (4.5)

15 (7)

Twin pregnancy, n (%)

67 (30)

74 (34.6)

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

ACS, antenatal corticosteroids; ETOH, alcohol; GA, gestational age; GBS, group B Streptococcus; SD, standard deviation. ................................................................................................................................................................................................................................................................................................................................................................................

Garite. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009.

fetal medicine practices and 4 other practices staffed by maternal-fetal medicine attending physicians. The population was largely private/nongovernment-funded patients. After screening a total of 2122 patients for eligibility (Figure), 437 were consented and randomized, 223 to the ACS group and 214 to the placebo group. There were a total of 289 babies in the ACS group (67 women were pregnant with twins, although 1 woman had a fetal death before enrollment in the study) and 288 babies in the placebo group (74 women had twins). Neonatal data were missing for 12 and 6 babies in the ACS and placebo groups, respectively, resulting in 276 and 282 babies available for analysis of the primary efficacy outcome.

In all, 196 (88%) of the ACS group and 184 (86%) of the placebo group received a full course of antenatal steroid or placebo. In all, 31 patients received dexamethasone and 30 received the dexamethasone placebo of which 23 and 22 received a full course, respectively. As the protocol specified, primary outcome of the study was neonatal composite morbidity at ⬍ 34 weeks; there were 124 (56%) ACS and 119 (55%) placebo patients who actually delivered at ⬍ 34 weeks. The mean intervals between randomization and delivery were 24.5 and 25.1 days, respectively. Premature delivery (⬍ 36 weeks) was also similar between the 2 groups: ACS (168/218; 77.1%) and placebo (173/212; 81.6%). At enrollment and at delivery the groups

were similar in all evaluated variables (Tables 1 and 2). The maternal outcomes did not differ between the 2 groups. In particular, rates of chorioamnionitis (6 vs 9) and sepsis (2 vs 1) were similar for the ACS vs placebo groups, respectively. There was 1 maternal death in a placebo group patient who withdrew from the study before receiving any injection. For the primary endpoint, there was a significant reduction in composite morbidity at ⬍ 34 weeks in the ACS group vs placebo group (Table 3). In addition, at this gestational age in the ACS group there were fewer cases of RDS, less need for surfactant, and less frequent need for ventilator support. There were no differences in mortality or any of the other

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TABLE 2

Comparison of groups at delivery All patients No. in each group

ACS

34 wk at delivery Placebo

P

ACS

Placebo

P

Enrolled mothers

223

214

124

119

Fetuses/newborns (each baby counted in twin pairs)

289

288

167

166

Report of tocolysis, n (%)

181 (81.2)

173 (80.8)

.931

99 (79.8)

92 (77.3)

.631

Antibiotics reported, n (%)

149 (66.8)

139 (65.0)

.681

78 (62.9)

82 (68.9)

.324

.877

30.9 ⫾ 2.0

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Gestational age (wk) at delivery, mean (SD)

33.1 ⫾ 3.1

33.0 ⫾ 3.1

30.8 (1.8)

.705

................................................................................................................................................................................................................................................................................................................................................................................

Birth weight (g), mean (SD)

1905 ⫾ 738

1920 ⫾ 667

.805

1517 ⫾ 478

1506 ⫾ 413

.861

................................................................................................................................................................................................................................................................................................................................................................................

Head circumference (cm)

30.2 ⫾ 3.0

30.0 ⫾ 2.9

.523

28.5 ⫾ 2.5

28.6 ⫾ 2.7

.760

................................................................................................................................................................................................................................................................................................................................................................................

Delivery reason, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Maternal hemorrhage/abruption

9 (3.1)

11 (3.8)

.643

6 (3.6)

6 (3.6)

Amniocentesis for ⫹FLM or term

.989

.......................................................................................................................................................................................................................................................................................................................................................................

20 (6.9)

34 (11.8)

.106

0

4 (2.4)

Clinical chorioamnionitis

2 (0.7)

2 (0.7)

.997

2 (1.2)

2 (1.2)

.995

Fetal distress

4 (1.4)

16 (5.6)

.022

3 (1.8)

13 (7.8)

.041

Incompetent cervix

1 (0.4)

4 (1.4)

.167

1 (0.6)

4 (1.2)

.170

Maternal complication

15 (5.2)

14 (4.9)

.904

12 (7.2)

6 (3.6)

.205

Nonreassuring fetal testing

20 (6.9)

17 (5.9)

.399

16 (9.6)

16 (9.6)

.635

3 (1.0)

4 (1.4)

.768

2 (1.2)

PIH

14 (4.8)

18 (6.3)

.742

10 (6.0)

16 (9.6)

.404

Preterm labor unstoppable or not stopped

89 (30.1)

93 (32.3)

.554

53 (31.7)

59 (35.5)

.297

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

Oligohydramnios

0

NC

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

PROM infection

1 (0.4)

0

NC

1 (0.6)

0

NC

.......................................................................................................................................................................................................................................................................................................................................................................

PROM/labor

35 (12.1)

25 (8.7)

.3290

25 (15.0)

17 (10.2)

.358

Severe IUGR

7 (2.4)

6 (2.1)

.742

5 (3.0)

1 (0.6)

.100

Worsening fetal condition

14 (4.8)

11 (3.8)

.665

11 (6.6)

10 (6.0)

.831

Other

43 (14.9)

27 (9.4)

.070

17 (10.2)

10 (6.0)

.159

Unknown

12 (4.2)

5 (1.7)

.125

3 (1.8)

1 (0.6)

.574

....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................

Route of delivery, n (%)

.......................................................................................................................................................................................................................................................................................................................................................................

Cesarean section

186 (64.4)

202 (70.1)

.244

119 (71.3)

132 (79.5)

.211

80 (27.7)

76 (26.4)

.692

40 (24.0)

31 (18.7)

.350

9 (3.1)

4 (1.4)

.258

4 (2.4)

1 (0.6)

.378

14 (4.8)

6 (2.1)

.145

4 (2.4)

2 (1.2)

.622

.......................................................................................................................................................................................................................................................................................................................................................................

Spontaneous vaginal delivery

.......................................................................................................................................................................................................................................................................................................................................................................

Operative vaginal delivery

.......................................................................................................................................................................................................................................................................................................................................................................

Unknown (lost to follow-up)

................................................................................................................................................................................................................................................................................................................................................................................

Cord pH arterial median

7.27 ⫾ .07

7.28 ⫾ .08

.753

7.29 ⫾ .07

7.27 ⫾ .09

.128

Cord pH venous median

7.33 ⫾ .07

7.32 ⫾ .08

.277

7.34 ⫾ .07

7.32 ⫾ .08

.062

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Apgar 1 min ⬍ 5, n (%)

32 (11.1)

43 (14.9)

.166

27 (16.2)

33 (19.9)

.274

Apgar 5 min ⬍ 7, n (%)

18 (6.2)

23 (8)

.338

17 (10.2)

18 (10.8)

.636

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

ACS, antenatal corticosteroids; FLM, fetal lung maturity; IUGR, intrauterine growth restriction; NC, not calculable; PIH, pregnancy induced hypertension; PROM, premature rupture of membranes; SD, standard deviation. ................................................................................................................................................................................................................................................................................................................................................................................

Garite. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009.

morbidities at this gestational age including IVH, sepsis, and pneumonia. Including all babies at all gestational ages, there was also a statistically significant 248.e5

reduction in composite morbidity, RDS, and use of surfactant, but not in need for ventilator therapy; and there were no differences in the remainder of the morbid-

American Journal of Obstetrics & Gynecology MARCH 2009

ities or mortality. The rates of perinatal death were also similar (Table 4). There was 1 stillbirth and 4 neonatal deaths in the ACS group and 1 stillbirth and 6 neo-

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TABLE 3

Neonatal morbidity and mortality-delivery < 34 weeks Neonatal morbidity

ACS n/N (%)

Placebo n/N (%)

ORa (95% CI)

P valuea

Composite morbidity

71/163 (43.9)

105/165 (63.6)

0.45 (0.27-0.75)

.002

RDS

67/162 (41.4)

101/164 (61.6)

0.45 (0.27-0.75)

.002

BPD

27/160 (16.9)

20/163 (12.3)

1.53 (0.77-3.07)

.228

Surfactant

61/162 (37.7)

91/164 (55.5)

0.49 (0.30-0.80)

.004

Ventilator

59/157 (37.6)

83/157 (52.9)

0.56 (0.33-0.92)

.023

ROP

21/153 (13.7)

19/151 (12.6)

0.12 (0.54-2.34)

.760

3/153 (2.0)

2/151 (1.3)

2.47 (0.25-24.58)

.442

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

ROP grade 3 or 4

................................................................................................................................................................................................................................................................................................................................................................................

IVH

17/160 (10.6)

23/163 (14.1)

0.72 (0.34-1.50)

.378

IVH grade 3 or 4

5/160 (3.1)

4/162 (2.5)

1.34 (0.32-5.57)

.684

NEC

8/162 (4.9)

11/163 (6.8)

0.70 (0.26-1.90)

.485

Sepsis

7/162 (4.3)

12/164 (7.3)

0.54 (0.19-1.58)

.262

Perinatal death

5/162 (3.1)

7/166 (4.2)

0.61 (0.17-2.21)

.451

Pneumothorax

3/162 (1.9)

4/164 (2.3)

0.77 (0.17-3.45)

.734

PVL

3/159 (1.9)

4/161 (2.5)

0.76 (0.17-3.41)

.720

Pneumonia

3/161 (1.9)

5/164 (3.1)

0.64 (0.14-3.01)

.577

25/162 (15.4)

20/161 (12.4)

1.33 (0.70-2.55)

.383

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

IUGR (⬍ 10th percentile)

................................................................................................................................................................................................................................................................................................................................................................................

ACS, antenatal corticosteroids; BPD, bronchopulmonary dysplasia; CI, confidence interval; IUGR, intrauterine growth restriction; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; OR, odds ratio; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROC, retinopathy of prematurity. a

OR, 95% CI, and P value are determined using a repeated measures model where each twin is considered a repeated measure.

................................................................................................................................................................................................................................................................................................................................................................................

Garite. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009.

natal deaths in the placebo group. Of the neonatal deaths, 3 in the ACS group and 4 in the placebo group were related to complications of prematurity (IVH, necrotizing enterocolitis, sepsis). We also analyzed the questions regarding the timing and duration of effectiveness of this second rescue course of ACS. The largest and most significant difference in composite morbidity was seen between 2 and 7 days elapsed from the first dose of the rescue course (Table 5). Although not a predesignated analysis, it is also clinically important to examine in which gestational ages the greatest efficacy was seen. The reduction in composite morbidity with ACS was limited to babies ⬍ 33 weeks: 62/129 (48%) ACS vs 95/131 (72.5%) placebo (odds ratio, 0.40; 95% confidence interval, 0.23-0.71; P ⬍ .002). There was no difference in outcome at ⱖ 33 weeks: 26/147 (18%) ACS vs 25/155 (17%) placebo (P ⫽ .811). These 2 groups were otherwise similar in gestational age at randomization and latency to delivery and other entry variables.

Neonatal anthropomorphic measurements are of particular interest, and there was no difference in birth weight, rates of IUGR, or head circumference (Table 2). As lagging body or head growth due to repetitive corticosteroids may not be reflected in babies who deliver soon after treatment, we also analyzed these parameters in babies delivering after 36 weeks and ⬎ 14 days after treatment (n ⫽ 49 ACS and 45 placebo). This subanalyses demonstrated similar mean head circumferences (33.0 cm study vs 32.5 cm placebo), mean birth weights (2821g vs 2803 g), and rates of IUGR (0 vs 1; 2.2%). In neither analysis was there a statistical difference or a trend toward reduced body or head growth in rescue steroid–treated pregnancies; however, the sample size of this analysis may not be sufficient to detect even modest differences.

C OMMENT There are 2 important clinical questions addressed by this study. The first is

whether the use of rescue steroids reduces morbidity and/or mortality in patients who have been previously treated with ACS but who again threaten to deliver before 34 weeks. The results of this study demonstrate a benefit in composite morbidity and decrease in the presence and severity of RDS, but not mortality or other morbidities at ⬍ 34 weeks. This benefit was also seen in the overall group, but of course this is affected by the magnitude of benefit in the earlier gestations and the fact that the majority delivered before 34 weeks. The second important question addressed is whether this discretionary method of ACS administration based on the clinician’s judgment of impending risk as compared with simply giving repeated doses to all patients at risk (eg, all twins, all previous preterm deliveries) more correctly identifies babies who will actually deliver before 34 weeks (and, therefore, would potentially benefit by treatment). This is the only prospective and randomized study to date evaluating

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Obstetrics

www.AJOG.org

TABLE 4

Neonatal morbidity–all newborns Neonatal morbidity

ACS n/N (%)

Placebo n/N (%)

ORa (95% CI)

P valuea

Composite morbidity

88/276 (32.1)

120/282 (42.6)

0.65 (0.44-0.97)

.034

RDS

83/275 (30.2)

116/281 (41.3)

0.64 (0.43-0.95)

.026

BPD

27/273 (9.9)

20/278 (7.2)

1.50 (0.76-2.94)

.239

Surfactant

70/273 (25.6)

99/280 (35.4)

0.65 (0.43-0.98)

.038

Ventilator

70/267 (26.2)

95/273 (34.8)

0.70 (0.46-1.06)

.088

ROP

21/260 (8.1)

19/267 (7.1)

1.15 (0.56-2.34)

.704

3/260 (1.2)

2/267 (0.8)

2.51 (0.25-24.83)

.432

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

ROP grade 3 or 4

................................................................................................................................................................................................................................................................................................................................................................................

IVH

19/272 (7.0)

25/274 (9.1)

0.76 (0.38-1.49)

.422

IVH grade 3 or 4

6/272 (2.2)

4/274 (1.5)

1.65 (0.43-6.31)

.462

NEC

8/275 (2.9)

11/280 (3.9)

0.72 (0.27-1.91)

.503

Sepsis

7/275 (2.6)

12/288 (4.3)

0.55 (0.19-1.60)

.275

Perinatal death

5/276 (1.8)

7/282 (2.5)

0.60 (0.17-2.18)

.440

Pneumothorax

4/275 (1.5)

4/281 (1.4)

1.03 (0.26-4.13)

.967

PVL

3/269 (1.1)

4/272 (1.5)

0.76 (0.17-3.40)

.718

Pneumonia

3/274 (1.1)

5/281 (1.8)

0.66 (0.14-3.04)

.589

29/275 (10.6)

28/278 (10.1)

1.07 (0.61-1.86)

.822

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

IUGR (⬍ 10th percentile)

................................................................................................................................................................................................................................................................................................................................................................................

ACS, antenatal corticosteroids; CI, confidence interval; IUGR, intrauterine growth restriction; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; OR, odds ratio; RDS, respiratory distress syndrome. a

OR, 95% CI, and P value are determined using a repeated measures model where each twin is considered a repeated measure.

................................................................................................................................................................................................................................................................................................................................................................................

Garite. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009.

this rescue approach to ACS treatment. One retrospective study by Vermillion et al13 did demonstrate a reduction in RDS using a rescue approach, but that study also differed in that a single dose of betamethasone was used rather than a full 2-dose course. A previous prospective randomized study by Peltoniemi et al14

also used a single booster dose of betamethasone in patients, but showed no benefit, as 79% of their patients delivered in ⬍ 24 hours. In contrast, 89% of our patients received a full rescue course of ACS, and 55% of patients did deliver before 34 weeks. Overall, 78% of our patients delivered before 36 weeks. Of the

TABLE 5

Neonatal composite morbidity by days from first dose to delivery ACS n/N (%)

Placebo n/N (%)

P valuea

0 or 1 d

13/25 (52.0)

15/20 (75.0)

.067

2-7 d

24/61 (39.3)

37/53 (69.8)

.035

8-14 d

15/37 (40.5)

24/47 (51.5)

.328

15-21 d

9/22 (40.9)

21/32 (65.6)

.173

22-28 d

13/31 (41.9)

12/39(30.8)

.550

⬎ 28 d

14/100 (14.0)

11/91 (12.1)

.588

.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................

ACS, antenatal corticosteroids. a

Odds ratio, 95% confidence interval, and P value are determined using a repeated measures model where each twin is considered a repeated measure.

..............................................................................................................................................................................................................................................

Garite. Impact of a ‘rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. Am J Obstet Gynecol 2009.

248.e7

American Journal of Obstetrics & Gynecology MARCH 2009

previous multicenter studies that used routine repetitive doses of ACS, 2 of the 3 included patients with preterm premature rupture of membranes (PPROM), who are obviously at much higher risk of imminent delivery than the patients included in this study.4,6 The only other previous study that also excluded patients with PPROM had only 36% of patients who delivered before 34 weeks and 56% who delivered before 36 weeks.5 Therefore, it appears with this discretionary method, as opposed to routine repetitive dosing, we were better able to correctly identify patients who would truly benefit by this treatment and avoid unnecessarily treating those who would not (ie, deliver at or near term). In clinical practice the potential downside to this rescue steroid approach, however, is the question of how many babies who might have benefited by a routine repetitive dosing approach may not have been treated due to delivery shortly after admission. This issue could not be answered by this study as there

Obstetrics

www.AJOG.org was no opportunity to enroll or randomize patients at or immediately after their first course of ACS because many patients were maternal transfers who had received the course previously at another institution. However, only 38 (9%) of our patients delivered before receiving a complete rescue course of ACS and only 10 (2%) delivered before receiving the first dose of the rescue course. The NIH consensus conference on ACS3 concluded that even delivering 24 hours after the first dose of steroids imparts benefit, although this is only proven with the first course. Thus, it is possible that many of these 38 babies in our study who delivered before a full rescue course of ACS may have derived some benefit. The answer to whether a routine second course of steroids as opposed to a rescue course is the more optimal method could and perhaps should only be answered in a randomized trial comparing the 2 methods. From a purely scientific standpoint this is not a true intent-to-treat study as the primary endpoint was reduction in morbidity in patients who delivered at ⬍ 34 weeks as opposed to the entire population enrolled in the study. Technically, it could be said that this is a subgroup analysis. This argument is mitigated by the fact that the benefit in both composite and respiratory morbidity is seen in the entire study group including all patients who delivered before and after 34 weeks. We are compelled to use this primary endpoint of ⬍ 34 weeks as this was the actual hypothesis of the study. This endpoint was chosen for 2 reasons. First, virtually all studies have shown respiratory benefit of ACS at ⬍ 34 weeks. And the second question we wanted to an-

swer was whether such a selective approach actually better identifies those patients who will deliver ⬍ 34 weeks as opposed to the routine repetitive approach, the downside of which is that more patients are unnecessarily treated, ultimately delivering beyond 34 weeks. We chose not to include patients with PPROM in this study for 2 reasons. Two previous studies have shown an increase in serious maternal and neonatal infectious morbidity in patients receiving a second course of ACS in the setting of ruptured membranes.15,16 In addition, the efficacy of ACS in studies of patients with ruptured membranes is not as consistently demonstrated as compared with those studies of patients with intact membranes.3 One previous RCT of multiple courses of ACS and follow-up studies on babies in previous ACS trials suggested that multiple courses of ACS decreased overall fetal growth and the growth of the fetal brain as reflected in head circumference.5,7,8 The 2-year follow-up study of Crowther et al,9 however, did not show any differences with multiple doses of corticosteroids except that more babies in the steroid group required medical attention at 2 years than in the placebo group. However, in the studies that did suggest a deleterious effect, minimal or no apparent effects were seen until ⱖ3 courses of ACS were administered. Although acknowledging that our study was not powered to address these safety issues, we did not observe a difference or a trend toward reduction in birth weight or head circumference in the ACStreated group including the subanalysis of just those babies where sufficient time

Research

elapsed to reflect this lack of growth was allowed. A recent follow-up study of babies from the National Institute of Child Health and Human Development randomized trial who received multiple course of ACS showed similar neurologic developmental testing scores, and similar growth. There was, however, a nonstatistically significant increase in the number of babies with cerebral palsy (6 ACS vs 1 in control) but 5 of 6 babies with cerebral palsy in the ACS group had been exposed to ⱖ 4 courses of ACS.17 Nonetheless, given the suggestions of potential harm with more frequent courses of ACS, it would seem prudent to limit the absolute number of courses given and to limit treatment to those babies most likely to deliver at a gestational age where they would benefit from ACS treatment. Thus, the rescue approach to retreatment used in this study would be most likely to achieve these goals. We, therefore, conclude that choosing to administer a rescue course of ACS in pregnant women treated initially ⬎ 2 weeks prior, and who are judged by the clinician to be likely to deliver within the next week and before 34 weeks of gestation, is a beneficial approach that significantly decreases respiratory complications of prematurity and is without apparent immediate or short-term adverse effects to the mother or baby. f ACKNOWLEDGMENTS The following individuals and institutions participated as investigators and research nurses: primary study coordinator, Diana Abril, RN, BSN; statistical analysis by Anita F. Das, PhD, AxiStat Inc, San Francisco, CA; and data safety monitoring board, Reese Clark, MD, Debra Guinn, MD, and Amy Kelleher, RT.

Principal investigator

Research nurse(s)

Good Samaritan Hospital San Jose CA

Andrew Combs, MD

Kimberly Ireland, RN

Phoenix Perinatal Associates, Obstetrix Banner Good Samaritan Medical Center Banner Desert Samaritan Medical Center Phoenix, AZ

Garrett Lam, MD

Eastside Maternal–Fetal Medicine, Obstetrix Evergreen Hospital Kirkland, WA

Martin Walker, MD

Practice/hospital site

................................................................................................................................................................................................................................................................................................................................................................................

Melissa Ingersoll, RN Ana Braescu, MSN

................................................................................................................................................................................................................................................................................................................................................................................

Sally Ann de-Vitry Smith, RN

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www.AJOG.org (Cont’d)

Principal investigator

Research nurse(s)

Fetal Diagnostic Center, Obstetrix Saddleback Memorial Medical Center Laguna Hills, CA

James Kurtzman, MD

Sandy Grose, RN

Obstetrix Medical Group of Washington Swedish Medical Center Seattle, WA

David Luthy, MD

Kansas City Obstetrix St. Luke’s Hospital Kansas City, MO

George Lu, MD

Obstetrix Medical Group of Arizona Tucson Medical Center Tucson AZ

Hugh Miller, MD

Southern California Obstetrix Long Beach Memorial Medical Center Long Beach, CA

Michael Nageotte, MD

University of California Irvine Orange, CA

Manuel Porto, MD

Obstetrix Medical Group of Colorado Presbyterian St. Lukes Medical Center Swedish Medical Center Rose Medical Center Denver, CO

Robert Stettler, MD

Erlanger Medical Center Chattanooga, TN University of Tennessee Medical Center Knoxville, TN

C. David Adair, MD

Tufts New England Medical Center Boston, MA

Michael House, MD Adam Wolfberg, MD

St. John’s Regional Health Center Springfield, MO

Robert Fraser, MD

Sunrise Hospital Las Vegas NV

Brian Iriye, MD

Practice/hospital site

................................................................................................................................................................................................................................................................................................................................................................................

Tina Lopez, RN

................................................................................................................................................................................................................................................................................................................................................................................

Mary Jean Brown, RN

................................................................................................................................................................................................................................................................................................................................................................................

Diane Mercer, RN

................................................................................................................................................................................................................................................................................................................................................................................

Christine Preslicka, RN Bethany Vinson, RN Deysi Caballero, LVN

................................................................................................................................................................................................................................................................................................................................................................................

Pamela Rumney, RN Lizette Spiers

................................................................................................................................................................................................................................................................................................................................................................................

Leslie Harden, MSN Mari Gambotto, PNNP Maryanne Bruno, PNP Marilyn Hall, CNM Gwen Dubois, RN

................................................................................................................................................................................................................................................................................................................................................................................

Lorrie Mason, MSN Stephanie Frazer, MSN

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

Carla Weber, RN

................................................................................................................................................................................................................................................................................................................................................................................

Judy Hancock, RNC

REFERENCES 1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25. 2. Crowley P. Antenatal corticosteroid therapy: a metaanalysis of the randomized trials 19721994. Am J Obstet Gynecol 1995;173:322-35. 3. National Institutes of Health Consensus Conference Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. JAMA 1995;273:413-8. 4. Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial. JAMA 2001;286:1581-7. 5. Wapner RJ, Sorokin Y, Thom EA, et al. Single vs weekly courses of antenatal corticosteroids: evaluation of safety and efficacy; National Institute of Child Health and Human Development maternal fetal medicine units network. Am J Obstet Gynecol 2006;195:633-42. 6. Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS, for the Australian Collabora-

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tive Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress after repeat exposure to antenatal corticosteroids: a randomized controlled trail. Lancet 2006;367:1913-9. 7. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114-21. 8. Thorp JA, Jones PG, Knox E, Clark RH. Does antenatal corticosteroid therapy affect birth weight and head circumference? Obstet Gynecol 2002;99:101-8. 9. Crowther CA, Doyle LW, Haslam RR, et al. Outcomes at 2 years after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1179-89. 10. National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: repeat courses; National Institutes of Health consensus statement. 2000;17:1-18. 11. ACOG committee opinion no. 402: antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol 2008;11:805-7.

American Journal of Obstetrics & Gynecology MARCH 2009

12. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22. 13. Vermillion ST, Bland ML, Soper DE. Effectiveness of a rescue dose of antenatal betamethasone after an initial single dose. Am J Obstet Gynecol 2001;185:1086-9. 14. Peltoniemi OM, Kari MA, Tammela O, et al. Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics 2007;119:290-8. 15. Vermillion ST, Soper DE, Chasedunn-Roark J. Neonatal sepsis after betamethasone to patients with preterm premature rupture of membranes. Am J Obstet Gynecol 1999;181:320-7. 16. Lee M, Davies J, Guinn D, et al. Single vs weekly course of antenatal corticosteroids in preterm premature rupture of membranes. Obstet Gynecol 2004;103:274-81. 17. Wapner RJ, Sorokin Y, Mele L, et al. Long term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357: 1190-8.