Antenatal corticosteroid therapy: A meta-analysis of the randomized trials, 1972 to 1994

Antenatal corticosteroid therapy: A meta-analysis of the randomized trials, 1972 to 1994 Patricia A. Crowley, MRCOG, FRCPI Dublin, Ireland, and Oxford, United Kingdom Respiratory distress syndrome (RDS) and its complications are a key factor affecting mortality and immediate and long-term morbidity in preterm babies. In the course of investigating the initiation of parturition in sheep in 1969, Liggins’ observed that lambs born preterm after exposure to corticosteroids in utero survived longer than control lambs. Subsequently, a randomized, placebo-controlled trial of betamethasone administration in women who were expected to give birth preterm found a statistically significant reduction in the frequency of respiratory distress in babies born before 32 weeks gestation and a fivefold reduction in neonatal mortality among preterm babies born after corticosteroid administration, compared with administration of a placebo.* In the 22 years since this initial study, numerous investigations have suggested that antenatal corticosteroid administration reduces neonatal morbidity. However, obstetricians were slow to incorporate into clinical practice this ability to manipulate fetal lung maturity pharmacologically. A 1980 survey of self-reported practices among fellows and members of the Royal College of Obstetricians and Gynecologists resident in the United Kingdom showed that 42% used this treatment “frequently,” 40% used it “sometimes,” and 18% “never” used it.3 In a similar study of practices in northern Belgium and The Netherlands, Keirse4 found that only 32.5% of respondents used the treatment “routinely.” The recorded use of antenatal corticosteroids during the randomized controlled trials of surfactant therapy for neonatal RDS suggests that use of corticosteroids continued to be low on both sides of the Atlantic until the late 1980s and early 1990s. Cortico-

From the Department of Obstetrics and Gynaecology Trinity College Dublin, Coombe Women’s Hospital, and Cochrane Collaboration, Oxford. Funded in part by Trinity College Dublin, the Coombe Women’s Hospital, and the National Institute of Child Health and Development. The Cochrane Collaboration is funded by the United Kingdom Department of Health. Based on an initial study that appeared in the British Journal of Obstetrics and Gynecology 1990;97:11-25 and on an article that appeared in the National Institute of Child Health and Human Development (US). Report of the Consensus Development Conference on the Effect of Corticosteroials for Fetal Maturation on Perinatal Outcomes; 1994 Feb 2%Mar 2;Bethesda, MD. Bethesda (MD): The Institute; 1994 Nov. b.161-205 (NIH tiublication: No. 95-3784). Reprint requests: Pa&a Crowley,‘MRC’OG, FRCPI, Coombe Wok en’s Hospital, Dolphins Barn, Dublin 8, Ireland. Au J OBSTET GYNECOL 1995;173:322-35. 6/O/62909

322

steroids were administered antenatally in 12% of the babies in the United Kingdom’s Ten Center trial” and 20% of the babies in the U.S. Exosurf trial.6 The use of corticosteroids antenatally continues to vary widely from hospital to hospital.’ In an observational study conducted during a 3-month period in collaborating neonatal units in Europe in 1991-92, Parry and Tarnow-Mordi reported that the use of antenatal corticosteroids varied between 30% and 80% in babies of less than 3 1 weeks gestation (unpublished data, 1993). Only in 1993 did the Royal College of Obstetricians and Gynecologists (RCOG) advise its members to use antenatal corticosteroids in all cases in which there was a possibility of RDS occurring after delivery’ (RCOG, 1993). The relatively low usage of this treatment may relate to varied interpretations of the evidence concerning the efficacy of antenatal corticosteroids, innate conservatism, or fear of long-term ill effects. The fact that none of the relevant corticosteroids was patented specifically for acceleration of fetal lung maturity may have resulted in a lack of aggressive marketing by pharmaceutical companies. Conflicting advice from neonatologists may also have influenced practice. Roberton,’ for example, suggested that corticosteroid use benefits only white male infants and that even for them, the benefit is mainly among those born between 30 and 32 weeks’ gestation. Avery,” by contrast, chided the obstetric community for its reluctance to accept antenatal corticosteroid administration as “an essential intervention to prevent respiratory distress syndrome.” These differences of opinion may result from inappropriate or biased interpretation of the evidence from a single trial or “data dredging” among secondary outcomes within a particular trial. Because many of the trials of antenatal corticosteroid therapy are small, estimates of the effects of corticosteroids are likely to vary widely as a result of the play of chance (random error). These small trials may also have given rise to “type two error,” where a real benefit of corticosteroid therapy was not detected because the numbers in the trial were too small.

Material and methods In an attempt to make an unbiased assessment of the evidence concerning antenatal corticosteroid therapy, this review is largely confined to evidence derived from placebo-controlled randomized trials. Evidence from observational studies is mentioned only when there is a lack of information from randomized trials. The pro-

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cess by which all such trials, both published and unpublished, were sought out, assessed, and incorporated into a single analysis using the Cochrane Database of Systematic Reviews” is described elsewhere.‘2-‘4 In an attempt to locate unpublished trials, letters were sent to 42,000 obstetricians and pediatricians in 18 countries.” All acceptably controlled comparisons of antenatal corticosteroids (betamethasone, dexamethasone, or hydrocortisone) given to women before anticipated preterm delivery (elective, or after spontaneous labor) were eligible for inclusion. All trials identified by the methods described in the search strategy were scrutinized by the reviewer. A number of “trials” that proved not to be randomized controlled trials on thorough examination were exc1uded.‘6~‘9 Where data from randomized trials were amalgamated with observational data, the data from randomized trials were separated out for analysis. Where this proved to be impossible, the studies were discarded.“‘, *’ The quality of the trials included was assessed using the specified criteria for the elimination of bias at trial entry, after randomization, and during assessment. These criteria are described by Chalmers et al.ll In some trials, outcomes were published in the form of percentages or graphs. In these cases the number of events was calculated. When maternal outcomes were presented, numerators and denominators were calculated on the basis of the number of mothers, whereas fetal or neonatal outcomes were presented using the number of babies or fetuses as numerators and denominators. Methodological quality of included trials. Overall, the trials included in the review are of good quality; the potential for bias was reduced by pharmacy-controlled randomization, the use of placebo injections, and the blinding of those assessing neonatal morbidity to treatment allocation. Exclusions occurred after randomization in all trials because some women treated with corticosteroids did not deliver until term and were lost to follow-up. There is no evidence to suggest that these postrandomization losses occurred systematically in one or the other arm of the trials. Three recent trials”“~“4 have been published in abstract form only, resulting in insufficient information about measures taken to reduce bias. These trials have been given low scores for methodological quality pending more complete reports. In each array of trial results to be subsequently presented, studies have been ranked according to the reviewer’s assessments of the likelihood that the comparisons may have been biased. Trials of equivalent quality are ranked by date of publication. Statistical methods. The results of each trial have been presented using the odds ratio with its 95% confidence interval. The odds ratio is the ratio of the odds of a negative outcome (for example, respiratory distress) versus the odds of a positive outcome (no respiratory distress) among those allocated to corticosteroid use compared with the odds of the negative outcome versus

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the positive outcome among the controls. Because random variation may lead to an overestimation or an underestimation of the odds ratio in individual trials, we used statistical methods devised by Peto and collaboratorsZ5-” to handle data within a framework of an overview (meta-analysis) of information derived from each of the relevant trials identified.14 The effect of corticosteroids in each trial is measured by O-E, where 0 is the observed number of persons having the outcome in question among those who were allocated to corticosteroid use and E is the number that would be expected on the basis of the experience of the corticosteroid and placebo group combined. The sum of the differences derived from each individual trial [$(0-E)], combined with the sum of the variances of these differences [$Var(O-E)], have been used to provide an estimate 0f.a “typical odds ratio”: Exp [$(O-E)/$Var(O-E)]. This statistic is an expression of any tendency that may exist for those receiving steroids to do better or worse than those who received placebo. Its 95% confidence interval is calculated as follows: Exp[$(O-E)/$Var(OE)] + 1.96/$Var (O-E). Characteristics of trials contributing to this overview. The search for randomized trials has yielded 15 trials that provide information on clinical outcomes after corticosteroid therapy in general: The Auckland trial’. z8-34with follow-up data55-37; the Collaborative Group on Antenatal Steroid Therapy38-4’ with follow-up data from the Collaborative Group Tria142-44; the Amsterdam tria14’, 46 with follow-up data from this trial”, 48; and smaller trials. “, 49-‘9 Five further randomized trials were confined to cases of preterm, prelabor rupture of the mem,,raneS.22-24. 56. 60 In addition, there were seven reports that referred to laboratory outcomes only. Three trials6’-63 assessed the effects of antenatal corticosteroid use on amniotic fluid phospholipids. Trials by Whitt et aLG4 and Haning et a1.65 dealt with effects on maternal steroid hormones. Other studies examined the effects of corticosteroids on maternal white cell numbers and function.66. 67 Because failure to report the outcome of all randomized cases and selective reporting of data may lead to biased estimates of treatment effect, we contacted investigators in an effort to obtain missing data. Unpublished data from the New Zealand trial,’ from Morrison et al.,“’ and from Gamsu et a1.5’ have been incorporated into this overview.

Results Neonatal respiratory distress syndrome. Antenatal corticosteroid therapy results in an overall reduction of approximately 50% in the odds of contracting neonatal RDS (Fig. 1). A secondary analysis (Fig. 2), stratified by the time interval between trial entry and delivery, indicates that babies delivered between 24 hours and 7 days after corticosteroid administration show a more marked benefit (typical odds ratio of RDS, 0.35;

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95% CI, 0.26-0.46). The odds ratios for RDS in infants delivered less than 24 hours (0.80; 95% CI, 0.56-1.15) or more than 7 days after trial entry (0.63; 95% CI, 0.38-1.07) suggest a trend towards a treatment effect that does not attain statistical significance at the 5% level (Figs. 3 and 4). Effect of gestational age. Contrary to opinions expressed in previous reviews of this subject,’ the beneficial effect of corticosteroids is not confined to babies delivered between 30 and 34 weeks’ gestation. Eight trialsZ. 38, j0, j2, jg, j* supply data allowing a secondary analysis of the risk of RDS in babies born at less than 3 1 weeks gestation (Fig. 5). This secondary analysis shows an unambiguous reduction in the risk of RDS in this high-risk group (typical odds ratio, 0.41; 95% CI, 0.270.62). Only 29 babies from eight trials had RDS after 34 weeks’ gestation, so the typical odds ratio of 0.62 is surrounded by wide confidence limits (0.29 to 1.30) and is thus compatible with either a beneficial effect or a chance variation (Fig. 6). Race and gender. There is no evidence from the few trials referring to gender that the gender of the infant determines its likelihood of benefitting from antenatal corticosteroids. The typical odds ratio for male infants is 0.43, with a 95% CI of 0.29 to 0.64, and for female infants it is 0.36, with a 95% CI of 0.23 to 0.57 (Figs. 7 and 8). Secondary analyses of the Collaborative Group Trial of 1981 suggested that black babies benefitted more than white babies from the effects of antenatal corticosteroids. Only one other trial provided an analysis of RDS by race (Figs. 9 and 10). The results, combined with the knowledge that most babies from the Auckland and Amsterdam trials were white, belies any important effect of race on the efficacy of the treatment. Other forms of neonatal morbidity. The beneficial effect on respiratory morbidity has a domino effect on other forms of neonatal morbidity. Corticosteroid therapy reduces the odds of both periventricular hemorrhage (typical odds ratio, 0.38; 95% CI, 0.23-0.94) (Fig. 11) and necrotizing enterocolitis (typical odds ratio, 0.32; 95% CI, 0.16-0.64) (Fig. 12). No effect was seen on the incidence of patent ductus arteriosus or bronchopulmonary dysplasia (Figs. 13 and 14). Only one trial reported on the incidence of neonatal jaundice and this result suggested a reduction in neonatal hyperbilirubinemia in infants treated with corticosteroids compared with contro1s.57 Neonatal mortality. Most importantly, neonatal mortality is substantially reduced (typical odds ratio, 0.60; 95% CI, 0.48-0.76) (Fig. 15). The magnitude of this effect is greatest in trials conducted before 1980, when the case-fatality rate for RDS was higher. Long-term effects on children. Lessons learned from medical history dictate caution in the use of hormonal preparations during pregnancyG8 and underline the importance of long-term follow-up studies of children exposed to antenatal corticosteroids. Children

July 1995 Gynecol

from three large trials have been monitored in childhood. 34, Q, *’ Follow-up data have been published on physical growth and development up to 3 years of age in children from the U.S. triaP; up to six years of age in children from the Auckland triaP; and up to 12 years of age in children from the Amsterdam tria1.48 None of these studies indicates that antenatal corticosteroid therapy has any effect on these parameters, nor is there any evidence that lung growth is affected.34, 4*, 48 A variety of psychometric tests have been applied to survivors of these three trials at the ages already mentioned. 37, 43, 47 Again, there is no evident difference in the scores achieved by the two groups, despite the fact that the preferential neonatal survival of children born after corticosteroid administration might be expected to have increased their risk of long-term neurologic sequelae; in fact, the available evidence suggests that, if anything, antenatal corticosteroid administration may protect against neurologic abnormality such as hemiparesis, diplegia, and quadriplegia (Fig. 16). In light of these results, further follow-up studies of growth or psychomotor development would appear to be unnecessary. In the follow-up of the Dutch cohorts,48 fewer boys in the corticosteroid group had reached puberty than in the placebo group. This observation probably reflects chance, and the Dutch investigators will presumably investigate this finding by extending their follow-up until all of the children in the study have passed through puberty. The meaning of the observation might also be clarified in further follow-up of the New Zealand and United States cohorts. Adverse

maternal

effects

Maternal infection. An increased risk of infection in mothers or an altered immunologic response to an infectious process is one potential hazard of therapy. Nine trials reported this outcome (Fig. 17). The pooled odds ratio of 1.15, with a 95% CI of 0.84 to 1.57, is compatible with either an increase in maternal infection or with no effect. Maternal pulmonary edema. Instances of pulmonary edema have been reported in women being treated with corticosteroids in combination with intravenous fluids and other drugs, typically tocolytics.69 Case reports of such adverse events are important but lack denominators on which incidence rates can be based. Two cases of pulmonary edema were reported by Morales et al.j6 in women who had received both corticosteroids and magnesium sulfate- an incidence rate of 1.6%. Reports of cases of pulmonary edema in women treated with corticosteroids and betamimetics are numerous. Katz et a1.70 reported an incidence rate of 5%. Fluid overload, the presence of underlying heart disease, and multiple pregnancy are significant risk factors.7’-‘3 There appear to be no reports of the condition occurring in women treated with corticosteroids only. Economic effects of antenatal corticosteroid therapy. Tables I and II summarize the substantial effects of antenatal

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Study reference Liggins 1972 Block 1977 Schutte 1979 Taeusch 1979 Doran 1960 Teramo 1960 Gamsu 1969 U.S. Collaborative 1961 Morales 1966 Papageorgiou 1979 Morrison 1978 Kari 1994 Garite 1992 Schmidt 1964 Carlan 1991 m Total (95% Cl)

No. events treatment

No. entered control

491532 5169 11164 7156 41 al 3138 71131 421371 301121 7171 6167 35194 21140 9134 1111

841538 12/6i 17158 14/71 10163 3142 161137 591372 63/ 124 23175 14159 45194 28142 10/31 4113

23711780

40211790

Odds ratio (95% Cl) treatment : control

-=Er---

-T-t-

-z= --+-I3 ----g-I

Study reference Liggins 1972 Block 1977 Schutte 1979 Taeusch 1979 Doran 1960 Teramo 1960 Gamsu 1969 U.S. Collaborative 1961 Morales 1966 Papageorgiou 1979 Morrison 1978 Kari 1994 Schmidt 1964 n

Total (95% Cl)

No. events treatment

No. entered control

,1#111,

161182 4136 0122 2115 1118 1138 11131 141151 16/64 6129 3149 19194 4126

371156 6129 6/25 7128 1113 1142 21137 291144 3i/48 19132 a/45 30/ 94 a/i9

871 a55

ia51 at2

Odds ratio (95% Cl) treatment : control

II

Study reference

I

use before preterm delivery: outcome of RDS overall (15 trials).

Typical odds ratio: 0.35 X* (12) for heterogeneity: 0.46

Fig. 2. Effect of corticosteroid (13 trials).

I

0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse

Typical odds ratio: 0.51 X2 (14) for heterogeneity: 11.76

Fig. 1. Effect of corticosteroid

325

11#111

c

1

111,111

0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

use before preterm delivery: outcome of RDS after optimal treatment

No. events treatment

Liggins 1972 Block 1977 Schutte 1979 Taeusch 1979 Doran 1960 Teramo 1960 U.S. Collaboratb Je 1981 Morales 1966 Morrison 1976 Kari 1994 Garite 1992 Schmidt 1964

19196 1113 5/10 5119 3126 2/11 11156 7127 3/ia 11194 616 517

m Total (95% Cl)

781383

No. entered control 251107 6/ 15 6112 5119 5120 2111 a150 19135 6114 7/ 94 a/a 2112

Odds ratio (95% Cl) treatment : control JTI #I I I I t +

I II I II I I I

99/ 397

Typical odds ratio: 0.60 X* (11) for heterogeneity: 16.24

0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

Fig. 3. Effect of corticosteroid use before preterm delivery: outcome of RDS when delivery occurred less than 24 hours after corticosteroid administration (12 trials).

corticosteroid therapy on the duration and cost of hospital stay in trials that reported this outcome. Avery,“’ who used contemporary estimates of the cost of neonatal hospitalization and of the number of babies at

risk of RDS, estimated a potential annual savings to the United States of $35 million. Present-day estimates of the economic implications of antenatal corticosteroid therapy are altered by the availability of neonatal sur-

326

Crowley Am J Obstet

Study reference Liggins 1972 Schutte 1979 Doran 1980 Teramo 1980 U.S. Collaborative 1981 Morales 1986 Garite 1992 n

No. events treatment 81180 6117 0130 O/6 61102 7130 5114

No. entered control 41188 519 3128 oi 12 111105 13130 5112

321379

41 I384

Total (95% Cl)

Odds ratio (95% Cl) treatment : control I ! II I ,I , I II

-

I

I ,111

Typical odds ratio: 0.63 X2 (6) for heterogeneity: 7.13 Fig. 4. Effect of corticosteroid use before preterm more than 7 days after corticosteroid administration

Study reference

n

delivery: outcome (7 trials).

No. events treatment

No. entered control

10136 l/3 4129 6110 17153 215 6136 21140

15126 416 7139 7116 32152 11112 11128 28142

671212

1151221

Liggins 1972 Taeusch 1979 Gamsu 1989 U.S. Collaborative 1981 Morales 1986 Papageorgiou 1979 Morrison 1978 Garite 1992 Total (95% Cl)

Study reference Liggins 1972 Block 1977 Schutte 1979 Taeusch 1979 DoranCollaborative 1980 U.S. 1981

use before

preterm

No. entered control 4174 3125 oi 12 0125 1126 81166

0125 l/77

0117 1167

121474

171412

H Total (95% Cl)

use before

preterm

7. Effect

Liggins 1972 U.S. Collaborative 1981 Morales 1986

6195 241161 19163

26181 241170 36157

W Total (95% Cl)

491319

86/ 306

of corticosteroid

occurred

outcome

of RDS

in babies

less than

31

Odds ratio (95% Cl) treatment : control III II I, I 1 I

delivery:

No. entered control

Typical odds ratio: 0.43 X2 (2) for heterogeneity: 15.21 Fig.

delivery

1

0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse

No. events treatment

Study reference

of RDS when

II I I I I

Typical odds ratio: 0.62 X2 (7) for heterogeneity: 4.26 Fig. 6. Effect of corticosteroid 34 weeks’ gestation (8 trials).

I111111

Odds ratio (95% CII treatment :‘controi

delivery:

No. events treatment 4173 1136 0113 1123 0144 51183

Papageorgiou Schmidt 1984 1979

I

- II I 0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse

Typical odds ratio: 0.41 Xa (7) for heterogeneity: 8.34 Fig. 5. Effect of corticosteroid weeks’ gestation (8 trials).

I

0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

use before

preterm

outcome

of RDS

in babies

greater

than

Odds ratio (95% Cl) treatment : control I -I

II --Y-

I -+ I I , , , ,, , , , , , , , ,, 0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse delivery:

outcome

of RDS in male babies

(3 trials).

July 1995 Gynecol

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Crowley

1

Study reference

No. events treatment

No. entered control

10187 71146 11/58

1’1/75 24/ 128 27161

281291

621264

Liggins 1972 US. Collaborative 1981 Morales 1986 n

Total (95% Cl)

2

of corticosteroid

Study reference

use

before

preterm

No. events treatment

delivery:

No. entered control

U.S. Collaborative 1981 Morales 1986

231138 19154

28/ 142 42176

w Total (95% Cl)

421192

701218

9. Effect

of corticosteroid

use before

preterm

No. events treatment

No. entered control

U.S. Collaborative 1981 Morales 1986

81169 11167

201157 21148

m Total (95% Cl)

191236

41 I205

Study reference

delivery:

Effect

of corticosteroid

Study reference

use before

preterm

No. events treatment

No. entered control

Liggins 1972 Doran 1980 Gamsu 1989 Morales 1986 Kari 1994 Garite 1992 n

Total (95% Cl)

6/ 532 1181 2/131 i/121 8194 l/40

141538 3163 41137 21124 18/94 9142

191999

501998

of corticosteroid

in female

babies

outcome

of RDS in white

babies

(2 trials).

Odds ratio (95% Cl) treatment : control II_ 1 +

II II

delivery:

outcome

of RD.3

in nonwhite

babies

Odds ratio (95% Cl) treatment : control I II-I _ I I !_ I

I I

IIkI,I,I I I1111111 0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse

Typical odds ratio: 0.38 X2 (5) for heterogeneity: 1.86 Fig. 11. Effect (6 trials).

of RDS

0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

Typical odds ratio: 0.31 X2 (1) for heterogeneity: 0.33 Fig. 10. (2 trials).

outcome

Odds ratio (95% Cl) treatment : control II_ II II - II J,,, I I I111111 0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse

Typical odds ratio: 0.63 X2 (1) for heterogeneity: 1.60 Fig.

_I

I + I I, , ,, , , , , , , , ,, 0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

Typical odds ratio: 0.36 X2 (2) for heterogeneity: 3.54 Fig. 8. Effect (3 trials).

Odds ratio (95% Cl) treatment : control II _

use before

preterm

No. events

No. entered

delivery:

outcome

of periventricular

hemorrhage

Odds ratio (95% Cl)

~

0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse

Typical odds ratio: 0.35 X2 (3) for heterogeneity: 1.40 Fig. 12. (4 trials).

Effect

of corticosteroid

use before

preterm

delivery:

outcome

of necrotizing

enterocolitis

327

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Crowley

Am J Obstet

Study reference U.S. Collaborative 1981 Gariie 1992 n

Total (95% Cl)

No. events treatment

No. entered control

231371 23140

371372 18142

461411

551414

Odds ratio (95% Cl) treatment : control I --e+ J _ I I -I Ia I I I111111 0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

Typical odds ratio: 0.81 X2 (1) for heterogeneity: 4.42 Fig. 13. Effect (2 trials).

of corticosteroid

Study reference Taeusch 1979 Kari 1994 n

use before

No. events treatment 0156 6194

Total (95% Cl)

preterm

delivery:

N;;;toed

Effect of (2 trials),

oi 71 1194

61150

11165

use

before

No. events treatment 36 / 532 1169 3164 5156 2181 0138 141131 36 I371 7/121 i/71 2167 4194 9140 5134

601538 5161 12158 7171 10163 0142 20/ 137 371372 131124 5175 7159 6194 11142 5131

H Total (95% Cl)

12511769

19811767

of corticosteroid

use before

preterm

No. entered control

U.S. Collaborative 1984 Smolders 1990 Howie 1986

91200 2164 121139

151206 2158 151111

H Total (95% Cl)

231403

32/ 375

Typical odds ratio: 0.62 X2 (2) for heterogeneity: 0.14 Fig. 16. follow-up

Effect of corticosteroid (3 trials).

I II 1 II

use before

outcome

of

bronchopulmonary

Odds ratio (95% Cl) treatment : control

0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

No. events treatment

Study reference

delivery:

No,;$r,,d

Liggins 1972 Block 1977 Schutte 1979 Taeusch 1979 Doran 1980 Teramo 1980 Gamsu 1989 U.S. Collaborative 1981 Morales 1986 Papageorgiou 1979 Morrison 1978 Kari 1994 Garite 1992 Schmidt 1984

15. Effect

arteriosus

I I

preterm

Typical odds ratio: 0.60 X2 (13) for heterogeneity: 18.31 Fig,

ductus

0.1 0.3 0.5 1 2 4 10 Treatment better Tregment worse

corticosteroid

Studv reference

of patent

Odds ratio (95% Cl) treatment : control

Typical odds ratio: 4.38 X* (1) for heterogeneity: 0.00 Fig. 14. dysplasia

outcome

preterm

delivery:

outcome

of neonatal

deaths

(14 trials).

Odds ratio (95% Cl) treatment : control JI ,1 II i-

I I, ,, , , , , ,,, , 0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse delivery:

outcome

of neurological

abnormality

at

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Crowley

No. events treatment

Study reference

No. entered control

Liggins 1972 Taeusch 1979 Gamsu 1989 U.S. Collaborative 1981 Morales 1986 Papageorgiou 1979 Morrison 1978 Schmidt 1984 Carlan 1991

51108 14156 6/126 271349 f6/ 121 9171 4167 13132 3111

6191 8171 61125 291347 181124 9175 z/59 9129 0113

W Total (95% Cl)

971941

871934

Odds ratio (95% Cl) treatment :‘controi

Typical odds ratio: 1.I 5 X2 (8) for heterogeneity: 8.80

Fig.

17.

Effect

of corticosteroid

Study reference

0.1

preterm

No. events treatment

No. entered control

Kari 1994

9194

Total (95% Cl)

n

0.3 0.5

1

Treatment better

use before

9194

delivery:

outcome

Study reference Block 1977 Morales 1986 U.S. Collaborative 1981 Morales 1989 Schmidt 1988 1984 Parsons Carlan 1991 Cararach 1990 n

Total (95% Cl)

Fig.

19. Effect

No. events treatment

No. entered control

3125 301121 151153 23187 7124 3123

5126 631124 171135 41178 6117 3122

1111 1112

4113 016

831456

Typical odds ratio: X2 (10) for heterogeneity

preterm

I 11,111 0.3 0.5 1

delivery:

factant therapy and by the possibility of using it either as prophylaxis or as treatment for RDS. Only one trial reported on the effect of antenatal corticosteroid therapy on surfactant usage,s9 and it showed a reduced use of surfactant in treated babies (odds ratio, 0.41; 95% CI, 0.19-0.90) (Fig. 18). Observational data from the Survanta TriaP suggests that antenatal corticosteroid therapy potentiates the effect of surfactant therapy. In 1991, Mugford et a1.75 attempted to estimate the cost implications of antenatal corticosteroid therapy in eligible patients on the basis of a study of the cost of caring for neonates with and without respiratory distress syndrome at a variety of gestational ages. By using odds ratios for reduction in RDS similar to those quoted in this article and allowing for the deliveries that take place soon after admission to the hospital, they estimated that a policy of intending to administer an-

, 2

1111111 4 IO

of surfactant

therapy

(1 trial).

I I

4 --A-

I I I I I I I 0.3 0.5

1

Treatment better use after

(9 trials).

Odds ratio (95% Cl) treatment : control 4

0.1

of corticosteroid

infection

Treatment worse

outcome

1391421

9.90

10

i 0.1

use before

4

of maternal

Treatment better of corticosteroid

2

Treatment worse

Odds ratio (95% Cl) treatment : control I

20194 20194

Typical odds ratio: 0.41

Fig. 18. Effect

329

PROM:

outcome

2

4

10

Treatment worse of RDS

(8 trials)

tenatal corticosteroids before delivery of all babies less than 35 weeks’ gestation would result in a reduction in the average cost per baby of lo%, with a 14% reduction in the average cost per survivor. When applied only to mothers of babies with gestational ages of less than 31 weeks, prenatal administration of corticosteroids would increase total costs by 7% because of the greater cost of caring for babies of this gestation who would have survived; however, this policy would have reduced the cost per survivor by 9%. Efficacy of corticosteroids in particular circumstances Preterm rupture of the membranes. The aforementioned evidence of efficacy of antenatal corticosteroids in a mixed population of preterm babies prompts a separate analysis of their effects in cases of prelabor, preterm

rupture

of the

membranes

(PROM).

Data

for

this

330

Crowley Am J Obstet

Table

I. Mean duration

of hospital

stay in days

Study

Treated

Control

Collaborative group43 (1984) Morales et al.56 (1986) Garite et al.” (1992) Carlan et al.‘* (1991)

21

25

Table

22.2

-r- 2.8 52.8

14.1

II. Mean cost of neonatal study

Morales et al.j6 (1986) Carlan et al.” (1991)

I

38 t 3.07 78.8

Treated

$10,300 f 850 $13,378

21.4

care I

Control $27,600

f 2080

$19,013

analysis are available from several sources. From three of the trials already discussed,38’ 49, 55 it was possible to abstract cases where ruptured membranes were present at the time of entry into the trial. Three further trials deal with cases of PROM only.‘“, z+, ” In two other trials,“4’ so a factorial design allows comparison of two groups of women with ruptured membranes; one group received corticosteroids and one group didn’t receive them. An earlier meta-analysis of randomized trials of corticosteroid therapy’6 included three trials in which corticosteroid therapy was used along with the cointervention of early delivery in cases of spontaneous rupture of the membranes.7’-‘9 Because the odds ratio of important outcomes such as RDS may be confounded by these cointerventions, these trials have been removed from the analysis. Figure 19 demonstrates the meta-analysis of the effect of antenatal corticosteroids in each of these eight trials. Notwithstanding any effect that prelabor rupture of the membranes itself may have on fetal pulmonary maturity, the incidence of respiratory distress syndrome was substantially reduced by corticosteroid administration (typical odds ratio, 0.44; 95% CI, 0.32-0.60). The use of corticosteroids in cases of PROM has been a source of controversy because of their immunosuppressive effects. There has been concern that the inherent susceptibility to infection of women with PROM might be increased or that the signs of infection might be masked, thereby causing a delay in its diagnosis. Ten randomized controlled trials reported on the incidence of fetal or neonatal infection in corticosteroid cases compared with control subjects given a plaCebo.31, 38,51.53,55-59No increase in perinatal infection was evident (typical odds ratio, 0.84; 95% CI, 0.57-1.23) (Fig. 20). In Fig. 21 the analysis is confined to cases where the membranes were ruptured at entry into the trial. The results give an imprecise estimate of the effect, surrounded by wide confidence limits (odds ratio, 0.82; 95% CI, 0.42-1.60).

July 1995 Gym01

Maternal diabetes. Maternal diabetes predisposes the preterm infant to RDS, especially when poorly controlled diabetes gives rise to fetal hyperinsulinism, which blocks surfactant production by type 2 pulmonary cells. Tight control of diabetes mellitus in pregnancy reduces the incidence of respiratory distress.‘O The results of the randomized trials previously reviewed do not permit an authoritative statement on the efficacy and safety of antenatal corticosteroid use in women with insulin-dependent diabetes, because only 35 women with diabetes were randomized. Glucocorticoid therapy is likely to provoke insulin resistance and a deterioration in diabetic control, which could potentially cause cortisol resistance in the fetal lung. Maternal hypertensive disease. Hypertensive disease constitutes one of the main indications for elective preterm delivery.‘l Respiratory distress syndrome is a major problem in the infants of women with hypertension.8” Ninety women with hypertension were included in the first randomized trial of antenatal corticosteroid therapy.3’ Twelve intrauterine fetal deaths occurred in 47 treated women, compared with 3 fetal deaths among 43 controls (odds ratio, 3.75; 95% CI, 1.24-11.30). This understandably led to a great reluctance to administer antenatal corticosteroids to women with hypertension. Subsequent analysis of these fetal deaths revealed that they occurred in women with proteinuria of greater than 2 gm per day for more than 14 days. Women with hypertensive disease were included in three other trials3*, ‘a. 5’ but only two other trials were able to provide a secondary analysis of intrauterine fetal deaths in this subgroup of women. No deaths occurred in either the treatment or control arms of these trials (Fig. 22). A consistent adverse effect of corticosteroid therapy would have resulted in an increased incidence of stillbirth overall. No such effect is seen (Fig. 23). Observational data have not reproduced an excess risk of fetal death in association with corticosteroid therapy in this group of women.83 Multifetal gestations. Only one group of investigators conducted a secondary analysis of multifetal gestations. Burkett et a1.4o quoted data from the Collaborative Group Study to indicate that the effect of antenatal corticosteroid therapy is suboptimal in this situation. The odds ratio (0.79; 95% CI, 0.33-1.91) quoted for the risk of RDS in this group of babies is compatible with a treatment effect of equal magnitude to that seen in babies born singly (Fig. 24). The diminished effect apparently seen in multifetal gestations in the Collaborative Group Trial may represent a type 2 error or may result from the subtherapeutic maternal plasma corticosteroid levels observed by Burkett et al. in 1986. Effect of antenatal corticosteroids on amniotic &id phospholipids. Three randomized trials compared the effect of corticosteroid therapy versus placebo on amniotic fluid phospholipids.6’-63, ‘* In all of the studies the in

Volume

173, Number Gym01

Crowley

1

Am J Obstet

Study reference Howie 1977 Taeusch 1979 Doran 1980 Gamsu 1989 US. Collaborative 1981 Morales 1986 Papageorgiou 1979 Kari 1994 Garite 1992 Schmidt 1984 w Total (95% Cl)

No. events treatment 51532 7/56 l/El 41126 41371 111121 4171 7194 1140 5134

No. entered control 61538 4171 3 / 63 71125 101372 11 1124 4 I 75 6 I 94 3142 5 I31

4911526

5911535

Typical odds ratio: 0.84 X2 (9) for heterogeneity: 7.28 Fig. 20. Effect (10 trials).

of corticosteroid

Study reference

use before

No. events treatment

preterm

Odds ratio (95% Cl) treatment : control I II AI I I I I _ I LI II -- I \ I , I , I I I II 0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse delivery:

No. entered control

outcome

of fetal

or neonatal

infection

Odds ratio (95% Cl) treatment : control

~

Typical odds ratio: X2 (6) for heterogeneity: 11.49 Fig.

21.

Effect

of corticosteroid

Study reference Liggins 1972 Gamsu 1989 U.S. Collaborative 1981 n

Total (95% Cl)

0.1 0.3 0.5 1 ’ 2 4 IO Treatment better Treatment worse

use after

PROM:

12/47 o/ 12 0140

3143 016 0143

:

12199

3192

+

use before

preterm

No. entered control

Liggins 1972 Block 1977 Schutte 1979 Taeusch 1979 Doran 1980 Teramo 1980 Gamsu 1989 U.S. Collaborative 1981 Morales 1986 Papageorgiou 1979 Kari 1994 Garite 1992

311532 3/69 Z/64 2156 1181 0138 41131 6/371 01121 0171 1194 3140

(95% Cl)

5311668

281538 Oi 61 0158 2171 3163 0142 51137 8/ 372 O/124 2175 0194 1142 4911677

n Total

infection

No. entered control

No. events treatment

Studv reference

of neonatal

No. events treatment

Typical odds ratio: 3.75 X2 (2) for heterogeneity: 0.00 Fig. 22. Effect of corticosteroid hypertension (3 trials).

outcome

Odds ratio (95% Cl) treatment : control

II I II, , , , , , , 0.1 0.3 0.5 1 2 4 IO Treatment better Treatment worse delivery:

outcome

of fetal

death

with

maternal

Odds ratio (95% Cl) treatment : control t I I I I II I II I I I -II I II

use

I

I

I

I

I11111

0.1 0.3 0.5 I 2 4 IO Treatment better Treatment worse

Typical odds ratio: 1.09 X2 (11) for heterogeneity: 10.61 Fig. 23. Effect of corticosteroid malformation (12 trials).

(4 trials).

before

preterm

delivery:

outcome

of stillbirths

without

lethal

331

332

Crowley Am J Obstet

Study reference Kari 1994

No. events treatment 11150

No. entered control 15157

w Total (95% Cl)

11150

15157

Typical odds ratio: 0.79

Fig.

24.

Effect

of corticosteroid

use

July 1995 Gynecol

Odds ratio (95% Cl) treatment : control 1 I I I I, , I I111111 0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse

before preterm delivery: outcome of RDS in multifetal gestations

(1 trial)

Odds ratio (95% Cl) treatment : control

Effect on: RDS, overall RDS following optimal treatment RDS following delivery ~24 hours RDS following delivery >7 days RDS in babies ~31 weeks gestation RDS in babies >34 weeks gestation RDS in male babies RDS in female babies Periventricular haemorrhage Necrotising enterocolitis Stillbirths without lethal malformation Fetal death with maternal hypertension Neonatal deaths Maternal infection Fetal or neonatal infection Fetal or neonatal infection-ruptured membranes Neurological abnormality at follow-up Bronchopulmonary dysplasia Patent ductus arteriosus

-m t -

0.1 0.3 0.5 1 2 4 10 Treatment better Treatment worse Fig.

25.

Summary of effect of corticosteroid

use before preterm delivery (15 trials).

vivo effect of antenatal corticosteroid therapy is matched by a significant change in amniotic fluid phospholipids. Clinicians may be able to use this finding to monitor treatment response in cases where delivery does not occur soon after an initial course of treatment. If the risk of preterm delivery persists, amniotic fluid phospholipids may be used as a basis for repeating or withholding antenatal corticosteroids. It should be noted, however, that increased phospholipid synthesis is only one of the mechanisms by which neonatal respiratory fimction is altered by corticosteroids. Maternal immune function. The available evidence from in vitro studies of maternal white cell countP. 67 are consistent with the in vivo evidence that there are no serious maternal hazards resulting from immunosuppressive effect of corticosteroid therapy. Maternal adrenal function. The predicted effect of antenatal corticosteroid therapy on maternal adrenal function is confirmed by the studies of Whitt et a1.64 and Haning et a1.65These studies may have several clinically relevant outcomes. Estriol measurement as a biochemical means of assessing fetoplacental function may be invalidated by corticosteroid administration; however, this is not currently a widely used method of fetal surveillance. There is no evidence of any lasting adrenal suppression after this treatment. The study by Haning et a1.6’ suggests that greater consideration should be

given to intravenous hydrocortisone as the corticosteroid of choice because evidence shows that it has a more rapid onset of action than the more widely used intramuscular dexamethasone regimen. Antenatal questions

corticosteroid

therapy-

unanswered

The meta-analysis of the randomized trials of corticosteroid therapy has provided irrefutable evidence of the efficacy and safety of antenatal corticosteroid therapy in the majority of clinical situations in which its use might be considered (Fig. 25). A few outstanding questions remain. A more precise estimate is needed of the effect of corticosteroids on maternal and fetal infection in the presence of ruptured membranes. The benefits of treatment in this situation are not in doubt. Because women with diabetes were excluded from the randomized trials as a result of obvious concerns about the effects of treatment on blood glucose control, we have no information regarding any safe means of promoting lung maturity in infants of women with diabetes except by control of blood sugars. There are insufficient data on pregnancies of less than 28 weeks gestation to allow confident statements concerning the limits of efficacy of this treatment. Further trials concerning the dose regimens to be used with women who have multifetal gestations are also needed.

Volume 173, Number Am J Obstet Gynecol

I acknowledge Health, National Development, in this article. Dr. support.

1

the support of National Institutes of Institute of Child Health and Human the preparation and publication of Linda Wright provided invaluable

REFERENCES 1. Liggins 2.

3.

4.

5.

6.

7. 8.

9. 10.

11.

12.

13.

14.

15.

16.

17.

18

GC. Premature delivery of fetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515-23. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the RDS in premature infants. Pediatrics 1972;50:515-25. Lewis PJ, de Swiet M, Boylan P, Bulpitt CJ. How obstetricians in the United Kingdom manage preterm labor. Br J Obstet Gynaecol 1980;87:574-7. Keirse MJNC. Obstetrical attitudes to glucocorticoid treatment for lung maturation: time for a change? Em J Obstet Gynaecol Reprod Biol 1984;17:247-55. Ten Centre Study Group. Ten centre trial of artificial surfactant (artificial lung expanding compound) in very premature babies. Br Med J 1987;294:991-6. Corbet A, Bucciarelli R, Goldman S, Mammel M, Wold D, Long W, U.S. Exosurf Pediatric Group 1. Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: a multicenter controlled trial. J Pediatr 1991;118:277-84. Khanna R, Richmond S. The OSIRIS Trial. Lancet 1993; 341:174. Scientific Advisory Committee, Royal College of Obstetricians and Gynecologists. Antenatal corticosteroid administration reduces the incidence of neonatal respiratory distress syndrome. London: Royal College of Obstetricians and Gynecologists, 1992. Roberton NRC. Advances in respiratory distress syndrome. Br Med I 1982:284:917-8. Avery ME. The&gument for prenatal administration of dexamethasone to prevent respiratory distress syndrome. J Pediatr 1984;104:240. Crowley P. Corticosteroids prior to preterm delivery. In: Enkin ‘MW, Keirse MJNC, kenfrewMJ, Neilson JP; eds. Preenancv and childbirth module. Cochrane Database of Sy&ma& Reviews, Review No. 02955, 5 May 1994. Published through Cochrane Updates on Disk. Oxford: Update Software, 1994: Disk Issue 1. Dickersin K, Hewitt P, Mutch L, Chalmers I, Chalmers TC. Perusing the literature: comparison of MEDLINE searching with a Perinatal Trials Database. Control Clin Trials 1985;6:306-17. Chalmers I, Hetherington 1, Newdick M, Mutch L, Grant A, Enkin M, Enkin E, Dick&sin K. A register of controlled trials in nerinatal medicine. Control Clin Trials 1986;7: 306-24. ’ Chalmers I, Hetherington J, Elbourne D, Keirse MJNC, Enkin M. Materials and methods used in svnthesizing evidence to evaluate the effects of care during’pregnancy and childbirth. In: Chalmers I, Enkin M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. Oxford: Oxford University Press, 1989:39-65. Hetherington J, Dickersin K, Chalmers I, Meinert CM. Retrospective and prospective identification of unpublished controlled trials: lessons from a survey of obstetricians and pediatricians. Pediatrics 1989;84:374-80. Baillie CR, Malan AF, Saunders MC, Davey DA. The active management of preterm labor and its effects on fetal outcome. Aust N Z J Obstet Gynaecol 1976;16:94-9. Dluholucky S, Babic J, Taufer J. Reduction of incidence and mortality of respiratory distress syndrome by administration of hydrocortisone to the mother. Arch Dis Child 1976;51:420-3. Kleinschmidt R, Schroeder M, Preibsch W, Mattheus R, Hofman D. Induction of lung maturity in pending premature delivery and scheduled premature delivery. Zentralbl Gynakol 1977;99:147-54.

Crowley

333

19. Szabo I, Csabo I, Novak P, Drozgynik I. Single dose glucocorticoid for prevention of respiratory distress syndrome. Lancet 1977;2:243. GF, Harbert GM. Use of betamethasone in man20. Simpson agement of preterm gestation with premature rupture of membranes. Obstet Gynecol 1985;66:168-75. 21. Kuhn RJP, Speirs AL, Pepperell RJ, Eggers TR, Doyle LW, Hutchison A. Betamethasone, albuterol, and threatened premature delivery: benefits and risks. Obstet Gynecol 1982;60:403-8. 22. Carlan SJ, Parsons M, O’Brien WF, Krammer J. Pharmacologic pulmonary maturation in preterm premature rupture of membranes. AM J OBSTET GYNECOL 1991;164:371. 23. Cararach V, Sentis J, Botet F, De Los Rios L. A multicentric prospective randomized study in premature rupture of membranes (PROM): respiratory and infectious complications in the newborn. In: Proceedings of the Twelfth European Congress of Perinatal Medicine. Lyon, France: European Congress of Perinatal Medicine, 1990:216. MT, Sobel D, Cummiskey K, Constantine L, 24. Parsons Roitman J. Steroid, antibiotic and tocolytic versus no steroid, antibiotic and tocolytic management in patients with preterm PROM at 25-32 weeks. In: Proceedings of the eighth annual meeting of the Society of Perinatal Obstetricians. Las Vegas: Society of Perinatal Obstetricians, 1988:44. 25. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient: 1: introduction and design. Br J Cancer 1977;34:585-612. R, Yusuf S, Peto R. Overview of randomized trials 26. Collins of diuretics in pregnancy. Br Med J 1985;290:17-23. S, Peto R. Lewis T. Collins R. Sleight P. Beta 27. Yusuf blockade during and after myocardial infarct&n: an overview of the randomized trials. Prog Cardiovasc Dis 1985; 5:336-71. GC, Howie RN. Prevention of respiratory distress 28. Liggins syndrome by antepartum corticosteroid therapy. In: Proceedings of the Sir Joseph Barcroft Centenary Symposium on Fetal and Neonatal Physiology. Cambridge: Cambridge University Press, 1973:613-7. 29. Liggins GC, Howie RN. The prevention of RDS by maternal steroid therapy. In: Gluck L, ed. Modern perinatal medicine. Chicago: Year-Book Medical Publishers, 1974: 415-24. 30. Howie RN, Liggins GC. Prevention of respiratory distress syndrome in premature infants by antepartum glucocorticoid treatment. In: Villee CA, Villee DB, Zuckerman J, eds. Respiratory distress syndrome. London: Academic Press, 1973:369-80. 31. Howie RN, Liggins GC. Clinical trial of antepartum betamethasone therapy for prevention of respiratory distress in preterm infants. In: Preterm labor: proceedings of the Fifih Study Group of the Royal College of Ob&ricians and Gynecologists. London: Royal College of Obstetricians and Gynecologists, 1977:281-g. 32. Howie RN, Liggins GC. The New Zealand study of antenartum elucocorticoid treatment. fn: Farrell PM, ed. L&g deveibpment: biological and clinical perspectives, II. London: Academic Press, 1982:255-65. 33. Liggins GC. Prenatal glucocorticoid treatment: prevention of respiratory distress syndrome. In: Moore TD, ed. Lung maturation and the prevention of hyaline membrane disease: report of 70th Ross Conference on Pediatric Research. Columbus, Ohio: Ross Labs, 1976:97-103. 34. Howie RN. Pharmacological acceleration of lung maturation. In: Villee CA, Villee DB, Zuckerman J, eds. Respiratory distress syndrome. London: Academic Press, 1973: 385-96. 35 MacArthur BA, Howie RN, Dezoete JA, Elkins J. Cognitive and psychosocial development of 4-year-old children whose mothers were treated antenatally with betamethasone. Pediatrics 1981;68:638-43. 36. MacArthur BA, Howie RN, Dezoete JA, Elkins J. School progress and cognitive development of 6-year-old children

334

Crowley Am J Obstet

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

whose mothers were treated antenatally with betamethasone. Pediatrics 1982;70:99-105. MacArthur B, Howie RN, DeZoete A, Elkins J, Liang AYL. Long-term follow-up of children exposed to betamethasone in utero. In: Tejani N, ed. Obstetrical events and developmental sequalae. Boca Raton: CRC Press, 1983: 81-9. Collaborative Group on Antenatal Steroid Therapy. Effect of antenatal steroid administration on prevention of respiratory distress syndrome. AM J OBSTET GYNECOL 1981; 141:276-87. Bauer CR, Morrison JC, Poole WK, Korones SB, Boehm JJ, Rigatto H, Zachman RD. A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy. Pediatrics 1984;73:682-8. Burkett G, Batter CR, Morrison JC, Curet LB. Effect of prenatal dexamethasone administration on prevention of respiratory distress syndrome in twin pregnancies. J Perinatal 1986;6:304-8. Curet LB, Rao AV, Zachman RD, Morrison J, Burkett G, Poole K, and the Collaborative Group on Antenatal Steroid Therapy. Maternal smoking and respiratory distress syndrome. AM J OBSTET GYNECOL 1988;147:446-50. Zachman RD. The NIH multicentre study and miscellaneous clinical trials of antenatal corticosteroid administration In: Farrell PM, ed. Lung development: biological and clinical perspectives, II. London: Academic Press, 1982: 275-96. Collaborative Group on Antenatal Steroid Therapy. Effect of antenatal steroid administration on the infant: longterm follow-up. J Pediatr 1984;104:259-67. Wiebicke W, Poynter A, Chernick V. Normal lung growth following antenatal dexamethasone treatment for respiratory distress syndrome. Pediatr Pulmonol 1988;5:27-30. Schutte MF, Treffers PE, Koppe JG, Breur W. The influence of betamethasone and orciprenaline on the incidence of respiratory distress syndrome in the newborn after premature labor. Br J Obstet Gynaecol 1980;87:127-31. Schutte MF, Treffers PE, Koppe JG, Breuer W, Filedt Kok JC. The clinical use of corticosteroids for acceleration of foetal lung maturity. Ned Tijdschr Geneeskd 1979;123: 420-7. Schmand B, Neuvel J, Smolders-de Haas H, Hoeks J, Treffers PE, Koppe JG. Psychological development of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome. Pediatrics 1990; 86:58-64. Smolders-de Haas H, Neuvel J, Schmand B, Treffers PE, Koppe JG, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10 to 12 year follow-up. Pediatrics 1990;86:65-70. Block MF, Kling OR, Crosby WM. Antenatal glucocorticoid therapy for the prevention of respiratory distress syndrome in the premature infant. Obstet Gynecol 1977; 50: 186-90. Morrison JC, Whybrew WD, Bucovaz ET, Schneider JM. Injection of corticosteroids to the mother to prevent neonatal respiratory distress syndrome. AM J OBSTET GYNECOL 1978;13:358-66. Papageorgiou AN, Desgranges MF, Masson M, Colle E, Shatz R, Gelfand MM. The antenatal use of betamethasone in the prevention of respiratory distress syndrome: a controlled double-blind study. Pediatrics 1979;63:73-9. Tauesch HW, Frigoletto F, Kitzmiller J, et al. Risk of respiratory distress syndrome after prenatal dexamethasone treatment. Pediatrics 1979;63:64-72. Doran TA, Swyer P, MacMurray B, et al. Results of a double-blind controlled study on the use of betamethasone in the prevention of respiratory distress syndrome. AM J OBSTET GYNECOL 1980;136:313-20. Teramo K, Hallman M, Raivio KO. Maternal glucocorticoid in unplanned premature labor. Pediatr Res 1980;14:326-9. Schmidt PL, Sims ME, Strassner HT, Paul RH, Mueler E, McCart D. Effect of antepartum glucocorticoid adminis-

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

July 1995 Gynecol

tration upon neonatal respiratory distress syndrome and perinatal infection. AM J OBSTET G~NECOL 1984;148:17886. Morales WJ, Diebel ND, Lazar AJ, Zadrozny D. The effect of antenatal dexamethasone on the prevention of respiratory distress syndrome in preterm gestation with premature rupture of membranes. AM J OBSTET GYNECOL 1986; 154:591-5. Gamsu HR, Mullinger BM, Donnai P, Dash CH. Antenatal administration of betamethasone to prevent respiratory distress syndrome in preterm infants: report of a UK multicentre trial. Br J Obstet Gynaecol 1989;96:401-10. Garite TJ, Rumney PJ, Briggs GG, Harding JA, Nageotte MP, Towers CV, Freeman RK. A randomized placebocontrolled trial of betamethasone for the prevention of respiratory distress syndrome at 24 to 28 weeks’ gestation. AM J OBSTET GYNECOL 1992; 166:646-5 1. Kari AM, Hallman M, Eronen M, Teramo K, Virtanen M, Koivisto M, Ikonen RS. Prenatal dexamethasone in conjunction with rescue therapy of human surfactant: a randomized placebo-controlled multicentre study. Pediatrics 1994;93:730-6. Morales WJ. Angel JL, O’Brien WF, Knuppel RA. Use of ampicillin and corticosteroids in premature rupture of membranes: a randomized study. Obstet Gynecol 1989; 73:721-6. Farrell PM, Engle MJ, Zachman RD, Curet LB, Morrison JC, Rao AV, Poole WK. Amniotic fluid phospholipids after maternal administration of dexamethasone. AM J OBSTET GYNECOL 1983;145:484-90. Gunston KD, Davey DA. Effects of prenatal fenoterol, phenobarbitone and dexamethasone administration on the total phospholipid content of amniotic fluid. S Afr Med J 1978;54:1141-3. Morrison JC, Schneider JM, Whybrew WD, Bucovaz ET. Effect of corticosteroids and fetomaternal disorders on the L:S ratio. Obstet Gynecol 1980;56:583-90. Whitt GG, Buster JE, Killiam AP, Scragg WH. A comparison of two glucocorticoid regimens for acceleration of fetal lung maturation in premature labor. AM J OBSTET GYNECOL 1976;124:479-82. Haning RV, Curet LB, Poole K, Boehelin LM, Kuzma DL, Meier SM. Effect of fetal sex and dexamethasone on preterm maternal serum concentration of human chorionic gonadotrophin, progesterone, estrone, estradiol and estriol. AM J OBSTET GYNECOL 1989;161:1549-53. Zachman RD, Bauer CR, Boehm J, Korines SB, Rigoletto H, Rao AV. Effect of antenatal dexamethasone on neonatal leukocyte count. J Perinatal 1988;8:11 l-3. Cunningham DS, Evan EE. The effects of betamethasone on maternal cellular resistance to infection. AM J OBSTET GYNECOL 1991;165:610-5. Bibbo M, Gill WB, Azizi F, et al. Follow-up study of male and female offspring of DES-exposed mothers. Obstet Gynecol 1977;49:1-8. Stubblefield PG. Pulmonary edema occurring after therapy with dexamethasone and terbutaline for premature labor: a case report. AM J OBSTET GYNECOL 1978;155:829-34. Katz M, Robertson PA, Greasy RK. Cardiovascular complications associated with terbutaline treatment for preterm labor. AM J OBSTET GYNECOL 1981;139:605-8. Finley J, Katz M, Rojas-Perez M, Roberts JM, Greasy RK, Schiller NB. Cardiovascular consequences of beta-agonist tocolysis: an electro-cardiographic study. Obstet Gynecol 1984;64:787-91. King JF, Grant A, Keirse MJNC, Chalmers I. Beta-mimetits in preterm labor: an overview of the randomized controlled trials. Br J Obstet Gynaecol 1988;95:211-22. Robertson PA, Herron M, Katz M, Greasy RK. Maternal morbidity associated with isoxuprine and terbutaline tocolysis. Eur J Obstet Gynecol Reprod Biol 1981;ll: 371-8. Jobe AH, Mitchell BR, Gunkel JH. Beneficial effects of the combined use of prenatal corticosteroids and postnatal surfactant on preterm infants. AM J OBSTET GYNECOL 1993; 168:508-13.

75.

Mugford M, Piercy J. Chalmers I. Cost implications of different approaches to the prevention of respiratory distress syndrome. Arch Dis Child 1991;66:757-64. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97: 1 l-25. Garite TJ, Freeman RK, Linzey EM, Braly PS, Dorchester WL. Prospective randomized study of corticosteroids in the management of premature rupture of the membranes and the premature gestation. AM J OBSTET GYNECOL 1981; 141:508-15. Iams JD, Talbert ML, Barrows H, Sachs L. Management of prematurely ruptured membranes: a prospective randomized comparison of observation versus steroids and timed delivery. AM J OBSTET GYNECOL 1985;151:32-8. Nelson LH, Meis PJ, Hatjis CG, Ernest JM, Dillard R, Schey HM. Premature rupture of membranes; a prospective, randomized evaluation of steroids, latent phase and expectant management. Obstet Gynecol 1985;66:55-8.

76.

77.

78.

79.

80.

Farrag OAM. Prospective study of three metabolic regimensin pregnant diabetics. A&t N Z J Obstet Gynaecol 1987;27:6-9. Keirse MJNC, Kanhai HHH. An obstetrical viewpoint on preterm birth with particular reference to perinatal mortality and morbidity. In: Huisjes HJ, ed. Aspects of perinatal morbidity. Groningen: Universitaire Boekhandel Nederaland, 1981:1-35. Tubman TRJ, Rollins MD, Patterson C, Halliday HL. Increased incidence of respiratory distress syndrome in babies of hypertensive mothers. Arch Dis Child 1991;66: 52-4. Lamont RF, Dunlop PDM, Levene MI, Elder MI. Use of glucocorticoids in pregnancies complicated by severe hypertension and proteinuria. Br J Obstet Gynaecol 1983; 90:199-202. Farrell PM, Engle MJ, Zachman RD, et al., and the Collaborative Group on Antenatal Steroid Therapy. Amniotic fluid phospholipids after maternal administration of dexamethasone. AV J OSSTET GYNECOL 1983;145:484-90.

81.

82.

83.

84.

Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respiratory distress syndrome: Discussion*“f John

C. Sinclair,

Hamilton,

MD

Ontario,

Canada

A meta-analysis rize

results

research.

estimate

defined

population because

trials,

it must

a systematic in

the

the

to obtain

effect

for

each

of

estimate

of

that

the can

lead

trials

treatment of interest.

results

Table I. Structure effect of treatment

to summaof scientific

an unbiased,

outcome

include review

review

of randomized

seeks of

methods

a systematic review

intervention

mary

sion

quantitative

from

A systematic

medical

over,

uses

derived

of

a

in

a

More-

$3.00

-t 0

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Total

a

b

n,

C

d m.

no T

Treated Control

ml

effect and greater than can review of any single

treatment

generalizability of findings study. The opportunity to draw more definitive conclusions from a series of similar studies is not restricted to medicine or to randomized trials. Some of the first

0002.9378/95

Event

Exposure

preci-

From the Departments of Pediatrics and Clinrcal Epidemiolog? and Biostatistics, McMaster University. Reprint requests: John C. Sinclair, MD, Departments of Pedialrics and Clinical Epidemiology and Biostatistics, McMaster University, 1200 Main St. West, Hamilton, Ontario, Canada, L8N 325. *This article is based on the data presented by Dr. Crowley at the Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes, Bethesda, Maryland, February S-March 2, 1994. tA similar report based on this presentation has been previously published: Sinclair JC. Meta-analysis of randomized controlled trials: Antenatal corticosteroid for prevention of respiratory distress syndrome, Prospettive in Pediatria 1994;24:199-206. A.u J OBSTET GYNEC~L 1995;173:335-44. Copyright 0 1995 by Mosby-Year Book, Inc. 6/O/63092

the

Outcome

sum-

of all qualifying

to increased

of a study to evaluate

Event Event

rate rate

Relative

risk

Odds

= a/n,. = c/n,.

0

risk reduction = a/n, - c/n,. risk reduction = 1 - relative risk. needed to treat = l/absolute risk reduction.

attempts clinical

= 2

group group

alb = a.

ratio

Absolute Relative Number

made

in treated in control

to synthesize

research

in the social sciences.‘, trials,

which

have

rather

in an empiric

* However, standard

way

were

randomized methodology,

particularly suited to meta-analysis.3 Since the early 198Os, there has been a sharp increase in the rate of publication of meta-analyses of randomized controlled are

trials4 which ized

Two

textbooks

essentially trials

of

consist therapy

have of covering

recently

been

meta-analyses an

entire

published, of

random-

discipline.‘,

’ 335