Brownfoot 2013 Different Corticoste

Different corticosteroids and regimens for accelerating fetal
lung maturation for women at risk of preterm birth (Review)

Brownfoot FC, Gagliardi DI, Bain E, Middleton P, Crowther CA
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 8
http://www.thecochranelibrary.com
Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth (Review)
Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
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REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Dexamethasone versus betamethasone, Outcome 1 Neonatal death. . . . . . . .
Analysis 1.2. Comparison 1 Dexamethasone versus betamethasone, Outcome 2 Respiratory distress syndrome. . .
Analysis 1.3. Comparison 1 Dexamethasone versus betamethasone, Outcome 3 Intraventricular haemorrhage. . . .
Analysis 1.4. Comparison 1 Dexamethasone versus betamethasone, Outcome 4 Neurosensory disability as a child (18
months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.5. Comparison 1 Dexamethasone versus betamethasone, Outcome 5 Apgar score < 7 at 5 minutes. . . .
Analysis 1.6. Comparison 1 Dexamethasone versus betamethasone, Outcome 6 Apgar score at 5 minutes. . . . .
Analysis 1.8. Comparison 1 Dexamethasone versus betamethasone, Outcome 8 Birthweight (kg). . . . . . . .
Analysis 1.10. Comparison 1 Dexamethasone versus betamethasone, Outcome 10 Low birthweight. . . . . . .
Analysis 1.11. Comparison 1 Dexamethasone versus betamethasone, Outcome 11 Head circumference (cm). . . .
Analysis 1.12. Comparison 1 Dexamethasone versus betamethasone, Outcome 12 Neonatal intensive care unit admission.
Analysis 1.13. Comparison 1 Dexamethasone versus betamethasone, Outcome 13 Vasopressor use.
. . . . . .
Analysis 1.14. Comparison 1 Dexamethasone versus betamethasone, Outcome 14 Bronchopulmonary dysplasia. . .
Analysis 1.15. Comparison 1 Dexamethasone versus betamethasone, Outcome 15 Severe intraventricular haemorrhage.
Analysis 1.16. Comparison 1 Dexamethasone versus betamethasone, Outcome 16 Periventricular leukomalacia. . .
Analysis 1.17. Comparison 1 Dexamethasone versus betamethasone, Outcome 17 Neonatal sepsis. . . . . . . .
Analysis 1.18. Comparison 1 Dexamethasone versus betamethasone, Outcome 18 Necrotising enterocolitis. . . .
Analysis 1.19. Comparison 1 Dexamethasone versus betamethasone, Outcome 19 Retinopathy of prematurity. . .
Analysis 1.20. Comparison 1 Dexamethasone versus betamethasone, Outcome 20 Patent ductus arteriosus. . . . .
Analysis 1.21. Comparison 1 Dexamethasone versus betamethasone, Outcome 21 Fetal heart rate, bpm (day 2). . .
Analysis 1.23. Comparison 1 Dexamethasone versus betamethasone, Outcome 23 Accelerations per hour. . . . .
Analysis 1.25. Comparison 1 Dexamethasone versus betamethasone, Outcome 25 Fetal movements in 30 minutes. .
Analysis 1.26. Comparison 1 Dexamethasone versus betamethasone, Outcome 26 Fetal movements per hour (maternal
perception). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.27. Comparison 1 Dexamethasone versus betamethasone, Outcome 27 Fetal movements per hour (ultrasound).
Analysis 1.29. Comparison 1 Dexamethasone versus betamethasone, Outcome 29 Fetal breathing movements per hour.
Analysis 1.30. Comparison 1 Dexamethasone versus betamethasone, Outcome 30 Duration of breathing time at 2 days
(seconds in 30 minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.31. Comparison 1 Dexamethasone versus betamethasone, Outcome 31 Length of admission to birth (days).
Analysis 1.32. Comparison 1 Dexamethasone versus betamethasone, Outcome 32 Neonatal intensive care unit stay
(days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 1 Neonatal death. . . . . . .
Analysis 2.2. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 2 Respiratory distress syndrome. .
Analysis 2.3. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 3 Intraventricular haemorrhage. .
Analysis 2.4. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 4 Birthweight (kg). . . . . . .
Analysis 2.5. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 5 Neonatal sepsis. . . . . . .
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Analysis 2.6. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 6 Necrotising enterocolitis. . . .
Analysis 3.1. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 1 Neonatal
death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 2 Respiratory
distress syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.3. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 3
Intraventricular haemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Neurodevelopmental disability. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.5. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 5 Birthweight
(kg). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.6. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 6 Low
birthweight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.7. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 7 Neonatal
intensive care unit admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Bronchopulmonary dysplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.9. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate, Outcome 9 Periventricular
leukomalacia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.1. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 1 Perinatal death. . . . . .
Analysis 4.2. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 2 Respiratory distress syndrome.
Analysis 4.3. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 3 Intraventricular hemorrhage.
Analysis 4.4. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 4 Maternal fever > 100.4 F. .
Analysis 4.5. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 5 Birthweight (g). . . . . .
Analysis 4.6. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 6 Small-for-gestational age. .
Analysis 4.7. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 7 Neonatal intensive care unit
admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 4.8. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 8 Chronic lung disease. . . .
Analysis 4.9. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 9 Neonatal sepsis. . . . . .
Analysis 4.10. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 10 Neonatal antibiotic use (> 5
days).
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Analysis 4.11. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 11 Necrotising enterocolitis.
Analysis 4.12. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 12 Retinopathy of prematurity.
Analysis 4.13. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 13 Postpartum maternal length of
stay (days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
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[Intervention Review]
Different corticosteroids and regimens for accelerating fetal

lung maturation for women at risk of preterm birth
Fiona C Brownfoot1 , Daniela I Gagliardi2 , Emily Bain2 , Philippa Middleton2 , Caroline A Crowther2,3
1 Mercy Hospital for Women, Heidelberg, Australia. 2 ARCH: Australian Research Centre for Health of Women and Babies, The
Robinson Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Adelaide, Australia. 3 Liggins Institute, The
University of Auckland, Auckland, New Zealand
Contact address: Fiona C Brownfoot, Mercy Hospital for Women, Heidelberg, Australia. fiona.brownfoot@gmail.com.
Editorial group: Cochrane Pregnancy and Childbirth Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 8, 2013.
Review content assessed as up-to-date: 1 May 2013.
Citation: Brownfoot FC, Gagliardi DI, Bain E, Middleton P, Crowther CA. Different corticosteroids and regimens for accelerating
fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006764.
DOI: 10.1002/14651858.CD006764.pub3.
ABSTRACT
Background
Despite the widespread use of antenatal corticosteroids to prevent respiratory distress syndrome in preterm infants, there is currently
no consensus as to the type of corticosteroid to use; nor the dose, frequency, timing of use or the route of administration.
Objectives
To assess the effects of different corticosteroid regimens for women at risk of preterm birth.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (13 February 2013).
Selection criteria
All identified published and unpublished randomised controlled trials or quasi-randomised control trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens
(including frequency and timing of administration) in women at risk of preterm birth were included. We planned to exclude cross-over
trials and cluster-randomised trials. We included studies published as abstracts only along with studies published as full-text manuscripts
Data collection and analysis
Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were
checked for accuracy.
Main results
For this update, 12 trials (1557 women and 1661 infants) were included. Dexamethasone was associated with a reduced risk of
intraventricular haemorrhage (IVH) compared with betamethasone (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.21 to 0.92;
four trials, 549 infants). No statistically significant differences were seen for other primary outcomes: respiratory distress syndrome
(RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials, 753 infants) and perinatal death (neonatal death RR 1.41, 95% CI 0.54 to 3.67; four
trials, 596 infants). Similarly, very few differences were seen for secondary outcomes such as rate of admission to the neonatal intensive
care unit (NICU) although in one trial, those infants exposed to dexamethasone, compared with betamethasone, had a significantly
shorter length of NICU admission (mean difference (MD) -0.91 days, 95% CI -1.77 to -0.05; 70 infants). Results for biophysical
parameters were inconsistent, but mostly no clinically important differences were seen.
Compared with intramuscular dexamethasone, oral dexamethasone significantly increased the incidence of neonatal sepsis (RR 8.48,
95% CI 1.11 to 64.93) in one trial of 183 infants. No statistically significant differences were seen for other outcomes reported.
Apart from a reduced maternal postpartum length of stay for women who received betamethasone at 12-hourly intervals compared to
24-hourly intervals in one trial (MD -0.73 days, 95% CI -1.28 to -0.18; 215 women), no differences in maternal or neonatal outcomes
were seen between the different betamethasone dosing intervals assessed. Similarly, no significant differences in outcomes were seen
when betamethasone acetate and phosphate was compared with betamethasone phosphate in one trial.
Authors conclusions
It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another.
Dexamethasone may have some benefits compared with betamethasone such as less IVH, and a shorter length of stay in the NICU.
The intramuscular route may have advantages over the oral route for dexamethasone, as identified in one small trial. Apart from the
suggestion that 12-hour dosing may be as effective as 24-hour dosing of betamethasone based on one small trial, few other conclusions
about optimal antenatal corticosteroid regimens were able to be made. No long-term results were available except for a small subgroup
of 18 month old children in one trial. Trials comparing the commonly used corticosteroids are most urgently needed, as are trials of
dosages and other variations in treatment regimens.
PLAIN LANGUAGE SUMMARY

Corticosteroid treatments before early birth for reducing death, lung problems and brain haemorrhage in babies
Babies born early are at risk of death, lung problems (respiratory distress syndrome) and bleeding of the brain (intraventricular
haemorrhage). Corticosteroids are given to the mother to help stop these problems occurring and there is high-quality evidence that
they are effective in preventing many of these problems. These drugs work by maturing the babys lungs before birth. There are different
types of corticosteroids and they can be given in different ways and in different doses. Since there is no clear or agreed best type or dose,
hospitals may vary in how they give this drug.
Most trials have compared the two most commonly used corticosteroids before early birth, dexamethasone and betamethasone. In this
review of 12 trials (involving 1557 women and 1661 infants) of moderate quality, 10 trials compared dexamethasone and betamethasone;
one trial compared two different ways of giving dexamethasone and one trial compared two different ways of giving betamethasone.
We found that dexamethasone and betamethasone showed similar results, although there was less bleeding of the brain and a shorter
length of neonatal intensive care unit hospital stay for dexamethasone compared with betamethasone. On the basis of one trial, giving
dexamethasone by injection (intramuscularly) may be better than giving the drug to the mother by mouth (orally). Usually the drug is
given in two doses 24 hours apart and one trial showed that this interval could perhaps be reduced to 12 hours if required. We need
more studies to establish which is the best drug and what is the best way to give it, and babies in these trials need to be followed up
over a long period to monitor any effects on child and adult development.
BACKGROUND
Preterm birth (less than 37 weeks gestation) poses a significant
health burden affecting approximately 5% to 18% of all babies
born globally (Goldenberg 2007; Haram 2003; March of Dimes
2012), with over 60% of all preterm births occurring in Africa and
South Asia (March of Dimes 2012). Preterm infants, especially

those born before 32 weeks gestation, are at high risk of respiratory distress syndrome (RDS), a serious complication that remains
the primary cause of early neonatal death and disability (Haram
2003). Those infants born preterm who do survive the neonatal
period are at a significantly increased risk of long-term neurological disability (Johnson 1993; Saigal 2007). RDS develops as a
consequence of surfactant deficiency and immature lung development. The risk of RDS and neonatal mortality reduces as gestation
increases, reflecting maturity of organ systems (Doyle 2001; Moise
1995; Saigal 2007). Treatments that may reduce the incidence of
respiratory distress syndrome (RDS) in infants born preterm, including antenatal corticosteroids, have therefore received considerable attention (Roberts 2006).
Corticosteroids
Corticosteroids act by altering gene expression resulting in glucocorticoid effects, including gluconeogenesis, proteolysis, lipolysis,
suppression of immune responses and mineralocorticoid effects,
including hypertension, sodium and water retention and potassium loss (AMH 2006). In the fetal lung, the action of corticosteroids leads to an increase in protein production, biosynthesis of
phospholipids and the appearance of surfactant (Ballard 1995).
Liggins 1969 demonstrated that the lungs of lambs born preterm
became functionally mature following antenatal corticosteroid administration. Following these initial animal studies, Liggins and
other investigators conducted several clinical trials to assess the
effects of corticosteroids before preterm birth in humans.
The Cochrane review Antenatal corticosteroids for accelerating fetal
lung maturation for women at risk of preterm birth showed that
a single course of antenatal corticosteroids significantly reduced
the incidence of RDS (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.73; 21 trials, 4038 infants) (Roberts 2006).
Other beneficial effects included a reduction in neonatal death,
cerebroventricular haemorrhage, necrotising enterocolitis, infectious morbidity, need for respiratory support and neonatal intensive care unit admission. For the mother, corticosteroid use was
not shown to increase the risk of death, chorioamnionitis or puerperal sepsis (Roberts 2006). Contrary to the concern that corticosteroid treatment may increase infection in those with preterm
prelabour rupture of membranes (Imseis 1996), or increase the rate
of stillbirth in those with pregnancy-related hypertension (Liggins
1976), this Cochrane review confirmed that antenatal corticosteroid treatment is effective in women at risk of preterm birth with
these complications (Roberts 2006). Corticosteroids have become
the standard of care for women at risk of preterm birth before 32
to 34 weeks gestation in many countries (Jobe 2004; NIH 1995).
Despite their widespread use, there is currently variation in clinical practice as to the type of corticosteroid used, the dose and
frequency given, and the route of administration of corticosteroid
doses.
Corticosteroid type
Currently either betamethasone or dexamethasone are the recommended corticosteroid regimens used in clinical practice (NIH
1995). Betamethasone is available in two different forms: betamethasone sodium phosphate, a solution with a short biological half-life of 36 to 72 hours; and betamethasone acetate, a suspension with a relatively long half-life (Jobe 2004; Katzung 2004;
NNF6 2011). These forms of betamethasone are often used in
combination to maximize the drugs efficiency while reducing the
number of injections given to the mother (NNF6 2011). Dexamethasone generally comes in the form of dexamethasone sodium
phosphate, a solution with a short biological half-life of 36 to 72
hours (Ballard 1995; Jobe 2004; Katzung 2004; NNF6 2011).
Both betamethasone and dexamethasone are able to cross the placenta in their active form and have comparable properties (NNF6
2011). The chemical composition of betamethasone and dexamethasone are virtually identical except for the configuration
of a methyl group in position 16 (Bar-Lev 2004; NNF6 2011).
Some dexamethasone preparations contain a sulphite preservative (NNF6 2011). Sulphites have been linked to neurotoxicity in
the newborn especially when in combination with peroxy nitrite
(Bar-Lev 2004; Baud 1999; Goldenberg 2001; Walfisch 2001).
The optimal type of corticosteroid to use for prenatal treatment
remains unclear. The indirect subgroup comparison of betamethasone and dexamethasone in the Roberts 2006 Cochrane review
indicated similar short-term neonatal outcomes for both drugs.
Maternal outcomes were also similar although the risk of puerperal sepsis was higher in the dexamethasone versus placebo or no
treatment group, while betamethasone did not show an increase
in puerperal sepsis over placebo or no treatment (Roberts 2006).
The results from observational studies are not always consistent
with the results from randomised trials. For instance, a National
Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) cohort study of over 300 infants reported a link between betamethasone and reduced risk of
neonatal death, whereas dexamethasone was associated with an increased risk of neonatal death (Lee 2006). In contrast, the Roberts
2006 Cochrane review showed a reduced risk for fetal and neonatal death for both the betamethasone and dexamethasone groups
compared with placebo/no treatment. In a later NICHD NRN
report of part of this cohort, Lee 2008 reported reduced adverse
childhood neurological outcomes at 18 to 22 months for dexamethasone but not for betamethasone.
The long-term outcomes related to corticosteroid use have largely
been positive. Within the Roberts 2006 Cochrane review, overall antenatal corticosteroid treatment was shown to be associated
with less developmental delay in childhood, and a trend towards
fewer children having cerebral palsy when compared with no corticosteroid treatment. It is not known if the long-term outcomes
vary by type of corticosteroid used. While follow-up at 30 years
following use showed no clinical differences in adults who were
exposed or not exposed to betamethasone in utero (Dalziel 2005),
there have been no similar long-term follow-up studies reported

on dexamethasone use. There are no published data on the longterm effects of antenatal betamethasone compared directly with
dexamethasone.
Corticosteroid dose, timing and frequency

The optimal corticosteroid dose to use, timing of use and frequency of administration similarly remains unclear. The common
regimens of two doses of 12 mg of betamethasone given intramuscularly 24 hours apart and the treatment of four doses of 6
mg of dexamethasone given intramuscularly 12 hours apart was
recommended by the National Institutes of Health (NIH) Consensus Development Panel on the Effect of Corticosteroids for
Fetal Maturation on Perinatal Outcomes (NIH 1995). This dose
corresponds to a high occupancy of steroid receptors in fetal tissues. While the benefits of corticosteroids are well-known, there
is concern regarding their potential for adverse effects, particularly at high doses. There is a suggestion that the current antenatal doses used may be higher than needed (Jobe 2004). Similarly,
the rationale for two doses of betamethasone and four doses of
dexamethasone and the effects of using different formulations for
the initial and subsequent injections remain unclear (Jobe 2004;
NNF6 2011).
maturation for women at risk of preterm birth (Brownfoot 2008).

This review found that while dexamethasone may have some benefits compared to betamethasone such as less intraventricular haemorrhage, it may also be associated with a higher rate of NICU admission (seen in one trial). Few other conclusions about optimal
antenatal corticosteroid regimens could be made, and thus the review concluded that high-quality evidence from randomised trials
was urgently needed in this area.
Despite the widespread use of antenatal corticosteroids to prevent
RDS in preterm infants, there is still no consensus as to the type
of corticosteroid to use; nor the dose, frequency, timing of use or
the route of administration. This review assesses studies making a
head-to-head comparison of different regimens of corticosteroid
type, dose, timing, frequency of dose per treatment course and
route of administration. Other corticosteroid Cochrane reviews
have examined inter-study differences between drug regimens, in
subgroup analysis. We have assessed these indirect comparisons
comparing any corticosteroid with placebo following the methods
outlined in an appendix accompanying Song 2003, and by performing subgroup interaction tests on the trials from the Roberts
2006 review (Table 1).
OBJECTIVES
Corticosteroid route
The optimal route of administration of antenatal betamethasone
and dexamethasone is also uncertain. Both drugs may be administered as intramuscular injections. Betamethasone can be given intra-amniotically (Lefebvre 1976; Murphy 1982) and intravenously
(Petersen 1983) and dexamethasone can be given orally (Egerman
1998).
To assess the effects on fetal and neonatal morbidity and mortality,

on maternal morbidity and mortality, and on the child and adult in
later life, of administering different types of corticosteroids (dexamethasone or betamethasone), or different corticosteroid dose
regimens, including timing, frequency and mode of administration.
METHODS
Repeat doses of corticosteroid
The reduction in the incidence of RDS by antenatal corticosteroid
therapy has been shown to be effective up to seven days after
treatment (Roberts 2006). A single dose of antenatal corticosteroid
does not prevent RDS if it is administered seven days or more
prior to birth (Crowther 2011; Roberts 2006). Whether antenatal
corticosteroids for women who remain at risk of preterm birth
need to be repeated seven days after the initial course is assessed in
another Cochrane review (Crowther 2011); therefore, this review
will not cover repeat steroid doses compared with single doses.
Why it is important to do this review

This review updates a previously published Cochrane review on
different corticosteroids and regimens for accelerating fetal lung
Criteria for considering studies for this review
Types of studies
All identified published and unpublished randomised controlled
trials or quasi-randomised control trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose
regimens (including frequency and timing of administration) in
women at risk of preterm birth were included. We planned to exclude cross-over trials and cluster-randomised trials. We included
studies published as abstracts only along with studies published as
full-text manuscripts.
Types of participants
Women with a singleton or multiple pregnancy expected to give
birth preterm (before 37 weeks) as a result of either spontaneous
preterm labour, preterm prelabour rupture of membranes or elective preterm birth.
Types of interventions
Different types of corticosteroids including dexamethasone,
betamethasone, hydrocortisone or any other corticosteroid that
can cross the placenta.
Different corticosteroid regimens including dose,
frequency, timing and route of administration.
Trials which tested the effect of corticosteroids with other interventions have been excluded. Trials assessing repeat corticosteroid
doses versus a single corticosteroid dose have also been excluded.
Types of outcome measures
These cover outcomes of maternal morbidity, perinatal morbidity
and mortality, child morbidity and mortality, child as adult morbidity and mortality and the use of health services by the mother
and by the neonate or child.
They are divided into primary outcomes, thought to be the most
clinically relevant, and secondary outcomes of importance, including possible complications and also additional measures of effectiveness. Groups include: women; fetuses/neonates; children; children as adults; health services.
Primary outcomes
For the woman

Death;
chorioamnionitis (however defined by authors);
puerperal sepsis (however defined by authors).
For the fetus/neonate
Death (fetal or neonatal);
respiratory distress syndrome (RDS);
intraventricular haemorrhage (IVH) (diagnosed by
ultrasound, diagnosed by autopsy).
For the child
Death;
neurodevelopmental disability at follow-up (blindness,
deafness, moderate/severe cerebral palsy (however defined by
authors), or developmental delay/intellectual impairment
(defined as developmental quotient or intelligence quotient less
than -2 standard deviations below population mean) or variously

defined).
For the child as adult
Death;
neurodevelopmental disability at follow-up (blindness,
deafness, moderate/severe cerebral palsy (however defined by
authors), or developmental delay/intellectual impairment
(defined as developmental quotient or intelligence quotient less
than -2 standard deviations below population mean) or variously
defined.
Secondary outcomes
For the woman
Fever after trial entry requiring the use of antibiotics;

intrapartum fever requiring the use of antibiotics;
postnatal fever requiring the use of antibiotics;
admission to intensive care unit;
adverse effects of therapy;
glucose intolerance (however defined by authors);
hypertension (however defined by authors).
For the fetus/neonate

Apgar score less than seven at five minutes;
interval between trial entry and birth;
birthweight;
low birthweight;
mean length at birth;
mean head circumference at birth;
mean skin fold thickness at birth;
small-for-gestational age (however defined by authors);
mean placental weight;
neonatal blood pressure;
admission to neonatal intensive care;
need for inotropic support (days);
need for mechanical ventilation/continuous positive
airways pressure;
mean duration of mechanical ventilation/continuous
positive airways pressure (days);
air leak syndrome;
need for oxygen supplementation;
duration of oxygen supplementation (days);
surfactant use;
severity of RDS;
chronic lung disease (need for continuous supplemental
oxygen at 28 days postnatal age or 36 weeks postmenstrual age,
whichever was later);
bronchopulmonary dyplasia (variously defined);
severe IVH;
periventricular leukomalacia;
systemic infection in first 48 hours of life (neonatal sepsis);
proven infection while in the NICU;
necrotising enterocolitis;
retinopathy of prematurity;
patent ductus arteriosus;
hypothalamo-pituitary-adrenal (HPA) axis function
(however defined by authors);
biophysical parameters (however defined by the authors).
For the child
Mean weight;
mean head circumference;
mean length;
mean skin fold thickness;
abnormal lung function (however defined by authors);
mean blood pressure;
HPA axis function (however defined by authors);
dyslipidaemia (however defined by authors);
any neurodisability;
visual impairment (however defined by authors);
hearing impairment (however defined by authors);
developmental delay (defined as developmental quotient
less than -2 standard deviations below population mean);
intellectual impairment (defined as intelligence quotient
cerebral palsy (however defined by authors);
behavioural/learning difficulties (however defined by
authors).
For the child as an adult
Mean weight;
mean head circumference;
mean length;
mean skin fold thickness;
abnormal lung function (however defined by authors);
mean blood pressure;
HPA axis function (however defined by authors);
dyslipidaemia (however defined by authors);
mean age at puberty;
bone density (however defined by authors);
educational achievement (completion of high school, or
however defined by authors);
any neurodisability;
visual impairment (however defined by authors);
hearing impairment (however defined by authors);
intellectual impairment (defined as intelligence quotient
behavioural/learning difficulties (however defined by

authors).
For health services

Mean length of antenatal hospitalisation for women (days);
mean length of postnatal hospitalisation for women (days);
mean length of neonatal hospitalisation (days).
Search methods for identification of studies
Electronic searches
We contacted the Trials Search Co-ordinator to search the
Cochrane Pregnancy and Childbirth Groups Trials Register (13
February 2013).
The Cochrane Pregnancy and Childbirth Groups Trials Register
is maintained by the Trials Search Co-ordinator and contains trials
identified from:
1. monthly searches of the Cochrane Central Register of
Controlled Trials (CENTRAL);
2. weekly searches of MEDLINE;
3. weekly searches of Embase;
4. handsearches of 30 journals and the proceedings of major
conferences;
5. weekly current awareness alerts for a further 44 journals
plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and
Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the Specialized Register section
within the editorial information about the Cochrane Pregnancy
and Childbirth Group.
Trials identified through the searching activities described above
are each assigned to a review topic (or topics). The Trials Search
Co-ordinator searched the register for each review using the topic
list rather than keywords.
We did not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors independently assessed for inclusion all the
potential studies we identified as a result of the search strategy. We
resolved any disagreement through discussion or, if required, we
consulted a third person.
Data extraction and management

We designed a form to extract data. For eligible studies, at least
two review authors extracted the data using the agreed form. We
resolved discrepancies through discussion or, if required, we consulted a third person. We entered data into Review Manager software (RevMan 2011) and checked for accuracy.
When information regarding any of the above was unclear, we
attempted to contact authors of the original reports to provide
further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each
study using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). We resolved
any disagreement by discussion or by involving a third author.
(1) Random sequence generation (checking for possible
selection bias)
We described for each included study the methods used to generate

the allocation sequence in sufficient detail to allow an assessment
of whether it should produce comparable groups.
We assessed the methods as:
low risk of bias (any truly random process, e.g. random
number table; computer random number generator);
high risk of bias (any non-random process, e.g. odd or even
date of birth; hospital or clinic record number);
unclear risk of bias.
(2) Allocation concealment (checking for possible selection
bias)
We described for each included study the method used to conceal

the allocation sequence and determined whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
low risk of bias (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or nonopaque envelopes, alternation; date of birth);
(3.1) Blinding of participants and personnel (checking for
possible performance bias)
We described for each included study, the methods, if any, used to

blind study participants and personnel from knowledge of which
intervention a participant received. We considered studies to be
at a low risk of bias if they were blinded, or if we judged that the
lack of blinding would be unlikely to affect results. We assessed
blinding separately for different outcomes or classes of outcomes.

low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible
detection bias)
We described for each included study the methods used, if any, to

blind outcome assessors from knowledge of which intervention a
participant received. We assessed blinding separately for different
outcomes or classes of outcomes.
We assessed methods used to blind outcome assessment as:
low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition
bias due to the amount, nature and handling of incomplete
outcome data)
We described for each included study and for each outcome or

class of outcomes,the completeness of data including attrition and
exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at
each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.
Where sufficient information was reported or was supplied by the
trial authors, we included missing data in the analyses which we
undertook.
low risk of bias (e.g. where there was no missing data or
where reasons for missing data were balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data
imbalanced across groups; as treated analysis done with
substantial departure of intervention received from that assigned
at randomisation);
(5) Selective reporting bias (checking for reporting bias)
We described for each included study how the possibility of selective outcome reporting bias was examined by us and what we
found.
low risk of bias (where it was clear that all of the studys prespecified outcomes and all expected outcomes of interest to the
review had been reported);
high risk of bias (where not all the studys pre-specified
outcomes had been reported; one or more reported primary
outcomes were not pre-specified; outcomes of interest were
reported incompletely and so could not be used; study failed to
include results of a key outcome that would have been expected
to have been reported);
(6) Other sources of bias (checking for bias due to problems

not covered by (1) to (5) above)
We described for each included study any important concerns we

had about other possible sources of bias. We assessed whether each
study was free of other problems that could put it at risk of bias:
low risk of other bias;
high risk of other bias;
unclear whether there is risk of other bias.
randomised minus any participants whose outcomes were known

to be missing.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta-analysis using
the T, I and Chi statistics. We regarded heterogeneity as substantial if the I was greater than 30% and either the T was greater
than zero, or there was a low P value (less than 0.10) in the Chi
test for heterogeneity.
(7) Overall risk of bias
We made explicit judgements about whether studies were at a

high risk of bias, according to the criteria given in the Cochrane
Handbook for Systematic Reviews of Interventions (Higgins 2011).
With reference to (1) to (6) above, we assessed the likely magnitude
and direction of the bias and whether we considered it is likely
to impact on the findings. We planned to explore the impact of
the level of bias through undertaking sensitivity analyses - see
Sensitivity analysis.
Assessment of reporting biases

In future updates of this review, if there are 10 or more studies
in the meta-analysis, we will investigate reporting biases (such as
publication bias) using funnel plots. We will assess funnel plot
asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as risk ratio with 95%

confidence intervals.
Continuous data
For continuous data, we used the mean difference when outcomes

were measured in the same way between trials. If necessary, we
would have used the standardised mean difference to combine trials that measured the same outcome, but used different methods.
Unit of analysis issues

We considered cross-over trials and cluster-randomised trials inappropriate for this research question.
We carried out statistical analysis using the Review Manager software (RevMan 2011). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were
estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials populations and methods were judged sufficiently similar. Where there
was clinical heterogeneity sufficient to expect that the underlying
treatment effects differed between trials, or where substantial statistical heterogeneity was detected, we used random-effects metaanalysis to produce an overall summary if an average treatment
effect across trials was considered clinically meaningful. The random-effects summary was treated as the average range of possible
treatment effects and we have discussed the clinical implications of
treatment effects differing between trials. If the average treatment
effect was not clinically meaningful, we would not have combined
trials.
Where we have used random-effects analyses, we have presented
the results as the average treatment effect with its 95% confidence
interval, and the estimates of T and I.
Dealing with missing data

For included studies, we noted levels of attrition. We planned to
explore the impact of including studies with high levels of missing
data in the overall assessment of treatment effect by sensitivity
analysis.
For all outcomes, we carried out analyses, as far as possible, on
an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention.
The denominator for each outcome in each trial was the number
Subgroup analysis and investigation of heterogeneity

If we had identified substantial heterogeneity, we planned to investigate it using subgroup analyses and sensitivity analyses. We
planned to consider whether an overall summary was meaningful,
and if it was, use random-effects analysis to produce it.
We performed separate comparisons for different types of corticosteroids; and different preparations, timings and routes of administration.
We planned the following subgroup analyses:
singleton versus multiple pregnancy;
preterm prelabour rupture of membranes (at trial entry: yes

versus no);
gestational age at trial entry (24 to 26 weeks, 27 to 29
weeks, 30 to 34 weeks, 35 to 37 weeks);
pregnancy-induced hypertension syndrome (yes or no).
However, we were only able to perform a subgroup analysis based
on gestational age at trial entry for one included trial, and we were
not able to perform the other subgroup analyses due to paucity of
data. We used only primary outcomes in the subgroup analysis.
We assessed subgroup differences by interaction tests available in
within RevMan (RevMan 2011). We have reported the results of
the subgroup analysis quoting the Chi statistic and P value, and
the interaction test I value.
Sensitivity analysis
We planned sensitivity analyses to explore the effect of trial quality
assessed by concealment of allocation, by excluding studies with
clearly inadequate allocation of concealment, rated at high risk
of bias for this component. However, only one quasi-randomised
trial was included in this version of the review and since no other
trials reported the same outcomes as this trial, a sensitivity analysis
by adequacy of allocation could not be carried out.
RESULTS
Description of studies
Results of the search

The updated searches of the Pregnancy and Childbirth Group
Trials Register identified three trial reports (Danesh 2012;
Khandelwal 2012; Shanks 2010). We have included two trials in
the review (Danesh 2012; Khandelwal 2012), and have excluded
the other trial (Shanks 2010).
Therefore, of the 20 trials that were identified for possible inclusion, 12 trials met our pre-selected inclusion criteria in that they
compared any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), or
compared different dose regimens and timing or frequency and
route of administration in women at risk of preterm birth (Chen
2005; Danesh 2012; Egerman 1998; Elimian 2007; Khandelwal
2012; Magee 1997; Mulder 1997; Mushkat 2001; Rotmensch
1999; Senat 1998; Subtil 2003; Urban 2005).
We excluded eight trials from the review (Egerman 1997; Kurz
1993; Liu 2006; Romaguera 1997; Salzer 1982; Shanks 2010;
Vytiska 1985; Whitt 1976); one trial is awaiting classification (
Romejko-Wolniewicz 2013); and one trial is ongoing (Crowther
2010). See Characteristics of studies awaiting classification and

Characteristics of ongoing studies.
Included studies
Description of interventions used in the included trials
In the 12 trials included in this review, 1557 women and 1661

infants were recruited (1159 women and 1213 infants in the 10
trials that compared dexamethasone with betamethasone). Four
different corticosteroid regimens were used:
six trials compared 24 mg dexamethasone (6 mg, 12 hourly,
four doses) and 24 mg betamethasone (12 mg, 24 hourly, two
doses) (Chen 2005; Danesh 2012; Elimian 2007; Rotmensch
1999; Subtil 2003; Urban 2005);
two trials compared 24 mg dexamethasone (12 mg, 12
hourly, two doses) and 24 mg betamethasone (12 mg, 12 hourly,
two doses) (Magee 1997; Mushkat 2001);
one trial compared 16 mg dexamethasone (4 mg, 12 hourly,
four doses) and 24 mg betamethasone (6 mg,12 hourly, four
doses) (Senat 1998);
one trial compared 24 mg dexamethasone (12 mg, 12
hourly, two doses) and 24 mg betamethasone (12 mg, 24 hourly,
two doses) (Mulder 1997).
One trial of 170 women and 188 infants compared 32 mg oral
dexamethasone (8 mg, 12 hourly, four doses) and 24 mg intramuscular dexamethasone (6 mg, 12 hourly, four doses) (Egerman
1998), and one trial of 228 mothers and 260 fetuses compared
dosing intervals of betamethasone; 12 mg, 24 hourly, two doses
versus 12 mg, 12 hourly, two doses (Khandelwal 2012).
The Subtil 2003 trial compared two forms of betamethasone (acetate and phosphate versus phosphate alone) as a third arm.
Four of the trials allowed repeat weekly doses of the allocated
corticosteroid (Egerman 1998; Magee 1997; Mushkat 2001; Senat
1998).
The gestational age at trial entry varied widely between trials (from
23 to 35 weeks of gestation). All women were at increased risk of
preterm birth or had a medical indication for birth at a preterm
gestational age (see Characteristics of included studies).
The included studies came from a range of healthcare systems.
Three of the trials were conducted in the USA (Egerman 1998;
Elimian 2007, Khandelwal 2012), two in France (Senat 1998;
Subtil 2003), two in Israel (Mushkat 2001; Rotmensch 1999) and
one in each of Taiwan (Chen 2005), UK (Magee 1997), Netherlands (Mulder 1997), Poland (Urban 2005) and Iran (Danesh
2012). The trials were conducted over more than two decades
from 1990 to 2012.
The primary outcomes varied between the trials. The primary outcomes of six of the trials focused on neonatal outcomes including RDS, IVH and death and at times, child outcomes of neurodisability at 18 months (Chen 2005; Egerman 1998; Elimian
2007; Khandelwal 2012; Senat 1998; Subtil 2003), while the five
other trials concentrated on biophysical parameters of the fetus
(Magee 1997; Mulder 1997; Mushkat 2001; Rotmensch 1999;
Urban 2005). One trial focused on effects on maternal serum indicators of infection (Danesh 2012).
Excluded studies
Eight trials were excluded: three because L-carnitine added to a
corticosteroid was compared against a corticosteroid to assess the
effect of L-carnitine (Kurz 1993; Salzer 1982; Vytiska 1985); one
trial was excluded as thyroxine added to a corticosteroid was compared against a corticosteroid to assess the effects of thyroxine
(Romaguera 1997); one trial was excluded as vitamin K added to

a corticosteroid was compared against a corticosteroid, vitamin K
and no treatment to assess the effects of vitamin K (Liu 2006);
one trial was excluded because it was a cross-over trial (Egerman
1997); one trial was excluded because it compared corticosteroids
(either dexamethasone or betamethasone) with placebo (Shanks
2010); and one trial was not randomised (Whitt 1976). For further details see Characteristics of excluded studies.
Risk of bias in included studies

Overall, the trials were judged to be at a moderate risk of bias, see
Figure 1 and Figure 2.
Figure 1. Risk of bias graph: review authors judgements about each risk of bias item presented as
percentages across all included studies.
10
Figure 2. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
11
For further details on the risk of bias in individual studies, see

Characteristics of included studies.
Allocation
Methods of sequence generation and allocation concealment were
both considered adequate in five of the 12 trials (Danesh 2012;
Elimian 2007; Khandelwal 2012; Magee 1997; Urban 2005).
In four further trials, while methods of random sequence generation were adequate, methods to conceal allocation were unclear
(Egerman 1998; Rotmensch 1999; Senat 1998; Subtil 2003). Two
trials were judged to be at an unclear risk of selection bias, with
methods of sequence generation and allocation concealment being
unclear (Chen 2005; Mulder 1997).
The remaining trial, Mushkat 2001 was quasi-randomised and
assessed as having a high risk of selection bias.
Selective reporting
There was no obvious risk of selective reporting in three trials
(Elimian 2007; Khandelwal 2012; Subtil 2003).
While two trials pre-specified their outcomes in the manuscript
methods, the risk of reporting bias was judged to be unclear, with
outcome data reported incompletely for some clinical outcomes,
e.g.gestational age, birthweight and Agpar score at five minutes
did not differ between the two groups (Egerman 1998; Mushkat
2001).
The remaining seven trials reported some important clinical outcomes however with no access to a trial protocol it was difficult
to confidently assess selective reporting; we therefore judged these
studies to be at an unclear risk of reporting bias (Chen 2005;
Danesh 2012; Magee 1997; Mulder 1997; Rotmensch 1999; Senat
1998; Urban 2005).
Blinding
Three trials were judged to be at a low risk of performance bias,
with blinding of women and personnel (Elimian 2007; Magee
1997; Mushkat 2001). For four trials, the risk of performance bias
was judged to be unclear, as blinding of women and personnel was
not detailed (Chen 2005; Mulder 1997; Rotmensch 1999; Urban
2005). The remaining five trials were judged to be at a high risk of
performance bias, with no blinding of women and study personnel
(or blinding considered unfeasible) (Danesh 2012; Egerman 1998;
Khandelwal 2012; Senat 1998; Subtil 2003).
Four trials were judged to be at a low risk of detection bias, with
blinding of outcome assessment (Egerman 1998; Elimian 2007;
Khandelwal 2012; Magee 1997). One trial was judged to be at a
high risk of detection bias, with no blinding of outcome assessors
(Subtil 2003); for the other seven trials, the risk of detection bias
was judged to be unclear (Chen 2005; Danesh 2012; Mulder 1997;
Mushkat 2001; Rotmensch 1999; Senat 1998; Urban 2005).
Incomplete outcome data

Five trials were judged to be at low risk of attrition bias (Danesh
2012; Egerman 1998; Khandelwal 2012; Senat 1998; Urban
2005).
Losses to follow-up were unclear and not documented in the
Rotmensch 1999 and Mushkat 2001 trials. Mulder 1997 reported
a 17% loss to follow-up (6/30 from the dexamethasone group and
4/30 from the betamethasone group), and in Elimian 2007 less
than 60% of all infants were assessed for IVH and PVL. In Magee
1997 and Subtil 2003, losses were greater than 50% at the end of
follow-up for some of the biophysical parameters.
The Chen 2005 trial was judged at a high risk of attrition bias, as
data were excluded for 16% of women, with no indication from
which groups the losses had occurred.
Other potential sources of bias

For eight trials, groups were comparable at baseline and there were
no other obvious sources of bias identified (Danesh 2012; Egerman
1998; Elimian 2007; Magee 1997; Mulder 1997; Mushkat 2001;
Rotmensch 1999; Subtil 2003; Urban 2005).
Other bias was judged as unclear in the Chen 2005 and
Khandelwal 2012 trials due to some baseline imbalances between
groups regarding age and ethnicity.
Effects of interventions
Twelve trials involving 1557 women and 1661 babies were included.
The results are presented by type of corticosteroid or method of
administration compared:
dexamethasone versus betamethasone (Chen 2005; Danesh
2012; Elimian 2007; Magee 1997; Mulder 1997; Mushkat 2001;
Rotmensch 1999; Senat 1998; Subtil 2003; Urban 2005);
oral versus intramuscular dexamethasone (Egerman 1998);
betamethasone acetate and phosphate versus betamethasone
phosphate (Subtil 2003);
betamethasone dosing interval (12 hourly doses versus 24
hourly doses) (Khandelwal 2012).
1. Dexamethasone versus betamethasone

Ten trials with 1159 women and 1213 infants were included in
this comparison.
Primary outcomes
12
Women
Infants
No primary outcomes for women were reported in any of the

included trials.
No statistically significant differences between those exposed to

dexamethasone or betamethasone were seen for Apgar score less
than seven at five minutes (RR 0.97, 95% CI 0.43 to 2.18; two trials, 207 infants) (Analysis 1.5), Apgar score at five minutes (mean
difference (MD) 0.23, 95% CI -0.23 to 0.70; two trials, 307 infants) (Analysis 1.6, random-effects, T = 0.11; I = 64%), mean
birthweight (MD 0.01 kg, 95% CI -0.11 to 0.12; five trials, 734
infants) (Analysis 1.8), low birthweight less than 2500 g (RR 0.89,
95% CI 0.65 to 1.24; one trial, 105 infants) (Analysis 1.10), or
head circumference (MD -0.50 cm, 95% CI -1.55 to 0.55; one
trial, 157 infants) (Analysis 1.11).
Overall, therefore, there was no significant difference in the risk
of NICU admission (RR 1.72, 95% CI 0.44 to 6.72; two trials,
345 infants) (Analysis 1.12). As we identified substantial statistical
heterogeneity for this outcome (T = 0.80; I = 81%) a randomeffects model was used. It is possible that the differences in reasons
for risk of preterm birth, or other clinical factors, between these
trials contributed to this level of heterogeneity.
In one of the trials, significantly more infants were admitted to the
NICU in the dexamethasone group compared with the betamethasone group. Seven of the eight infants in the dexamethasone group
were transferred to the NICU because of respiratory distress and
the remaining infant was transferred due to suspected infection.
The reason for all four infants in the betamethasone group being
transferred to NICU was because of respiratory distress. In the
other trial of 240 infants (Danesh 2012), however, there was no
significant difference in NICU admissions with 34 admissions in
the dexamethasone group, compared with 36 in the betamethasone group. It appears that all 70 infants were transferred to NICU
due to respiratory distress, however this was unclear.
No significant differences between the dexamethasone and betamethasone groups were seen for the outcomes vasopressor use
(RR 0.44, 95% CI 0.17 to 1.11; one trial, 359 infants) (Analysis
1.13), bronchopulmonary dysplasia (RR 2.50, 95% CI 0.10 to
61.34; two trials, 464 infants) (Analysis 1.14), severe IVH (RR
0.40, 95% CI 0.13 to 1.24; four trials, 549 infants) (Analysis 1.15),
periventricular leukomalacia (RR 0.83, 95% CI 0.23 to 3.03; four
trials, 703 infants) (Analysis 1.16), neonatal sepsis (RR 1.30, 95%
CI 0.78 to 2.19; two trials, 516 infants) (Analysis 1.17), necrotising enterocolitis (RR 1.29, 95% CI 0.38 to 4.40; three trials,
598 infants) (Analysis 1.18), retinopathy of prematurity (RR 0.93,
95% CI 0.59 to 1.47; two trials, 516 infants) (Analysis 1.19),
or patent ductus arteriosus (RR 1.19, 95% CI 0.56 to 2.49; one
trial, 359 infants) (Analysis 1.20). Considering the outcome bronchopulmonary dysplasia, there was substantial statistical heterogeneity (T = 4.40; I = 80%), and thus a random-effects model
was used.
Some differences in biophysical parameters were seen:
the dexamethasone group had a significantly lower fetal
heart rate than the betamethasone group at day two (MD -4.20
beats per minute, 95% CI -7.17 to -1.23; one trial, 46 infants -
Infants
dexamethasone or betamethasone were seen for neonatal death
(risk ratio (RR) 1.41, 95% confidence interval (CI) 0.54 to 3.67;
four trials, 596 infants) (Analysis 1.1) or respiratory distress syndrome (RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials; 753
infants) (Analysis 1.2).
Danesh 2012 reported on the number of infants admitted to the
neonatal intensive care unit (NICU) because of respiratory distress
syndrome for women with intact membranes; 9/60 in the dexamethasone group were admitted versus 12/60 in the betamethasone
group. It was unclear however as to whether this represented all
cases of RDS or only those admitted to the NICU, and thus these
data have not been included in the review meta-analysis for RDS.
Dexamethasone significantly decreased the risk of intraventricular haemorrhage (IVH) compared with betamethasone (RR 0.44,
95% CI 0.21 to 0.92; four trials, 549 infants) (Analysis 1.3).
Children
Out of a small subgroup assessed at 18 months in the Subtil 2003
trial, one child in the dexamethasone group was recorded as having
a neurosensory disability (RR 1.67, 95% CI 0.08 to 33.75; one
trial, 12 infants - Subtil 2003) (Analysis 1.4). Death in childhood
was not reported as an outcome in any of the included trials.

No primary outcomes for the child as an adult were reported in
any of the included trials.
Secondary outcomes
Women
No secondary outcomes for women were reported in any of the
included trials. While in Danesh 2012 no data regarding adverse
effects were reported for inclusion in a meta-analysis, it was stated
that Both, dexamethasone and betamethasone treatment was tolerated well and most of the adverse events reported were mild in
severity.
13
Rotmensch 1999) (Analysis 1.21), in Senat 1998 (see Other

data table (Analysis 1.22)); but not in Magee 1997;
the dexamethasone group had a significantly higher level of
fetal movements detected via ultrasound than the betamethasone
group (MD 7.0 movements per hour, 95% CI 2.15 to 11.85;
one trial, 33 infants - Mushkat 2001) (Analysis 1.27);
at day two, the dexamethasone group had significantly
higher breathing times than the betamethasone group (MD
32.00 more seconds per 30 minutes, 95% CI 4.37 to 59.63; one
trial, 46 infants - Rotmensch 1999) (Analysis 1.30).
betamethasone or dexamethasone were seen for other biophysical
parameters including accelerations per hour (MD 2.80, 95% CI
-0.15 to 5.75; one trial, 46 infants - Rotmensch 1999) (Analysis
1.23), fetal movements in 30 minutes (MD 2.30, 95% CI -0.74
to 5.34; one trial, 46 infants - Rotmensch 1999) (Analysis 1.25),
fetal movement via maternal perception (MD 3.00 movements
per hour, 95% CI -3.20 to 9.20; one trial, 33 infants - Mushkat
2001) (Analysis 1.26), and fetal breathing movements per hour
(MD 0.00, 95% CI -2.05 to 2.05; one trial, 33 infants - Mushkat
2001) (Analysis 1.29) .
Some additional data in the form of median and interquartile
ranges are shown in Other data tables, with no differences seen
between dexamethasone and betamethasone except for a lower
heart fetal rate in Senat 1998 for dexamethasone (Analysis 1.22).
A range of fetal heart rate indicators were measured in Subtil 2003
but only reported in graphical form; the trial authors reported
that none of the indicators showed significant differences between
dexamethasone and betamethasone.
Where statistical heterogeneity has not been reported for outcomes
discussed above (if more than one trial was included in the metaanalysis), there was no heterogeneity observed between trials (I =
0).
Children
No secondary outcomes for children were reported in any of the
included trials.

No secondary outcomes for children as adults were reported in
any of the included trials.
Health services
Mean length of antenatal admission to birth (days) was reported
in one trial of 240 women (Danesh 2012), and no significant
difference was observed overall between the dexamethasone and
betamethasone groups (MD 3.48 days, 95% CI -3.38 to 10.34;
240 women) (Analysis 1.31). The Danesh 2012 trial reported data
separately for women with intact and ruptured membranes, and
a substantial level of heterogeneity was observed for this outcome

across these subgroups (T = 61.91; I = 98%). Women with intact
membranes who received betamethasone were significantly more
likely to have a shorter length of admission to birth than women
who received dexamethasone; this was not the case for women
with ruptured membranes.
The Danesh 2012 trial also reported on mean length of NICU
admission (for the 70 infants admitted to the NICU), and found
a significant reduction in length of stay for infants who had been
exposed to dexamethasone, as compared with betamethasone (MD
-0.91 days, 95% CI -1.77 to -0.05; 70 infants) (Analysis 1.32).
Indirect comparisons and subgroup interaction tests

Using the methods outlined in the additional material accompanying Song 2003, we calculated indirect comparisons of the trials of
betamethasone versus placebo/no treatment, and dexamethasone
versus placebo/no treatment that were included in the Roberts
2006 Cochrane review (see Table 1). We also performed subgroup
interaction tests on these trials from the Roberts 2006 Cochrane
review (see Table 1).
Considering fetal/neonatal death, the indirect estimate and subgroup interaction test were compatible with the findings of this review, indicating no significant difference between dexamethasone
and betamethasone for this outcome.
For the outcome RDS, while the discrepancy between the direct
estimate from this review and the indirect estimate was not significant, the indirect comparison did indicate a significant difference between dexamethasone and betamethasone in favour of betamethasone (RR 1.40, 95% CI 1.02 to 1.90) that was inconsistent with the non significant difference shown in this review. In
addition, the subgroup interaction test for RDS was inconsistent
with the direct comparison in this review, indicating a significant
difference between subgroups and a possible differential effect between the two steroids in favour of betamethasone (Chi statistic:
4.68 and P value: 0.03, I value: 78.6%).
While the indirect estimate for IVH did not reveal a significant
difference between the two steroids as was shown in the direct
comparison in this review (in favour of dexamethasone), the discrepancy between the indirect and direct estimates was non significant. The subgroup interaction test was however inconsistent
with the direct estimate from this review, failing to show a significant difference between the two steroids for IVH (Chi statistic:
0.78 and P value: 0.38, I value: 0%).
Although chorioamnionitis and puerperal sepsis were not reported
in any trials directly comparing betamethasone and dexamethasone included in this review, we estimated the indirect estimates
and tested for subgroup differences in the trials from the Roberts
2006 review. While the indirect estimate and subgroup interaction
test suggested no significant difference between dexamethasone
and betamethasone for puerperal sepsis, both the indirect estimate
(RR 1.90, 95% CI 1.10 to 3.28) and the subgroup interaction test
14
(Chi statistic: 5.41 and P value 0.02, I value: 81.5%) indicated a

significant difference between the two steroids for chorioamnionitis, in favour of betamethasone.
2. Dexamethasone (oral versus intramuscular

injection)
One trial with 170 women and 188 infants (Egerman 1998) was
included in this comparison.
Primary outcomes
Infants
There was no statistically significant difference between oral and
intramuscular dexamethasone seen for birthweight (MD -0.05 kg,
95% CI -0.17 to 0.27) (Analysis 2.4) or necrotising enterocolitis
(RR 5.09, 95% CI 0.63 to 41.45) (Analysis 2.6).
Treatment with oral dexamethasone was associated with an increase in neonatal sepsis compared with intramuscular dexamethasone (RR 8.48, 95% CI 1.11 to 64.93) (Analysis 2.5) with all
neonatal sepsis cases occurring in the less than 34 weeks gestation
subgroup (RR 9.84, 95% CI 1.30 to 74.60).
Children
No secondary outcomes for children were reported in this trial.
Women
No primary outcomes for women were reported in this trial.

No secondary outcomes for children as adults were reported in
this trial.
Infants
No statistically significant differences between oral or intramuscular dexamethasone were seen for neonatal death (RR 1.48, 95%
CI 0.45 to 4.90) (Analysis 2.1), or RDS (RR 1.15, 95% CI 0.75
to 1.77) (Analysis 2.2). No significant difference was seen between
oral and intramuscular dexamethasone for IVH (RR 4.24, 95%
CI 0.96 to 18.33), although this did reach statistical significance
in favour of the intramuscular route when looking at only the less
than 34 weeks gestation at birth subgroup (RR 4.92, 95% CI 1.12
to 21.55) (Analysis 2.3). All instances of IVH (10 in oral group
and two in the intramuscular group) occurred in babies born before 34 weeks.
3. Betamethasone acetate + phosphate versus

betamethasone phosphate
One trial with 69 infants (Subtil 2003) was included in this comparison.
Primary outcomes
Women
Children
Infants
No primary outcomes for children were reported in this trial.

betamethasone acetate and phosphate versus betamethasone phosphate were seen for neonatal death (RR 0.32, 95% CI 0.01 to 7.69)
(Analysis 3.1), RDS (RR 0.19, 95% CI 0.01 to 3.91) (Analysis
3.2), or IVH (RR 0.32, 95% CI 0.01 to 7.69) (Analysis 3.3).

No primary outcomes for children as adults were reported in this
trial.
Children
Secondary outcomes
None of the children were reported to have a neurodevelopmental

disability at 18 months (Analysis 3.4).

Women
No secondary outcomes for women were reported in this trial.

trial.
15
Secondary outcomes
Infants
betamethasone acetate and phosphate versus betamethasone phosphate were seen for birthweight (MD -0.10 kg, 95% CI -0.44 to
0.24) (Analysis 3.5) or low birthweight (RR 1.21, 95% CI 0.86
to 1.72) (Analysis 3.6). No infants from the betamethasone acetate and phosphate group were transferred to NICU compared
with four in the betamethasone phosphate group, all four due
to respiratory distress (RR 0.11, 95% CI 0.01 to 1.93) (Analysis
3.7); this difference was not statistically significant. No instances
of bronchopulmonary dysplasia (Analysis 3.8) or periventricular
leukomalacia (Analysis 3.9) were reported in this trial.
A range of fetal heart rate indicators were measured but only reported in graphical form. The trial authors reported that none of
the indicators showed significant differences between the different
betamethasone formulations.
4. Betamethasone dosing interval: 12 hourly versus 24

hourly
One trial with 260 infants (Khandelwal 2012) was included in
this comparison.
Primary outcomes
Women
Infants
No statistically significant differences were seen when a 12-hour
dosing interval of betamethasone (12 mg) was compared to a 24hour dosing interval for perinatal mortality (fetal and neonatal
mortality were not reported separately) (RR 0.93, 95% CI 0.46
to 1.87) (Analysis 4.1), RDS (RR 0.98, 95% CI 0.69 to 1.40)
(Analysis 4.2), or IVH (RR 1.40, 95% CI 0.76 to 2.56) (Analysis
4.3).
Subgroup analysis
The Khandelwal 2012 trial considered separately women at the
following gestational age categories at trial entry: 23+1 to 26+0
weeks gestation; 26+1 to 29+0 weeks gestation; 29+1 to 32+0
weeks gestation; and 32+1 to 34+0 weeks gestation.
No significant differences were shown for the three infant primary
outcomes that were reported (perinatal death, RDS and IVH) for
any of the subgroups, and subgroup interaction tests were not significant for any of the three outcomes, indicating no differential
treatment effect by gestational age at trial entry (perinatal mortality: Chi statistic: 0.93 and P value: 0.92, I value: 0%; Analysis
4.1) (RDS: Chi statistic: 5.62 and P value: 0.23, I value: 28.8%;
Analysis 4.2) (IVH: Chi statistic: 2.42 and P value: 0.66, I value:
0%; Analysis 4.3).
Secondary outcomes
Women
Maternal fever (defined as greater than 100.4F) was not significantly different between groups (RR 0.71, 95% CI 0.25 to 2.02)
(Analysis 4.4).
Infants
No statistically significant differences between groups were seen for
birthweight (MD 84.00 g, 95% CI -144.63 to 312.63) (Analysis
4.5), small-for-gestational age (RR 0.61, 95% CI 0.36 to 1.05)
(Analysis 4.6), chronic lung disease (RR 0.79, 95% CI 0.49 to
1.26) (Analysis 4.8), neonatal sepsis (RR 1.15, CI 0.47 to 2.81)
(Analysis 4.9), neonatal antibiotic use of more than five days (RR
0.94, 95% CI 0.61 to 1.46) (Analysis 4.10) or retinopathy of
prematurity (RR 0.94, 95% CI 0.53 to 1.66) (Analysis 4.12).
A trend towards reduced admission to NICU for the 12-hourly
regimen group as compared with the 24-hourly regimen group
was observed (P = 0.05) (RR 0.89, 95% CI 0.79 to 1.00) (Analysis
4.7).
No infants in the 24-hour group developed necrotising enterocolitis while 10 infants in the 12-hour group developed necrotising enterocolitis, however this was not statistically significant (RR
9.20, 95% CI 0.55 to 154.92) (Analysis 4.11).
Health services
Children
No primary outcomes for children were reported in this trial.
Women who received the 12-hour dosing interval of betamethasone had a significantly shorter mean maternal postpartum length
of stay than women who received the 24-hour dosing interval (MD
-0.73 days, 95% CI -1.28 to -0.18) (Analysis 4.13).

trial.
DISCUSSION
16
That antenatal corticosteroids are effective in preventing neonatal

morbidity is not in dispute (Roberts 2006) and this life-saving
therapy is now widely used throughout the world (Chow 2013;
Brocklehurst 1999; Foix-LHelias 2008; NIH 2000; Quinlivan
1998; Saengwaree 2005). However, it is not yet clear which corticosteroid and which regimens perform best. Determining the optimal corticosteroid and optimal regimens is very important since
most pregnant women at risk of preterm birth will be considered
candidates for antenatal corticosteroid treatment (NIH 2000) and
these numbers may continue to grow as rates of preterm birth
are increasing in a number of countries (Chow 2013; Goldenberg
2007).
There is considerable variation reported between countries as to
whether dexamethasone or betamethasone is preferred by health
practitioners, with many likely reasons for these differences including availability and costs (dexamethasone is cheaper than betamethasone so is widely used in low- and middle-income countries) (Henderson-Smart 2007; Saengwaree 2005), impact of inconsistent findings from observational studies (Baud 1999; Lee
2006) and influence of opinion leaders (Jobe 2004).
Although we were able to include 12 trials (involving 1557 women
and 1661 infants) rated of moderate quality, including one quasirandomised trial in this review (Mushkat 2001), our ability to
reach conclusions was limited by the small number of comparisons
of different antenatal steroid regimens. Most of the data available
focused on the type of corticosteroid used, with 10 of the studies
comparing the two most commonly used corticosteroids, dexamethasone and betamethasone (with some variation in frequency
and timing of administration).
The results of this review are broadly consistent with results of the
Roberts 2006 Cochrane review of antenatal corticosteroids when
they are recalculated as indirect comparisons of dexamethasone
versus betamethasone (see Table 1) (with no significant discrepancies between the direct and indirect estimates found). However, the suggestion of increased benefit of dexamethasone over
betamethasone from this review for IVH is not sufficient evidence
to support dexamethasone over betamethasone; while the discrepancy between the indirect and direct estimates for IVH was not
significant, the indirect comparison from the Roberts 2006 review
did not support the significant difference between the two steroids
for IVH shown in this review, and neither did the subgroup interaction test. A recent observational study, which reported reduced
adverse neurological outcomes at 18 to 22 months for betamethasone but not for dexamethasone, highlights the persisting uncertainty, stating that to elucidate more fully predictive or causative
neonatal or neurodevelopmental outcomes, a randomised clinical trial comparing dexamethasone and betamethasone should be
performed (Lee 2008). Such a trial would need to measure longterm effects, particularly for dexamethasone, as there has been no
long-term follow-up reported in studies that have used this type
of corticosteroid. One such trial has just completed recruitment
(Crowther 2010).
Very few maternal outcomes were reported in the trials included in
this review, with none of the reviews primary or secondary maternal review outcomes reported in the 10 trials that compared dexamethasone and betamethasone. As noted in the results section,
while the indirect comparison of dexamethasone and betamethasone from the Roberts 2006 review for puerperal sepsis suggested
no significant difference between the two steroids, both the indirect estimate and subgroup interaction test suggested a significant difference for chorioamnionitis (in favour of betamethasone),
which requires further evaluation. This review has not been able
to provide any further evidence as none of the included trials reported on chorioamnionitis.
Although extensively reported in several of the included trials
(Magee 1997; Mushkat 2001; Rotmensch 1999; Senat 1998;
Subtil 2003), the clinical significance of differences in biophysical
parameters such as fetal heart rate and respiratory rate is not clear
(Rotmensch 1999). Overall, these trials generally showed few differences between dexamethasone and betamethasone, except for
a significantly lower heart rate at day two, a longer duration of
breathing time at day two, and more fetal movements detected via
ultrasound for the dexamethasone group. Some authors suggest
that the influence of antenatal corticosteroids on parameters such
as fetal heart rate is not clinically important, being a transient physiological response (Magee 1997; Rotmensch 1999; Subtil 2003).
Evidence about optimal doses, timing and frequency of administration of specific antenatal corticosteroids was even more sparse
than that for type of corticosteroid, with three of the 12 trials
contributing data to three separate comparisons. In regards to oral
versus intramuscular dexamethasone, some benefits were shown
for intramuscular administration, in regards to less neonatal sepsis,
and a reduction in IVH for infants born before 34 weeks gestation. No differences were seen for any of the reported outcomes
when betamethasone acetate and phosphate was compared with
betamethasone phosphate alone, although information was only
available from one trial of 69 infants. In the trial that compared
12-hourly versus 24-hourly betamethasone administration, no differences were shown between regimens for the reviews primary
outcomes, however a reduction in maternal postpartum length of
stay for women who received betamethasone at 12-hourly intervals was observed, and a trend towards reduced NICU admissions
was also seen for infants in the 12-hourly group.
AUTHORS CONCLUSIONS
Implications for practice
Dexamethasone may have some benefits compared with betamethasone such as less IVH, possibly some improved biophysical parameters and a shorter length of NICU stay. Apart from the
17
superiority of an intramuscular compared with an oral route for

dexamethasone in one trial and the similar efficacy of 24-hour versus 12-hour dosing of betamethasone, so far there is little evidence
to guide clinical practice about optimal antenatal corticosteroid
regimens.
ACKNOWLEDGEMENTS
For this update, we thank Frances Kellie, Leanne Jones, Denise
Atherton and Lynn Hampson of the Cochrane Pregnancy and
Childbirth Group for their support.
Special thanks to Sonja Henderson, Denise Atherton and Lynn
Hampson for their support and guidance throughout previous
versions of this review. Thanks to Dr Reinaldo Figueroa and Dr
Laura Magee, authors of included trials, for providing additional
information for the previous update of this review.
Implications for research

Further trials directly comparing the type, dose, frequency and
route of betamethasone with dexamethasone for women at risk of
preterm birth are required. They should be of high quality, large
enough to assess morbidity and mortality of the fetus/infant, longterm outcomes and maternal outcomes; one such study has just
completed recruitment (Crowther 2010). High-quality trials are
needed to establish which of the commonly used corticosteroids
(dexamethasone or betamethasone) is most effective and causes
least harm (including at longer-term, assessments), as are trials of
dosages and other variations in regimens.
As part of the pre-publication editorial process, this review has

been commented on by three peers (an editor and three referees
who are external to the editorial team) and the Groups Statistical
Adviser.
The National Institute for Health Research (NIHR) is the largest
single funder of the Cochrane Pregnancy and Childbirth Group.
The views and opinions expressed therein are those of the authors
and do not necessarily reflect those of the NIHR, NHS or the
Department of Health.
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Liggins 1976
Liggins GC. Prenatal glucocorticoid treatment: prevention
of respiratory distress syndrome. Lung maturation and the
prevention of hyaline membrane disease. Report of the
Seventieth Ross Conference on Paediatric Research; 1976;
Columbus, Ohio. 1976:97103.
Roberts 2006
Roberts D, Dalziel S. Antenatal corticosteroids for
accelerating fetal lung maturation for women at risk of
preterm birth. Cochrane Database of Systematic Reviews 2006,
Issue 3. [DOI: 10.1002/14651858.CD004454.pub2]
March of Dimes 2012

March of Dimes, PMNCH, Save the Children, WHO.
Executive summary. In: Howson CP, Kinney JE, Lawn
JE editor(s). Born Too Soon: The Global Action Report on
Preterm Birth. Geneva: World Health Organization, 2012.
Moise 1995
Moise AA, Wearden ME, Kozinetz CA, Gest AL, Welty SE,
Hansen TN. Antenatal steroids are associated with less need
for blood pressure support in extremely premature infants.
Pediatrics 1995;95:84550.
Murphy 1982
Murphy BE. The absorption by the human fetus of intraamniotically injected cortisol. Journal of Steroid Biochemistry
1982;16(3):4157.
NIH 1995
Anonymous. Effect of corticosteroids for fetal maturation
on perinatal outcomes. NIH Consensus Development
panel on the effect of corticosteroids for fetal maturation on
perinatal outcomes. JAMA 1995;273(5):4138.
NIH 2000
NIH Consensus Panel. Antenatal corticosteroids revisited.
NIH Consensus Statement 2000; Vol. 17, issue 2:110.
NNF6 2011
Hey E, editor. The Neonatal Formulary: Drug Use in
Pregnancy and the First Year of Life 6th Edition (NNF6).
Oxford: BMJ Books/Wiley Blackwell, 2011.
Saengwaree 2005
Saengwaree P, Liabsuetrakul T. Changing practice on
corticosteroids. Journal of the Medical Association of
Thailand 2005;88:30713.
Saigal 2007
Saigal S, Doyle LW. An overview of mortality and sequelae
of preterm birth from infancy to adulthood. Lancet 2007;
371(9608):2619.
Song 2003
Song F, Altman D, Glenny AM, Deeks J. Validity of
indirect comparison for estimating efficacy of competing
interventions: empirical evidence from published metaanalyses. BMJ 2003;326:4727.
Walfisch 2001
Walfisch A, Hallak M, Mazor M. Multiple courses of
antenatal steroids: risks and benefits. Obstetrics and
Gynecology 2001;98:4917.
References to other published versions of this review

Brownfoot 2008
Brownfoot FC, Crowther CA, Middleton P. Different
corticosteroids and regimens for accelerating fetal lung
maturation for women at risk of preterm birth. Cochrane
Database of Systematic Reviews 2008, Issue 4. [DOI:
10.1002/14651858.CD006764.pub2]
Indicates the major publication for the study
21
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Chen 2005
Methods
Randomised controlled trial.
Participants
168 women received antenatal corticosteroids so we have assumed 168 was the number
randomised
After exclusions 140 women, who gave birth to 157 infants (17 sets of twins), were
included
Setting: Mackay Memorial Hospital, Taiwan (from December 2001 to September 2003)
Inclusion criteria: preterm prelabour rupture of membranes between 24 and 32 weeks
and preterm labour between 24 and 34 weeks
Interventions
Dexamethasone group (n = 76 infants)

24 mg: 4 x 6 mg doses IM 12 hours apart.
Betamethasone group (n = 81 infants)
24 mg: 2 x 12 mg doses IM 24 hours apart.
Outcomes
Infant:
RDS; IVH (grade 3 to 4); PVL; birthweight; Apgar score < 7 at 5 mins; head circumference; neonatal sepsis; NEC; ROP
Mother:
Caesarean birth.
Notes
Funding source was not detailed.
Risk of bias
Bias
Authors judgement
Support for judgement
Random sequence generation (selection Unclear risk

bias)
Quote: These women were randomly divided into two

groups,
Allocation concealment (selection bias)
As above, no further detail provided.
Unclear risk
Blinding of participants and personnel Unclear risk

(performance bias)
All outcomes
Unclear, not reported.
Blinding of outcome assessment (detection Unclear risk

bias)
All outcomes
Incomplete outcome data (attrition bias)

All outcomes
Data were excluded for 28/168 (16%) women (1 intrauterine fetal death, 15 women gave birth after 37
weeks gestation, 4 neonates died immediately after delivery, 8 women gave birth at another hospital); it was
High risk
22
Chen 2005
(Continued)
not reported in which groups (dexamethasone or betamethasone) the losses occurred

Selective reporting (reporting bias)
Unclear risk
Insufficient information to permit judgement (while a

number of important outcomes were reported, no protocol was available, and thus it was difficult to assess selective reporting)
Other bias
Unclear risk
While groups were comparable at baseline, women in the

betamethasone group were approximately 3 years older
compared to women in the dexamethasone group
Danesh 2012
Methods
Participants
240 women randomised.

Setting: Isfahan University of Medical Sciences Obstetrics Department, Iran (from
February to November 2011)
Inclusion criteria: pregnant women of low parity; 16 to 45 years of age; between 24
and 34 weeks gestation; hospitalised because of high risk of preterm birth that justified
preventative corticosteroid therapy; with or without intact membranes; low Bishop score
5; non-smokers; singleton pregnancy; residence in Isfahan; hospitalisation planned to
last at least 3 days
Preterm rupture of membranes was diagnosed in the presence of a gush of fluid from the
vagina, followed by persistent, uncontrolled leakage, or pooling of fluid on speculum
examination, with positive nitrazine and Fern testing. Preterm labour was diagnosed in
the presence of uterine contractions of 4 in 20 minutes or 8 in 60 minutes, plus progressive
change in the cervix, cervical dilatation greater than 1 cm and cervical effacement 80%
or greater
Exclusion criteria: women were excluded if they had evidence of fetal distress, substantial abnormalities in neurological, psychiatric, cardiac, endocrinological, haematologic,
hepatic, renal or metabolic function; had signs of infection; positive urine culture; vaginal bleeding due to placental praevia or abruption
Interventions
Betamethasone group (n = 120)

2 IM injections of 12 mg betamethasone sodium at 24-hour intervals
Dexamethasone group (n = 120)
4 IM injections of 6 mg dexamethasone phosphate at 12-hour intervals
Outcomes
Infant:
Fetal plasma glucose; Apgar scores (1 minute and 5 minute); NICU stay
Mother:
Maternal WBC and differential count; ESR; maternal fasting plasma glucose; length of
admission to birth; preterm birth; gestational age at birth
Notes
23
Danesh 2012
(Continued)
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Low risk

bias)
Quote: women were randomised with a list of computer-generated numbers
Group assignments were concealed in an opaque sealed

envelope until just before entry into the study. It was not
stated whether the envelopes were consecutively numbered
Low risk
Blinding of participants and personnel High risk

(performance bias)
All outcomes
Quote: due to the different injection frequency and

treatment period of dexamethasone and betamethasone,
it was not possible to ensure patients were blinded

bias)
All outcomes

All outcomes
Low risk
Quote: all 240 women who completed treatment were

available for follow-up at delivery. It was assumed that
there was no attrition nor were there any exclusions
Unclear risk
With no access to a trial protocol, the review authors

cannot confidently assess selective reporting. In regards
to NICU admission, it is unclear as to whether the values
in the table represents all admissions, or only those due
to RDS (the text suggests it represents only those due to
RDS). In regards to adverse events, data is not reported,
quote Both, dexamethasone and betamethasone treatment was tolerated well and most of the adverse events
reported were mild in severity
Other bias
Low risk
The study appears to be free of other sources of bias.

Groups were comparable at baseline
Egerman 1998
Methods
Participants

Setting: Tennessee, USA (from July 1996 to July 2007).
Inclusion criteria: preterm birth between 24 to 33 weeks gestation, preterm labour,
preterm rupture of membranes, medical indication for delivery
Exclusion criteria: received corticosteroids during the pregnancy (except immediately
before transfer), anticonvulsant therapy, rifampin, infection other than cystitis or cervicitis, advanced cervical dilatation, fetal pulmonary maturity
24
Egerman 1998
(Continued)
Interventions
Oral dexamethasone group (n = 92 women; 99 infants)

32 mg oral dexamethasone: 4 x 8 mg, 12 hourly.
IV dexamethasone group (n = 78 women; 84 infants)
24 mg IM dexamethasone: 4 x 6 mg IM, 12 hourly.
Repeated weekly until 34 weeks gestation if birth had not yet occurred
Outcomes
Infant:
Death; RDS; IVH; birthweight; sepsis; NEC; gestational age at birth
Mother:
Gestational age at entry (weeks); dilatation (cm); latency; caesarean birth; antibiotic use
Notes
The study was discontinued at 39% enrolment (170 women) after a blinded review of
available outcomes
Risk of bias
Bias
Authors judgement

bias)
Participants were randomly assigned by computer-generated numbers (placed in sealed envelopes)
Sealed envelopes were used; no further details provided.
Unclear risk

(performance bias)
All outcomes
Due to the nature of the intervention, it is considered

unlikely that participants and personnel were blinded
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
An investigator not involved in recruitment or patient

care performed the analysis

All outcomes
Low risk
5/170 (3%) women were unavailable for follow-up.
Unclear risk
While the pre-specified primary and secondary outcomes from the methods were reported, no protocol was
available to assess selective reporting, and furthermore,
clinical outcomes were reported incompletely, for example quote No differences in Apgar scores at 1 and at 5
minutes were noted between the oral and intramuscular
groups
Other bias
Low risk
No other obvious sources of bias identified. Groups were

comparable at baseline
25
Elimian 2007
Methods
Participants

Setting: Stony Brook University Hospital, New York, USA (from August 2002 to July
2004)
Inclusion criteria: risk of preterm birth between 24 to 33 weeks gestation.
Exclusion criteria: clinical chorioamnionitis, major fetal structural abnormalities, major fetal chromosomal abnormalities, prior antenatal corticosteroid exposure, use of betamethasone or dexamethasone for other medical indications and quadruplets
Interventions
Dexamethasone group (n = 149 women; 178 infants)

24 mg dexamethasone: 4 x 6 mg doses of dexamethasone IM 12 hours apart
Betamethasone group (n = 150 women; 181 infants).
24 mg betamethasone: 2 x 12 mg doses of betamethasone IM 24 hours apart (placebo
2 doses given at 12-hour intervals)
Outcomes
Infant:
Death; IVH (diagnosed by ultrasound, diagnosed by autopsy); RDS; PVL; birthweight;
BPD; NEC; neonatal sepsis; surfactant use; ROP; neonatal blood pressure; need for inotropic support; mean duration of inotropic support (days); PDA; need for a vasopressor
Women:
Chorioamnionitis; fever after trial entry requiring the use of antibiotics; intrapartum
fever requiring the use of antibiotics
Notes
Risk of bias
Bias
Authors judgement

bias)
Computer-generated random numbers were used.
Allocation was conducted by pharmacy.
Low risk
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Participants and health care providers were reported as

being blind. Syringes were covered with opaque material. A placebo was used to ensure that the regimens for
administration did not differ

bias)
All outcomes
Outcome assessors were blind to group assignment.

All outcomes
No loss to follow-up; however only 105/178 infants

in the dexamethasone group and 100/181 in the betamethasone group were assessed for IVH and PVL
Unclear risk
26
Elimian 2007
(Continued)
Low risk
Data for all pre-specified outcomes (from the methods)

and many of the expected outcomes were reported
Other bias
Low risk
Groups were comparable at baseline. The study appears

to be free of other sources of bias
Khandelwal 2012
Methods
Participants
228 mothers, 260 fetuses were randomised.

Setting: Cooper University Hospital, Camden, New Jersey, USA (from July 2006 to
May 2009)
Inclusion criteria: steroids administered for any indication between 23 to 34 weeks.
gestation
Exclusion criteria: < 23 or > 34 weeks gestation; elapsed time > 12 hours since administration of the first dose of betamethasone; known drug allergy to betamethasone; given
steroids other than betamethasone for lung maturation; any contraindication to steroid
therapy were excluded
Interventions
12 hourly group (n = 161 women; 180 fetuses)

24 mg betamethasone: 2 x 12 mg doses, 12 hourly.
24 hourly group (n = 67 women; 80 fetuses)
24 mg betamethasone: 2 x 12 mg doses; 24 hourly.
No rescue steroid doses were offered in this trial.
Outcomes
For the fetus/neonate:

Death (fetal/neonatal); RDS; neonatal sepsis; antibiotic use; admission to NICU; mean
birthweight; mode of delivery LUSCS; SGA; NEC; ROP; IVH; CLD
For the mother:
Maternal fever; maternal postpartum length of stay.
Notes
Risk of bias
Bias
Authors judgement

bias)

Participants were allocated into four groups stratified by
3 gestational age categories:
Group A: 23.1 to 26.0 weeks;
Group B: 26.1 to 29.0 weeks;
Group C: 29.1 to 32.0 weeks;
Group D: 32.1 to 34.0 weeks.
The participants in each group were randomly assigned
to either the 12-hour arm or 24-hour arm. Randomisation sequence was generated in Excel using its random
function in 4 groups of 50 each. Randomisation was
27
Khandelwal 2012
(Continued)
performed in 2:1 ratio (for 12:24-hour dosing interval)

Low risk
Study assignments placed in sealed opaque envelopes

with a study number and group number on each envelope

(performance bias)
All outcomes
Participants and personnel were not blinded.

bias)
All outcomes
Outcome assessors were blinded; neonatologists were informed if women received steroids and whether 1 or 2
doses, but not informed of the dosing interval

All outcomes
Low risk
7 infants 3% (7/260) were lost to follow-up: incomplete

information was available for 4 neonates in the 12-hour
dosing group and 3 in the 24-hour dosing group (7/260:
3%)
Low risk
Outcome data for all pre-specified outcomes (from the

methods and trial registration) were reported
Other bias
Unclear risk
There were some baseline imbalances between groups:

approximately 70% (161/228 mothers; 180/260 fetuses)
were assigned to the 12-hour arm and only 30% (67/
228 mothers; 80/260 fetuses) were assigned to the 24hour arm
Women in the 24-hour arm were about 2 years older
than in the 12-hour arm; In the 24-hour cohort, there
were more African American women at risk for delivery
26 weeks and more Caucasians at risk in the 32 to 34
week group
Magee 1997
Methods
Participants
59 women were randomised.

Setting: John Radcliffe Hospital, Oxford, UK (from April 1995 to March 1996)
Inclusion criteria: women with singleton pregnancies at risk of birth between 26 to 34
weeks gestation inclusive, who had not received steroids in the preceding week
Interventions

24 mg dexamethasone: 2 x 12 mg IM; 12 hourly.
24 mg betamethasone: 2 x 12 mg IM; 12 hourly.
28
Magee 1997
(Continued)
Outcomes
Infant:
Biophysical parameters (day 0, 1, 2); FHR; LTV/STV; number of movements/hour;
number of accelerations; number of decelerations; Apgar score at 5 mins; caesarean birth
Notes
Funding source not mentioned.
Risk of bias
Bias
Authors judgement

bias)
Random number table was used to generate the random

sequence
Consecutively numbered, sealed, opaque envelopes were

used. The IM vials were labelled by the hospital pharmacy with A or B
Low risk

(performance bias)
All outcomes
Participant and clinicians were blinded.

bias)
All outcomes
Data were analysed in a blinded fashion.

All outcomes
Unclear risk
Losses to follow-up: > 20% in total: 1/30 post-randomisation exclusion in the betamethasone group (a woman
with a twin pregnancy was enrolled in error); then 9/29
losses from the betamethasone group at day 2 (1 transfer,
3 early births, 5 early discharges); 7/29 losses from the
dexamethasone group (1 self-discharge, 3 early births, 3
early discharges)
Unclear risk
The trial focused on the effects of steroids on FHR, and

very few clinical outcomes were reported. With no access
to a trial protocol it is difficult to assess selective reporting
Other bias
Low risk

Mulder 1997
Methods
Participants

Setting: University Hospital, Utrecht, The Netherlands.
Inclusion criteria: women with premature contractions or at risk of preterm labour,
between 26 to 33 weeks gestation, SGA (estimated fetal size < 5th centile), premature
29
Mulder 1997
(Continued)
contractions, placenta praevia or other cause of vaginal blood loss, preterm rupture of
membranes without evidence of intrauterine infection, pre-eclampsia, essential hypertension, poor obstetrical history, or leiomyoma
Exclusion criteria: cervical dilatation > 5 cm, signs of intrauterine infection, ritodrine
hydrochloride treatment for < 4 days at the start of the study
Interventions

24 mg dexamethasone: 2 x 12 mg IM, 12 hourly.
24 mg betamethasone: 2 x 12 mg IM, 24 hourly.
Outcomes
Infant:
Birthweight; biophysical parameters - FHR, LTV/STV, breathing movement, breathing
bout length, number of breaths, breath-to-breath interval, body movement incidence,
body movement number of bursts, body movement burst length; Apgar score less than
7 at 5 mins; mode of birth
Notes
Risk of bias
Bias
Authors judgement
Random sequence generation (selection Unclear risk

bias)
Quote: eligible women were randomised (sealed envelope method). No further detail provided
As above.
Unclear risk

(performance bias)
All outcomes
Unclear, not reported; however considered unlikely in

view of the intervention (12-hourly dexamethasone versus 24-hourly betamethasone)

bias)
All outcomes

All outcomes
Unclear risk
17%; 6 of 30 from the dexamethasone group and 4 of

30 from the betamethasone group were lost to followup
Unclear risk
The trial focused on the effects of steroids on FHR

and behaviour and clinical outcomes were not reported.
With no access to a trial protocol it is difficult to assess
selective reporting
Other bias
Low risk

30
Mushkat 2001
Methods
Quasi-randomised controlled trial.
Participants

Setting: Israel.
Inclusion criteria: women with preterm labour between 26 to 33 weeks gestation.
Exclusion criteria: chronic or acute hypertension, gestational diabetes, vaginal bleeding
due to placenta praevia or abruption placenta, IUGR, fetal distress
Interventions

24 mg betamethasone: 12 mg betamethasone sodium and 12 mg betamethasone acetate
IM, divided into 2 doses 12 hours apart
Outcomes
Infant:
Biophysical parameters (0, 6, 12, 18, 36 hours): maternal perception of fetal movements,
body movement, breathing movements; gestational age
Notes
Funding source not documented.
Risk of bias
Bias
Authors judgement

bias)
The participants were randomly assigned to 2

groups according to computer-generated randomisation schedule
Quasi-randomised design each consecutive candidate got an even or an uneven number drawn out
of performed random computer-generated list.
Even numbers were assigned to betamethasone
treatment, while uneven numbers were assigned
to dexamethasone treatment
High risk

(performance bias)
All outcomes
Participants and clinicians were blinded, with

treatment regimens being similar, and both drugs
being identical in appearance

bias)
All outcomes
While the study was described as double blind

it was not made clear as to whether outcome assessment was performed blind

All outcomes
Unclear risk
Losses to follow-up were unclear.
Unclear risk
While the trial focused on fetal biophysical parameters, it also reported a number of clinical
outcomes incompletely, example: gestational age,
31
Mushkat 2001
(Continued)
birthweight and Agpar score at 5 min did not differ between the 2 groups
Other bias
Low risk
Groups were comparable at baseline for age, parity

and gestational age. The study appears to be free
of other sources of bias
Rotmensch 1999
Methods
Participants

Setting: Israel and Italy (from June 1995 to March 1997).
Inclusion criteria: women with preterm birth at 27 to 34 weeks gestation, preterm
premature rupture of membranes with no clinical evidence of infection, pregnancyinduced hypertension syndromes, IUGR, third trimester bleeding due to placenta praevia
Interventions

Outcomes
Infant:
Birthweight; biophysical parameters (0, 2 ,4 days): FHR, acceleration > 10 bpm, deceleration > 10 bpm, LTV/STV, breathing time (sec in 30 mins), movement in 30 mins
Notes
Funding source not documented.
Risk of bias
Bias
Authors judgement

bias)
Randomised by computer-generated randomisation tables.
Unclear, details were not reported.
Unclear risk

(performance bias)
All outcomes
Unclear if participants were blinded. Examiners were

blinded to the administered drugs.

bias)
All outcomes
As above; unclear if outcome assessors were blinded.

All outcomes
Attrition or exclusions were not documented.
Unclear risk
32
Rotmensch 1999
(Continued)
Unclear risk
The trial focused on the effects of steroids on FHR and

biophysical activities and clinical outcomes were not reported. With no access to a trial protocol it is difficult
to assess selective reporting
Other bias
Low risk
Groups were comparable at baseline.The study appears

Senat 1998
Methods
Participants

Setting: Clamart, France (between October 1994 to October 1995).
Inclusion criteria: women with preterm labour < 34 weeks gestation.
Exclusion criteria: uncertain pregnancy history, clinical infection in women, vaginal
bleeding, suspicion of premature rupture of membranes
Interventions
Dexamethasone group (n = 40 women, 44 babies - 39 babies analysed)

Betamethasone group (n = 42 women, 53 babies - 42 babies analysed).
24 mg betamethasone: 4 x 3 mg betamethasone sodium and 3 mg betamethasone acetate
IM, 12 hourly
Outcomes
Infant:
Death; RDS; IVH; PVL; birthweight; NEC; biophysical parameters (0, 24-48 hours, 47 days): FHR, LTV/STV, high/low variation, acceleration > 10 bpm; deceleration > 10
bpm; uterine contractions; gestational age; CTG
Notes
In the case of multiple pregnancy, one fetus was randomly selected for analysis
Risk of bias
Bias
Authors judgement

bias)
A table of random numbers was used.
The table of random numbers was held by an independent investigator. Women were allocated to either
one of two different corticosteroid regiments in a non
blinded fashion.
Unclear risk

(performance bias)
All outcomes
Participants and clinicians were not blinded.
33
Senat 1998
(Continued)

bias)
All outcomes
Unclear if outcome assessors were blinded.

All outcomes
Low risk
1 neonate from the dexamethasone group died; this case

was excluded from the study and statistics were therefore
derived from the analysis of 39 pregnancies
Unclear risk
The trial focused on the effects of steroids on FHR variability in preterm labour; while some clinical outcomes
were reported in addition, with no access to a trial protocol it is difficult to assess selective reporting
Other bias
Unclear risk
In the case of multiple pregnancy, one fetus was randomly selected for analysis
Subtil 2003
Methods
Participants

Setting: Lille, France (from November 1997 to February 1999).
Inclusion criteria: women at high risk of preterm birth, recruited at 27 to 35 weeks
gestation, with singleton pregnancies
Exclusion criteria: imminent birth, multiple pregnancy, previously participated in the
protocol, received corticosteroid therapy < 10 days prior
Interventions
Betamethasone acetate and phosphate group (n = 35)

24 mg betamethasone acetate and phosphate: 2 x 12 mg IM, 24 hourly
Betamethasone phosphate group (n = 34)
24 mg betamethasone phosphate: 4 x 6 mg IM, 12 hourly.
Dexamethasone phosphate group (n = 36)
24mg dexamethasone phosphate: 4 x 6 mg IM, 12 hourly.
Outcomes
Infant:
Death; RDS; BPD; IVH (grade 1 and 2); severe IVH (grade 3 and 4); hyperechoic > 10
days; PVL; birthweight; NICU admission; GA at delivery; biophysical parameters: duration of tracing; STV/LTV; FHR; acceleration/deceleration number per hr; movement
number per hr.
For the child (18 months):
Neurodevelopmental disability at follow-up.
Other:
Tests of the specific drug effect, time effect, and interaction by analysis of variance
Notes
Funding source not mentioned.
Risk of bias
34
Subtil 2003
(Continued)
Bias
Authors judgement

bias)
A random number table was used.
Women were allocated randomly to treatment groups

through a system of envelopes that had been numbered
from 1 to 105. The randomisation was performed with
a random number table, by random distribution of the
3 formulations
Unclear risk

(performance bias)
All outcomes
The midwives and participants were not blinded. The

manuscript details that physicians were blinded, however it is unclear as to whether this would have been
successfully achieved, quote physicians were blinded to
the product; both midwives and patients were instructed
that no physician was to be informed of the rhythm of
injections or of the product that was being administered
Blinding of outcome assessment (detection High risk

bias)
All outcomes
Outcome assessment was not blinded.

All outcomes
Unclear risk
High numbers lost to follow-up for FHR (due to discharge and birth): none at day 0; 1 of 105 (1%) at day
1; 16 (15%) at day 2, 44 (42%) at day 3; and 57 (54%)
at day 4 (due to discharge and birth). The percentage of
missing recordings for the relevant time period averaged
8.6% and remained stable from day 0 through to day 4.
The percentage of women who went home or gave birth
before day 4 (and were lost to follow-up) did not differ
significantly between groups
Low risk
While this trial focused on the effects of steroids on

FHR, the manuscript also reports the pre-specified and
expected clinical outcomes
Other bias
Low risk
Groups were comparable at baseline. The study appears

Urban 2005
Methods
Participants

Setting: Medical Academy of Bialystok, Poland.
Inclusion criteria: preterm contractions of the uterus, preterm premature rupture of
membranes, cervical length less than 20 mm, placenta praevia before 34 weeks, singleton
35
Urban 2005
(Continued)
pregnancy
Exclusion criteria: fetal major structural malformations or abnormal karyotype.
Interventions

Outcomes
Infant:
Birthweight; UA PI; MCA PI; abnormal FHR patterns (at 0, 24 and 72 hours); Apgar
score at 1 and 5 minutes; umbilical cord artery pH; base deficit
Notes
Funding sources not mentioned.
Risk of bias
Bias
Authors judgement

bias)
A computer-generated randomisation table was used.
Consecutively numbered and sealed opaque envelopes

were used
Low risk

(performance bias)
All outcomes
Blinding not stated; considered unlikely for participants

and personnel in view of the different timings of administration of the dexamethasone versus betamethasone

bias)
All outcomes
Blinding of outcome assessors was not detailed.

All outcomes
Low risk
It was assumed that there were no exclusions or attrition.
Unclear risk
The trial focused on the effects of steroids on fetal

Doppler flow velocity waveforms; while some important
clinical outcomes were reported in addition, with no access to a trial protocol it is difficult to assess selective
reporting
Other bias
Low risk
The study appears to be free of other sources of bias. The

groups were comparable at baseline for maternal age and
gestational age
BPD: biparietal diameter

bpm: beats per minute
CTG: cardiotocography
36
ESR: erythrocyte sedimentation rate

FHR: fetal heart rate
GA: gestational age
hr: hour
IM: intramuscular
IUGR: intrauterine growth restriction
IVH: intraventricular haemorrhage
LUSCS: lower uterine segment caesarean section
LTV: long-term variation
MCA PI: middle cerebral artery pulsatility index
mins: minutes
NEC: necrotising enterocolitis
NICU: neonatal intensive care unit
PDA: patent ductus arteriosus
PVL: periventricular leukomalacia
RDS: respiratory distress syndrome
ROP: retinopathy of prematurity
secs: seconds
SGA: small-for-gestational age
STV: short-term variation
UA PI: umbilical artery pulsatility index
WBC: white blood cell
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Egerman 1997
Assessed bioavailability of dexamethasone post oral or IM administration; parallel cross-over trial
Kurz 1993
L-carnitine was added to betamethasone and compared against betamethasone alone to assess the effect it had on
RDS
Liu 2006
Vitamin K was added to dexamethasone and compared with dexamethasone injection alone, vitamin K injection
alone or no treatment to determine which treatment was most effective in reducing the incidence of IVH
Romaguera 1997
Intra-amniotic thyroxine and intramuscular betamethasone versus betamethasone alone to assess the effect it had
on maturity
Salzer 1982
Carnitine and dexamethasone versus dexamethasone to assess the effect it had on lung maturity
Shanks 2010
Corticosteroids (either betamethasone or dexamethasone) were compared with placebo
Vytiska 1985
Carnitine and betamethasone versus betamethasone to assess the effects on RDS prophylaxis
Whitt 1976
Trial not randomised.
IM: intramuscular
37
Characteristics of studies awaiting assessment [ordered by study ID]

Romejko-Wolniewicz 2013
Methods
Participants
121 women who gave birth by gestational week 35 and within 7 days after the completion of a full course of steroid
treatment (24 mg)
Interventions
6 4 mg doses of betamethasone every 8 hours was compared with 2 12 mg doses of betamethasone separated by 24
hours
Outcomes
Maternal rheological parameters and C-reactive protein concentrations; leucocyte blood counts; gestational age;
method of delivery; neonatal birthweight, status, and complications
Notes
Randomisation unclear: The dosage regimen was chosen in a randomized manner; awaiting contract from trialists
Characteristics of ongoing studies [ordered by study ID]

Crowther 2010
Trial name or title
Australasian Antenatal Study To Evaluate the Role of Intramuscular Dexamethasone versus Betamethasone
prior to preterm birth to increase survival free of childhood neurosensory disability- a randomised controlled
trial (A*STEROID)
Methods
The randomised schedule will use balanced variable blocks and will be created using computer software
(computerised sequence generation) by researchers not involved in clinical care. Assignment to either group
will be stratified for collaborating centre, gestational age (< 28 weeks, > 28 weeks gestation), and number of
fetuses (1 or 2)
Participants
Women at risk of preterm birth at less than 34 weeks gestation, who have a singleton or twin pregnancy, have
no contraindications to the use of antenatal corticosteroids and give informed consent
Interventions
Intervention:
Dexamethasone (antenatal corticosteroid),
2 syringes of 12 mg dexamethasone sodium phosphate- a non-sulphite containing preparation
Administered as 2 intramuscular injections, 24 hours apart.
Control:
Betamethasone (antenatal corticosteroid),
2 syringes of 11.4mg betamethasone (as Clestone Chronodose 11.4 mg)
Administered as 2 intramuscular injections, 24 hours apart.
Outcomes
Primary outcome:
Composite of incidence of death (defined as stillbirths, deaths from live born infants before and after hospital
discharge) or any neurosensory disability in the children (includes cerebral palsy, blindness, deafness and any
developmental delay defined as a standardised score more than 1 SD below the mean (< -1 SD)
38
Crowther 2010
(Continued)
Secondary outcomes:
Neonatal outcomes:
IVH; severe IVH; PVL; ROP requiring treatment; PDA requiring treatment; use of inotropes; RDS; Severity
of any neonatal lung disease; CLD; use of mechanical ventilation; confirmed infection within the first 48
hours; infection after the first 48 hours; birthweight
Childhood outcomes:
Developmental domains as measured by Ages & Stages Questionnaire; body size; general health (including
use of health services since primary hospitalisation; childhood respiratory morbidity; blood pressure z scores
and proportions in hypertensive ranges and behaviour
Maternal outcomes:
Maternal perinatal infectious morbidity (defined as clinical chorioamnionitis requiring intrapartum antibiotics, use of postpartum antibiotics)
Starting date
1/12/2008
Contact information
Professor Caroline Crowther

Australian Research Centre for Health of Women and Babies (ARCH)
Discipline of Obstetrics and Gynaecology
The University of Adelaide
Womens and childrens Hospital
King William Road
North Adelaide
South Australia 5006
Australia
Tel: +61 8 8161 7747
Fax: +61 8 8161 7652
Notes
SD: standard deviation

PVL: periventricular leukomalacia
ROP: retinopathy of prematurity
PDA: patent ductus arteriosus
CLD: chronic lung disease
39
DATA AND ANALYSES
Comparison 1. Dexamethasone versus betamethasone
Outcome or subgroup title

1 Neonatal death
1.1 Dexamethasone (24 mg
- 4 x 6 mg; 12 hourly) v
betamethasone (24 mg - 2 x 12
mg; 24 hourly)
mg; 12 hourly)
mg; 24 hourly)
2 Respiratory distress syndrome
mg; 24 hourly)
mg; 12 hourly)
mg; 24 hourly)
3 Intraventricular haemorrhage
3.1 Intraventricular
haemorrhage (any dose)
mg; 24 hourly)
mg; 12 hourly)
4 Neurosensory disability as a
child (18 months)
mg; 24 hourly)
No. of
studies
No. of
participants
4
2
596
464
Risk Ratio (M-H, Fixed, 95% CI)

1.41 [0.54, 3.67]

1.12 [0.38, 3.33]
82
3.15 [0.13, 75.05]
50
3.24 [0.14, 75.91]
5
3
753
621

1.06 [0.88, 1.27]

1.08 [0.89, 1.30]
82
0.35 [0.01, 8.34]
50
0.36 [0.02, 8.43]
4
4
549

Subtotals only
0.44 [0.21, 0.92]
467
0.44 [0.21, 0.92]
82
0.0 [0.0, 0.0]
12
1.67 [0.08, 33.75]
12
1.67 [0.08, 33.75]
Statistical method
Effect size
40
5 Apgar score < 7 at 5 minutes

mg; 24 hourly)
mg; 24 hourly)
6 Apgar score at 5 minutes
mg; 24 hourly)
6.2 Dexamethasone (24
mg - 4 x 6 mg; 12 hourly)
v betamethasone (24 mg - 2
x 12 mg; 24 hourly); intact
membranes
betamethasone (24 mg - 2 x
12 mg; 24 hourly); ruptured
membranes
7 Apgar score at 5 minutes
8 Birthweight (kg)
mg; 24 hourly)
9 Birthweight (kg)
10 Low birthweight
mg - 4 x 6 mg; 12 hourly) v
mg; 24 hourly)
11 Head circumference (cm)
mg; 24 hourly)
12 Neonatal intensive care unit
admission
mg; 24 hourly)
13 Vasopressor use
mg; 24 hourly)
2
1
207
157

0.97 [0.43, 2.18]

1.07 [0.45, 2.54]
50
0.54 [0.05, 5.60]
2
1
307
67
Mean Difference (IV, Random, 95% CI)

0.23 [-0.23, 0.70]

-0.20 [-0.89, 0.49]
120
0.60 [0.26, 0.94]
120
0.10 [-0.37, 0.57]
5
5
734
734
Other data
Mean Difference (IV, Fixed, 95% CI)
No numeric data
0.01 [-0.11, 0.12]
0.01 [-0.11, 0.12]
1
1
105
105
Other data
No numeric data
0.89 [0.65, 1.24]
0.89 [0.65, 1.24]
1
1
157
157

-0.5 [-1.55, 0.55]

-0.5 [-1.55, 0.55]
345
Risk Ratio (M-H, Random, 95% CI)
1.72 [0.44, 6.72]
345
1.72 [0.44, 6.72]
1
1
359
359

0.44 [0.17, 1.11]

0.44 [0.17, 1.11]
41
14 Bronchopulmonary dysplasia
mg - 4 x 6 mg, 12 hourly) v
mg, 24 hourly)
15 Severe intraventricular
haemorrhage
mg; 24 hourly)
mg; 12 hourly)
16 Periventricular leukomalacia
mg; 24 hourly)
mg; 12 hourly)
17 Neonatal sepsis
mg; 24 hourly)
18 Necrotising enterocolitis
mg; 24 hourly)
mg; 12 hourly)
19 Retinopathy of prematurity
mg; 24 hourly)
20 Patent ductus arteriosus
mg; 24 hourly)
21 Fetal heart rate, bpm (day 2)
2
2
464
464

2.50 [0.10, 61.34]

2.50 [0.10, 61.34]
549
0.40 [0.13, 1.24]
467
0.40 [0.13, 1.24]
82
0.0 [0.0, 0.0]
4
3
703
621

0.83 [0.23, 3.03]

0.83 [0.23, 3.03]
82
0.0 [0.0, 0.0]
2
2
516
516

1.30 [0.78, 2.19]

1.30 [0.78, 2.19]
3
2
598
516

1.29 [0.38, 4.40]

1.29 [0.38, 4.40]
82
0.0 [0.0, 0.0]
2
2
516
516

0.93 [0.59, 1.47]

0.93 [0.59, 1.47]
1
1
359
359

1.19 [0.56, 2.49]

1.19 [0.56, 2.49]
46
-4.20 [-7.17, -1.23]
42

mg; 24 hourly)
22 Fetal heart rate (day 2)
23 Accelerations per hour
mg, 24 hourly)
24 Accelerations per hour
25 Fetal movements in 30 minutes
mg; 24 hourly)
26 Fetal movements per hour
(maternal perception)
mg; 12 hourly)
(ultrasound)
mg; 12 hourly)
29 Fetal breathing movements per
hour
mg; 12 hourly)
30 Duration of breathing time at 2
days (seconds in 30 minutes)
mg; 24 hourly)
31 Length of admission to birth
(days)
membranes
46
-4.20 [-7.17, -1.23]
1
1
46
46
Other data
No numeric data
2.80 [-0.15, 5.75]
2.80 [-0.15, 5.75]
1
1
46
46
Other data
No numeric data
2.3 [-0.74, 5.34]
2.3 [-0.74, 5.34]
33
3.0 [-3.20, 9.20]
33
3.0 [-3.20, 9.20]
33
7.00 [2.15, 11.85]
33
7.00 [2.15, 11.85]
33
Other data
No numeric data
0.0 [-2.05, 2.05]
33
0.0 [-2.05, 2.05]
46
32.0 [4.37, 59.63]
46
32.0 [4.37, 59.63]
240
3.48 [-3.38, 10.34]
120
7.0 [5.56, 8.44]
43

membranes
stay (days)
membranes
membranes
120
0.0 [-0.99, 0.99]
70
-0.91 [-1.77, -0.05]
21
-2.2 [-4.52, 0.12]
49
-0.70 [-1.63, 0.23]
Comparison 2. Dexamethasone: oral versus intramuscular

1 Neonatal death
1.1 Dexamethasone: oral (32
mg - 4 x 8 mg, 12 hourly) v IM
(24 mg - 4 x 6 mg, 12 hourly)
1.2 < 34 weeks gestation
(24 mg - 4 x 6 mg, 12 hourly)
(24 mg - 4 x 6 mg, 12 hourly)
4 Birthweight (kg)
(24 mg - 4 x 6 mg, 12 hourly)
5 Neonatal sepsis
(24 mg - 4 x 6 mg, 12 hourly)
No. of
studies
No. of
participants
1
1
183
Subtotals only
1.48 [0.45, 4.90]

1.72 [0.53, 5.59]

Subtotals only
1.15 [0.75, 1.77]

1.26 [0.85, 1.86]

Subtotals only
4.24 [0.96, 18.83]
183

4.92 [1.12, 21.55]

Subtotals only
0.05 [-0.17, 0.27]
183

Subtotals only
8.48 [1.11, 64.93]

9.84 [1.30, 74.60]

Subtotals only
125
1
1
1
125
1
1
1
125
1
1
Effect size

1
1
1
1
1
Statistical method
183
183
125
44

(24 mg - 4 x 6 mg, 12 hourly)
183
5.09 [0.63, 41.45]
125
4.92 [0.59, 40.92]
Comparison 3. Betamethasone acetate + phosphate versus betamethasone phosphate

1 Neonatal death
1.1 24 mg beta a+p (2 x 12
mg, 24 hourly) v 24 mg beta p
(4 x 6 mg, 12 hourly)
2.1 24 mg beta a+p (2 x 12
3.1 24 mg beta a+p (2 x 12
4 Neurodevelopmental disability
4.1 24 mg beta a+p (2 x 12
5 Birthweight (kg)
5.1 beta a+p (2 x 12 mg,
24hrly) and beta p (4 x 6
mg,12hrly)
6 Low birthweight
6.1 24 mg beta a+p (2 x 12
admission
7.1 24 mg beta a+p (2 x 12
mg, 24 hourly) x 24 mg beta p
8 Bronchopulmonary dysplasia
8.1 24 mg beta a+p (2 x 12
9 Periventricular leukomalacia
9.1 24 mg beta a+p (2 x 12
No. of
studies
No. of
participants
1
1
69
69

0.32 [0.01, 7.69]

0.32 [0.01, 7.69]
1
1
69
69

0.19 [0.01, 3.91]

0.19 [0.01, 3.91]
1
1
69
69

0.32 [0.01, 7.69]

0.32 [0.01, 7.69]
1
1
69
69

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
1
1
69
69

-0.10 [-0.44, 0.24]

-0.10 [-0.44, 0.24]
1
1
69
69

1.21 [0.86, 1.72]

1.21 [0.86, 1.72]
69
0.11 [0.01, 1.93]
69
0.11 [0.01, 1.93]
1
1
69
69

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
1
1
69
69

0.0 [0.0, 0.0]

0.0 [0.0, 0.0]
Statistical method
Effect size
45
Comparison 4. Betamethasone 12 hour versus 24 hour dosing
No. of
studies
No. of
participants
1 Perinatal death
1.1 Betamethasone: 12 mg 12
hourly v 12 mg 24 hourly
1.2 23+1 to 26+0 weeks at
trial entry
1.3 26+1 to 29+0 weeks at
trial entry
1.4 29+1 to 32+0 weeks at
trial entry
1.5 32+1 to 34+0 weeks at
trial entry
2.2 23+1 to 26+0 weeks at
trial entry
2.3 26+1 to 29+0 weeks at
trial entry
2.4 29+1 to 32+0 weeks at
trial entry
2.5 32+1 to 34+0 weeks at
trial entry
3 Intraventricular hemorrhage
3.2 23+1 to 26+0 weeks at
trial entry
3.3 26+1 to 32+0 weeks at
trial entry
3.4 29+1 to 32+0 weeks at
trial entry
3.5 32+1 to 34+0 weeks at
trial entry
4 Maternal fever > 100.4 F
5 Birthweight (g)
1
1
255

Subtotals only
0.93 [0.46, 1.87]
56
0.80 [0.43, 1.50]
43
1.93 [0.24, 15.71]
81
1.45 [0.06, 34.35]
75
1.75 [0.09, 35.00]
1
1
242

Subtotals only
0.98 [0.69, 1.40]
49
0.83 [0.69, 0.99]
40
2.73 [0.97, 7.67]
81
0.95 [0.43, 2.06]
72
1.43 [0.17, 12.04]
1
1
135

Subtotals only
1.40 [0.76, 2.56]
38
1.57 [0.76, 3.24]
31
3.27 [0.48, 22.52]
45
1.0 [0.29, 3.45]
21
0.31 [0.02, 4.14]
1
1
213
213

0.71 [0.25, 2.02]

0.71 [0.25, 2.02]
255
6 Small-for-gestational age
admission
255
1
1
255
255

84.0 [-144.63, 312.

63]
84.0 [-144.63, 312.
63]
0.61 [0.36, 1.05]
0.61 [0.36, 1.05]
247
0.89 [0.79, 1.00]
Statistical method
Effect size
46
8 Chronic lung disease
9 Neonatal sepsis
10 Neonatal antibiotic use (> 5
days)
10.1 Betamethasone: 12 mg
12 hourly v 12 mg 24 hourly
12 Retinopathy of prematurity
13 Postpartum maternal length of
stay (days)
247
0.89 [0.79, 1.00]
1
1
230
230

0.79 [0.49, 1.26]

0.79 [0.49, 1.26]
1
1
236
236

1.15 [0.47, 2.81]

1.15 [0.47, 2.81]
236
0.94 [0.61, 1.46]
236
0.94 [0.61, 1.46]
1
1
231
231

9.20 [0.55, 154.92]

9.20 [0.55, 154.92]
1
1
109
109

0.94 [0.53, 1.66]

0.94 [0.53, 1.66]
215
-0.73 [-1.28, -0.18]
215
-0.73 [-1.28, -0.18]
Analysis 1.1. Comparison 1 Dexamethasone versus betamethasone, Outcome 1 Neonatal death.

Review:
Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth
Comparison: 1 Dexamethasone versus betamethasone

Outcome: 1 Neonatal death
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)

Elimian 2007
6/178
5/181
71.2 %
1.22 [ 0.38, 3.93 ]
Subtil 2003
0/36
1/69
14.9 %
0.63 [ 0.03, 15.10 ]
214
250
86.1 %
1.12 [ 0.38, 3.33 ]
Subtotal (95% CI)
Total events: 6 (Dexamethasone), 6 (Betamethasone)

Heterogeneity: Chi2 = 0.15, df = 1 (P = 0.70); I2 =0.0%
Test for overall effect: Z = 0.20 (P = 0.84)
Senat 1998
Subtotal (95% CI)
1/40
0/42
7.0 %
3.15 [ 0.13, 75.05 ]
40
42
7.0 %
3.15 [ 0.13, 75.05 ]
0.001 0.01 0.1

Favours dexamethasone
10 100 1000
Favours betamethasone
(Continued . . . )
47
(. . .
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Heterogeneity: not applicable
Mulder 1997
Subtotal (95% CI)
1/24
0/26
6.9 %
3.24 [ 0.14, 75.91 ]
24
26
6.9 %
3.24 [ 0.14, 75.91 ]
318
100.0 %
1.41 [ 0.54, 3.67 ]

Total (95% CI)
278

Test for subgroup differences: Chi2 = 0.68, df = 2 (P = 0.71), I2 =0.0%
0.001 0.01 0.1

10 100 1000
48
Analysis 1.2. Comparison 1 Dexamethasone versus betamethasone, Outcome 2 Respiratory distress

syndrome.
Review:

Outcome: 2 Respiratory distress syndrome
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
Elimian 2007
Subtil 2003
Subtotal (95% CI)
39/76
44/81
35.7 %
0.94 [ 0.70, 1.27 ]
79/178
73/181
60.7 %
1.10 [ 0.86, 1.40 ]
4/36
2/69
1.1 %
3.83 [ 0.74, 19.94 ]
290
331
97.6 %
1.08 [ 0.89, 1.30 ]

Heterogeneity: Chi2 = 3.05, df = 2 (P = 0.22); I2 =34%
Senat 1998
Subtotal (95% CI)
0/40
1/42
1.2 %
0.35 [ 0.01, 8.34 ]
40
42
1.2 %
0.35 [ 0.01, 8.34 ]

Mulder 1997
Subtotal (95% CI)
0/24
1/26
1.2 %
0.36 [ 0.02, 8.43 ]
24
26
1.2 %
0.36 [ 0.02, 8.43 ]
399
100.0 %
1.06 [ 0.88, 1.27 ]

Total (95% CI)
354

0.001 0.01 0.1

10 100 1000
49
Analysis 1.3. Comparison 1 Dexamethasone versus betamethasone, Outcome 3 Intraventricular

haemorrhage.
Review:

Outcome: 3 Intraventricular haemorrhage
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Risk Ratio
Chen 2005
2/76
3/81
0.71 [ 0.12, 4.14 ]
Elimian 2007
6/105
17/100
0.34 [ 0.14, 0.82 ]
Senat 1998
0/40
0/42
0.0 [ 0.0, 0.0 ]
Subtil 2003
1/36
1/69
1.92 [ 0.12, 29.75 ]
257
292
0.44 [ 0.21, 0.92 ]
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Intraventricular haemorrhage (any dose)
Subtotal (95% CI)

Chen 2005
2/76
3/81
0.71 [ 0.12, 4.14 ]
Elimian 2007
6/105
17/100
0.34 [ 0.14, 0.82 ]
Subtil 2003
1/36
1/69
1.92 [ 0.12, 29.75 ]
217
250
0.44 [ 0.21, 0.92 ]
Subtotal (95% CI)

Senat 1998
Subtotal (95% CI)
0/40
0/42
0.0 [ 0.0, 0.0 ]
40
42
0.0 [ 0.0, 0.0 ]

Test for overall effect: Z = 0.0 (P < 0.00001)
0.001 0.01 0.1

10 100 1000
50
Analysis 1.4. Comparison 1 Dexamethasone versus betamethasone, Outcome 4 Neurosensory disability as

a child (18 months).
Review:

Outcome: 4 Neurosensory disability as a child (18 months)
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
Total (95% CI)
1/8
0/4
100.0 %
1.67 [ 0.08, 33.75 ]
100.0 %
1.67 [ 0.08, 33.75 ]

Test for subgroup differences: Not applicable
0.001 0.01 0.1

10 100 1000
51
Analysis 1.5. Comparison 1 Dexamethasone versus betamethasone, Outcome 5 Apgar score < 7 at 5
minutes.
Review:

Outcome: 5 Apgar score < 7 at 5 minutes
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
Subtotal (95% CI)
9/76
9/81
81.9 %
1.07 [ 0.45, 2.54 ]
76
81
81.9 %
1.07 [ 0.45, 2.54 ]

Mulder 1997
Subtotal (95% CI)
1/24
2/26
18.1 %
0.54 [ 0.05, 5.60 ]
24
26
18.1 %
0.54 [ 0.05, 5.60 ]
107
100.0 %
0.97 [ 0.43, 2.18 ]

Total (95% CI)
100

0.001 0.01 0.1

10 100 1000
52
Analysis 1.6. Comparison 1 Dexamethasone versus betamethasone, Outcome 6 Apgar score at 5 minutes.
Review:

Outcome: 6 Apgar score at 5 minutes
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Mean
Difference
Weight
IV,Random,95% CI
IV,Random,95% CI

Urban 2005
33
Subtotal (95% CI)
9.3 (1.72)
34
33
24.3 %
9.5 (1.1)
34
-0.20 [ -0.89, 0.49 ]
24.3 % -0.20 [ -0.89, 0.49 ]

2 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); intact membranes
Danesh 2012
60
Subtotal (95% CI)
9.7 (0.8)
60
60
9.1 (1.1)
60
41.1 %
0.60 [ 0.26, 0.94 ]
41.1 %
0.60 [ 0.26, 0.94 ]
34.6 %
0.10 [ -0.37, 0.57 ]

3 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); ruptured membranes
Danesh 2012
60
Subtotal (95% CI)
9 (1.4)
60
60
8.9 (1.2)
60
34.6 % 0.10 [ -0.37, 0.57 ]
154
100.0 % 0.23 [ -0.23, 0.70 ]

Total (95% CI)
153
Heterogeneity: Tau2 = 0.11; Chi2 = 5.54, df = 2 (P = 0.06); I2 =64%

Test for subgroup differences: Chi2 = 5.54, df = 2 (P = 0.06), I2 =64%
-2
-1
Analysis 1.7. Comparison 1 Dexamethasone versus betamethasone, Outcome 7 Apgar score at 5 minutes.
Apgar score at 5 minutes
Study
Dexamethasone
Betamethasone
Magee 1997
24 mg - 2 x 12 mg; 12 hourly
24 mg - 2 x 12 mg; 12 hourly
Magee 1997
median 10: IQR 8.8 to 10 (n = 22)
median 10: IQR 10 to 10 (n = 20)
53
Analysis 1.8. Comparison 1 Dexamethasone versus betamethasone, Outcome 8 Birthweight (kg).

Review:

Outcome: 8 Birthweight (kg)
Study or subgroup
Dexamethasone
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Chen 2005
76
1.61 (0.67)
81
1.66 (0.58)
32.8 %
-0.05 [ -0.25, 0.15 ]
178
2.04 (0.83)
181
1.98 (0.81)
44.0 %
0.06 [ -0.11, 0.23 ]
Rotmensch 1999
24
2.48 (1.02)
22
2.25 (0.88)
4.2 %
0.23 [ -0.32, 0.78 ]
Subtil 2003
36
2.59 (0.89)
69
2.72 (0.72)
11.2 %
-0.13 [ -0.47, 0.21 ]
Urban 2005
34
3.04 (0.81)
33
3.04 (0.86)
7.9 %
0.0 [ -0.40, 0.40 ]
Elimian 2007
Total (95% CI)
348
100.0 % 0.01 [ -0.11, 0.12 ]
386

-1
-0.5
0.5
Analysis 1.9. Comparison 1 Dexamethasone versus betamethasone, Outcome 9 Birthweight (kg).

Birthweight (kg)
Study
Dexamethasone
Betamethasone
Magee 1997
24 mg - 2 x 12 mg; 12 hourly
24 mg - 2 x 12 mg; 12 hourly
Magee 1997
median 1.843 IQR 1.211 to 3.363 (n = 20)
median 2.001 IQR 1.150 to 3.121 (n = 22)
Mulder 1997
24 mg - 2 x 12 mg; 12 hourly
24 mg - 2 x 12 mg; 24 hourly
Mulder 1997
median 2.02 IQR 0.75 to 3.5 (n = 24)
median 1.79 IQR 0.84 to 3.75 (n = 26)
Senat 1998
16 mg - 4 x 4 mg; 12 hourly
Senat 1998
median 2.55 IQR 1.13 to 3.91 (n = 40)
median 2.5 IQR 0.98 to 3.84 (n = 42)
54
Analysis 1.10. Comparison 1 Dexamethasone versus betamethasone, Outcome 10 Low birthweight.

Review:

Outcome: 10 Low birthweight
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
21/36
45/69
100.0 %
0.89 [ 0.65, 1.24 ]
36
69
100.0 %
0.89 [ 0.65, 1.24 ]
Total (95% CI)

0.1 0.2
0.5
10
Analysis 1.11. Comparison 1 Dexamethasone versus betamethasone, Outcome 11 Head circumference

(cm).
Review:

Outcome: 11 Head circumference (cm)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Chen 2005
Total (95% CI)
76
76
28.2 (3.5)
81
28.7 (3.2)
100.0 %
81
-0.50 [ -1.55, 0.55 ]
100.0 % -0.50 [ -1.55, 0.55 ]

-10
-5
10
55
Analysis 1.12. Comparison 1 Dexamethasone versus betamethasone, Outcome 12 Neonatal intensive care
unit admission.
Review:

Outcome: 12 Neonatal intensive care unit admission
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI

Danesh 2012
Subtil 2003
Total (95% CI)
34/120
36/120
57.4 %
0.94 [ 0.64, 1.40 ]
8/36
4/69
42.6 %
3.83 [ 1.24, 11.87 ]
156
189
100.0 %
1.72 [ 0.44, 6.72 ]

0.005
0.1
10
200
Analysis 1.13. Comparison 1 Dexamethasone versus betamethasone, Outcome 13 Vasopressor use.

Review:

Outcome: 13 Vasopressor use
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Elimian 2007
6/178
14/181
100.0 %
0.44 [ 0.17, 1.11 ]
Total (95% CI)
178
181
100.0 %
0.44 [ 0.17, 1.11 ]

0.02
0.1
10
50
56
Analysis 1.14. Comparison 1 Dexamethasone versus betamethasone, Outcome 14 Bronchopulmonary

dysplasia.
Review:

Outcome: 14 Bronchopulmonary dysplasia
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
1 Dexamethasone (24 mg - 4 x 6 mg, 12 hourly) v betamethasone (24 mg - 2 x 12 mg, 24 hourly)

Elimian 2007
Subtil 2003
Total (95% CI)
18/178
27/181
59.5 %
0.68 [ 0.39, 1.19 ]
4/36
0/69
40.5 %
17.03 [ 0.94, 307.74 ]
214
250
100.0 %
2.50 [ 0.10, 61.34 ]

0.001 0.01 0.1

10 100 1000
57
Analysis 1.15. Comparison 1 Dexamethasone versus betamethasone, Outcome 15 Severe intraventricular

haemorrhage.
Review:

Outcome: 15 Severe intraventricular haemorrhage
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
2/76
3/81
0.71 [ 0.12, 4.14 ]
Elimian 2007
2/105
7/100
0.27 [ 0.06, 1.28 ]
Subtil 2003
0/36
0/69
0.0 [ 0.0, 0.0 ]
217
250
0.40 [ 0.13, 1.24 ]
Subtotal (95% CI)

Senat 1998
Subtotal (95% CI)
0/40
0/42
0.0 [ 0.0, 0.0 ]
40
42
0.0 [ 0.0, 0.0 ]
292
0.40 [ 0.13, 1.24 ]

Total (95% CI)
257

0.01
0.1
10
100
58
Analysis 1.16. Comparison 1 Dexamethasone versus betamethasone, Outcome 16 Periventricular

leukomalacia.
Review:

Outcome: 16 Periventricular leukomalacia
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
2/76
1/81
2.13 [ 0.20, 23.03 ]
Elimian 2007
2/178
4/181
0.51 [ 0.09, 2.74 ]
Subtil 2003
0/36
0/69
0.0 [ 0.0, 0.0 ]
290
331
0.83 [ 0.23, 3.03 ]
Subtotal (95% CI)

Senat 1998
Subtotal (95% CI)
0/40
0/42
0.0 [ 0.0, 0.0 ]
40
42
0.0 [ 0.0, 0.0 ]
373
0.83 [ 0.23, 3.03 ]

Total (95% CI)
330

0.05
0.2
20
59
Analysis 1.17. Comparison 1 Dexamethasone versus betamethasone, Outcome 17 Neonatal sepsis.

Review:

Outcome: 17 Neonatal sepsis
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
Elimian 2007
Total (95% CI)
11/76
7/81
29.9 %
1.67 [ 0.68, 4.10 ]
18/178
16/181
70.1 %
1.14 [ 0.60, 2.17 ]
254
262
100.0 %
1.30 [ 0.78, 2.19 ]

0.1 0.2
0.5
10
60
Analysis 1.18. Comparison 1 Dexamethasone versus betamethasone, Outcome 18 Necrotising

enterocolitis.
Review:

Outcome: 18 Necrotising enterocolitis
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
Elimian 2007
Subtotal (95% CI)
3/76
4/81
0.80 [ 0.18, 3.46 ]
2/178
0/181
5.08 [ 0.25, 105.15 ]
254
262
1.29 [ 0.38, 4.40 ]

Senat 1998
Subtotal (95% CI)
0/40
0/42
0.0 [ 0.0, 0.0 ]
40
42
0.0 [ 0.0, 0.0 ]
304
1.29 [ 0.38, 4.40 ]

Total (95% CI)
294

0.01
0.1
10
100
61
Analysis 1.19. Comparison 1 Dexamethasone versus betamethasone, Outcome 19 Retinopathy of

prematurity.
Review:

Outcome: 19 Retinopathy of prematurity
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Chen 2005
Elimian 2007
5/76
6/81
17.3 %
0.89 [ 0.28, 2.79 ]
26/178
28/181
82.7 %
0.94 [ 0.58, 1.54 ]
254
262
100.0 %
0.93 [ 0.59, 1.47 ]
Total (95% CI)

0.1 0.2
0.5
10
Analysis 1.20. Comparison 1 Dexamethasone versus betamethasone, Outcome 20 Patent ductus arteriosus.
Review:

Outcome: 20 Patent ductus arteriosus
Study or subgroup
Dexamethasone
Betamethasone
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Elimian 2007
Total (95% CI)
14/178
12/181
100.0 %
1.19 [ 0.56, 2.49 ]
178
181
100.0 %
1.19 [ 0.56, 2.49 ]

0.1 0.2
0.5
10
62
Analysis 1.21. Comparison 1 Dexamethasone versus betamethasone, Outcome 21 Fetal heart rate, bpm
(day 2).
Review:

Outcome: 21 Fetal heart rate, bpm (day 2)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI

Rotmensch 1999
24
Total (95% CI)
24
136.7 (6.4)
22
100.0 %
140.9 (3.6)
22
-4.20 [ -7.17, -1.23 ]
100.0 % -4.20 [ -7.17, -1.23 ]

-10
-5
10
Analysis 1.22. Comparison 1 Dexamethasone versus betamethasone, Outcome 22 Fetal heart rate (day 2).
Fetal heart rate (day 2)
Study
Dexamethasone
Betamethasone
p-value
Magee 1997
24 mg - 2 x 12 mg; 12 hourly
24 mg - 2 x 12 mg; 12 hourly
Magee 1997
median change from baseline (bpm) median change from baseline (bpm) - pns
1.5: IQR -5.9 to 9.0 (n=22)
2.0: IQR -6.0 to 5.0 (n=20)
Senat 1998
Senat 1998
median bpm 142 IQR 137 to 149 (n= median bpm 147 IQR 141 to 154 (n= p=0.01 (for change data)
40)
42)
63
Analysis 1.23. Comparison 1 Dexamethasone versus betamethasone, Outcome 23 Accelerations per hour.
Review:

Outcome: 23 Accelerations per hour
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg, 24 hourly)

Rotmensch 1999
24
Total (95% CI)
24
8.1 (5.3)
22
5.3 (4.9)
100.0 %
2.80 [ -0.15, 5.75 ]
100.0 % 2.80 [ -0.15, 5.75 ]
22

-4
-2
Favours dexamthasone
Analysis 1.24. Comparison 1 Dexamethasone versus betamethasone, Outcome 24 Accelerations per hour.
Accelerations per hour
Study
Dexamethasone
Betamethasone
Magee 1997
24 mg - 2 x 12 mg; 12 hourly
24 mg - 2 x 12 mg, 12 hourly
Magee 1997
median change -1.0 IQR -4.0 to 0 (n=22)
median change 0.5 IQR -2.5 to 2.5 (n=20)
Senat 1998
Senat 1998
median 5.0 IQR 2.2 to 10 (n=40)
median 7.0 IQR 3.0 to 10 (n=42)
64
Analysis 1.25. Comparison 1 Dexamethasone versus betamethasone, Outcome 25 Fetal movements in 30

minutes.
Review:

Outcome: 25 Fetal movements in 30 minutes
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Rotmensch 1999
24
Total (95% CI)
24
6.7 (6.6)
22
4.4 (3.6)
100.0 %
22
2.30 [ -0.74, 5.34 ]
100.0 % 2.30 [ -0.74, 5.34 ]

-10
-5
10
Analysis 1.26. Comparison 1 Dexamethasone versus betamethasone, Outcome 26 Fetal movements per
hour (maternal perception).
Review:

Outcome: 26 Fetal movements per hour (maternal perception)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Mushkat 2001
16
Total (95% CI)
16
19 (10)
17
16 (8)
100.0 %
17
3.00 [ -3.20, 9.20 ]
100.0 % 3.00 [ -3.20, 9.20 ]

-10
-5
10
65
hour (ultrasound).
Review:

Outcome: 27 Fetal movements per hour (ultrasound)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Mushkat 2001
16
Total (95% CI)
16
18 (8)
17
100.0 %
11 (6)
17
7.00 [ 2.15, 11.85 ]
100.0 % 7.00 [ 2.15, 11.85 ]

-10
-5
10
hour.
Fetal movements per hour
Study
Dexamethasone
Betamethasone
Magee 1997
24 mg - 2 x 12 mg; 12 hourly
24 mg - 2 x 12 mg; 12 hourly
Magee 1997
median 2.5 IQR -27.0 to 32.0 (n=22)
median 4.0 IQR -15.0 to 18.5 (n=20)
66
Analysis 1.29. Comparison 1 Dexamethasone versus betamethasone, Outcome 29 Fetal breathing

movements per hour.
Review:

Outcome: 29 Fetal breathing movements per hour
Study or subgroup
Dexamethasone
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Mushkat 2001
16
Total (95% CI)
16
6 (3)
17
6 (3)
100.0 %
17
0.0 [ -2.05, 2.05 ]
100.0 % 0.0 [ -2.05, 2.05 ]

-10
-5
10
Analysis 1.30. Comparison 1 Dexamethasone versus betamethasone, Outcome 30 Duration of breathing

time at 2 days (seconds in 30 minutes).
Review:

Outcome: 30 Duration of breathing time at 2 days (seconds in 30 minutes)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI

Rotmensch 1999
24
Total (95% CI)
24
44 (67)
22
12 (16)
100.0 %
22
32.00 [ 4.37, 59.63 ]
100.0 % 32.00 [ 4.37, 59.63 ]

-50
-25
25
50
67
Analysis 1.31. Comparison 1 Dexamethasone versus betamethasone, Outcome 31 Length of admission to

birth (days).
Review:

Outcome: 31 Length of admission to birth (days)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Mean
Difference
Weight
IV,Random,95% CI
IV,Random,95% CI
Danesh 2012
60
Subtotal (95% CI)
21 (4.4)
60
60
14 (3.6)
60
49.7 %
7.00 [ 5.56, 8.44 ]
49.7 %
7.00 [ 5.56, 8.44 ]
50.3 %
0.0 [ -0.99, 0.99 ]
50.3 %
0.0 [ -0.99, 0.99 ]

Danesh 2012
60
Subtotal (95% CI)
7.1 (2.9)
60
60
60
120
120
7.1 (2.6)

Total (95% CI)
100.0 % 3.48 [ -3.38, 10.34 ]
Heterogeneity: Tau2 = 24.10; Chi2 = 61.91, df = 1 (P<0.00001); I2 =98%

-20
-10
10
20
68
Analysis 1.32. Comparison 1 Dexamethasone versus betamethasone, Outcome 32 Neonatal intensive care
unit stay (days).
Review:

Outcome: 32 Neonatal intensive care unit stay (days)
Study or subgroup
Dexamethasone
N
Mean
Difference
Betamethasone
Mean(SD)
Mean(SD)
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
Danesh 2012
Subtotal (95% CI)
3 (1.7)
12
5.2 (3.6)
13.7 %
12
-2.20 [ -4.52, 0.12 ]
13.7 % -2.20 [ -4.52, 0.12 ]

Danesh 2012
Subtotal (95% CI)
25
2.9 (1.6)
25
24
86.3 %
3.6 (1.7)
-0.70 [ -1.63, 0.23 ]
24
86.3 % -0.70 [ -1.63, 0.23 ]
36
100.0 % -0.91 [ -1.77, -0.05 ]

Total (95% CI)
34

-2
-1
69
Analysis 2.1. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 1 Neonatal death.
Review:
Comparison: 2 Dexamethasone: oral versus intramuscular

Study or subgroup
Oral
IM
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)

Egerman 1998
Subtotal (95% CI)
7/99
4/84
100.0 %
1.48 [ 0.45, 4.90 ]
99
84
100.0 %
1.48 [ 0.45, 4.90 ]
7/63
4/62
100.0 %
1.72 [ 0.53, 5.59 ]
63
62
100.0 %
1.72 [ 0.53, 5.59 ]
Total events: 7 (Oral), 4 (IM)

2 < 34 weeks gestation
Egerman 1998
Subtotal (95% CI)

0.1 0.2
0.5
Favours oral
10
Favours IM
70
Analysis 2.2. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 2 Respiratory distress
syndrome.
Review:

Study or subgroup
Oral
IM
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Egerman 1998
Subtotal (95% CI)
34/99
25/84
100.0 %
1.15 [ 0.75, 1.77 ]
99
84
100.0 %
1.15 [ 0.75, 1.77 ]
32/63
25/62
100.0 %
1.26 [ 0.85, 1.86 ]
63
62
100.0 %
1.26 [ 0.85, 1.86 ]

Egerman 1998
Subtotal (95% CI)

0.1 0.2
0.5
Favours oral
10
Favours IM
71
Analysis 2.3. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 3 Intraventricular

haemorrhage.
Review:

Study or subgroup
Oral
IM
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Egerman 1998
Subtotal (95% CI)
10/99
2/84
100.0 %
4.24 [ 0.96, 18.83 ]
99
84
100.0 %
4.24 [ 0.96, 18.83 ]
10/63
2/62
100.0 %
4.92 [ 1.12, 21.55 ]
63
62
100.0 %
4.92 [ 1.12, 21.55 ]

Egerman 1998
Subtotal (95% CI)

0.05
0.2
Favours oral
20
Favours IM
Analysis 2.4. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 4 Birthweight (kg).
Review:

Study or subgroup
Oral
N
Mean
Difference
IM
Mean(SD)
Mean(SD)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI

Egerman 1998
Subtotal (95% CI)
99
1.81 (0.82)
99
84
1.76 (0.71)
84
100.0 %
0.05 [ -0.17, 0.27 ]
100.0 %
0.05 [ -0.17, 0.27 ]

-0.5
-0.25
Favours IM
0.25
0.5
Favours oral
72
Analysis 2.5. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 5 Neonatal sepsis.
Review:

Study or subgroup
Oral
IM
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Egerman 1998
Subtotal (95% CI)
10/99
1/84
100.0 %
8.48 [ 1.11, 64.93 ]
99
84
100.0 %
8.48 [ 1.11, 64.93 ]
10/63
1/62
100.0 %
9.84 [ 1.30, 74.60 ]
63
62
100.0 %
9.84 [ 1.30, 74.60 ]

Egerman 1998
Subtotal (95% CI)

0.02
0.1
Favours oral
10
50
Favours IM
73
Analysis 2.6. Comparison 2 Dexamethasone: oral versus intramuscular, Outcome 6 Necrotising

enterocolitis.
Review:

Study or subgroup
Oral
IM
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Egerman 1998
Subtotal (95% CI)
6/99
1/84
100.0 %
5.09 [ 0.63, 41.45 ]
99
84
100.0 %
5.09 [ 0.63, 41.45 ]
5/63
1/62
100.0 %
4.92 [ 0.59, 40.92 ]
63
62
100.0 %
4.92 [ 0.59, 40.92 ]

Egerman 1998
Subtotal (95% CI)

0.02
0.1
Favours oral
10
50
Favours IM
74
Analysis 3.1. Comparison 3 Betamethasone acetate + phosphate versus betamethasone phosphate,

Outcome 1 Neonatal death.
Review:
Comparison: 3 Betamethasone acetate + phosphate versus betamethasone phosphate

Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)

Subtil 2003
0/35
1/34
100.0 %
0.32 [ 0.01, 7.69 ]
35
34
100.0 %
0.32 [ 0.01, 7.69 ]
Total (95% CI)
Total events: 0 (Betamethasone a+p), 1 (Betamethasone p)

0.02
0.1
Favours beta a+p
10
50
Favours beta p

Outcome 2 Respiratory distress syndrome.
Review:

Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
0/35
2/34
100.0 %
0.19 [ 0.01, 3.91 ]
35
34
100.0 %
0.19 [ 0.01, 3.91 ]
Total (95% CI)

0.01
0.1
Favours beta a+p
10
100
Favours beta p
75

Outcome 3 Intraventricular haemorrhage.
Review:

Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
0/35
1/34
100.0 %
0.32 [ 0.01, 7.69 ]
35
34
100.0 %
0.32 [ 0.01, 7.69 ]
Total (95% CI)

0.02
0.1
Favours beta a+p
10
50
Favours beta p

Outcome 4 Neurodevelopmental disability.
Review:

Outcome: 4 Neurodevelopmental disability
Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
Total (95% CI)
0/35
0/34
0.0 [ 0.0, 0.0 ]
35
34
0.0 [ 0.0, 0.0 ]

Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%
0.1 0.2
0.5
Favours beta a+p
10
Favours beta p
76

Outcome 5 Birthweight (kg).
Review:

Study or subgroup
Betamethasone
a+p
Betamethasone p
N
Mean(SD)
Mean
Difference
Mean(SD)
35
2.77 (0.66)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI
1 beta a+p (2 x 12 mg, 24hrly) and beta p (4 x 6 mg,12hrly)

Subtil 2003
34
Total (95% CI)
2.67 (0.77)
34
100.0 %
-0.10 [ -0.44, 0.24 ]
100.0 % -0.10 [ -0.44, 0.24 ]
35

-2
-1
Favours beta a+p
Favours beta p

Outcome 6 Low birthweight.
Review:

Outcome: 6 Low birthweight
Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
25/35
20/34
100.0 %
1.21 [ 0.86, 1.72 ]
35
34
100.0 %
1.21 [ 0.86, 1.72 ]
Total (95% CI)

0.1 0.2
0.5
Favours beta a+p
10
Favours beta p
77

Outcome 7 Neonatal intensive care unit admission.
Review:

Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 24 mg beta a+p (2 x 12 mg, 24 hourly) x 24 mg beta p (4 x 6 mg, 12 hourly)

Subtil 2003
0/35
4/34
100.0 %
0.11 [ 0.01, 1.93 ]
35
34
100.0 %
0.11 [ 0.01, 1.93 ]
Total (95% CI)

0.005
0.1
Favours beta a+p
10
200
Favours beta p

Outcome 8 Bronchopulmonary dysplasia.
Review:

Outcome: 8 Bronchopulmonary dysplasia
Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
Total (95% CI)
0/35
0/34
0.0 [ 0.0, 0.0 ]
35
34
0.0 [ 0.0, 0.0 ]

0.1 0.2
0.5
Favours beta a+p
10
Favours beta p
78

Outcome 9 Periventricular leukomalacia.
Review:

Outcome: 9 Periventricular leukomalacia
Study or subgroup
Betamethasone a+p
Betamethasone p
n/N
n/N
Risk Ratio
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Subtil 2003
Total (95% CI)
0/35
0/34
0.0 [ 0.0, 0.0 ]
35
34
0.0 [ 0.0, 0.0 ]

0.1 0.2
0.5
Favours beta a+p
10
Favours beta p
Analysis 4.1. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 1 Perinatal death.
Review:
Comparison: 4 Betamethasone 12 hour versus 24 hour dosing

Outcome: 1 Perinatal death
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI
1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly

Khandelwal 2012
Subtotal (95% CI)
21/177
10/78
100.0 %
0.93 [ 0.46, 1.87 ]
177
78
100.0 %
0.93 [ 0.46, 1.87 ]
14/37
9/19
100.0 %
0.80 [ 0.43, 1.50 ]
37
19
100.0 %
0.80 [ 0.43, 1.50 ]
Total events: 21 (12 hourly), 10 (24 hourly)

2 23+1 to 26+0 weeks at trial entry
Khandelwal 2012
Subtotal (95% CI)

0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
(Continued . . . )
79
(. . .
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
M-H,Fixed,95% CI
Continued)
Risk Ratio
M-H,Fixed,95% CI

Khandelwal 2012
4/29
1/14
100.0 %
1.93 [ 0.24, 15.71 ]
29
14
100.0 %
1.93 [ 0.24, 15.71 ]
1/55
0/26
100.0 %
1.45 [ 0.06, 34.35 ]
55
26
100.0 %
1.45 [ 0.06, 34.35 ]
2/56
0/19
100.0 %
1.75 [ 0.09, 35.00 ]
56
19
100.0 %
1.75 [ 0.09, 35.00 ]
Subtotal (95% CI)


Khandelwal 2012
Subtotal (95% CI)


Khandelwal 2012
Subtotal (95% CI)


0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
80
Analysis 4.2. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 2 Respiratory distress
syndrome.
Review:

Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
Subtotal (95% CI)
61/167
28/75
100.0 %
0.98 [ 0.69, 1.40 ]
167
75
100.0 %
0.98 [ 0.69, 1.40 ]
26/32
17/17
100.0 %
0.83 [ 0.69, 0.99 ]
32
17
100.0 %
0.83 [ 0.69, 0.99 ]
17/27
3/13
100.0 %
2.73 [ 0.97, 7.67 ]
27
13
100.0 %
2.73 [ 0.97, 7.67 ]
14/55
7/26
100.0 %
0.95 [ 0.43, 2.06 ]
55
26
100.0 %
0.95 [ 0.43, 2.06 ]
4/53
1/19
100.0 %
1.43 [ 0.17, 12.04 ]
53
19
100.0 %
1.43 [ 0.17, 12.04 ]

Khandelwal 2012
Subtotal (95% CI)

Khandelwal 2012
Subtotal (95% CI)

Khandelwal 2012
Subtotal (95% CI)

Khandelwal 2012
Subtotal (95% CI)


0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
81
Analysis 4.3. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 3 Intraventricular
hemorrhage.
Review:

Outcome: 3 Intraventricular hemorrhage
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
32/94
10/41
100.0 %
1.40 [ 0.76, 2.56 ]
94
41
100.0 %
1.40 [ 0.76, 2.56 ]
17/26
5/12
100.0 %
1.57 [ 0.76, 3.24 ]
26
12
100.0 %
1.57 [ 0.76, 3.24 ]
8/22
1/9
100.0 %
3.27 [ 0.48, 22.52 ]
22
100.0 %
3.27 [ 0.48, 22.52 ]
6/30
3/15
100.0 %
1.00 [ 0.29, 3.45 ]
30
15
100.0 %
1.00 [ 0.29, 3.45 ]
1/16
1/5
100.0 %
0.31 [ 0.02, 4.14 ]
16
100.0 %
0.31 [ 0.02, 4.14 ]
Subtotal (95% CI)

Khandelwal 2012
Subtotal (95% CI)

Khandelwal 2012
Subtotal (95% CI)


Khandelwal 2012
Subtotal (95% CI)

Khandelwal 2012
Subtotal (95% CI)


0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
82
Analysis 4.4. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 4 Maternal fever >
100.4 F.
Review:

Outcome: 4 Maternal fever > 100.4 F
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
9/153
5/60
100.0 %
0.71 [ 0.25, 2.02 ]
Total (95% CI)
153
60
100.0 %
0.71 [ 0.25, 2.02 ]

0.01
0.1
10
Favours 12 hourly
100
Favours 24 hourly
Analysis 4.5. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 5 Birthweight (g).
Review:

Outcome: 5 Birthweight (g)
Study or subgroup
12 hourly
N
Mean
Difference
24 hourly
Mean(SD)
Mean(SD)
78
1720 (847.6)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI

Khandelwal 2012
177
Total (95% CI)
177
1804 (882.2)
78
100.0 %
84.00 [ -144.63, 312.63 ]
100.0 %
84.00 [ -144.63, 312.63 ]

-1000
-500
Favours 24 hourly
500
1000
Favours 12 hourly
83
Analysis 4.6. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 6 Small-forgestational age.
Review:

Outcome: 6 Small-for-gestational age
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
25/177
18/78
100.0 %
0.61 [ 0.36, 1.05 ]
Total (95% CI)
177
78
100.0 %
0.61 [ 0.36, 1.05 ]

0.5
0.7
Favours 12 hourly
1.5
Favours 24 hourly
Analysis 4.7. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 7 Neonatal intensive
care unit admission.
Review:

Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
131/169
68/78
100.0 %
0.89 [ 0.79, 1.00 ]
Total (95% CI)
169
78
100.0 %
0.89 [ 0.79, 1.00 ]

0.5
0.7
Favours 12 hourly
1.5
Favours 24 hourly
84
Analysis 4.8. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 8 Chronic lung
disease.
Review:

Outcome: 8 Chronic lung disease
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
36/160
20/70
100.0 %
0.79 [ 0.49, 1.26 ]
Total (95% CI)
160
70
100.0 %
0.79 [ 0.49, 1.26 ]

0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
Analysis 4.9. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 9 Neonatal sepsis.
Review:

Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
16/165
6/71
100.0 %
1.15 [ 0.47, 2.81 ]
Total (95% CI)
165
71
100.0 %
1.15 [ 0.47, 2.81 ]

0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
85
Analysis 4.10. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 10 Neonatal
antibiotic use (> 5 days).
Review:

Outcome: 10 Neonatal antibiotic use (> 5 days)
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
46/165
21/71
100.0 %
0.94 [ 0.61, 1.46 ]
Total (95% CI)
165
71
100.0 %
0.94 [ 0.61, 1.46 ]

0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
Analysis 4.11. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 11 Necrotising
enterocolitis.
Review:

Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
10/161
0/70
100.0 %
9.20 [ 0.55, 154.92 ]
Total (95% CI)
161
70
100.0 %
9.20 [ 0.55, 154.92 ]

0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
86
Analysis 4.12. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 12 Retinopathy of
prematurity.
Review:

Outcome: 12 Retinopathy of prematurity
Study or subgroup
12 hourly
24 hourly
n/N
n/N
Risk Ratio
Weight
Risk Ratio
M-H,Fixed,95% CI
M-H,Fixed,95% CI

Khandelwal 2012
26/78
11/31
100.0 %
0.94 [ 0.53, 1.66 ]
Total (95% CI)
78
31
100.0 %
0.94 [ 0.53, 1.66 ]

0.01
0.1
Favours 12 hourly
10
100
Favours 24 hourly
Analysis 4.13. Comparison 4 Betamethasone 12 hour versus 24 hour dosing, Outcome 13 Postpartum
maternal length of stay (days).
Review:

Outcome: 13 Postpartum maternal length of stay (days)
Study or subgroup
12 hourly
N
Mean
Difference
24 hourly
Mean(SD)
Mean(SD)
60
3.55 (2.04)
Mean
Difference
Weight
IV,Fixed,95% CI
IV,Fixed,95% CI

Khandelwal 2012
155
Total (95% CI)
155
2.82 (1.24)
60
100.0 %
-0.73 [ -1.28, -0.18 ]
100.0 %
-0.73 [ -1.28, -0.18 ]

-2
-1
Favours 12 hourly
Favours 24 hourly
87
ADDITIONAL TABLES
Table 1. Comparison of direct and indirect estimates and interaction tests
Outcome
Direct comparison
Indirect comparison
Discrepancy
Interaction test
Fetal/neonatal death
Direct comparison from

this review: dexamethasone v betamethasone RR
1.41, 95% CI 0.54 to 3.
67 (4 trials, 596 infants)
Indirect
comparison from Roberts 2006
Cochrane review: RR 0.
92, 95% CI 0.57 to 1.49.
Nonsignificant discrepancy between direct and

indirect results (MD 0.
42, 95% CI -0.65 to 1.
49)
Test for subgroup differences in trials in

Roberts 2006 Cochrane
review was non significant (Chi statistic: 0.
00 and P value: 0.98, I
value: 0%)
RDS

this review: dexamethasone v betamethasone:
RR 1.06, 95% CI 0.88
to 1.27 (5 trials, 753 infants)
Indirect
40, 95% CI 1.02 to 1.90.

indirect results (MD -0.
28, 95% CI -0.64 to 0.
08)

review was significant
(Chi statistic: 4.68 and
P value 0.03, I value: 78.
6%)
IVH (any)

this review: dexamethasone v betamethasone:
RR 0.44, 95% CI 0.21
to 0.92 (4 trials, 549 infants)
Indirect
96, 95% CI 0.35 to 2.66.

indirect results (MD -0.
78, 95% CI -2.04 to 0.
48)

value: 0%)
Chorioamnionitis
No direct comparison
(outcome not reported in
any trials included in this
review)
Indirect
compar- NA.
ison from Roberts 2006
90, 95% CI 1.10 to 3.28.

review was significant
(Chi statistic: 5.41 and
P value 0.02, I value: 81.
5%)
Puerperal sepsis
No direct comparison
(outcome not reported in
any trials included in this
review)
Indirect
compar- NA.
ison from Roberts 2006
68, 95% CI 0.60 to 4.66.

value: 0%)
CI: confidence interval

MD: mean difference
NA: not applicable
RR: risk ratio
88
v: versus
WHATS NEW
Last assessed as up-to-date: 1 May 2013.
Date
Event
Description
1 May 2013
New citation required but conclusions have not Review updated - the overall conclusions have not
changed
changed. However, in this update, the increase in
NICU admission for the infants in the dexamethasone
group (compared with the betamethasone group), is no
longer statistically significant, with the inclusion of the
Danesh 2012 trial.
13 February 2013
New search has been performed
Search updated. Two new trials included (Danesh

2012; Khandelwal 2012); and one new report excluded
(Shanks 2010).
HISTORY
Protocol first published: Issue 4, 2007
Review first published: Issue 4, 2008
Date
Event
Description
9 May 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
For this update of the review, Daniela Gagliardi, Fiona Brownfoot and Emily Bain extracted data and assessed the risk of bias for the
two new trials, and all authors contributed to the final draft of the review. Daniela Gagliardi and Emily Bain updated the indirect
comparison estimates, and performed the subgroup interaction tests.
Fiona Brownfoot researched and wrote the initial draft of the previous version of the review, and extracted data together with Philippa
Middleton. Caroline Crowther and Philippa Middleton edited the subsequent drafts.
89
DECLARATIONS OF INTEREST
Two of the review authors (Caroline Crowther and Philippa Middleton) are investigators on the A*STEROID trial, and Daniela
Gagliardi is a Research Officer with the A*STEROID trial, which may be considered for inclusion in this review on completion and
publication (see Ongoing studies).
SOURCES OF SUPPORT
Internal sources
ARCH, The Robinson Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.
External sources
Department of Health and Ageing, Australia.
National Health and Medical Research Council, Australia.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

In this update of the review: we have clarified that cross-over trials and cluster-randomised trials will be excluded, and that studies
reported as abstracts only will be included.
We have reduced the number of primary outcomes for the baby to three (death, RDS and IVH) and have re-classified the remaining
outcomes as secondary outcomes.
In previous versions of the review: we added the outcome of any neurodisability for the child, and for the child as an adult.
We have included a previously excluded subgroup (see below) in the review methods of this update as we believe that this maternal
characteristic may affect health outcomes. However we were unable to perform this subgroup analysis due to insufficient data available
in this update:
preterm prelabour rupture of membranes (at trial entry: yes versus no).
In the previous update of this review, we deleted the following subgroup from the review methods, as it may be influenced by the
intervention:
gestational age at birth (24 to 26 weeks, 27 to 29 weeks, 30 to 34 weeks, 35 to 37 weeks).
INDEX TERMS
Medical Subject Headings (MeSH)
Premature Birth; Adrenal Cortex Hormones [ administration & dosage]; Beclomethasone [administration & dosage]; Dexamethasone
[administration & dosage]; Fetal Organ Maturity [ drug effects]; Intracranial Hemorrhages [prevention & control]; Lung [drug effects;
embryology]
90
MeSH check words

Female; Humans; Pregnancy
91

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Different corticosteroids and regimens for accelerating fetal

lung maturation for women at risk of preterm birth (Review)

Different corticosteroids and regimens for accelerating fetal

PLAIN LANGUAGE SUMMARY

South Asia (March of Dimes 2012). Preterm infants, especially

there have been no similar long-term follow-up studies reported

Corticosteroid dose, timing and frequency

maturation for women at risk of preterm birth (Brownfoot 2008).

To assess the effects on fetal and neonatal morbidity and mortality,

Why it is important to do this review

Criteria for considering studies for this review

For the woman

than -2 standard deviations below population mean) or variously

For the woman

Fever after trial entry requiring the use of antibiotics;

For the fetus/neonate

behavioural/learning difficulties (however defined by

For health services

Search methods for identification of studies

Data collection and analysis

Data extraction and management

We described for each included study the methods used to generate

We described for each included study the method used to conceal

We described for each included study, the methods, if any, used to

We assessed the methods as:

We described for each included study the methods used, if any, to

We described for each included study and for each outcome or

(6) Other sources of bias (checking for bias due to problems

We described for each included study any important concerns we

randomised minus any participants whose outcomes were known

(7) Overall risk of bias

We made explicit judgements about whether studies were at a

Assessment of reporting biases

For dichotomous data, we presented results as risk ratio with 95%

For continuous data, we used the mean difference when outcomes

Unit of analysis issues

Dealing with missing data

Subgroup analysis and investigation of heterogeneity

preterm prelabour rupture of membranes (at trial entry: yes

Results of the search

2010). See Characteristics of studies awaiting classification and

Description of interventions used in the included trials

In the 12 trials included in this review, 1557 women and 1661

(Romaguera 1997); one trial was excluded as vitamin K added to

Risk of bias in included studies

For further details on the risk of bias in individual studies, see

Incomplete outcome data

Other potential sources of bias

1. Dexamethasone versus betamethasone

No primary outcomes for women were reported in any of the

No statistically significant differences between those exposed to

For the child as adult

Rotmensch 1999) (Analysis 1.21), in Senat 1998 (see Other

For the child as adult

a substantial level of heterogeneity was observed for this outcome

Indirect comparisons and subgroup interaction tests

(Chi statistic: 5.41 and P value 0.02, I value: 81.5%) indicated a

2. Dexamethasone (oral versus intramuscular

For the child as adult

3. Betamethasone acetate + phosphate versus

No primary outcomes for children were reported in this trial.

No statistically significant differences between those exposed to

For the child as adult

None of the children were reported to have a neurodevelopmental