Antenatal Betamethasone Compared With
Dexamethasone (Betacode Trial)
A Randomized Controlled Trial
Andrew Elimian, MD, David Garry, DO, Reinaldo Figueroa,
Vandy Wiencek, RN, and J. Gerald Quirk, MD, PhD
OBJECTIVE: To compare betamethasone with dexa-
methasone in terms of effectiveness in reducing perinatal
morbidities and mortality among preterm infants.
METHODS: We enrolled 299 women at risk for preterm
delivery in a double-blind, placebo-controlled, random-
ized trial of antenatal betamethasone compared with
dexamethasone at Stony Brook University Hospital from
August 2002 through July 2004. We excluded women
with clinical chorioamnionitis, fetal structural and chro-
mosomal abnormalities, prior antenatal steroid exposure,
and steroid use for other indications. Statistical analysis
was performed in accordance of the intention-to-treat
principle.
RESULTS: There were no significant differences between
the groups with regard to baseline characteristics. The
rate of respiratory distress syndrome, need for vasopres-
sor therapy, necrotizing enterocolitis, retinopathy of pre-
maturity, patent ductus arteriosus, neonatal sepsis, and
neonatal mortality were not significant different between
the groups. However, the rates of intraventricular hem-
orrhage (6 of 105 [5.7%] compared with 17 of 100 [17.0%],
relative risk [RR] 2.97, 95% confidence interval [CI] 1.22–
7.24, Pⴝ.02) and any brain lesion (7 of 105 [6.7%] com-
pared with 18 of 100 [18.0%], RR 2.7, 95% CI 1.18 – 6.19,
Pⴝ.02 ) were significantly lower in neonates exposed to
dexamethasone compared with betamethasone. The ab-
solute risk reduction in the rate of intraventricular hem-
See related editorial on page 7.
From the Department of Obstetrics, Gynecology and Reproductive Medicine and
Department of Pediatrics, Stony Brook University, Stony Brook, New York.
Corresponding author: Andrew Elimian, MD, Section of Maternal Fetal
Medicine, Department of Obstetrics and Gynecology, University of Oklahoma,
Health Sciences Center, WP 2450, Oklahoma City, OK 73190; e-mail:
andrew-elimian@ouhsc.edu.
Financial Disclosure
The authors have no potential conflicts of interest to disclose.
© 2007 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/07
26 VOL. 110, NO. 1, JULY 2007
MD Alan Spitzer, MD,
orrhage was 11.3 % ( 95% CI 2.7–11.9%), and the number
needed to treat was 9 (95% CI 5–37) in favor of dexa-
methasone.
CONCLUSION: Betamethasone and dexamethasone are
comparable in reducing the rate of most major neonatal
morbidities and mortality in preterm neonates. However,
dexamethasone seems to be more effective in reducing
the rate of intraventricular hemorrhage compared with
betamethasone.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
www.clinicaltrials.gov, NCT00418353
(Obstet Gynecol 2007;110:26–30)
LEVEL OF EVIDENCE: I
A dministration of a single course of antenatal steroids
results in decrease in neonatal morbidity and mor-
tality as well as substantial savings in health care costs by
specifically reducing the risk of respiratory distress syn-
drome, intraventricular hemorrhage, and neonatal
death among premature infants.1–3 The preferred corti-
costeroids for antenatal therapy are betamethasone ad-
ministered intramuscularly as two doses of 12 mg each
24 hours apart or dexamethasone four doses of 6 mg
given intramuscularly every 12 hours. These agents are
favored over other forms of steroids because they are the
most widely studied, seem to have identical biologic
activity, and readily cross the placenta. In addition, they
are devoid of mineralocorticoid activity, have relatively
weak immunosuppressive actions, and have longer
duration of action in comparison with cortisol and
methylprednisolone.4
However, there continue to be reports from uncon-
trolled studies of differences in effectiveness between
betamethasone and dexamethasone. A meta-
analysis3showed that although the two agents reduce the
risks of respiratory distress syndrome and intraventricu-
lar hemorrhage to a comparable extent, betamethasone
was more consistently associated with reduction in neo-
OBSTETRICS & GYNECOLOGY
natal death than dexamethasone. Furthermore a retro-
spective study5 found that betamethasone but not dexa-
methasone was associated with a decreased risk of
periventricular leukomalacia, a major precursor of cere-
bral palsy. On the other hand, dexamethasone is sub-
stantially cheaper, more readily available and less likely
to decrease fetal breathing movements and fetal heart
rate variability. In addition a recent retrospective
study6did not find any differences in effectiveness in the
reduction of neonatal mortality and morbidity, includ-
ing intraventricular hemorrhage and periventricular
leukomalacia.
The choice of which of these agents to use is
currently based on ease of administration, cost, availabil-
ity, and results from conflicting observational studies.
Our hypothesis was that there are no differences
between betamethasone and dexamethasone with re-
gards to effectiveness when used in the clinical setting
of anticipated preterm delivery. Our objective was to
compare betamethasone with dexamethasone in
terms of effectiveness in reducing perinatal morbidi-
ties and mortality among preterm infants.
MATERIALS AND METHODS
We conducted a randomized, double-blind, placebo-
controlled trial involving pregnant women at risk for
delivering preterm at Stony Brook University Hospital
from August 1, 2002, through July 31, 2004. These
included all women in preterm labor with intact mem-
branes, those with preterm premature rupture of mem-
branes, and those anticipated to deliver for fetal and
maternal indications between 24 and 33 weeks 6 days
gestation.
Preterm labor with intact membranes was diag-
nosed in the presence of six to eight contractions per
hour or four contractions in 20 minutes, associated
with cervical changes but with no prelabor rupture of
membranes. Preterm PROM included cases in which
delivery followed prelabor rupture of membranes,
documented by pooling of fluid on sterile speculum
examination, ferning, and alkaline pH of fluid col-
lected from the posterior vaginal fornix. Fetal and
maternal indications included mainly intrauterine
growth restriction, preeclampsia, and chronic hyper-
tension with superimposed preeclampsia. We ex-
cluded women with clinical chorioamnionitis, known
major fetal structural anomalies, known fetal chromo-
somal abnormalities, prior antenatal steroid exposure,
steroid use for other indications, and quadruplets, as
well as women who declined enrollment.
Subjects meeting inclusion criteria were ap-
proached by a resident or attending physician who
explained the study and sought consent to participate in
VOL. 110, NO. 1, JULY 2007
the study. Those who elected to participate in the study
signed a formal consent form approved by our institu-
tion’s Committee on Research on Human Subjects.
Consenting women were randomly allocated to one
of two groups. The random allocation sequence was
carried out by the Pharmacy using computer-generated
random numbers, and each participant was assigned to
one of two groups, ie, betamethasone or dexametha-
sone. One group received 12 mg of betamethasone
(Celestone Soluspan, Schering, Kenilworth, NJ) intra-
muscularly at 0 and 24 hours and similar-appearing
placebo at 12 and 36 hours. The second group received
6 mg of dexamethasone (dexamethasone sodium phos-
phate, Baxter Healthcare Corporation Anesthesia and
Critical Care, New Providence, NJ) intramuscularly at 0,
12, 24, and 36 hours. Concealment was achieved by
delivering all doses in identical-looking syringes covered
by opaque material. Both subjects and health care
providers were blinded as to the group to which partic-
ipants belonged.
After delivery, study personnel blinded to group
assignment reviewed the prenatal, delivery, neonatal,
and postpartum records and documented maternal
and neonatal independent outcome variables. The
primary outcome variables were respiratory distress
syndrome, intraventricular hemorrhage, and neonatal
death. Secondary outcome variables included the
need for exogenous surfactant, oxygen dependency at
28 days after birth or oxygen dependency at equiva-
lent of 36 completed weeks gestational age, retinopa-
thy of prematurity, inotropic support for hypotension
initiated during the first 24 hours of life, treatment for
patent ductus arteriosus, necrotizing enterocolitis,
neonatal sepsis, and histologic chorioamnionitis.
Other variables recorded were maternal age, clinical
diagnosis, gestational age at randomization and at
delivery, gender, and birth weight.
Respiratory distress syndrome was diagnosed
clinically, by the need for mechanical ventilation and
oxygen for at least 48 hours, and the presence of
radiologic chest findings. Each neonate had transfon-
tanelle head ultrasound scans on days 3 and 7 of life.
Neurosonograms were evaluated by an experienced
radiologist blinded to the antenatal steroid exposure
status of the parturient. Intraventricular hemorrhage
was graded as described by Papile et al7 Periventricu-
lar leukomalacia was diagnosed by the presence of
echolucent areas or persistent echogenicity in the
periventricular areas on coronal and sagittal views.
For study purposes, “any brain lesion” was defined as
any grade of intraventricular hemorrhage or periven-
tricular leukomalacia present exclusively or in com-
bination.⬙ Necrotizing enterocolitis was diagnosed
Elimian et al The Betacode Trial 27
clinically and radiologically and confirmed at surgery
or autopsy. Proven neonatal sepsis included positive
blood, cerebrospinal fluid, or urine cultures.
Data analysis was performed in accordance of the
intention-to-treat principle. Sample size computations
for an equivalence study were performed according to
the work of Blackwelder.8 We assumed that approxi-
mately 80% of neonates exposed to either betametha-
sone or dexamethasone will not develop respiratory
distress syndrome. We also defined a deviation in
effectiveness of 10% or less as been essentially equiva-
lent. A sample size of 354 neonates (177 exposed to
betamethasone compared with 177 exposed to dexa-
methasone) would provide more than 80% power to
detect differences of more than 10% for a two-tailed test
of significance at a critical level of 0.05. The distribu-
tional characteristics of the variables were examined.
Continuous data were normally distributed. As such,
differences between groups defined by exposure to
antenatal steroids were examined using Student t test for
continuous variables and ␹2 for categorical variables.
Fisher exact test was used when expected cell frequency
was equal to or less than five. A P value of ⬍.05 was Fig. 1. Betacode trial profile.
considered statistically significant. Elimian. The Betacode Trial. Obstet Gynecol 2007.

RESULTS
Five hundred forty-three women were screened for
eligibility. One hundred sixty (29.5%) received
antenatal steroids before their transport and subse-
quently had completion of their course based on
what was initiated in the transferring hospital.
Fifty-five (10.1%) women declined participation
and were given antenatal steroids based on the
discretion of the treating physician and availability,
whereas 29 (5.3%) women could not be approached
because of immediate or imminent delivery. Thus,
the study cohort consisted of 299 (55.1%) women
and their 359 neonates. The profile of the study
participants is shown in Figure 1. There were no
statistically significant differences between the
groups in terms of maternal age, race, body mass
index, smoking status, gestational age at random-
ization, and diagnoses between women who partic-
ipated in the trial and those who did not participate.
Similarly, the baseline characteristics of the women
and neonates randomly assigned to betamethasone
were not different from those that assigned to
dexamethasone, as depicted in Tables 1 and 2. No
adverse effect or side effects were reported in either
group.
There were no significant differences between
neonates exposed to betamethasone and those ex-
posed to dexamethasone with regard to the rates of
respiratory distress syndrome (73 of 181 [40.5%]
compared with 79 of 178 [44.4%], P⫽.53), necrotizing
enterocolitis (0 of 181 [0%] compared with 2 of 178
[1.1%], P⫽.25), retinopathy of prematurity (28 of 181
[15.5%] compared with 26 of 178 [14.6%], P⫽.92),
patent ductus arteriosus (12 of 181 [6.7%] compared
with 14 of 178 [7.9%], P⫽.81), neonatal sepsis (16 of
181 [8.9%] compared with 18 of 178 [10.1%], P⫽.83),
bronchopulmonary dysplasia (27 of 181 [15.0%] com-
pared with 18 of 178 [10.1%], P⫽.22), need for
vasopressor (14 of 181 [7.8%] compared with 6 of 178
[3.4%], P⫽.07), and neonatal mortality (5 of 181
[2.8%] compared with 6 of 178 [3.4%], P⫽.98) (Table
3). However, the rates of intraventricular hemorrhage
(6 of 105 [5.7%] compared with 17 of 100 [17.0%],
relative risk 2.97, 95% confidence interval [CI] 1.22–
7.24, P⫽.02) and any brain lesion (7 of 105 [6.7%]
compared with 18 of 100 [18.0%], relative risk 2.7,
95% CI 1.18 – 6.19, P⫽.02 ) were significantly lower in
neonates exposed to dexamethasone compared with
betamethasone (Table 3).
The rate of grades III and IV intraventricular
hemorrhage was 7% (7 of 100) in neonates exposed to
betamethasone compared with 1.9% (2 of 105) in
neonates exposed to dexamethasone, P⫽.09 (Table
3). Furthermore, the rate of periventricular leukoma-
lacia was 4.0% (4 of 100) in neonates exposed to

28 Elimian et al The Betacode Trial OBSTETRICS & GYNECOLOGY

Table 1. Baseline Characteristics of Mothers in the Betamethasone and Dexamethasone Groups
Maternal Characteristics Betamethasone (nⴝ150) Dexamethasone (nⴝ149) P
Maternal age (y) 30.6⫾6.1 29.9⫾6.2 .37
Race
White 105 (70.0) 105 (70.5) .97
African American 21 (14.0) 14 (9.4) .29
Hispanic 12 (8.0) 19 (12.7) .25
Other 12 (8.0) 11 (7.4) .99
GA presentation 29.3⫾2.9 29.5⫾2.9 .82
BMI 30.0⫾6.7 29.4⫾5.0 .41
Singleton gestation 124 (82.7) 125 (83.9) .90
Smoking 26 (17.3) 32 (21.5) .45
PTL 80 (53.3) 76 (51.0) .77
Preterm PROM 21 (14.0) 29 (19.5) .27
Medically indicated 49 (32.7) 44 (29.5) .64
HCA 27 (18.0) 30 (20.1) .75
GA, gestational age; BMI, body mass index; PTL, preterm labor; PROM, premature rupture of membranes; HCA, histologic chorioamnionitis.
Data are mean⫾standard deviation or n (%).

Table 2. Baseline Characteristics of Neonates in the Betamethasone and Dexamethasone Groups

Neonatal Characteristics Betamethasone (nⴝ181) Dexamethasone (nⴝ178) P
Mode of delivery .64
Vaginal 80 (44.2) 84 (47.2)
Cesarean 101 (55.8) 94 (52.8)
Sex .96
Male 90 (49.7) 89 (50)
Female 91 (50.3) 89 (50)
Birth weight 1983⫾814 2036⫾825 .56
Surfactant use 52 (28.7) 53 (29.8) .92
Data are mean⫾standard deviation or n (%).

Table 3. Neonatal Outcomes in the Betamethasone and Dexamethasone Groups

Outcome Betamethasone (nⴝ181) Dexamethasone (nⴝ178) RR 95% CI P
RDS 73 (40.5) 79 (44.4) 0.91 0.72–1.16 .53
IVH
Any grade 17/100 (17.0) 6/105 (5.7) 2.97 1.22–7.24 .02
Grade III/IV 7/100 (7.0) 2/105 (1.9) 3.67 0.78–17.27 .09
PVL 4/100 (4.0) 2/105 (1.9) 2.10 0.39–11.21 .44
Any brain lesion 18/100 (18) 7/105 (6.7) 2.7 1.18–6.19 .02
Neonatal death 5 (2.8) 6 (3.4) 0.82 0.26–2.65 .98
NEC 0 (0) 2 (1.1) 0.00 0.00–4.0 .25
ROP 28 (15.5) 26 (14.6) 1.06 0.65–1.74 .92
PDA 12 (6.7) 14 (7.9) 0.85 0.40–1.78 .81
Sepsis 16 (8.9) 18 (10.1) 0.88 0.46–1.67 .83
BPD 27 (15.0) 18 (10.1) 1.48 0.85–2.59 .22
Vasopressor use 14 (7.8) 6 (3.4) 2.31 0.91–5.87 .07
RR, relative risk; CI, confidence interval; RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia;
NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia.
Data are n (%) or n/N (%) unless otherwise specified.

betamethasone compared with 1.9% (2 of 105) in DISCUSSION

neonates exposed to dexamethasone, P⫽.44 (Table
3). The absolute risk reduction in the rate of intraven-
tricular hemorrhage was 11.3% (95% CI 2.7–11.9%),
and the number needed to treat was 9 (95% CI 5–37)
in favor of dexamethasone.
A single course of antenatal steroids before preterm
delivery results in a significant decrease in neonatal
morbidity and mortality as well as substantial savings in
health care costs. Betamethasone and dexamethasone
continue to be the preferred steroids because of their

VOL. 110, NO. 1, JULY 2007 Elimian et al The Betacode Trial 29

unique biologic properties, ability to readily cross the
placenta, and because of their weak immunosuppressive
and mineralocorticoid activities. The choice between
betamethasone and dexamethasone is currently based
on ease of administration, cost, availability, and results
from conflicting observational studies.
Our study found that both betamethasone and
dexamethasone are largely comparable in reducing
most morbidities and mortality among preterm neo-
nates. This finding is consistent with the reports of Baud
et al5 and Bar-lev and colleaques,6 who did not demon-
strate any differences in the rate of respiratory distress
syndrome, bronchopulmonary dysplasia, intraventricu-
lar hemorrhage, neonatal mortality, and other compli-
cations of prematurity among neonates exposed to
betamethasone and dexamethasone. However, contrary
to the finding of a higher rate of periventricular leu-
komalacia among neonates exposed to dexamethasone
compared with betamethasone reported by Baud et al,5
our study did not find any differences in the rate
periventricular leukomalacia between the groups. In
fact, the rate of periventricular leukomalacia in the
dexamethasone-exposed neonates was lower among
neonates exposed to betamethasone, although our study
was underpowered to detect differences in periventricu-
lar leukomalacia. Three other groups of investigators6,9,10
have reported no differences in the rates of periventricu-
lar leukomalacia among neonates exposed to beta-
methasone and dexamethasone.
The differences in intraventricular hemorrhage
after steroid exposure seen in our study may be
related to potency, duration of exposure, and fetal
response after exposure. Dexamethasone is five times
more potent than betamethasone in nongenomic ef-
fects in addition to the stereoisomer difference of a
methyl group at position 16 of ring D in their
molecular structure.11,12 Derks et al12 described a more
rapid fall in fetal sheep progesterone levels and a
sharper rise in serum cortisol levels after betametha-
sone administration compared with dexamethasone,
and the cortisol levels continued to rise at 72 hours
postexposure in the dexamethasone-treated fetal
sheep. Ballard and Liggins13,14 showed umbilical cord
cortisol levels increased more rapidly and with a
higher zenith after each 12 mg of betamethasone
compared with 6 mg of betamethasone, with no
reported increased benefit to 24 mg betamethasone
dosing. The exact difference in physiologic responses
of these stereoisomer molecules is not known and
requires further investigation.
Our study largely supports the continuing use of
both betamethasone and dexamethasone in the treat-
ment of women at risk of preterm delivery. However,
30 Elimian et al The Betacode Trial
we found dexamethasone to be superior to betametha-
sone in reducing the rate of intraventricular hemor-
rhage. Other potential advantages of dexamethasone
include lower cost, widespread availability, and less
effect on fetal biophysical variables that might lead to
premature intervention or delivery. On the other hand,
betamethasone requires two injections as opposed to the
four injections of dexamethasone.
REFERENCES
1. National Institutes of Health. Report of the Consensus Develop-
ment Conference on the Effect of Corticosteroids for Fetal
Maturation on Perinatal Outcomes (NIH Publication No.
95–3784). Bethesda (MD): National Institutes of Health, National
Institute of Child Health and Human Development; 1994
2. Liggins GC, Howie RN. A controlled trial of antepartum
glucocorticoid treatment for prevention of distress syndrome in
premature infants. Pediatrics 1972;50:515–25.
3. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis
of the randomized trials, 1972 to 1994. Am J Obstet Gynecol
1995;173:322–35.
4. Ballard PL, Ballard RA. Scientific basis and therapeutic regi-
mens for use of antenatal glucocorticoids. Am J Obstet
Gynecol 1995;173:254–62.
5. Baud O, Foix-L’Helias L, Kaminski M, Audibert F, Jarreau
PH, Papiernik E, et al Antenatal glucocorticoid treatment and
cystic periventricular leukomalacia in very premature infants.
N Engl J Med 1999;341:1190–6.
6. Bar-Lev MR, Maayan-Metzger A, Matok I, Heyman Z, Sivan
E, Kuint J. Short-term outcomes in low birth weight infants
following antenatal exposure to betamethasone versus dexa-
methasone. Obstet Gynecol 2004;104:484–8.
7. Papile LA, Burstein J, Koffler H. Incidence and evolution of
subependymal and intraventricular hemorrhage: a study of
infants with birth weights less than 1,500 gm. J Pediatr 1978;
92:529–34.
8. Blackwelder WC. “Proving the null hypothesis” in clinical
trials. Control Clin Trials 1982;3:345–53.
9. LeFlore JL, Salhab WA, Broyles RS, Engle WD. Association of
antenatal and postnatal dexamethasone exposure with out-
comes in extremely low birth weight neonates. Pediatrics
2002;110:275–9.
10. Lee BH, Stoll BJ, McDonald SA, Higgins RD, National
Institute of Child Health and Human Development Neonatal
Research Network. Adverse neonatal outcomes associated
with antenatal dexamethasone versus antenatal betametha-
sone. Pediatrics 2006;117:1503–10.
11. Derks JB, Giussani DA, Van Dam LM, Jenkins SL, Winter JA,
Zhao XF, et al. Differential effects of betamethasone and
dexamethasone fetal administration of parturition in sheep.
J Soc Gynecol Investig 1996;3:336–41.
12. Buttgereit F, Brand MD, Burmester GR. Equivalent doses and
relative drug potencies for non-genomic glucocorticoid effects:
a novel glucocorticoid hierarchy. Biochem Pharmacol 1999;
58:363–8.
13. Ballard PL, Liggins GC. Glucocorticoid activity in cord serum:
comparison of hydrocortisone and betamethasone regimens.
J Pediatr 1982;101:468–70.
14. Ballard PL. Scientific rationale for the use of antenatal glu-
cocorticoids to promote fetal development. Pediatr Rev
2000;1:E83–90.
OBSTETRICS & GYNECOLOGY