Effect of Antenatal Corticosteroids on Fetal

Growth and Gestational Age at Birth

Kellie E. Murphy, MD, Andrew R. Willan, PhD, Mary E. Hannah, MDCM, Arne Ohlsson, MD,
Edmond N. Kelly, MB, Stephen G. Matthews, PhD, Saroj Saigal, MD, Elizabeth Asztalos, MD,
Susan Ross, PhD, Marie-France Delisle, MD, Kofi Amankwah, MD, Patricia Guselle, MSc,
Amiram Gafni, DSc, Shoo K. Lee, MB, BS, and B. Anthony Armson, MD,
for the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study Collaborative Group*
OBJECTIVE: To estimate the effect of multiple courses of
antenatal corticosteroids on neonatal size, controlling for
gestational age at birth and other confounders, and to
determine whether there was a doseresponse relationship between number of courses of antenatal corticosteroids and neonatal size.
METHODS: This is a secondary analysis of the Multiple
Courses of Antenatal Corticosteroids for Preterm Birth
Study, a double-blind randomized controlled trial of
single compared with multiple courses of antenatal corticosteroids in women at risk for preterm birth and in
*For a list of other members of the Multiple Courses of Antenatal Corticosteroids
for Preterm Birth Study collaborative group, see the Appendix online at
http://links.lww.com/AOG/A296.
From the Departments of Obstetrics and Gynaecology and Paediatrics, Mount Sinai
Hospital, the Program in Child Health Evaluative Sciences, SickKids Research
Institute and Division of Biostatistics, the Departments of Obstetrics and Gynaecology and Newborn & Developmental Paediatrics and the Centre for Mother, Infant
and Child Research, Sunnybrook Health Sciences Centre, the Departments of
Physiology, Obstetrics and Gynecology, and Medicine, and the Dalla Lana School
of Public Health, University of Toronto, Toronto, Ontario, Canada; the Department
of Paediatrics and the Centre for Health Economics and Policy Analysis, and the
Department of Clinical Epidemiology and Biostatistics, McMaster University
Medical Centre, Hamilton, Ontario, Canada; the Departments of Obstetrics and
Gynaecology, University of Calgary, Calgary, Alberta, Canada, BC Womens
Hospital, University of British Columbia, Vancouver, British Columbia, Canada,
and IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada; the
Department of Gynecology-Obstetrics, Womens and Childrens Hospital, State
University of New York at Buffalo, Buffalo, New York; and the Division of
Neonatology, Hospital for Sick Children, Toronto, Ontario, Canada.
Supported by Canadian Institutes of Health Research grant number MCT 38142.

which fetuses administered multiple courses of antenatal

corticosteroids weighed less, were shorter, and had
smaller head circumferences at birth. All women
(n1,858) and children (n2,304) enrolled in the Multiple
Courses of Antenatal Corticosteroids for Preterm Birth
Study were included in the current analysis. Multiple
linear regression analyses were undertaken.
RESULTS: Compared with placebo, neonates in the antenatal corticosteroids group were born earlier (estimated
difference and confidence interval [CI]: 0.428 weeks, CI
0.10264 to 0.75336; P.01). Controlling for gestational
age at birth and confounding factors, multiple courses of
antenatal corticosteroids were associated with a decrease in
birth weight (33.50 g, CI 66.27120 to 0.72880; P.045),
length (0.339 cm, CI 0.6212 to 0.05676]; P.019), and
head circumference (0.296 cm, 0.45672 to 0.13528;
P<.001). For each additional course of antenatal corticosteroids, there was a trend toward an incremental decrease in
birth weight, length, and head circumference.
CONCLUSION: Fetuses exposed to multiple courses of
antenatal corticosteroids were smaller at birth. The reduction in size was partially attributed to being born at an
earlier gestational age but also was attributed to decreased fetal growth. Finally, a doseresponse relationship exists between the number of corticosteroid courses
and a decrease in fetal growth. The long-term effect of
these findings is unknown.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,
www.clinicaltrials.gov, NCT00187382.

Corresponding author: Kellie E. Murphy, MD, MSc, FRCSC, FACOG, Mount

Sinai Hospital, Maternal Fetal Medicine, Department of Obstetrics and
Gynaecology, Third Floor Room 3097, Ontario Power Generation Building,
700 University Ave., Toronto, Ontario, M5R 1X5, Canada; e-mail:
kmurphy@mtsinai.on.ca.

(Obstet Gynecol 2012;119:91723)

DOI: 10.1097/AOG.0b013e31825189dc

Financial Disclosure
The authors did not report any potential conflicts of interest.

2012 by The American College of Obstetricians and Gynecologists. Published

by Lippincott Williams & Wilkins.
ISSN: 0029-7844/12

VOL. 119, NO. 5, MAY 2012

LEVEL OF EVIDENCE: II

he Multiple Courses of Antenatal Corticosteroids

for Preterm Birth Study was an international,
multicenter, double-blind, randomized controlled
trial of single compared with multiple courses of

OBSTETRICS & GYNECOLOGY

917

antenatal corticosteroids in women at increased risk

for preterm birth. Although newborns born to women
in the antenatal corticosteroids group experienced
similar composite morbidity (severe respiratory distress syndrome, intraventricular hemorrhage [grade
III or IV], periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis) and
mortality as compared with those in the placebo
group (12.9% antenatal corticosteroids compared with
12.5% placebo, odds ratio 1.04, confidence interval
[CI] 0.771.39; P.83),1 a recent Cochrane review
has found a reduced risk of composite serious neonatal outcome if antenatal corticosteroid courses are
repeated.2 In the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, when compared
with the placebo group, neonates in the antenatal
corticosteroids group were smaller. They weighed less
(2,216 g compared with 2,330 g; P.003), were
shorter (44.5 cm compared with 45.4 cm; P.001),
and had smaller head circumferences (31.1 cm compared with 31.7 cm; P.001) at birth.1
The mean gestational age at birth was 34.5 weeks
(standard deviation 3.6) for the antenatal corticosteroids group and 34.9 weeks (standard deviation 3.6)
for the placebo group. It is possible that the neonates
in the antenatal corticosteroids group were smaller
partly because they were born earlier.
The primary objective of this secondary analysis
was to determine whether the effect of multiple
courses of antenatal corticosteroids on neonatal size
was a direct effect of the corticosteroids on fetal
growth, or whether it was attributable to a reduction
in gestational age at birth, or both. The secondary
objective was to determine whether there was a
doseresponse relationship between the number of
courses of antenatal corticosteroids and decrease in
fetal size.

MATERIALS AND METHODS

After an initial course of antenatal corticosteroids,
pregnant women 25 0/7 weeks of gestation or more
and 32 6/7 weeks of gestation or less who remained at
increased risk for preterm birth 14 to 21 days after an
initial course of antenatal corticosteroids were eligible
for the Multiple Courses of Antenatal Corticosteroids
for Preterm Birth Study. Women were excluded if
they had a contraindication to receiving corticosteroids, required chronic doses of corticosteroids, had
evidence of chorioamnionitis, carried a fetus with a
known lethal congenital anomaly, had the initial
course of antenatal corticosteroids before 23 weeks of
gestation, or previously participated in the Multiple
Courses of Antenatal Corticosteroids for Preterm

918

Murphy et al

1858 pregnant women randomised

937 women allocated to repeated ACS

(1171 fetuses)

921 women allocated to placebo

(1147 fetuses)

2 women (2 fetuses)
Lost to follow-up

3 women (3 fetuses)
Lost to follow-up

935 had maternal outcomes analysed

918 had maternal outcomes analysed

5 fetuses/infants
excluded*

1164 infants had perinatal

outcomes analysed

4 fetuses/infants
excluded*

1140 infants had perinatal

outcomes analysed

Fig. 1. Multiple Courses of Antenatal Corticosteroids for

Preterm Birth Study profile. *Stillbirths within multiple
gestations that occurred before randomization. Reprinted
from Murphy KE, Hannah ME, Willan AR, Hewson SA,
Ohlsson A, Kelly E, et al. Multiple courses of antenatal
corticosteroids for preterm birth: a randomized controlled
trial. Lancet 2008;372:214351.
Murphy. Antenatal Corticosteroids, Growth, and Gestational
Age. Obstet Gynecol 2012.

Birth Study. Women carrying multiple gestations

were considered eligible for the Multiple Courses of
Antenatal Corticosteroids for Preterm Birth Study if a
fetus died before 13 weeks of gestation; however, the
fetus that died was not considered part of the pregnancy. Women were not eligible if fetal death occurred in one or more fetuses after 13 weeks of
gestation.
After institutional approval at each site and informed consent, 1,858 women from 80 centers in 20
countries (see Appendix online at http://links.lww.
com/AOG/A296) were randomized using a 24-hour
telephone randomization service to receive multiple
courses of antenatal corticosteroids compared with
placebo every 14 days until 33 6/7 weeks of gestation
or birth, whichever came first. Women randomized to
a study treatment number corresponding to antenatal
corticosteroids received multiple courses of betamethasone. A course consisted of two doses of betamethasone, 12 mg per dose intramuscularly administered 24 hours apart. Women randomized to a study
treatment number corresponding to placebo received
courses of a similar-appearing placebo.1 The first
woman was randomized on April 9, 2001, and the last
woman was randomized on August 31, 2006 (Fig. 1).
The baseline characteristics were similar between the
two groups, as were the number of courses of study
drug administered1 (Table 1). Most women received
one or two courses of study drug (74% in the antenatal
corticosteroids group and 70% in the placebo group).

Antenatal Corticosteroids, Growth, and Gestational Age

OBSTETRICS & GYNECOLOGY

Table 1. Baseline Characteristics of Enrolled

Women and Children and Number of
Courses of Study Drug Received

Total no. of women

Maternal age (y)
Total no. of neonates
Male*
Female*
Courses of study drug
0
1
2
3
4
No. of fetuses
1
2
3
Gestational age at
randomization (wk)
No. of previous
pregnancies*
0
14
More than 4
Principal reasons for study
participation
Signs or symptoms of
preterm labor
Fetal problems
Maternal medical
condition
Multiple pregnancy
Obstetric history
Maternal smoking

Antenatal
Corticosteroids
Group

Placebo
Group

935
29.16.23
1,164
616 (53)
546 (47)

918
29.16.18
1,140
598 (53)
540 (48)

5 (less than 1)
385 (41)
305 (33)
150 (16)
90 (10)

5 (less than 1)
365 (40)
273 (30)
169 (18)
104 (11)

737 (79)
162 (17)
36 (4)
29.32.0

726 (79)
158 (17)
34 (4)
29.42.0

263 (28.1)
577 (61.7)
95 (10.2)

252 (27.5)
571 (62.2)
91 (9.9)

773 (82.7)

777 (84.6)

115 (12.3)
199 (21.3)

103 (11.2)
190 (20.7)

191 (20.4)
287 (30.7)
108 (11.6)

179 (19.5)
280 (30.5)
93 (10.1)

Data are meanstandard deviation or n (%).

* Few values were missing from this variable; percentages are
calculated with data available.

All women received a prestudy course of antenatal

corticosteroids; study drug was antenatal corticosteroids in
the antenatal corticosteroids group and placebo in the
placebo group.
Modified from Murphy KE, Hannah ME, Willan AR, Hewson SA,
Ohlsson A, Kelly E, et al. Multiple courses of antenatal
corticosteroids for preterm birth: a randomised controlled
trial. Lancet 2008;372:214351.

The outcome of interest in the secondary analyses

was neonatal size (weight, length, and head circumference at birth) after controlling for gestational age at birth
and other known confounding variables. The information from all children in the primary Multiple Courses of
Antenatal Corticosteroids for Preterm Birth Study analysis was included in these secondary analyses.1
To determine whether the effect of multiple
courses of antenatal corticosteroids on neonatal size

VOL. 119, NO. 5, MAY 2012

Murphy et al

was a direct effect of the corticosteroids on fetal

growth, whether it was attributable to a reduction in
gestational age at birth, or both, we first compared
randomized groups with respect to mean gestational age at birth. We then undertook multiple
linear regression analyses to estimate, first, the
effect of multiple courses of antenatal corticosteroids (antenatal corticosteroids compared with placebo groups) on birth weight, length, and head
circumference, controlling for gestational age at
birth and, second, the effect of multiple courses of
antenatal corticosteroids (antenatal corticosteroids
compared with placebo groups) on birth weight,
length, and head circumference, controlling for gestational age at birth, as well as other known confounders (neonatal sex [male compared with female], parity
[1 or more compared with 0], maternal smoking
[smoker compared with nonsmoker], and number of
fetuses).
Finally, to determine whether there was a dose
response relationship between the number of courses
of antenatal corticosteroids and decrease in birth
weight, length, and head circumference, a multiple
linear regression analysis was undertaken that included the number of courses of antenatal corticosteroids (2, 3, 4, or 5 each compared with 1), gestational
age at birth, neonatal sex (male compared with female), parity (1 or more compared with 0), maternal
smoking (smoker compared with nonsmoker), and
number of fetuses.
All models included a random intercept to adjust
for the dependence of multiple gestations within the
pregnancy. In each model, the normally distributed
error term consists of a between-pregnancy component and a within-pregnancy component.3 Because
the effect of gestational age at birth on the outcomes
was potentially nonlinear, we included this variable in
the models with linear and quadratic terms. The
multiple linear regression analyses were used to estimate the differences (and CIs) in birth weight, length,
and head circumference between the compared
groups. The level of statistical significance was twotailed type I error of 0.05.
The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study is funded by the Canadian Institutes of Health Research. Canadian Institutes of Health Research did not participate in the
design, management, data collection, analysis, or interpretation of this study. Canadian Institutes of Health
Research played no role in the writing of this manuscript
or in the decision to submit for publication.

Antenatal Corticosteroids, Growth, and Gestational Age

919

RESULTS
Neonates in the antenatal corticosteroids group were
born earlier as compared with those in the placebo
group (34.51 compared with 34.94 weeks of gestation;
estimated difference and CI: 0.428 weeks, CI
0.75336 to 0.10264; P.001). After controlling for
gestational age at birth, neonates in the antenatal
corticosteroids group weighed less (estimated difference and CI for antenatal corticosteroids minus placebo groups: 35.30 g, CI 68.2868 to 2.3132];
P.036), were shorter (estimated difference and CI
for antenatal corticosteroids minus placebo groups:
0.352 cm, CI 0.63816 to 0.06584; P.016), and
had a smaller head circumferences (estimated difference and CI for antenatal corticosteroids minus placebo groups: 0.307 cm, CI 0.46968 to 0.14432;
P.001; Table 2). The highly significant positive
linear coefficients for gestational age at birth indicate,
as expected, that the growth factors increase with
gestational age. However, the highly significant negative quadratic coefficients for length and head circumference indicate that for those factors, the incremental increase diminishes with gestational age. After
controlling for gestational age at birth and the other
known confounding factors, multiple courses of antenatal corticosteroids compared with placebo were associated with a decrease in weight (estimated difference and
CI: 33.50 g, CI 66.27120 to 0.72880; P.045),
length (estimated difference and CI: 0.339 cm,
CI0.62124 to 0.05676; P.019), and head circumference (estimated difference and CI: 0.296 cm, CI
0.45672 to 0.13528; P.001 at birth; Table 3).
Last, controlling for gestational age at birth and
other confounding factors, there was a general trend
toward an incremental decrease in weight, length, and
head circumference at birth for each additional course
of antenatal corticosteroids (Table 4). The estimated
difference and CI for two courses compared with one

course was 26.58 g (CI 68.68080 to 15.52080;

P.22) for weight, 0.267 cm (CI 0.64528 to
0.11128; P.17) for length, and 0.294 cm (CI
0.50900 to 0.07820; P.008) for head circumference at birth. Whereas the estimated difference and
CI for five courses compared with one course was
84.75 g (CI 164.73760 to 4.76240; P.038) for
weight, 0.467 cm (CI 0.97464 to 0.04064; P.071)
for length, and 0.527 cm (CI 0.82501 to
0.22799; P.001) for head circumference at birth.

DISCUSSION
Exposure to multiple courses of antenatal corticosteroids
was associated with being born earlier. In 1969, Liggins4
reported that corticosteroid exposure, in sheep, could
induce preterm birth. It was through this work that he
observed that newborn sheep exposed to corticosteroids
appeared more mature in comparison with those that
did not. These observations led to the hypothesis that
antenatal corticosteroid exposure could accelerate fetal
lung maturation and, subsequently, to the hallmark
randomized controlled trial of Liggins and Howie.5
Differences in gestational age at birth have not been
previously described in any of the other randomized
controlled trials investigating repeated courses of antenatal corticosteroids. In some trials there were nonstatistical differences in the gestational age at birth, with the
women who were randomized to antenatal corticosteroids delivering before those in the placebo group.6,7 It is
possible that other trials have not observed this finding
secondary to smaller sample sizes (eg, Eunice Kennedy
Shriver National Institute of Child Health and Human
Development [NICHD]) or because in other trials there
was less overall cumulative corticosteroid exposure (eg,
the Australasian Collaborative Trial of Repeat Doses of
Steroids).
Despite controlling for gestational age at birth,
along with other factors known to be associated with a

Table 2. Effect of Treatment Group on Birth Weight, Length, and Head Circumference, Controlling for
Gestational Age at Birth
Birth
Weight (g)
Treatment group
35.30 (68.28680 to 2.31320)
(antenatal
corticosteroids
minus placebo)
Gestational age
145.5 (61.74920229.25080)
at birth
(linear term)
Gestational age
0.6518 (0.59848 to 1.90248)
at birth
(quadratic
term)

Level of
Significance
.036

.001

.307

Birth
Length (cm)

Level of
Significance

0.3520 (0.63816 to 0.06584)

4.178 (3.399884.95612)

0.0443 (0.05606 to 0.03254)

.016

.001
.001

Birth Head
Circumference (cm)

Level of
Significance

0.3071 (0.46968 to 0.14432)

.001

3.212 (2.755323.66868)

0.0365 (0.04288 to 0.03112)

.001
.001

Data are estimated difference (confidence interval) unless otherwise specified.

920

Murphy et al

Antenatal Corticosteroids, Growth, and Gestational Age

OBSTETRICS & GYNECOLOGY

Table 3. Effect of Treatment Group on Birth Weight, Length, and Head Circumference, Controlling for
Gestational Age at Birth, Neonatal Sex, Parity, Maternal Smoking, and Number of Fetuses
Birth
Weight (g)
Treatment group
33.50 (66.27120 to 0.72880)
(antenatal
corticosteroids
minus placebo)
Gestational age
136.3 (52.49040220.10960)
at birth
(linear term)
Gestational age
0.7873 (0.46152 to 2.03552)
at birth
(quadratic
term)
Neonatal sex
64.03 (31.0824096.97760)
(boysgirls)
Parity (referent
84.28 (47.78480120.77520)
para 0)
Maternal smoking 91.91 (143.83040 to 39.98960)
(smokers minus
nonsmokers)
No. of fetuses
45.24* (130.04920 to 39.56920)
(estimated
change for
each
additional
neonate)

Level of
Significance
.045

.001

.217

Birth
Length (cm)
0.3386 (0.62124 to 0.05676)

4.0989 (3.324804.87320)

0.0431 (0.05486 to 0.03134)

.001

0.6852 (0.398840.97116)

.001

0.3257 (0.007200.65920)

.001

.296

0.8438 (1.25756 to 0.43044)

0.4017* (1.13112 to 0.32712)

Level of
Significance
.019

.001
.001

Birth Head
Circumference (cm)

Level of
Significance

0.2963 (0.45672 to 0.13528)

.001

3.150 (2.691363.60864)

0.0356 (0.04188 to 0.03012)

.001
.001

.001

0.4429 (0.282280.60372)

.001

.055

0.2725 (0.077000.46900)

.006

.001

0.4686 (0.74928 to 0.18872)

.001

.280

0.3901 (0.71536 to 0.06464)

.019

Data are estimated difference (confidence interval) unless otherwise specified.

* Not in final model.

decrease in fetal anthropomorphic measurements

(smoking, nulliparity compared with multiparity, multiple gestation compared with singleton), multiple courses
of antenatal corticosteroids were negatively associated
with fetal growth. Specifically, there was a negative
doseresponse relationship observed; higher corticosteroid exposure was associated with a progressively larger
decrease in newborn weight, length, and head circumference at birth. This is biologically plausible and has
been demonstrated in many animal models.8 Corticosteroids are known to force differentiation at the cost of
cellular hyperplasia. Information from other randomized trials has suggested this association. Although the
NICHD trial did not demonstrate an effect of multiple
courses of antenatal corticosteroids on birth weight
overall, possibly because of its smaller sample size, there
was a lower birth weight in neonates exposed to four or
more courses of antenatal corticosteroids compared with
those who received placebo (2,400 g compared with
2,561 g; P.01); in addition, more neonates in the
antenatal corticosteroids group compared with placebo
were in less than the 10th percentile (24% compared with
15%; P.02).9 In the recent Cochrane systematic review, repeated doses of corticosteroids were associated
with a reduction in mean birth weight (mean difference
75.79 g, 95% CI 117.63 to 33.96, nine trials, 5,626
neonates).2
Some of the differential effects of multiple courses
of antenatal corticosteroids on fetal growth between

VOL. 119, NO. 5, MAY 2012

Murphy et al

the various antenatal corticosteroids trials may be

attributable to the different corticosteroid exposure
between studies. Most women in the Australasian
Collaborative Trial of Repeat Doses of Steroids and
the Multiple Courses of Antenatal Corticosteroids for
Preterm Birth Study received only one or two courses
of study drug (65.7% for the Australasian Collaborative Trial of Repeat Doses of Steroids; 72% for the
Multiple Courses of Antenatal Corticosteroids for
Preterm Birth Study)1,10; however, a repeated course
of antenatal corticosteroids in the Australasian Collaborative Trial of Repeat Doses of Steroids consisted
of only one dose of betamethasone,9 whereas in other
trials (Guinn, NICHD, and the Multiple Courses of
Antenatal Corticosteroids for Preterm Birth Study) a
repeated course was two doses of betamethasone 24
hours apart.1,6,9 Women in the Multiple Courses of
Antenatal Corticosteroids for Preterm Birth Study
received repeated courses of antenatal corticosteroids
every 14 days, whereas in several other trials (Guinn,
NICHD, and the Australasian Collaborative Trial of
Repeat Doses of Steroids) they received repeated
courses of antenatal corticosteroids every 7 days.
The long-term effect of weighing less or having a
smaller head circumference at birth is not known.
Therefore, it is critical that the children in these trials
are followed-up long-term. The NICHD monitored
the children in their study until age 2 to 3 years. At
that assessment, the neurocognitive and physical mea-

Antenatal Corticosteroids, Growth, and Gestational Age

921

Table 4. Effect of Number of Courses of Antenatal Corticosteroids on Birth Weight, Length, and Head
Circumference, Controlling for Gestational Age at Birth, Neonatal Sex, Parity, Maternal
Smoking, and Number of Fetuses
Birth
Weight (g)
No. of courses
(compared
to 1 course)
2
3
4
5
Gestational age
at birth
(linear term)
Gestational age
at birth
(quadratic
term)
Neonatal sex
(boysgirls)
Parity (referent
para 0)
Maternal smoking
(smokers
minus
nonsmokers)
No. of fetuses
(estimated
change for
each
additional
neonate)

Level of
Significance*

Birth
Length (cm)

Level of
Significance*

.069

Birth Head
Circumference (cm)

.155

Level of
Significance*
.001

26.58 (68.68080 to 15.52080)

52.50 (101.51960 to 3.48040)
10.93 (56.90560 to 78.76560)
84.75 (164.73760 to 4.76240)
133.8 (48.61840218.98160)

.216
.036
.752
.038
.002

0.2672 (0.64528 to 0.11128)

0.3681 (0.79920 to 0.06320)
0.4047 (0.96556 to 0.15556)
0.4673 (0.97464 to 0.04064)
4.126 (3.351804.90020)

.166
.094
.157
.071
.001

0.2936 (0.50900 to 0.07820)

0.3017 (0.52926 to 0.07414)
0.1831 (0.52884 to 0.16264)
0.5265 (0.82501 to 0.22799)
3.136 (2.673443.59856)

.008
.009
.299
.001
.001

0.8318 (0.43416 to 2.09816)

.198

0.0434 (0.05476 to 0.03124)

.001

0.0354 (0.04206 to 0.02874)

.001

63.43 (30.5804096.27960)

.001

0.6856 (0.399840.97216)

.001

0.4440 (0.283480.60452)

.001

84.67 (48.13560121.20440)

.001

0.3329 (0.001760.66424)

.049

0.2749 (0.078700.47110)

.006

91.41 (143.62440 to 39.19560)

43.42 (127.58240 to 40.74240)

.001

.312

0.8469 (1.26056 to 0.43344)

0.3980 (1.12712 to 0.33112)

.001

0.4668 (0.74728 to 0.18632)

.001

.284

0.3845 (0.71006 to 0.05894)

.021

Data are estimated difference (confidence interval) unless otherwise specified.

* Overall levels of statistical significance for birth weight, birth length, and head circumference.

Not in final model.

sures did not differ between the antenatal corticosteroids and placebo groups; however, there was a
nonsignificant increased risk of cerebral palsy in those
exposed to weekly courses of antenatal corticosteroids
(2.9% antenatal corticosteroids compared with 0.5%
placebo).11 The investigators of the Australasian Collaborative Trial of Repeat Doses of Steroids reported
on the outcome of their children at age 2 years.12 The
primary outcome, the rate of survival free of major
disability, was similar between the two groups. However, the children exposed to weekly courses of antenatal corticosteroids were more likely to warrant an assessment for attention problems than were those in the
control group (P.04).12 The follow-up assessment of
death, neurologic impairment, and anthropomorphic
measurements at 18 to 24 months for children in the
Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were similar between those in the
antenatal corticosteroids and placebo groups.13 Although the results of these longer-term studies are
reassuring, the studies are too small to rule out an
adverse effect of multiple courses of antenatal corticosteroids on infrequent but serious outcomes. We are
reminded of the randomized controlled trials of postnatal corticosteroid treatment that initially demon-

922

Murphy et al

strated short-term benefits and then over time, with

the completion of long-term studies demonstrating
the potential for adverse neurologic impairment.14
Regarding antenatal corticosteroids, longer-term follow-up studies to age 5 years and older are underway
or planned, and these studies will provide additional
information regarding the long-term effects, if any, of
multiple courses of antenatal corticosteroids.15,16 Finally, an individual patient data meta-analysis is in
progress.17 This meta-analysis will provide additional
information regarding the relationship between antenatal corticosteroids and gestational age at birth and
regarding the doseresponse relationship between
antenatal corticosteroids and neonatal anthropomorphic measurements.
In summary, fetuses exposed to multiple courses
of antenatal corticosteroids were delivered earlier as
compared with those who received placebo. In addition, a doseresponse relationship was noted between
increasing number of courses of antenatal corticosteroids and a decrease in weight, length, and head
circumference at birth. The clinical importance of
being born smaller is not yet known.
Until further evidence is available, the short-term
neonatal benefits from repeat courses of antenatal

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OBSTETRICS & GYNECOLOGY

corticosteroids, as found in the recent Cochrane review,2 must be weighed against the possible risk of
harm that might come from a lower birth weight,
length, and head circumference. Because no benefit
was observed from multiple courses of antenatal
corticosteroids in the Multiple Courses of Antenatal
Corticosteroids for Preterm Birth Study, multiple
courses of antenatal corticosteroids every 14 days are
not recommended.
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dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics 2007;119:290 8.

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?pagesri_proj_cmicr_trial_macs5_home. Retrieved March
25, 2012.
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