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was associated with a decreased rate of RDS only when the ACS-todelivery interval was between 2 and 7 days.
Key words: antenatal corticosteroids, preterm delivery, respiratory
distress syndrome, steroid-to-delivery interval, twin pregnancy
Cite this article as: Kuk J-Y, An J-J, Cha H-H, et al. Optimal time interval between a single course of antenatal corticosteroids and delivery for reduction of respiratory
distress syndrome in preterm twins. Am J Obstet Gynecol 2013;209:256.e1-7.
From the Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Republic of Korea (Drs Kuk, An, Cha, Choi, Oh, Roh, and Kim),
and the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California,
San Francisco, School of Medicine, San Francisco, CA (Dr Vargas).
Received March 15, 2013; revised May 13, 2013; accepted June 10, 2013.
The authors report no conict of interest.
Presented as a poster at the 33rd annual meeting of the Society for Maternal-Fetal Medicine,
San Francisco, CA, Feb. 11-16, 2013.
Reprints: Suk-Joo Choi, MD, PhD, 50 Irwon-Dong, Gangnam-Gu, 135-710 Seoul, Republic of
Korea. drmaxmix.choi@samsung.com.
0002-9378/free 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2013.06.020
with an increased risk of neonatal mortality and morbidities including respiratory distress syndrome (RDS).7
It is well established that administration of antenatal corticosteroid (ACS) to
women with threatened preterm delivery
enhances fetal lung maturation and reduces the incidence of RDS and its
complications in babies born between 24
and 34 weeks of gestation.8,9 Although
current guidelines recommend the administration of ACS to women with a
twin pregnancy who are at risk of preterm delivery using the same protocol
applied for singleton pregnancies,10,11
they are based mainly on the extrapolation of data from singleton pregnancies
and randomized trials in which twin
pregnancies represent a small subpopulation. The safety and efcacy of ACS
treatment in twin pregnancies has not
been sufciently studied, and the current
available data in the literature present
inconsistent ndings.12-18
Another important issue in the use of
ACS is the optimal time interval for ACS
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to become benecial. The effect of a
single course of ACS appeared to be most
benecial when delivery occurs between
24 hours and 7 days after a complete
course of treatment, and its benet was
decreased when the ACS-to-delivery interval exceeded 7 days.9,19 However, the
existing evidence of the optimal time
period between ACS administration and
delivery is based mainly on studies of
singleton pregnancies.19-22 It is not well
understood whether the optimal ACSto-delivery interval seen in singleton
pregnancies can be applied to twin
pregnancies.
Therefore, we conducted this study to
determine whether ACS therapy has an
effect on reducing RDS in preterm twins
born between 24 and 34 weeks of
gestation and whether its benecial effect is related to the time interval between ACS administration and delivery.
M ATERIALS
AND
M ETHODS
necessity and duration of neonatal intensive care unit stay; mortality and morbidities including bronchopulmonary
dysplasia (BPD), patent ductus arteriosus (PDA), periventricular leukomalacia
(PVL), grade 3-4 intraventricular hemorrhage (IVH), grade 3-4 retinopathy of
prematurity (ROP), stage 2-3 necrotizing
enterocolitis (NEC), suspected or proven
early and late neonatal sepsis, and mortality. BPD was dened as the need for
supplementary oxygen for 28 days or
more or by diagnostic radiographic or
histological ndings. IVH and PVL were
diagnosed and graded by ultrasonographic
examination of the neonatal brain. IVH
was dened as intraventricular bleeding
without ventricular dilatation (grade 2) or
with ventricular dilatation (grade 3) or
with parenchymal involvement (grade 4).
PVL was dened as the presence of an
obvious hypoechoic cyst in the periventricular white matter. ROP was diagnosed by ophthalmologists, and its
grading was based on the International
Classication of Retinopathy of Prematurity.23 NEC was dened in the presence
of abdominal distention and feeding
intolerance for more than 24 hours with
radiological evidence of intramural air,
perforation, meconium plug syndrome,
or denitive surgical ndings. The diagnosis of neonatal sepsis was based on the
presence of a positive blood culture
(proven sepsis) or positive laboratory
evidences in clinically suspected neonates (suspected sepsis).
The unit of analysis for neonatal outcomes was the individual infant in a twin
pair, and each of the maternal exposure
variables was counted twice. For the
comparison of multiple means, analysis of variance or the Kruskal-Wallis
test was used, as appropriate, and the
Jonckheere-Terpstra test was used to
identify trends. Proportions were compared using the c2 test or Fisher exact
test, as appropriate, and linear-by-linear
association was used to identify trends.
The Bonferroni test was used for post
hoc analysis to correct for multiple
comparisons. Multiple logistic regression analysis was performed to evaluate
the effects of potential confounding
variables such as gestational age at delivery, indication for preterm birth at
256.e2
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TABLE 1
Nonuser (n [ 61)
<2 d (n [ 83)
2-7 d (n [ 57)
>7 d (n [ 33)
P valuea
31.0 4.1
30.7 3.9
31.2 4.9
31.2 3.2
.898
Nulliparity
46 (75.4%)
63 (75.9%)
49 (86.0%)
26 (78.8%)
.463
5 (8.2%)
3 (3.6%)
2 (3.5%)
3 (9.1%)
.449
.762
21 (34.4%)
34 (41.0%)
23 (40.4%)
12 (36.4%)
Ovulation induction
2 (3.3%)
4 (4.8%)
1 (1.8%)
2 (6.1%)
IUI
5 (8.2%)
2 (2.4%)
3 (5.3%)
1 (3.0%)
26 (42.6%)
34 (41.0%)
28 (49.1%)
16 (48.5%)
7 (11.5%)
9 (10.8%)
2 (3.5%)
2 (6.1%)
IVF
Unknown
Chorionicity
.924
Monochorionic
Dichorionic
Unknown
Gestational diabetes
Hypertension
9 (14.8%)
12 (14.5%)
9 (15.8%)
7 (21.2%)
50 (82.0%)
69 (83.1%)
47 (82.5%)
26 (78.8%)
2 (3.3%)
2 (2.4%)
1 (1.8%)
7 (11.5%)
2 (2.4%)
3 (5.3%)
2 (3.3%)
1 (1.2%)
11 (19.3%)
0 (0%)
c
2 (6.1%)
.157
2 (6.1%)
< .001
Intergroup difference by analysis of variance or the c2 test; b Significantly different compared with the nonuser group; c Includes preeclampsia, gestational hypertension, and chronic hypertension.
Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
R ESULTS
During the 16 year period of review,
1483 twin births (3.4%) were identied
from a total of 43,227 deliveries. Nine
hundred nine of all twin pregnancies
(61.3%) were delivered preterm (less
than 37 weeks of gestation), and 374 of
them (25.2%) were delivered between 24
and 34 weeks of gestation. One hundred
forty cases were excluded by the aforementioned exclusion criteria. Finally,
234 twin pregnancies (468 twin neonates) were included in the study: 61
in the ACS nonuser group (control
group), 83 in the group of ACS-todelivery interval of less than 2 days, 57
in the group of ACS-to-delivery interval
The median interval between admission and delivery and mean gestational
age at delivery of the group of ACSdelivery interval of more than 7 days
was signicantly higher than that of
the control group. Other pregnancy outcomes including occurrence of clinical or
histological chorioamnionitis, mode of
delivery, and intertwin birthweight discordance were not signicantly different
among the 4 groups (Table 2).
The mean birthweight of twins in the
group of ACS-to-delivery interval of
more than 7 days was higher than that in
the control group (Table 3). Twins born
at an ACS-to-delivery interval of 2-7
days were less likely to have a low 1
minute Apgar score at birth compared
with twins in the control group.
The median duration of stay in the
neonatal intensive care unit (NICU) of
the group of ACS-to-delivery interval of
more than 7 days was shorter than the
other 3 groups. The overall neonatal
mortality and morbidity rate in twins
born at an ACS-to-delivery interval of
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TABLE 2
Pregnancy outcome
Variable
Gestational age at admission (wks),
mean SD
Nonuser
(n [ 61)
ACS-to-delivery interval
<2 d (n [ 83)
2-7 d (n [ 57)
>7 d (n [ 33)
29.9 2.8
29.7 2.6
29.8 2.5
29.3 2.6
P valuea
.767
.095
Preterm labor
36 (59.0%)
53 (63.9%)
31 (54.4%)
PPROM
24 (39.3%)
29 (34.9%)
20 (35.1%)
9 (27.3%)
1 (1.6%)
1 (1.2%)
6 (10.5%)
1 (3.0%)
Dexamethasone
26 (31.3%)
12 (21.1%)
8 (24.2%)
Betamethasone
57 (68.7%)
45 (78.9%)
25 (75.8%)
0 (0e2)
3 (2e7)
17 (8e54)
< .001
Preeclampsia
23 (69.7%)
.379
73 (88.0%)c
54 (94.7%)c
32 (97.0%)c
< .001
0 (0e29)
1 (0e34)
4 (2e22)
16 (8e55)c
< .001
30.1 2.8
29.9 2.7
30.5 2.5
32.0 1.7c
.001
<28 wksb
14 (23.0%)
20 (24.1%)
10 (17.5%)
1 (3.0%)
.058
<32 wks
38 (62.3%)
55 (66.3%)
34 (59.6%)
13 (39.4%)
.062
1 (1.6%)
4 (4.8%)
2 (3.5%)
3 (9.1%)
.384
Clinical chorioamnionitis
Histological chorioamnionitis
11/52 (21.2%)
22/84 (29.7%)
15/55 (27.3%)
11/31 (34.5%)
.532
Cesarean delivery
54 (88.5%)
70 (84.3%)
49 (86.0%)
25 (75.8%)
.425
12 (19.7%)
11 (13.3%)
11 (19.3%)
8 (24.2%)
.508
Intergroup difference by analysis of variance or the c2 test; b Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables;
c
Significantly different compared with the nonuser group; d Denominators are the numbers of cases with available placental pathology results.
Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
C OMMENT
In this study, we evaluated the effect of
ACS on the incidence of RDS in preterm
twins according to the time interval between ACS administration and delivery.
Our data showed that the administration
of a single complete course of ACS was
associated with a signicantly reduced
incidence of RDS in preterm twins born
between 24 and 34 weeks of gestation
when the time interval between the rst
steroid dose and delivery was between
2 and 7 days. However, there was no
signicant reduction in the incidence
of RDS when twins were born before
the completion of the steroid course
or delivered within less than 2 days or
256.e4
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TABLE 3
Neonatal outcome
Nonuser
(n [ 122)
Variable
Sex (male)
Birthweight (g), mean SD
ACS-to-delivery interval
<2 d (n [ 166)
2-7 d (n [ 114)
61 (50.0%)
78 (47.0%)
61 (53.5%)
40 (60.6%)
1417.4 445.2
1484.4 424.2
1712.0 364.9b
8 (7.0%)
4 (6.1%)
.781
5 (7.6%)
.003
3 (4.5%)
.029
11 (9.0%)
10 (6.0%)
25 (20.5%)
29 (17.5%)
7 (6.1%)
21 (17.2%)
23 (13.9%)
9 (7.9%)
122 (100%)
166 (100%)
NICU admission
P valuea
1461.2 455.8
SGA
>7 d (n [ 66)
110 (96.5%)
65 (98.5%)
.022
36 [2-161]
23 [3-80]b
< .001
104 (62.7%)
55 (48.2%)
30 (45.5%)
.020
7 [1-94]
6.5 [1-89]
2 [6-36]b
.023
7 (5.7%)
7 (4.2%)
1 (1.1%)
0 (0%)
.064
62 (50.8%)
86 (51.8%)
38 (33.3%)b
37.5 [4-131]
Ventilator treatmentc
74 (60.7%)
10 [1-69]
Neonatal mortalityc
.281
< .001
39.5 [3-142]
Neonatal morbidity
RDSc
c
BPD
29 (23.8%)
35 (21.1%)
23 (20.2%)
7 (5.7%)
3 (1.8%)
3 (2.6%)
26 (39.4%)
.008
.001
1 (1.5%)
0 (0%)
.092
PVL
4 (3.3%)
7 (4.2%)
4 (3.5%)
2 (3.0%)
.964
PDAc
56 (45.9%)
70 (42.2%)
42 (36.8%)
20 (30.3%)
.162
14 (11.5%)
17 (10.2%)
10 (8.8%)
1 (1.5%)
.124
4 (3.3%)
5 (3.0%)
3 (2.6%)
1 (1.5%)
.909
16 (13.1%)
16 (9.6%)
20 (17.5%)
11 (16.7%)
.230
.043
.502
Composite morbidity
21 (17.2%)
21 (12.7%)
13 (11.4%)
2 (3.0%)
71 (58.2%)
99 (59.6%)
61 (53.5%)
33 (50.0%)
ACS, antenatal corticosteroids; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus;
PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; SGA, small-for-gestational age.
a
Intergroup difference by analysis of variance or the c2 test; b Significantly different compared with the nonuser group; c Significant trend by the Jonckheere-Terpstra test for continuous variables
and linear by linear association for categorical variables; d Analyzed with neonates who were admitted to NICU only; e Analyzed with neonates who were treated with assisted ventilation only;
f
Defined as having more than 1 of the following: death, RDS, BPD, IVH (grade 3 or higher), PVL, PDA, ROP (grade 3 or higher), NEC (stage 2 or higher), or suspected or proven early and late neonatal
sepsis.
Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
issue of reducing complications associated with preterm birth in these highrisk pregnancies is acquiring greater
importance.
Among the available interventions for
reducing the perinatal complications of
preterm birth, ACS treatment is the most
established method with a proven reduction in the rate of RDS, IVH, and
mortality.10,11 However, the effectiveness
of ACS therapy in improving neonatal
outcomes in twin pregnancies is still unproven.12-18 It has been hypothesized that
the suboptimal benets of ACS treatment
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TABLE 4
Adjusted odds
ratio (95% CI)
P value
0.452 (0.393e0.521)
< .001
PPROM
1.139 (0.657e1.974)
.643
Preeclampsia
2.902 (0.801e10.514)
.105
Gestational diabetes
3.264 (1.159e9.197)
.025
Dichorionic twin
0.994 (0.503e1.965)
.987
0.735 (0.347e1.560)
.423
Admission-to-delivery interval, d
1.010 (0.976e1.046)
.572
Cesarean section
1.565 (0.760e3.222)
.224
Female neonate
0.864 (0.518e1.439)
.573
1.902 (1.145e3.159)
.013
<2 d
1.089 (0.524e2.262)
.819
2-7 d
0.419 (0.181e0.968)
.042
>7 d
2.205 (0.773e6.292)
.139
Second twin
ACS-to-delivery interval
ACS, antenatal corticosteroids; CI, confidence interval; PPROM, preterm premature rupture of membranes.
a
Preterm labor was used as the reference; b ACS nonusers were used as the reference group.
Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
256.e6
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And the admission-to-delivery interval
was not shown to be associated with the
incidence of RDS in the multivariable
analysis.
There are several limitations of our
study. First, as a retrospective chart review, our study has potential biases
including misclassication bias. In addition, maternal steroid exposure and
the ACS-to-delivery interval may have
been biased by unidentiable confounding factors such as practice changes over a
long study period of 16 years (eg, regimens for tocolytics used to control preterm labor and antibiotics used in women
with preterm premature rupture of membranes [PPROM]) and other maternal
or fetal conditions not controlled for the
multivariable analysis.
The study is further limited by the
sample size. Our study may be underpowered because the sample size was
not enough to show a difference in the
neonatal outcome, especially between
the group with ACS-to-delivery interval
of more than 7 days and the nonuser
group. However, because this was a retrospective cohort analysis, we were not
able to calculate the sample size before
commencing this study. Therefore, welldesigned prospective studies with adequate sample sizes are needed to conrm
our ndings and to determine the effectiveness of ACS treatment and the optimal ACS-to-delivery interval in twin
pregnancies.
In conclusion, the administration of a
single complete course of ACS signicantly reduced the incidence of RDS in
preterm twins born between 24 and 34
weeks of gestation. However, the ACS
treatment was associated with a
decreased risk of RDS only when the
ACS-delivery interval was between 2 and
7 days. Because there is no evidence
identied for the efcacy and safety of a
rescue course of ACS in twins, careful
consideration must be given to predict
the risk of delivery within 7 days in twin
pregnancies with threatened preterm
delivery to administer ACS within an
optimal time interval.
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