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Optimal time interval between a single course of antenatal


corticosteroids and delivery for reduction of respiratory
distress syndrome in preterm twins
Jin-Yi Kuk, MD; Jung-Ju An, MD; Hyun-Hwa Cha, MD; Suk-Joo Choi, MD, PhD; Juan E. Vargas, MD;
Soo-young Oh, MD, PhD; Cheong-Rae Roh, MD, PhD; Jong-Hwa Kim, MD, PhD
OBJECTIVE: The objective of the study was to investigate the effect
of a single course of antenatal corticosteroid (ACS) therapy on the
incidence of respiratory distress syndrome (RDS) in preterm twins
according to the time interval between ACS administration and
delivery.
STUDY DESIGN: We performed a retrospective cohort study of twins
born between 24 and 34 weeks of gestation from November 1995 to
May 2011. Subjects were grouped on the basis of the time interval
between the first ACS dose and delivery: the ACS-to-delivery interval of
less than 2 days (n 166), 2-7 days (n 114), and more than 7 days
(n 66). Pregnancy and neonatal outcomes of each group were
compared with a control group of twins who were not exposed to ACS
(n 122). Multiple logistic regression analysis was used to examine
the association between the ACS-to-delivery interval and the incidence
of RDS after adjusting for potential confounding variables.

RESULTS: Compared with the ACS nonexposure group, the incidence


of RDS in the group with an ACS-to-delivery interval of less than 2 days
was not significantly different (adjusted odds ratio [aOR], 1.089; 95%
confidence interval [CI], 0.524e2.262; P .819). RDS occurred
significantly less frequently when the ACS-to-delivery interval was
between 2 and 7 days (aOR, 0.419; 95% CI, 0.181e0.968; P .042).
However, there was no significant reduction in the incidence of RDS
when the ACS-to-delivery interval exceeded 7 days (aOR, 2.205; 95%
CI, 0.773e6.292; P .139).
CONCLUSION: In twin pregnancies, a single course of ACS treatment

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.

he incidence of twin and higherorder multiple pregnancies has


signicantly increased over the past few
decades worldwide,1,2 mainly because of
the widespread use of assisted reproductive technologies (ART) and increasing
maternal age.3,4 Among infants conceived with ART, nearly half are born as
multiple-birth infants and they account
for 20% of all multiple-birth infants.4 The

most signicant and common complication of twin pregnancy is preterm delivery.


Nearly 60% of twins are born preterm
(<37 weeks of gestation), and 12-14.5%
of twins are born before 34 weeks of
gestation.5,6 This higher risk of preterm
delivery, especially before 34 weeks of
gestation, in twin gestations is associated

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

For Editors Commentary, see Contents

256.e1 American Journal of Obstetrics & Gynecology SEPTEMBER 2013

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

We performed a retrospective cohort


study of twins born between 24 and 34
weeks of gestation from January 1996 to
May 2011 in Samsung Medical Center, a
tertiary-care referral hospital in Seoul,
Korea. Subjects were grouped on the
basis of the time interval between
administration of the rst ACS dose and
delivery (ACS-to-delivery interval): less
than 2 days, 2-7 days, and more than
7 days. A single complete course of ACS
therapy constituted four 6 mg doses of
intramuscular dexamethasone at 12
hour intervals or two 12 mg doses of
intramuscular betamethasone at 24 hour
intervals. The decision about to whom
and when to give ACS was made at the
discretion of the attending physicians.
The group of ACS-to-delivery interval
of less than 2 days consisted of patients
who delivered within less than 48 hours
of administration of the rst dose.
Twin pregnancies that were not exposed
to ACS comprised the control group
(nonuser group). Twin pregnancies complicated by twin-to-twin transfusion
syndrome, 1 or more fetal deaths, fetal
chromosomal or nonchromosomal major anomalies, placenta previa, placental
abruption, serious maternal medical
diseases, and usage of multiple-course
ACS were excluded from this study.

Medical records of both mothers and


their twins were examined independently, with the researcher reviewing the
neonatal data for outcome blinded to
maternal data including the exposure to
ACS and the ACS-to-delivery interval.
This was a retrospective study and was
approved to be exempt from full institutional review board review in the
Samsung Medical Center.
Maternal data recorded included age,
parity, history of previous preterm delivery, type of twin pregnancy, gestational age at admission, indications for
admission, type of ACS used, tocolytic
treatment, ACS-to-delivery interval,
mode of delivery, occurrence of chorioamnionitis, placental chorionicity,
and intertwin birthweight discordance.
Gestational age was estimated based on
the last menstrual period, when reliable,
or on ultrasonography performed during the rst trimester. Placental chorionicity was determined by sonographic
ndings and/or by pathological examination of the placenta after delivery.
Histological chorioamnionitis was dened as the presence of acute inammatory change in 1 or more placentas.
Intertwin birthweight discordance was
dened as a difference of more than 20%
in birthweight between a twin pair calculated as 100  (birthweight of the
larger twin e birthweight of the smaller
twin)/birthweight of the larger twin.
Tocolytic treatment was dened as any
use of tocolytics, regardless of timing of
initiation, type, dose, duration, multiple
drugs, maintenance, or repeat therapy.
We compared the outcomes of twin
neonates in each ACS-to-delivery interval group with those of the control group.
The primary outcome was the incidence
of RDS, which was diagnosed as the
presence of diagnostic radiographic chest
ndings plus 1 or more clinical signs
of respiratory distress including respiratory grunting, retracting, and increased
oxygen requirement (fraction of inspired
oxygen of greater than 0.4) or the administration of exogenous pulmonary
surfactant.
Other secondary neonatal outcomes
analyzed were sex; birthweight; the Apgar
scores; small for gestational age; necessity and duration of ventilator therapy;

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

SEPTEMBER 2013 American Journal of Obstetrics & Gynecology

256.e2

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TABLE 1

Baseline maternal characteristics


ACS-to-delivery interval
Characterisitc

Nonuser (n [ 61)

<2 d (n [ 83)

2-7 d (n [ 57)

>7 d (n [ 33)

P valuea

Age (y, mean  SD)

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

History of preterm delivery


Type of pregnancy
Spontaneous

.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

ACS, antenatal corticosteroids; IUI, intrauterine insemination, IVF, in vitro fertilization.


a

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.

admission, chorionicity, gestational diabetes, hypertension, mode of delivery,


fetal sex, and birth order on the incidence of RDS. The results were considered statistically signicant when values
of P were < .05. For multiple comparisons, P value was adjusted to .0083
(0.05/6) by Bonferroni correction.

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

of 2-7 days, and 33 in the group of


ACS-to-delivery interval of more than
7 days.
The 4 groups were similar with respect
to baseline maternal characteristics except
for a higher proportion of hypertension in
women in the group of ACS-to-delivery
interval of 2-7 days compared with the
control group (Table 1). The mean
gestational age at admission, indications
for admission, and type of ACS used were
similar in the 4 groups. Among the 61
patients in the control group, 50 patients
were delivered on the day of admission
and 11 patients were delivered beyond 1
day after admission. The reasons for the
emergent preterm delivery without having a chance to receive ACS treatment
were mostly advanced preterm labor at
admission or rapid progression of preterm labor, nonreassuring fetal status, or
preeclampsia after admission. Women in
the control group were signicantly less
likely to receive any tocolytic treatment
compared with those in the other 3
groups.

256.e3 American Journal of Obstetrics & Gynecology SEPTEMBER 2013

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

Indication for preterm birth at admission

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%)

Type of ACS used

.379

ACS-to-delivery interval (d),


median (range)b
25 (41.0%)

73 (88.0%)c

54 (94.7%)c

32 (97.0%)c

< .001

Admission-to-delivery interval (d),


median (range)b

0 (0e29)

1 (0e34)

4 (2e22)

16 (8e55)c

< .001

Gestational age at delivery (wks),


mean  SDb

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

Use of any tocolytics

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

Intertwin birthweight discordance

12 (19.7%)

11 (13.3%)

11 (19.3%)

8 (24.2%)

.508

ACS, antenatal corticosteroids; PPROM, preterm premature rupture of membranes.


a

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.

less than 2 days was not signicantly


different compared with that in the
control group.
No reduction of RDS in the twins in
the group of ACS-to-delivery interval
of less than 2 days was conrmed by
multivariable analysis (adjusted odds
ratio [aOR], 1.089; 95% condence interval [CI], 0.524e2.262; P .819)
(Table 4). Compared with the control
group, RDS occurred signicantly less
frequently in twins born at an ACSdelivery interval of 2-7 days (33.3% vs
50.8%; aOR, 0.419; 95% CI, 0.181e
0.968; P .042) (Table 4). Twins in
the group of ACS-delivery interval of
more than 7 days (39.4%) had a lower

incidence of RDS than those in the


control group (50.8%), but the difference was not statistically signicant
(aOR, 2.205; 95% CI, 0.773e6.292; P
.139) (Table 4). Twins in the group of
ACS-delivery interval of more than 7
days had a lower incidence of BPD and
late sepsis (Table 3), but the differences
were not statistically signicant in the
multivariable analysis (data not shown).
We performed a subgroup analysis of
women whose indications for admission
were preterm labor or preterm premature rupture of membranes, but the results were not signicantly different
from those from the total study population (data not shown).

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

SEPTEMBER 2013 American Journal of Obstetrics & Gynecology

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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%)

1 minute Apgar score <4

25 (20.5%)

29 (17.5%)

7 (6.1%)

5 minute Apgar score <7

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

Duration of NICU stay (d),


median (range)c,d

37.5 [4-131]

Ventilator treatmentc

74 (60.7%)

Duration of assisted ventilation (d),


median (range)c,e

10 [1-69]

Neonatal mortalityc

.281
< .001

39.5 [3-142]

Neonatal morbidity
RDSc
c

BPD

IVH (grade 3 or higher)

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

ROP (grade 3 or higher)

NEC (stage 2 or higher)


Early sepsis
Late sepsis

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.

beyond 7 days of administration of the


rst dose of steroids.
The twin birth rate and preterm
delivery of twins before 37 weeks of
gestation in our study population is
comparable with other population-based
studies,2,6,24 but the rate of early preterm
delivery before 34 weeks of gestation
(25.2%) was higher than reported. This
may be due to the high proportion of
twin pregnancies presenting with threatened preterm delivery referred to our
tertiary care hospital from the community. Given the rising twin birth, the

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

256.e5 American Journal of Obstetrics & Gynecology SEPTEMBER 2013

in twin pregnancies may be attributable


to the greater degree of maternal physiological changes in twin pregnancies
compared with singleton pregnancies,
such as greater maternal blood volume
expansion, a shorter half-life, and greater
clearance of betamethasone.25 However,
this hypothesis was challenged by recent
studies that demonstrated no difference
in maternal pharmacokinetics of betamethasone26 and no differences in betamethasone concentrations in maternal
serum or cord blood27 between singleton
and twin pregnancies.

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TABLE 4

Multiple logistic regression analyses of neonatal respiratory distress


syndrome controlling for potential confounding variables
Variables

Adjusted odds
ratio (95% CI)

P value

Gestational age at delivery, wks

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

Indication for preterm birth at admissiona

Use of any tocolytics

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.

In our previous retrospective cohort


study of 117 twin pregnancies, we found
that ACS administration, either as a
single course or as multiple courses, did
not reduce the incidence of RDS of twins
born between 24 and 34 weeks of gestation.17 However, the study had limitations in that the number of twin
pregnancies was small and did not take
account of the time interval from ACS
administration to delivery. Therefore, we
were not able to evaluate whether the
lack of benet of ACS treatment in twins
was due to the diminished effect of ACS
in twins born more than 7 days after the
ACS exposure. In the current study, in
which the sample size was doubled and
the ACS-to-delivery interval was considered in the analysis, we found that a
single course of ACS treatment was
benecial in reducing the incidence of
RDS in twin pregnancies when the interval was between 2 and 7 days.
The optimal time period between ACS
administration and delivery in twin

pregnancies has not been sufciently


studied. Most of the studies that evaluated the effect of ACS on neonatal RDS in
twin pregnancies included only twins
born within 7 days after the ACS dose.12-14
In a large population-based cohort
study, Blickstein et al15 found that a complete course of ACS signicantly reduced the incidence of RDS in singletons
as well as in twins and triplets. However,
partial corticosteroid treatment, dened
as a delivery occurring less than 24 hours
after the rst dose or more than 7 days
after the last dose, was shown to have
the same effect on the incidence of RDS
as no treatment at all, irrespective of
plurality.
Similar to Blickstein et al,15 we found
that there was no signicant reduction in
the incidence of RDS when twins were
delivered at an ACS-to-delivery interval
of less than 2 days or more than 7 days.
In a study by Gyam et al,27 the concentrations of betamethasone in cord
blood decreased over time (from 0 days

to 6 days of last dose) for both singletons


and twins. Although the data beyond
7 days after the steroid dose were not
available, the levels of betamethasone in
cord blood after 7 days presumably
would never increase unless an additional course of ACS is given.
These results, taken together with our
current study, may suggest that the effects
of ACS decrease after 7 days of the treatment and may give rise to a concern of a
repeated or rescue course of ACS in
women who still confer a risk of preterm
birth after the rst course of ACS.
The efcacy and safety of repeated or
multiple courses of ACS are still debated,
and the issue is even more controversial
in twin pregnancies because it has been
assessed in only a few studies with conicting results.14,16,28 Regularly scheduled
repeated courses or multiple courses
(more than 2) of ACS are not recommended because of insufcient data
regarding the benet and concern for the
potential adverse impact on fetal growth
and brain development.29 Instead, a
recent American College of Obstetricians
and Gynecologists Committee Opinion
stated that a single rescue course could be
considered if the previous ACS treatment
was given more than 2 weeks previously.30 The efcacy of a rescue course of
ACS in twin pregnancies was investigated
in a recent retrospective cohort study,
which failed to nd any benet of rescue
ACS in reducing the incidence of RDS.31
However, a rescue course of ACS was
associated with fewer severe respiratory
morbidities and a lower incidence of
retinopathy of prematurity.
Most patients who were not exposed
to ACS in our study were in advanced
preterm labor or had a rapid progression
of preterm labor. This might inuence
the results of our study because these
women had a shorter admission-todelivery interval and they might be
more likely to be associated with intrauterine infection. However, we were not
able to control for this possibility because this study was a retrospective data
review. The only variables that indicate
the evidence of intrauterine infection
were the occurrence of clinical and histological chorioamnionitis, but their
incidence was similar in the 4 groups.

SEPTEMBER 2013 American Journal of Obstetrics & Gynecology

256.e6

SMFM Papers
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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