DOI: 10.1111/1471-0528.

14545
www.bjog.org

Timing of antenatal corticosteroid administration

and survival in extremely preterm infants:
a national population-based cohort study
H Norberg,a J Kowalski,a K Mar
sa
l,b M Normana,c
a
Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden b Department
of Obstetrics and Gynecology, Clinical Sciences, Lund University, Stockholm, Sweden c Department of Neonatal Medicine, Karolinska
University Hospital, Stockholm, Sweden
Correspondence: H Norberg, Department of Pediatrics, Karolinska University Hospital, B88, SE-141 86 Stockholm, Sweden.
Email hanna.norberg@karolinska.se

Accepted 29 December 2016. Published online 15 March 2017.

Objective To explore the association between administration-to-
birth interval of antenatal corticosteroids (ACS) and survival in
extremely preterm infants.
Design Population-based prospective cohort study.
Setting All obstetric and neonatal units in Sweden from 1 April
2004 to 31 March 2007.
Population All live-born infants (n = 707) born at 22–26
completed weeks of gestation.
Methods The relationship between time from first administration
of ACS to delivery and survival was investigated using Cox
proportional hazards regression analysis.
Main outcome measures Neonatal (0–27 days) and infant (0–
365 days) survival, and infant survival without major neonatal
morbidity (intraventricular haemorrhage grade ≥ 3, retinopathy of
prematurity stage ≥ 3, periventricular leukomalacia, necrotising
enterocolitis, or severe bronchopulmonary dysplasia).
Results Five-hundred and ninety-one (84%) infants were exposed
to ACS. In the final adjusted model, infant survival was lower in
infants unexposed to ACS [hazard ratio (HR) = 0.26; 95%
confidence interval 0.15–0.43], in infants born <24 h [HR = 0.53
(0.33–0.87)] and >7 days after ACS [HR = 0.56 (0.32–0.97)], but
not in infants born 24–47 h after ACS [HR = 1.60 (0.73–3.50)],
as compared with infants born 48 h to 7 days after
administration. The findings were similar for neonatal survival.
Survival without major neonatal morbidity among live-born
infants was 14% in unexposed infants and 30–39% in steroid-
exposed groups, indicating that any ACS exposure was valuable.
Conclusions Administration of ACS 24 h to 7 days before
extremely preterm birth was associated with significantly higher
survival than in unexposed infants and in infants exposed to ACS
at shorter or longer administration-to-birth intervals.
Keywords Administration-to-birth interval, antenatal
glucocorticoids, extremely preterm birth, major neonatal
morbidity, mortality.
Tweetable abstract Timing of antenatal corticosteroids is
important for extremely preterm infants’ survival.

Please cite this paper as: Norberg H, Kowalski J, Mar
sal K, Norman M. Timing of antenatal corticosteroid administration and survival in extremely preterm
infants: a national population-based cohort study. BJOG 2017; DOI: 10.1111/1471-0528.14545.

There are limited data on ACS for extremely preterm

Introduction
Administration of antenatal corticosteroids (ACS) to
women at risk for preterm delivery is one of the most
effective life-saving treatments in perinatal medicine. ACS
has been shown to significantly reduce the risk of respira-
tory distress syndrome, intraventricular haemorrhage
(IVH), necrotising enterocolitis (NEC), early sepsis and
neonatal death in preterm infants.1,2 Treatment with ACS
is therefore recommended to all women at risk for preterm
birth prior to 34 weeks of gestation.3–5
birth. A meta-analysis showed no reductions of neonatal
mortality and morbidity prior to 26 weeks gestation,6
whereas more recent studies have indicated similar7,8 or
even more pronounced benefits9 from ACS for extremely
preterm births. Whether the timing of ACS is of impor-
tance for outcome among extremely preterm infants has
also been sparsely investigated.10,11 In a recent large retro-
spective cohort study from the Canadian neonatal network,
higher odds for severe neonatal morbidity or mortality
were seen in preterm infants born at 24–33 weeks of

ª 2017 Royal College of Obstetricians and Gynaecologists 1

 Norberg et al.
gestation with an administration-to-birth interval of ACS
shorter or longer than 1–7 days and, if anything, these
findings were more pronounced in infants <29 weeks of
gestation.9
Given that pregnant women delivering high-risk infants
at extremely short gestations may deliver before ACS have
been administered, or deliver at various time intervals after
ACS, a better understanding of the effects and importance
of the administration-to-birth interval of ACS for outcome
in extremely preterm infants is needed. The objective of
this prospective population-based cohort study was to
investigate the impact of the administration-to-birth inter-
val of ACS on survival of extremely preterm infants.
Methods
The Extremely Preterm Infants in Sweden Study (EXPRESS)
included all pregnant women residing in Sweden and deliver-
ing extremely preterm infants, born at 22–26 completed
weeks of gestation, from 1 April 2004 to 31 March 2007. The
cohort studied herein consisted of all live-born infants
(n = 707), including multiple births and infants with malfor-
mations, whereas stillborn infants (n = 304) and infants
born outside Sweden and transferred after birth to Sweden
for neonatal care were excluded. Detailed characteristics of
EXPRESS have been reported elsewhere.12–14 Among live-
born infants, 520 survived the neonatal period and 497 were
alive at 1 year old (Figure S1).
The procedures for data collection and other method-
ological details have been previously described.13 In brief,
during the study period, Sweden had seven healthcare
regions, each served by a regional level III hospital. The
general policy was to centralise extremely preterm deliveries
to these regional hospitals. Data on mothers were collected
at the time of delivery. Data on live-born infants were col-
lected prospectively during the first 180 days of hospitalisa-
tion or until discharge or death. Information on infant
deaths after discharge home until 1 year was obtained from
the National Population Registry.
Maternal hypertensive disease was defined as essential
hypertension, preeclampsia or eclampsia. Information on
maternal smoking was obtained at the first antenatal visit,
and the information was dichotomised (smoking/non-
smoking). Preterm prelabour rupture of membranes
(PPROM) was defined as spontaneous rupture of the mem-
branes at least 1 h before the onset of contractions.
Live birth and perinatal mortality were defined according
with WHO.15 Gestational age was recorded in completed
weeks and based on ultrasound in 95% of pregnancies.
Birth weight was evaluated in accordance with the national
standard for normal fetal growth16 and expressed in stan-
dard deviation (SD) scores. Infants with birth weight more
than 2 SD below the mean were classified as small for
2 ª 2017 Royal College of Obstetricians and Gynaecologists
gestational age (SGA). IVH was graded in accordance with
data from Papile et al.,17 and periventricular leukomalacia
(PVL) was defined as proposed by de Vries et al.18
Retinopathy of prematurity (ROP) was defined in accor-
dance with the International Classification for Retinopathy
of Prematurity19 and NEC according to Bell et al., where
stage two or more were considered as diagnostic.20 Severe
bronchopulmonary dysplasia (BPD) was defined as the
need for ≥ 30% oxygen at a postmenstrual age of 36
weeks.21
A complete course with ACS to the pregnant mothers
consisted of two doses of 12 mg betamethasone 24 h apart.
In the EXPRESS-database, time from the first ACS dose to
delivery in hours had been prospectively collected. We cate-
gorised all live-born infants into four categories according
to the time interval from the first ACS dose to delivery:
<24 h; 24–47 h; 48 h to 7 days; and >7 days. The
EXPRESS-database also provided information whether an
incomplete (one dose) or complete course (two doses) had
been administered. The category <24 h comprised infants
that had received either an incomplete (one dose) or a
complete course (two doses) most likely reflecting that the
study was descriptive with no attempts in the study frame-
work to standardise treatment or compliance to treatment
protocols. Additional categories consisted of infants unex-
posed to ACS and those exposed to ACS but with
unknown timing.
Outcomes were neonatal (0–28 days) and infant survival
(0–365 days). Infant survival without major neonatal mor-
bidity, i.e. survival without IVH grade ≥ 3, ROP stage ≥ 3,
PVL, NEC or severe BPD, was also included as an out-
come.
The study was approved by the Regional Research Ethics
Board, Lund University, Lund, Sweden (date of approval 1
July 2004; reference number 42/2004). The parents pro-
vided oral informed consent for data acquisition.
Statistical analyses
Data are presented as numbers and proportions (percent-
ages) if not stated otherwise. The differences across ACS
administration-to-birth interval categories were presented
using descriptive statistics. Cox proportional hazards
regression analysis was used to estimate hazard ratios (HR)
for survival across the ACS administration-to-birth interval
categories, including one unexposed category and one
dummy category representing unknown ACS timing. Based
on available knowledge on optimal timing for ACS admin-
istration, the category 48 h to 7 days was considered as ref-
erence category, i.e. HR = 1.00. HRs for neonatal and
infant survival in relation to ACS administration-to-birth
intervals were evaluated in a multiple Cox proportional
hazards regression model adjusting for factors known to
affect infant mortality: maternal smoking;22 maternal blood
 Antenatal corticosteroids and survival in extremely preterm infants

pressure disease;23 placenta previa; placental abruption;
PPROM;24 regionalisation of care with birth at level III
hospital;23,24 gestational age;13,23 SGA;23,24 infant gender;23
and surfactant therapy within 2 h after birth. The rationale
for including surfactant therapy within 2 h after birth in
the model was that this intervention has been shown to be
associated with significantly reduced infant mortality in
randomised controlled trials and in the EXPRESS-study,
independently of ACS exposure.13,25 Nonetheless, because
early surfactant therapy may be in the causal pathway, we
ran a sensitivity analysis without surfactant in the model
for infant mortality. Cumulative neonatal and infant sur-
vival adjusted for covariates was also determined using
Kaplan–Meier survival analyses. The odds for surviving
without major neonatal morbidity were analysed using a
multiple logistic regression model adjusting for the same
factors as for the analysis in the Cox proportional hazards
regression. Results are presented as odds compared with
the reference category of ACS 48 h to 7 days before birth,
odds ratio (OR) = 1.00. We made no adjustments for
multiple births as our analyses are to be interpreted as
exploratory. All tests were two-sided, and a P-value of less
than 0.05 was considered as statistically significant.
Statistical calculations were performed using JMP 11.0
(SAS Institute, Cary, NC, USA) and the IBM SPSS Statistics
V22 or higher (IBM Corporation).
Results
Among 707 infants born alive at 22–26 weeks of gestation,
591 (84%) had been exposed to ACS, whereas 85 (12%)
were unexposed to ACS, and in 31 infants (4%) data
regarding ACS exposure were missing. Of the infants
exposed to ACS, 149 (25%) were born less than 24 h after
the first ACS dose, 66 (11%) were born within 24–47 h,
171 (29%) were born within 48 h to 7 days, and 103
(17%) infants were born more than 7 days after the first
ACS dose. One-hundred and two (17%) infants have been
exposed to ACS without any information on the adminis-
tration-to-birth time interval.
Maternal characteristics
Maternal smoking in pregnancy did not differ significantly
between ACS exposure categories. Pregnant women with
hypertensive disease had more often received ACS treat-
ment than women without such disease (Table 1).

Table 1. Perinatal characteristics of live-births according to the administration-to-birth interval of ACS

Administration-to-birth interval of ACS

no ACS <24 h 24–47 h 48 h–7 days >7 days ACS but unknown timing
n = 85 n = 149 n = 66 n = 171 n = 103 n = 102

Maternal characteristics
Smoker 9 (10.6) 15 (10.1) 5 (7.6) 27 (15.8) 12 (11.7) 16 (15.7)
Hypertensive disease* 3 (3.5) 12 (8.1) 9 (13.6) 29 (17.0) 12 (11.7) 21 (20.6)
Obstetric characteristics
Born at level III hospital 26 (30.6) 107 (71.8) 62 (93.9) 157 (91.8) 98 (95.2) 85 (83.3)
Tocolytic treatment 23 (27.1) 119 (79.9) 42 (63.6) 111 (64.9) 61 (59.2) 55 (53.9)
PPROM 12 (14.1) 11 (7.4) 11 (16.7) 31 (18.1) 20 (19.4) 18 (17.7)
Placenta previa 4 (4.7) 2 (1.3) 3 (4.6) 6 (3.5) 7 (6.8) 5 (4.9)
Placenta abruption 13 (15.3) 9 (6.0) 5 (7.6) 14 (8.2) 13 (12.6) 13 (12.8)
Infant characteristics
Gestational age at birth (weeks)
22 29 (34.1) 11 (7.4) 1 (1.5) 3 (1.8) 0 5 (4.9)
23 14 (16.5) 28 (18.8) 14 (21.2) 26 (15.2) 4 (3.9) 13 (12.8)
24 7 (8.2) 32 (21.5) 13 (19.7) 38 (22.2) 25 (24.3) 22 (21.6)
25 22 (25.9) 40 (26.9) 22 (33.3) 52 (30.4) 29 (28.2) 32 (31.4)
26 13 (15.3) 38 (25.5) 16 (24.2) 52 (30.4) 45 (43.7) 30 (29.4)
SGA 6 (7.1) 12 (8.1) 13 (20.0) 41 (24.0) 20 (19.4) 22 (21.6)
Male gender 44 (51.8) 78 (52.4) 32 (48.5) 92 (53.8) 58 (56.3) 67 (65.7)
Multiplets 15 (17.6) 41 (27.5) 18 (27.3) 30 (17.5) 23 (22.3) 26 (25.5)
Surfactant <2 h after birth 27 (31.8) 94 (63.1) 32 (48.5) 84 (49.1) 57 (55.3) 60 (58.8)

ACS, antenatal corticosteroids; PPROM, preterm prelabour rupture of membranes; SGA, small for gestational age (birthweight more than 2 SD
below the mean of a national fetal weight-based growth standard).
Data are numbers (percentages).
*Essential hypertension and/or preeclampsia and/or eclampsia.

ª 2017 Royal College of Obstetricians and Gynaecologists 3

 Norberg et al.
Obstetric characteristics
Among unexposed and those exposed to ACS <24 h before
delivery, the proportion of women delivered at level III
hospitals was lower than in all other ACS administration-
to-birth intervals. PPROM was less frequent in women
delivering <24 h after ACS administration compared with
all other ACS administration-to-birth intervals. Tocolytic
treatment was less frequent in pregnant women unexposed
to ACS than in women treated with ACS, irrespective of
administration-to-birth interval. The proportions of pla-
centa previa and placenta abruption did not vary in rela-
tion to administration-to-birth interval of ACS (Table 1).
Infant characteristics
Infants unexposed to ACS were more likely to be born at a
lower gestational age than infants exposed to ACS, were
less likely to be SGA and less likely to be treated with sur-
factant within 2 h after birth.
In the exposed groups, there was an association between
ACS administration-to-birth interval and gestational age:
the longer time interval, the higher gestational age. Accord-
ingly, proportions of infants born at 22–23 gestational
weeks ranged from 26% in the administration-to-birth
interval <24 h to 4% in the ACS-category >7 days. In
infants born at 26 weeks of gestation, the corresponding
proportions ranged from 26% in the administration-to-
birth interval <24 h to 44% in the time interval >7 days.
There were no significant differences between ACS cate-
gories regarding distributions of infant gender (P = 0.23)
or multiple births (P = 0.18; Table 1).
Neonatal and infant survival in relation to ACS
and administration-to-birth intervals
Of the 707 live-born infants, 520 (74%) were alive at
28 days and 497 (70%) were alive at 1 year old. Neonatal
survival was 39% in the unexposed group, and ranged from
Table 2. Survival among live-born infants according to the administration-to-birth interval of ACS
no ACS
n = 85
Neonatal survival 28 days 33 (38.8)
Infant survival 365 days 30 (35.3)
Infant survival 365 days without major morbidity* 12 (14.1)
ACS, antenatal corticosteroids.
Data are numbers (percentages).
*Survival without any of the following: IVH ≥3, cystic PVL, NEC, ROP ≥3 or severe BPD. The proportions of these morbidities among infant
survivors were 10% (IVH ≥3), 5.7% (cystic PVL), 5.8% (NEC), 34% (ROP ≥3) and 25% (severe BPD).10
4 ª 2017 Royal College of Obstetricians and Gynaecologists
71 to 85% in infants exposed to ACS at different adminis-
tration-to-birth intervals. Infant survival was 35% in the
unexposed group and ranged from 71–80% in the exposed
groups (Table 2).
In the fully adjusted model, the lowest HRs for neonatal
and infant survival were found among infants unexposed
to ACS [HR = 0.26; 95% confidence interval (CI) = 0.15–
0.43]. Extremely preterm infants born <24 h after ACS as
well as those born more than 7 days after ACS administra-
tion also had lower HRs for survival (HR = 0.53; 95%
CI = 0.33–0.87 and HR = 0.56; 95% CI = 0.32–0.97,
respectively) than infants born 48 h to 7 days after ACS
administration. Survival in infants born at 24–47 h did not
differ from that in infants born 48 h to 7 days after ACS
administration (Figure 1; Table 3).
The sensitivity analysis, excluding surfactant within 2 h
after birth, did not alter the interpretation in a significant
way: the estimated HR for infant survival in infants unex-
posed to ACS was 0.29 (versus 0.26 with surfactant in the
model); it was 0.72 (versus 0.53 with surfactant in the
model) for infants exposed to ACS <24 h before birth; 1.16
(versus 1.60) for those receiving ACS 24–48 h before birth;
0.63 (versus 0.56) for infants who received ACS >7 days
before birth; and 0.64 (versus 0.53) in the category with
unknown timing of ACS [in both models, the reference
category (HR = 1) was ACS 48 h to 7 days before birth].
Infant survival with no major morbidity in
relation to ACS and administration-to-birth
intervals
Of the 707 live-born infants, 226 (32%) survived to 1 year
old and without any major neonatal morbidity. Survival
without major neonatal morbidity among live-born infants
was 14% in unexposed infants and 30–39% in steroid-
exposed infants, indicating that any ACS exposure was
valuable (Table 2). There was no statistically significant
Administration-to-birth interval of ACS
<24 h 24–47 h 48 h–7 days >7 days ACS but unknown P-value
n = 149 n = 66 n = 171 n = 103 timing
n = 102
105 (70.5) 56 (84.9) 143 (83.6) 85 (82.5) 77 (75.5) <0.0001
105 (70.5) 52 (78.8) 137 (80.1) 79 (76.7) 74 (72.6) <0.0001
47 (31.5) 20 (30.3) 67 (39.2) 37 (35.9) 33 (32.4) 0.0018
 Antenatal corticosteroids and survival in extremely preterm infants

1.0

Cumulave neonatal survival

ACS 24-47 hours before birth
0.9
ACS 48 h to seven days before birth

0.8 ACS more than seven days before birth

ACS but no info on ming
ACS one-23 hours before birth
0.7

0.6
No ACS

0.5
0 7 14 21 28
Age, days
Figure 1. Survival curve adjusted for covariatesa for extremely preterm infants according to antenatal corticosteroid (ACS) treatment and
administration-to-birth intervals.

Table 3. Association between the administration-to-birth interval of ACS and survival among live-born infants

Administration-to-birth interval of ACS

no ACS <24 h 24–47 h 48 h–7 days >7 days ACS but unknown
n = 85 n = 149 n = 66 n = 171 n = 103 timing
n = 102

Adjusted* HR (95% CI)

Neonatal survival 28 days 0.22 (0.12–0.38) 0.44 (0.26–0.74) 2.08 (0.80–5.47) reference 0.54 (0.29–1.03) 0.46 (0.26–0.83)
Infant survival 0.26 (0.15–0.43) 0.53 (0.33–0.87) 1.60 (0.73–3.50) reference 0.56 (0.32–0.97) 0.53 (0.31–0.90)
365 days
Adjusted* OR (95% CI)
Infant survival without 0.33 (0.16–0.69) 0.65 (0.39–1.08) 0.67 (0.35–1.29) reference 0.59 (0.35–1.02) 0.75 (0.43–1.30)
major morbidity**

ACS, antenatal corticosteroids; CI, confidence interval; HR, hazard ratio; OR, odds ratio.
*Adjusted for maternal smoking, maternal blood pressure disease, placenta previa, placental abruption, PPROM, regionalisation of care,
gestational age, SGA, infant gender and surfactant therapy within 2 h after birth.
**Survival without any of the following: IVH ≥ 3, ROP ≥ 3, severe BPD, PVL or NEC.

difference in neonatal survival without morbidity in any of
the ACS groups (Table 3). In the fully adjusted model, the
OR for infant survival without major neonatal morbidity
was significantly lower in infants unexposed to ACS
(OR = 0.33; 95% CI = 0.16–0.69; Table 3).
Discussion
Main findings
We found clear associations between timing of ACS and
survival in extremely preterm infants. Shorter or longer
administration-to-birth intervals than 24 h to 7 days were
associated with a doubled risk for infant mortality. The
lowest survival was found in infants unexposed for ACS –
their adjusted infant mortality risk was five times higher
than in infants in the reference group exposed to ACS 48 h
to 7 days before birth. Similar results were found for
neonatal survival and infant survival without major neona-
tal morbidity.
Strengths and limitations
The strengths of this study include prospective enrollment
of all extremely preterm births – including delivery room
deaths – in Sweden over a 3-year period. The study is one

ª 2017 Royal College of Obstetricians and Gynaecologists 5

 Norberg et al.
of the largest7,9 and the only population-based cohort eval-
uated for effects of ACS, and of timing of ACS, in all live-
born infants born at 22–26 weeks of gestation. The ACS
administration-to-birth interval was prospectively collected
in hours. The outcomes were robust and clinically highly
relevant. The sample size allowed for adjusted analyses of
survival in relation to timing of ACS-administration and
several potential confounders. The case-mix of our
cohort12,13 is similar to what has been reported in other
contemporary cohorts of extremely preterm infants.
We excluded stillborn infants. Among stillborn infants
alive at onset of labour (n = 66/304; 22% of all stillborns),
a minority (n = 22/66; 30% of stillborns alive at onset of
labour) had been treated with ACS, meaning that these
fetuses had been proactively managed. Excluding intra-
partum mortality may therefore have introduced some bias,
overestimating the protective effects of ACS at the time it
was administered. However, under the premise that the
infant was live-born, our risk estimates of no or untimely
ACS are valid.
During the study period, a restricted treatment policy
was – if parents agreed – used in some but not all of the
participating hospitals in Sweden for births that were con-
sidered nonviable. The EXPRESS-database does not contain
specific information on reasons for not treating with ACS;
however, a recommendation to withhold treatment rested
mainly on regional guidelines focusing on management of
extremely short gestations or severe malformations. Among
infants born at 22 weeks of gestation, 29/49 (59%) did not
receive ACS, at 23 weeks of gestation the corresponding
proportion was 14/99 (14%), and in infants born at
24 weeks of gestation the proportion not receiving ACS
was 7/137 (5.1%). Accordingly, crude estimates of survival
in relation to ACS exposure and administration-to-birth
intervals are likely to be confounded by indication. To
resolve this issue, we only present mortality data adjusted
for gestational age.
Small numbers of 22-week fetuses, with only 20 exposed
to ACS and five survivors, make generalisability of our
findings to this group limited. And although based on 707
live-born infants, limitations in numbers may also con-
tribute to wide confidence intervals for some of our risk
estimates.
We cannot exclude that other confounding factors than
those included herein were unevenly distributed between
categories and affected our results. We excluded tocolysis
from our multivariate analyses because, in univariate test-
ing, survival was not related to this variable, and because
of some missing data (n = 29) on use of tocolysis. Other
and unknown differences in case-mix between the different
ACS categories may have occurred. Moreover, our results
cannot be extrapolated to other drugs or dosing regimens
than the ones used in Sweden. Finally, we had no data on
6 ª 2017 Royal College of Obstetricians and Gynaecologists
fetal–infant survival among pregnant women exposed to
ACS before 27 weeks of gestation but who, for various rea-
sons, did not deliver before this upper limit for inclusion.
Interpretation
Antenatal corticosteroid treatment has previously been
associated with reduced mortality in extremely preterm
infants born after 22–26 weeks of gestation.7,8,26 The mag-
nitude of an effect of ACS in those studies varied between
an adjusted HR of 0.38 and 0.72, which is similar to our
findings. In contrast, a meta-analysis concluded that there
were no effects from ACS on neonatal mortality and mor-
bidity in extremely preterm infants.6 Adding the data pro-
vided in our study is likely to change that conclusion.
Animal studies have shown the greatest benefits from
ACS on surfactant production when delivery occurs
between 24 h and 7 days after a complete course of
ACS.27,28 However, human studies are more contradictory.
Some studies have found a decline in the effectiveness of
ACS over time,9,10,29,30 whereas others failed to do so.11,31–
33
The conflicting results may be attributed partly to the
use of diverse outcome measures.
Our results are in line with a recent study where the
authors found that ACS for preterm birth at 24–34 weeks
of gestational age had maximum beneficial impact on
neonatal morbidity and mortality when administered 1–
7 days before birth. In that study, the decline in effective-
ness of ACS after 7 days was primarily observed among
neonates born at 24–28 weeks of gestation.9
We found decreased survival with an ACS administra-
tion-to-birth interval exceeding 7 days. The NIH Consen-
sus Development Panel in 2000 recommended that a repeat
course of corticosteroids should be reserved for women
participating in controlled trials.34 This recommendation
was subsequently endorsed by the Canadian Society of
Obstetricians and Gynecologists in 2003. Since then, large
randomised controlled trials have reported conflicting
results.35,36 The latest Cochrane review concluded that
repeat courses of corticosteroids were associated with a
reduction in the incidence and severity of neonatal lung
disease and a small reduction in size at birth.37 Recent
work indicate no harm at follow-up to school age in those
exposed to repeat courses of ACS at 24–28 weeks and born
later after on average 32 weeks of gestation.38 Observational
data from adolescence and young adult age also suggest
long-term safety after exposure to repeat ACS.39 Repeat or
rescue doses of glucocorticoids may therefore be considered
in women at continued risk of preterm birth 7 or more
days after an initial course.37
The included infants were born almost a decade ago.
Since then neonatal care has improved and the evidence
for less invasive ventilation strategies has become clearer.40
Still, we think our findings are generalisable for the current
 Antenatal corticosteroids and survival in extremely preterm infants
extreme preterm population as in 2013–2014, the propor-
tions of infants born at 22–26 weeks of gestation in Sweden
who were intubated at birth and mechanically ventilated
were similar to those in EXPRESS12 (unpublished data
from the Swedish Neonatal Quality registry).
Conclusion
In summary, this study suggests an optimal administration-
to-birth interval for ACS in extremely preterm infants of
1–7 days, but also that all ACS is valuable. This knowledge
is important for clinicians when managing extremely pre-
term births and trying to administer ACS within the most
beneficial window of time.
Given that pregnant women continue to deliver extre-
mely preterm at various ACS time intervals, future areas
for research include exploration of short (neonatal morbid-
ity) and longer term (developmental, neurocognitive) out-
comes in relation to administration-to-birth intervals. The
optimal dosing (one or two doses, dose in mg) and dosing
intervals (6, 12 or 24 h apart) should preferably also be
tested.
Disclosure of interests
None declared. Completed disclosure of interests form
available to view online as supporting Information.
Contribution to authorship
All authors had full access to all of the data in the study
and take responsibility for the integrity of the data. Study
concept and design: HN and MN; acquisition of data: HN,
KM and MN; statistical analyses: HN and JK; analysis and
interpretation of data: all authors; drafting of the manu-
script: HN and MN; critical revision of the manuscript for
important intellectual content: all authors; obtained fund-
ing: KM and MN; study supervision: MN.
Details of ethics approval
The study was approved by the Regional Research Ethics
Board, Lund University, Lund, Sweden (date of approval 1
July 2004; reference number 42/2004). The parents pro-
vided oral informed consent for data acquisition.
Funding
This project was supported by a regional agreement on
medical training and clinical research (ALF) between Stock-
holm County Council and Karolinska Institutet, the Swed-
ish Order of Freemasons’ Foundation for Children’s
Welfare, and the Swedish Research Council. The sponsors
had no role in the design of the study; in the collection,
analysis and interpretation of data; in the writing of the
report; or in the decision to submit the article for
publication.
ª 2017 Royal College of Obstetricians and Gynaecologists
Acknowledgements
The authors would like to acknowledge the EXPRESS
group and staff working at the maternal and neonatal units
in Sweden for all their help and assistance in collecting the
data. In particular, the authors would like to acknowledge
Professor Karin K€allen for providing us with data from the
EXPRESS database.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Flowchart of the study population. &
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