Key words antenatal corticosteroids - preterm birth - VLWB - perinatal outcome - respiratory
distress syndrome
Schlüsselwörter antenatale Kortikosteroide - Frühgeburt - VLWB - perinatales Outcome - Atemnotsyndrom
des Frühgeborenen
Introduction
Administration of antenatal corticosteroids (ACS) in threatened premature birth (PTB)
before 34 weeks of gestation (wks) is stated to be the most effective treatment known
for preventing
serious preterm complications in the newborn including respiratory distress syndrome
(RDS), intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC), as well
as reducing overall
mortality [1 ], [2 ]. Betamethasone 12 mg twice or dexamethasone 4 × 6 mg decrease mortality and morbidity
markedly for preterm
infants especially in very low birthweight infants (VLBW < 1500 g) [3 ], [4 ]. Data of extremely low birthweight infants (ELBW
< 1000 g) are still rare [3 ], [5 ], [6 ]. ACS enhances maturation of pulmonary structure and
function [1 ], [7 ], [8 ]. Nevertheless, it is still unknown how long these beneficial effects last.
There is evidence that the benefits of corticosteroids diminish over time. On
the other hand the absence of ACS or incomplete ACS are risk factors for poor neonatal
outcomes [9 ]. Current literature suggests a window of optimal efficacy between 48 hours and seven
days after administration of the first dose of ACS [5 ], [10 ], [11 ], [12 ]. Administration of a full course of ACS in PTB is recommended by
worldwide guidelines [13 ], [14 ], [15 ], [16 ], being used as a
quality marker for delivery room practice despite the unpredictable nature of
PTB, which leads to a liberal application of ACS to all PTB [17 ], [18 ]. Currently, only 23 to 40% of ACS are administered in the window of optimal efficacy,
which puts a large number of infants at risk for detrimental outcomes
[10 ], [19 ], [20 ].
The objective of this study was to evaluate the effects of ACS-to-delivery interval
on neonatal outcome parameters in a high-risk cohort of VLBW infants below 34 wks.
Materials and Methods
Cohort composition
From January 1, 2015 to December 31, 2018 487 women were treated in the tertiary perinatal
center of Jena university hospital because of threatened PTB before 34 wks. 248 women
delivered
after 34 wks or with a birthweight > 1500 g and were therefore excluded ([Fig. 1 ]).
Fig. 1 Cohort composition. Abbreviations: ACS – antenatal corticosteroids; NICU – neonatal
intensive care unit; wks – weeks of gestation.
We included 239 inborn neonates with a birthweight < 1500 g and a GA < 34 wks treated
in our Neonatal Intensive Care Unit (NICU). Seven of those received no ACS, 47 received
incomplete ACS and 185 received a complete course of ACS. A full course of ACS
was defined as two doses of betamethasone with 24 hours in between doses and delivery
at more than 48 hours
after first dose. Only one dose or delivery before 48 hours after first dose
was defined as incomplete course. Window of efficacy was defined as a delivery between
48 h and seven days after
the first 12 mg betamethasone dosage (group ACS ≤ 7 days). The other group, out
of this window, was defined as ACS > 7 days. No rescue courses or multiple dose regimens
were used in our
institution.
In the 185 cases of completed ACS neonatal outcomes were compared between those born
≤ 7 days (n = 90) and those born > 7 days after beginning of ACS (n = 95). To further
differentiate
concerning the effects of maturity and birthweight the cohort was stratified
for ELBW (< 1000 g) and VLBW (1000 – 1500 g) subgroups.
We do confirm that any research activities during this study were performed according
to ethical standards of the Declaration of Helsinki and the protocol for this research
project has been
approved by the Ethics Committee of the Friedrich-Schiller-University.
Ascertainment of clinical parameters and perinatal outcome
The main source for neonatal parameters was the prospectively collected data for the
German national nosocomial infection surveillance system, known as KISS
(Krankenhaus-Infektions-Surveillance-System) and combined with clinical patient
records retrospectively. KISS data were only entered by one of this studyʼs investigators.
Annual training and
skill-tests for the investigators were ensured. Regular quality control meetings
and reports from the KISS center secured data integrity. We assessed all infants < 1500 g
birth weight up
until either death or reaching a weight of 1800 g. Parameters included were need
for CPAP or need for surfactant via catheter or endotracheal tube and need for ventilation,
as well as
outcome parameters like mortality, neonatal sepsis, NEC and bronchopulmonary
dysplasia (BPD) for neonatal complications and age at birth, fetal birthweight, singleton
or multiple
pregnancies. We decided to use objective parameters like ventilation and surfactant
instead of the somewhat subjective radiographic interpretation of RDS [16 ].
Neonatal hypotrophy was defined as a birth weight below 10th percentile for gestational
age or the Z-Score below − 1.282 according to the revised Fenton Preterm Growth Charts
and is
represented as small for gestational age (SGA) in the tables [21 ].
BPD was diagnosed based on Walsh criteria (need for supplemental oxygen or ventilation
at 36/0 wks) [22 ] and NEC on Neo-KISS criteria (German neonatal
surveillance system) [23 ]. The infant morbidity was calculated using the CRIB-Score (Clinical Risk Index for
Babies), which is a robust predictor of neonatal
morbidity. It is a semiquantitative score that consists of six items (birthweight,
gestational age [GA], severe malformation, neonatal acidosis and maximum and minimum
oxygen requirements in
the first 12 hours of life) with a minimum of zero and a maximum of 23 achievable
points [24 ].
Pregnancy-related data including indication for delivery, mode of delivery and GA
at birth were retrieved from our perinatal database. Diagnosis of delivery was grouped:
1st PTB caused by
preterm premature rupture of membranes (PPROM) and/or chorioamnionitis; 2nd fetal
growth restriction (FGR), 3rd maternal indications (e.g., pre-eclampsia, HELLP, placenta
praevia) and 4th
others (e.g., placental abruption). Mode of delivery included C-section and any
type of vaginal delivery.
Statistical analysis
For the main group comparison all inborn infants with GA < 34 wks and birthweight
< 1500 g were considered (n = 239). For the subgroup comparisons and multivariate
logistic regression
analysis we included only preterm infants after a full course of ACS (n = 185).
In order to get unbiased estimates in the multivariate logistic regression model,
a prior sample size
estimation was performed for the primary outcome variables ventilation and surfactant
use [25 ]. χ2 test or Fisher exact test were used to compare
categorical data. Since most of the continuous data were not normally distributed,
we used the median and interquartile range for data presentation and description.
Mann-Whitney U test or
Kruskal-Wallis test were performed to compare continuous data between groups.
Adjusted odds ratios (ORs) for estimating the association of the ACS-to-delivery interval
(days) and gestational
age at birth (wks) with neonatal complications (ventilation, surfactant, CPAP,
BPD, neonatal sepsis and NEC) were determined using logistic regression. ORs with
95% confidence interval (CI)
are presented. The potential confounders like fetal sex, birthweight and sepsis
were included as covariates in the statistical analysis as presented in footnotes.
Regression models were
tested for an overall predictive value using Omnibus-Tests and only significant
overall predictive models are presented [26 ]. A p-value < 0.05 was
considered to indicate statistical significance (2-tailed). Statistical analysis
was performed with SPSS 24.0.
Results
Within the observation period, 346 of the 487 (71%) women with threatened PTB and
receiving ACS gave birth between 23/0 and 34/0 wks. Although this rate is quite better
than reported by
others [27 ], [28 ] it means that in hindsight 135 women unnecessarily received ACS.
A total of 239 neonates met our inclusion criteria (delivery in our hospital; NICU
admission; born between 23/0 and 34/0 wks and a birth weight < 1500 g), of which 185
received a complete
course of ACS. Seven neonates did not receive ACS prior birth and 47 neonates
received an incomplete ACS only. There was no significant difference between these
groups regarding fetal sex,
numbers of multiple pregnancies, gestational age at birth (weeks) and birth weight,
but in the mode of delivery and delivery indications.
As expected, newborns with missing or incomplete ACS demonstrated more adverse outcomes
with higher mortality, NEC rates and increasing need for invasive ventilation. The
entire cohort
characteristics and groups comparisons are presented in [Table 1 ].
Table 1 Cohort characteristics and univariate analysis of the subgroups: no ACS, incomplete
ACS and complete ACS (≤ 7 days and > 7days).
Entire cohort
No ACS
Incomplete ACS
ACS ≤ 7 days
ACS > 7 days
p-value†
p-value‡
Data are n (%) or median and interquartile range (IQR) unless otherwise specified.
Significant findings (p < 0.05) are highlighted in bold.
† Comparison between the four groups.
‡ Comparison ACS ≤ 7 days and ACS > 7days only.
ACS – antenatal corticosteroids; PPROM – preterm premature rupture of membranes; CPAP
– continuous positive airway pressure; SGA – small for gestational age; NEC – necrotizing
enterocolitis; BPD – bronchopulmonary dysplasia; CRIB- clinical risk index
for babies
Total, n
239
7
47
90 (48.6)
95 (51.4)
Sex
128 (53.6)
5 (71.4)
27 (57.4)
47 (52.2)
49 (51.6)
0.706
1
111 (46.4)
2 (28.6)
20 (42.6)
43 (47.8)
46 (48.4)
Multiples
0.032
0.022
72 (30.1)
2 (28.6)
20 (42.6)
19 (21.1)
33 (32.6)
4 (1.7)
–
–
–
4 (4.2)
Delivery indication
< 0.001
0.163
143 (59.8)
5 (71.4)
28 (59.6)
46 (51.1)
64 (67.4)
–
49 (20.5)
–
2 (4.3)
28 (31.1)
19 (20)
–
26 (10.9)
1 (14.3)
6 (12.8)
11 (12.2)
8 (8.4)
–
21 (8.8)
1 (14.3)
11 (23.4)
5 (5.6)
4 (4.2)
–
Mode of delivery
0.021
0.125
20 (8.4)
2 (28.6)
7 (14.9)
8 (8.9)
3 (3.2)
219 (91.6)
5 (71.4)
40 (85.1)
82 (91.1)
98 (96.8)
Gestational age (weeks)
28 (26 – 30)
27 (26 – 32)
26 (25 – 29)
28 (26 – 30)
29 (27 – 30)
0.002
0.042
ACS-to-delivery interval (days)
5 (2 – 12)
–
1 (1 – 2)
4 (3 – 5)
17 (10 – 26)
< 0.001
< 0.001
Birth weight (g)
1020 (790 – 1305)
1030 (855 – 1290)
945 (750 – 1310)
950 (683.75 – 1245)
1180 (935 – 1385)
0.003
< 0.001
SGA
56 (23.4)
3 (42.9)
7 (14.9)
28 (31.1)
18 (18.9)
0.060
0.063
CPAP
226 (95.4)
6 (85.7)
42 (91.3)
84 (94.4)
94 (98.9)
0.105
0.109
Surfactant
150 (63.3)
5 (71.4)
32 (69.6)
53 (59.6)
60 (63.2)
0.679
0.651
Ventilation
76 (32.2)
3 (42.9)
23 (50)
21 (23.6)
29 (30.9)
0.017
0.320
Sepsis
21 (8.8)
–
3 (6.4)
14 (15.6)
4 (4.3)
0.036
0.012
NEC
12 (5)
–
6 (12.8)
5 (5.6)
1 (1.1)
0.025
0.112
BPD
27 (11.3)
1 (14.3)
4 (8.5)
15 (16.7)
7 (7.4)
0.214
0.068
Neonatal death
18 (7.5)
2 (28.6)
7 (14.9)
7 (7.8)
2 (2.1)
0.007
0.093
CRIB-Score
2 (1 – 7)
6 (1 – 15)
3 (1 – 7.25)
2 (1 – 7)
1 (1 – 5)
0.003
0.013
Multivariate logistic regression analysis for complete ACS with confounders
Multivariate logistic regression analysis (including confounders: sex and birth weight)
in the subgroup of complete ACS showed a significant effect of the ACS-to-delivery
interval (time
between first dose and delivery) on the need for ventilation (OR 1.045; CI 1.011 – 1.080)
and surfactant administration (OR 1.050, CI 1.018 – 1.083) as shown in [Table 2 ]. When looking at the subgroup of complete ACS within the window of efficacy no significant
independent effect of ACS-to-delivery interval could be demonstrated for the need
for ventilation (OR 1.065; CI 0.724 – 1.566) nor for surfactant administration
(OR 1.290; CI 0.874 – 1.904). Each additional day between ACS and delivery increased
the risk for ventilation
by 4.5% and surfactant by 5% despite all the other confounders.
Table 2 Multivariate regression analysis of the association of ACS-to-delivery, gestational
age and neonatal complications.
Outcome variable
Influencing variable
Adjusted ORs*
CI (95%)
Adjusted ORs†
CI (95%)
* Adjusted for sex and birth weight; † adjusted for sex, birth weight and sepsis; significant findings (p < 0.05) are highlighted
in bold.
ACS – antenatal corticosteroids; CPAP – continuous positive airway pressure; BPD –
bronchopulmonary dysplasia; NEC – necrotizing enterocolitis
Ventilation (n = 183)
ACS-to-delivery interval (days)
1.045
1.011 – 1.080
1.048
1.013 – 1.084
Gestational age (weeks)
0.604
0.466 – 0.783
0.592
0.454 – 0.772
Surfactant (n = 184)
ACS-to-delivery interval (days)
1.050
1.018 – 1.083
1.050
1.018 – 1.083
Gestational age (weeks)
0.544
0.426 – 0.695
0.545
0.427 – 0.696
BPD (n = 185)
ACS-to-delivery interval (days)
1.032
0.970 – 1.099
1.026
0.958 – 1.097
Gestational age (weeks)
0.684
0.479 – 0.977
0.657
0.440 – 0.979
Sepsis (n = 184)
ACS-to-delivery interval (days)
0.948
0.860 – 1.045
Gestational age (weeks)
0.961
0.689 – 1.341
NEC (n = 184)
ACS-to-delivery interval (days)
0.834
0.613 – 1.135
0.824
0.596 – 1.141
Gestational age (weeks)
1.240
0.734 – 2.097
1.369
0.775 – 2.418
Gestational age at birth also revealed an independent impact on the need for ventilation
(OR 0.604, CI 0.466 – 0.783) and for surfactant use (OR 0.544 CI 0.426 – 0.695) as
well as for BPD
(OR 0.684; CI 0.479 – 0.977). Each additional week of intrauterine maturation
decreased the risk for ventilation by 38%, for surfactant application by 47% and for
the occurrence of BPD by
31% as expected. Adding sepsis as a potential confounder as presented in the
right column of [Table 2 ] did not affect prior results.
Univariate analysis: Comparison of complete ACS ≤ 7 days vs. ACS > 7 days
Timing of ACS was within the window of efficacy in 48.6% (n = 90) of the cases (ACS
≤ 7 days). Both subgroups ACS ≤ 7 days and ACS > 7 days did not differ in fetal sex,
delivery
indications and mode of delivery but were significantly different in GA (28 wks
[IQR 26 – 39] vs. 29 wks [IQR 27 – 30]; p < 0.05), birth weight (950 g [IQR 838.75 – 1245]
vs. 1180 g [IQR
935 – 1385]; p < 0.01) and CRIB-Score (2 [IQR 1 – 7] vs. 1 [IQR 1 – 5]; p < 0.05).
Less multiples were seen in the group with ACS ≤ 7 days (21.1% vs. 36.6%; p < 0.05).
The timing of ACS showed a strong trend towards the need for less CPAP, surfactant,
and ventilation in the subgroup ACS ≤ 7days. No statistically significant effect was
seen on the
incidence of NEC, BPD or neonatal death. Remarkably, there were more cases of
neonatal sepsis (15.6% vs. 4.3%; p < 0.05) in the group with ACS ≤ 7 days compared
to the group with ACS
> 7 days ([Table 1 ]).
Univariate analysis of complete ACS: VLBW and ELBW subgroups
To countervail the birthweight discrepancies in the main group, a subgroup analysis
was performed comparing ELBW and VLBW infants ([Table 3 ]). Within these
groups the efficacy of ACS timing was evaluated. The mean intervals between ACS
and delivery were significantly different when comparing ACS ≤ 7 days and ACS > 7
days in all
subgroups.
Table 3 Comparison of the subgroups ACS ≤ 7 days and ACS > 7 days depending on birthweight
categories: ELBW and VLBW.
ELBW < 1000 g
VLBW ≥ 1000 – 1500 g
Variable
ACS ≤ 7 days
ACS > 7 days
p-value†
ACS ≤ 7 days
ACS > 7 days
p-value†
Data are n (%) or median and interquartile range (IQR) unless otherwise specified.
Significant findings (p < 0.05) are highlighted in bold.
† Comparison between the subgroups ACS ≤ 7 days and ACS > 7 days using nonparametric
tests for each subgroup.
ACS – antenatal corticosteroids; ELBW – extreme low birthweight; VLBW – very low birthweight;
PPROM – preterm premature rupture of membranes; SGA – small for gestational age; CPAP
– continuous positive airway pressure; NEC – necrotizing enterocolitis;
BPD – bronchopulmonary dysplasia, CRIB – clinical risk index for babies
Total, n
51
31
39
64
Sex
0.820
0.1
27 (52.9)
15 (48.4)
20 (51.3)
34 (53.1)
24 (47.1)
16 (51.6)
19 (48.7)
30 (46.9)
Multiples
10 (19.6)
5 (16.1)
0.775
9 (23.1)
26 (40.6)
0.033
–
4 (6.3)
Delivery indication
0.966
0.033
30 (58.8)
19 (61.3)
16 (41.0)
45 (70.3)
17 (33.3)
9 (29.0)
11 (28.2)
10 (15.6)
3 (5.9)
2 (6.5)
8 (20.5)
6 (9.4)
1 (2)
1 (3.2)
4 (10.3)
3 (4.7)
0.245
0.632
6 (11.8)
1 (3.2)
2 (5.1)
2 (3.1)
45 (88.2)
30 (96.8)
37 (94.9)
62 (96.9)
Gestational age (weeks)
26 (24 – 27)
27 (25 – 27)
0.215
30 (29 – 32)
29 (29 – 30)
0.112
ACS-to-delivery interval (days)
4 (3 – 5)
13 (10 – 22)
< 0.001
4 (3 – 5)
20.5 (10 – 32)
< 0.001
Birth weight (g)
720 (550 – 920)
840 (675 – 935)
0.074
1290 (1150 – 1384)
1295 (1172.5 – 1427.5)
0.509
SGA
17 (33.3)
7 (22.6)
0.330
11 (28.2)
11 (17.2)
0.219
CPAP
47 (92.2)
31 (100)
0.292
37 (97.4)
63 (98.4)
1
Surfactant
43 (84.3)
25 (80.6)
0.765
10 (26.3)
35 (54.7)
0.007
Ventilation
19 (37.3)
13 (43.3)
0.642
2 (5.3)
16 (25)
0.014
Sepsis
11 (21.6)
4 (13.3)
0.555
3 (7.7)
–
0.052
NEC
4 (7.8)
1 (3)
0.646
1 (2.6)
–
0.379
BPD
13 (25.5)
6 (19.4)
0.598
2 (5.1)
1 (1.6)
0.555
Neonatal death
6 (11.8)
0
0.078
1 (2.6)
2 (3.1)
1
CRIB-Score
6 (2 – 9)
7 (2 – 8)
0.535
1 (0 – 2)
1 (0 – 2)
0.884
In the VLBW subgroup (birthweight 1000 – 1500 g) ACS ≤ 7 days reduced the risk for
a RDS with a reduced need for surfactant application (26.3% vs. 54.7%; p < 0.01) and
for ventilation
(5.3% vs. 25.0%; p < 0.05) significantly. In the VLBW group there were significant
differences concerning the indication for delivery, because more children in the ACS
≤ 7days group were
treated for FGR (28.2% vs. 15.6%) whereas more cases of PPROM (41.0% vs. 70.3%;
p > 0.05) and multiples (23.1% vs. 46.9%) could be seen in the ACS > 7 days group.
We did not see
differences in neonatal complications: death, BPD, NEC and sepsis in both subgroups.
In the ELWB subgroup < 1000 g (n = 82) no differences of patient characteristics,
indications, nor
perinatal complications could be found. There was again a trend towards the need
for less mechanical ventilation in the ACS ≤ 7 days subgroup.
A visualization of the cohort and the main respiratory complications (surfactant use
and mechanical ventilation) is summarized in [Fig. 2 ], according to
birthweight and ACS-to-delivery interval. The scatter plots show in a case by
case manner the higher percentage of interventions (e.g. more green dots) in the ACS
> 7 days group (right
upper quadrant) in VLBW infants (1000 – 1499 g – right quadrant) than in the
ACS < 7 days group (right lower quadrant).
Fig. 2 Scatterplots of respiratory complications (a mechanical ventilation, b surfactant use) matched to birthweight and ACS-to-delivery interval, horizontal line
at 7 days of ACS-to-delivery interval, vertical line at birthweight of 1000
grams. Empty plots mean no complication, full plots mean complication occurred. Abbreviations:
ACS – antenatal
corticosteroids.
Discussion
This analysis of a large well characterized cohort of high-risk preterm neonates below
1500 g birthweight could demonstrate a significantly increased risk of severe RDS
characterized by the
need for ventilation (OR 1.045; CI 1.011 – 1.080) and surfactant administration
(OR 1.050; CI 1.018 – 1.083) depending on the ACS-to-delivery interval irrespective
of other confounders. Every
additional day between ACS and delivery increased the risk for ventilation by
4.5% and for surfactant administration by 5% in our cohort ([Fig. 2 ]). However,
this could not be shown when the delivery occurred within 7 days in the window
of optimal efficacy. Additionally, every week of maturation decreased the risk of
pulmonary complications. This
finding emphasizes the importance of a careful timing as close to delivery as
possible versus a liberal use of ACS in all PTB. We focused on the patient group of
ELBW and VLBW infants as those
are at the highest risk of complications and long-term sequelae due to their immaturity
[23 ], [29 ], [30 ].
Our results also confirm previous data [3 ], [4 ] and demonstrate that a completed course of ACS reduces neonatal mortality by 83%
compared to no ACS and by 67% compared to an incomplete ACS course. We also report
a significant reduction of NEC and the need for ventilation as shown in [Table
1 ] in agreement to recent studies and meta-analysis [1 ], [3 ], [31 ]. This underlines the
need and benefits of a full course of ACS before the delivery of a preterm infant
whenever possible.
In the univariate analysis, reduced respiratory complications could be seen as a strong
trend but failed to reach statistical significance. Remarkably, the group ACS ≤ 7
days comprised
infants were born in mean 9 days earlier (28 wks vs. 29 wks; p < 0.05), with lower
BW (950 g vs. 1180 g; p < 0.01) and seen to be sicker (CRIB Score 2 vs. 1; p < 0.05)
than in the
group ACS > 7 days, which are all known risk factors for respiratory complications.
This imbalance could be a limitation due to the retrospective character of the analysis,
which is not
stratified to GA of ACS prophylaxis. There were also more cases of FGR in the
group ACS ≤ 7 days (31.1% vs. 20%). Neonatal sepsis occurred more often when ACS was
given within 7 days to birth.
Lower GA, lower BW and FGR are individual risk factors for neonatal sepsis, which
seems to be a possible explanation for this effect in our cohort [23 ], [32 ]. FGR fetuses were excluded from most studies [3 ], [32 ] since it is hypothesized that higher
catecholamine and steroid levels due to the fetal stress in FGR flatten the ACS
effect [33 ].
A subgroup analysis according to birthweight < 1000 g (ELBW) and 1000 – 1500 g (VLBW)
showed that VLBW infants did need significantly less ventilation (5.3% vs. 25%; p < 0.05)
and
surfactant (26.3% vs. 54.7%; p < 0.01) if they were born within 7 day after ACS.
We were able to show this positive effect in the group ACS ≤ 7 days, although FGR
is known to be a risk
factor for pulmonary complications [3 ], [32 ], [34 ] and the distribution of neonates with
hypotrophy in the two groups was somewhat unbalanced (28.2% vs. 17.2%, but n. s.).
Adding hypotrophy as an independent risk factor to the multivariate regression did
not change the results of
our analysis concerning the effect of the ACS-to-delivery interval. Nevertheless,
our results must be interpreted cautiously because of a higher rate of PPROM cases
(41 vs. 70.3%; p < 0.05)
in the VLBW group, albeit not neonatal sepsis (VLBW 7.7% vs. 0%; n. s.). Our data
consistently showed a strong trend towards less severe RDS as seen in less need for
ventilation in the ELBW
group with timely ACS but failed to reach statistical significance. Nearly all
infants needed surfactant therapy initially independent of ACS timing in this subgroup.
These infants are in the
highest risk group for neonatal complications (median age both 26 vs. 27 wks and
median weight 720 vs. 840 g) but constitute a major part of our study population (82/185
infants). It is still
unclear to what extent these extremely premature infants benefit from ACS. An
explanation for the uncertain effect of ACS on outcome could be the extreme immaturity
of the pulmonary system
[3 ], [35 ]. Additionally, the multitude of treatment options in NICU treatment nowadays may
reduce the prominent effectiveness
of ACS [16 ]. Our findings suggest that these infants also seem to benefit from a timely ACS
administration, adding valuable data for extremely premature infants
[3 ], [5 ], [6 ].
One strength of our study is the large number of VLBW and ELBW infants for which data
is rare and treatment algorithms are still unclear. As a single center study, we do
have high-quality
data records, clear treatment algorithms by SOP and therefore little intra-operator
variability. Nevertheless, the knowledge about ACS administration might have biased
the treatment of
infants. To account for these problems objective parameters like need of ventilation
and surfactant use were considered. The non-randomized character of the study caused
imbalances in the
group composition, which we could partially countervail by stratified subgroup
analysis. This could limit the generalizability of our results to other delivery populations.
These limitations can only be overcome by a randomized controlled trial to verify
these results, but this seems ethically questionable from our point of view.
Conclusion
In conclusion, our data strongly support the deliberate use and timing of ACS in women
at risk of preterm birth in contrast to unrestricted ACS administration as scattershot.
Quality
improvement measures should therefore focus on administration of ACS within the
window of efficacy instead of administration of ACS to every woman with threatened
PTB. Each additional day in
between ACS and delivery is relevant concerning major effects on the infant. VLBW
infants especially seem to profit from ACS in the window of efficacy concerning respiratory
complications.
Since prospective studies on ACS seem not ethically feasible, we believe that
our results based on prospective collected register data (KISS) are of high value.
