- Academic Editor
Background: Studies examining shorter intervals between antenatal
corticosteroid administration (ACS) and delivery are limited. This study analyzed
effects of the timing of ACS on short-term and long-term outcomes in premature
infants. Methods: This retrospective cohort study analyzed 534
deliveries between 22
Despite numerous advances in modern medicine, the medical community has been unable to substantially impact the number of worldwide preterm deliveries or mitigate the resulting morbidity, mortality, and long-term complications. In 2012, Liu et al. [1] estimated that approximately 1.1 million neonates die annually as a result of complications associated with preterm delivery. In 2018, an estimated 35% of neonatal deaths were attributed to complications of preterm delivery [2]. In high-income countries, the mortality rate for newborns born under 32 weeks is estimated to be 10–15%, with approximately 5–10% suffering from cerebral palsy [3].
As the rate of preterm deliveries continues to rise, the need for proven preventative interventions becomes increasingly essential in reducing of morbidity and mortality. Liggins and Howie [4] were responsible for the revolutionary introduction of corticosteroids as a preventive measure in the incidence of respiratory distress syndrome (RDS) among preterm infants in 1972. Since its introduction, the application has been researched multiple times in an effort to optimizing its use during childbirth. The 2006 Cochrane review of 21 studies including 3885 women and 4269 infants confirmed the efficacy in reduction of intraventricular hemorrhage (IVH), RDS, neonatal mortality, necrotizing enterocolitis (NEC), and need for respiratory support without an increased risk of chorioamnionitis, maternal death, or puerperal sepsis [5]. The updated 2017 Cochrane review (30 studies, 7774 women, 8158 infants) and the subsequent Cochrane review in 2020 (27 Studies, 11,272 women, 11,925 infants) both reconfirmed the risk reductions [6, 7].
The antenatal corticosteroid administration (ACS) has been integrated into standards for preterm delivery worldwide. The maximal benefit of corticosteroids can be observed 24 hours after antenatal administration and are considered most effective when delivery occurs within seven days of administration [8, 9]. It is widely accepted and reported that there is a significant reduction in neonatal brain injury after 48 hours [10]. Additional benefits include the reduction of infant mortality, RDS, IVH, and NEC [11, 12, 13].
There are limited studies examining narrower intervals between ACS and delivery. The Effective Perinatal Intensive Care in Europe (EPICE) Cohort reported an immediate and rapid decline in mortality after ACS. They reported a 20.6% mortality rate in infants unexposed to antenatal corticosteroids and observed a risk reduction of more than 50% with an interval between 18 and 36 hours. The authors concluded that ACS may be effective even with a short interval to delivery, suggesting a simulated reduction in mortality by 26% with administration 3 hours before delivery [10].
McDougall et al. [14] performed a systematic review in 2023 to examine studies researching other timing intervals for ACS. Across the ten trials included in the review (involving 4592 women, 5018 infants), a total of 37 different timing intervals were reported. The authors concluded that the studies were too heterogenous and the intervals with the best outcomes were too inconsistent to make generalized recommendations [14].
The purpose of this study was to analyze the effect ACS timing on short- and
long-term outcomes in premature infants delivered between 22
Institutional Review Board approval was obtained through the Ethics Commission
of the University of Ulm (Record Number 445/18, Accepted March 2019). This
retrospective cohort study analyzed deliveries between 22
Twin and multiple deliveries were not excluded. ACS was performed using 2 doses
of 12 mg betamethasone (Celestan®, SP Labo N.V.,
Heist-op-den-Berg, Antwerp, Belgium) intramuscular 24 hours apart. Time from
initiation of ACS to delivery was categorized using cutoffs of
Descriptive statistics for categorical variables were presented and summarized
using absolute and relative frequencies, while ordinal and metric data were
described using median, interquartile range, and range. Comparisons between
groups regarding categorical variables were performed using the Chi-square test
or Fisher’s exact test (if expected frequencies in 2
Median maternal age was 31 years (range 18 to 47 years). The newborn median
weight at delivery was 820 grams (range 265 to 1780 grams). 470 (88.0%) of the
newborns were delivered by caesarean section, 63 (12%) of the newborns were
delivered vaginally. 331 (62.0%) of the deliveries were primigravidas. There
were 170 multiple pregnancies (31.8% of the study population), consisting of 68
twin deliveries, 10 triplet deliveries, and 1 quadruplet delivery. An APGAR score
below 5 at 5 minutes after delivery was reported in 18 (3.4%), while at 10
minutes after delivery, 4 (0.7%) infants had an APGAR score below 5. An
umbilical artery pH
The most common diagnoses at admission were preterm labor (defined as birth
before 36
According to internal standards, 45 patients in the
Descriptive characteristics of the cohort are summarized in Table 1.
Age | Range 18–47 years | Median 31 years | |
Weight at Delivery | Range 265–1780 grams | Median 820 grams | |
Vaginal Delivery | 63/534 | 11.8% | |
Caesarean Section | 470/534 | 88.0% | |
Primigravida | 331/534 | 62.0% | |
Twins n = 68 | 136/534 | 25.0% | |
Triplets n = 10 | 30/534 | 6.0% | |
Quadruplets n = 1 | 4/534 | 0.7% | |
APGAR |
18/510 |
3.5% | |
APGAR |
4/510 |
0.8% | |
Umbilical artery (UA) pH | Range 6.84–7.55 | Median 7.34 | |
UApH |
453/493 |
91.9% | |
UApH 7.10–7.19 (mild acidosis) | 32/493 | 6.5% | |
UApH 7.00–7.10 (moderate acidosis) | 6/493 | 1.2% | |
UApH |
2/493 | 0.4% | |
BPD | 44.0% (223/507) | ||
Mild | 29.4% (149/507) | ||
Moderate | 9.3% (47/507) | ||
Severe | 5.3% (27/507) | ||
ROP | 54.1% (216/399) | ||
Stage 1 | 13.0% (52/399) | ||
Stage 2 | 13.8% (55/399) | ||
Stage 3 | 27.1% (108/399) | ||
Stage 4 | 0.3% (1/399) | ||
IVH | 16.8% (85/507) | ||
Grade 1 | 3.7% (19/507) | ||
Grade 2 | 6.9% (35/507) | ||
Grade 3–Grade 4 | 6.1% (31/507) | ||
PDA | 32.0% (162/507) | ||
NEC | 3.9% (20/507) |
APGAR, Appearance, Pulse, Grimace, Activity, and Respiration; UA, Umbilical
artery; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; IVH,
intraventricular hemorrhage; PDA, persistent ductus arteriosus; NEC, necrotizing
enterocolitis.
The time interval between ACS start and childbirth was less than 24 hours in 150
(28.1%) of the deliveries. Gestational ages were significantly more advanced in
the
ACS distribution by week of pregnancy. ACS, antenatal corticosteroid administration.
Newborns in the
Newborns born within 24 hours after ACS initiation more frequently had a 5-minute APGAR score below 5 compared to newborns born later than 24 hours after ACS initiation (6.3% vs. 2.5%, Chi-Square test, p = 0.035).
The proportion of newborns with a 10-minute APGAR below 5 and with an umbilical
artery pH
There were no significant differences regarding the incidence of ROP (60.7%
vs. 51.3%, p = 0.083) or NEC (4.2% vs. 3.8%,
p = 0.856) between newborns of the
There were no significant differences in mortality, MDI, or PDI, between
newborns of the
p value | ||||
Gestational age (weeks) | Median 25 | Median 26.5 | p | |
interquartiles = 23–28, range = 22–29 | interquartiles = 25–28, range = 22–29 | |||
5 min APGAR |
9/143 (6.3%) | 9/367 (2.5%) | p = 0.035 | |
10 min APGAR |
0/143 (0.0%) | 4/367 (1.1%) | p = 0.210 | |
UApH |
15/140 (10.7%) | 25/353 (7.1%) | p = 0.183 | |
Caesarean Section | 119/149 (79.9%) | 351/384 (91.4%) | p | |
BPD | 73/143 (51.0%) | 150/364 (41.2%) | p = 0.045 | |
NEC | 6/143 (4.2%) | 14/364 (3.8%) | p = 0.856 | |
IVH (Grade IV) | 15/143 (10.5%) | 11/364 (3.0%) | p = 0.001 | |
ROP | 74/122 (60.7%) | 142/277 (51.3%) | p = 0.083 | |
Surfactant | 103/143 (72.0%) | 225/364 (61.8%) | p = 0.030 | |
Death | 1/143 (0.7%) | 6/364 (1.6%) | p = 0.410 | |
MDI | p = 0.465 | |||
91/124 (73.4%) | 239/303 (78.9%) | |||
50–70 | 16/124 (12.9%) | 32/303 (10.6%) | ||
17/124 (13.7%) | 32/303 (10.6%) | |||
PDI | p = 0.116 | |||
92/115 (80.0%) | 237/281 (84.3%) | |||
50–70 | 8/115 (7.0%) | 25/281 (8.9%) | ||
15/115 (13.0%) | 19/281 (6.8%) |
ACS, antenatal corticosteroid administration; APGAR, Appearance, Pulse, Grimace,
Activity, and Respiration; UA, Umbilical artery; BPD, bronchopulmonary dysplasia; NEC, necrotizing
enterocolitis; IVH, intraventricular hemorrhage; ROP, retinopathy of prematurity;
MDI, mental development index; PDI, psychomotor development index. Bold is used
to show significance under p
75.0% of the newborns between 22
Weeks of pregnancy | Total | ||
22 |
6 | 2 | 8 |
23 |
32 | 21 | 53 |
24 |
19 | 42 | 61 |
25 |
20 | 70 | 90 |
26 |
21 | 57 | 78 |
27 |
13 | 68 | 81 |
28 |
26 | 54 | 80 |
29 |
13 | 70 | 83 |
Total | 150 | 384 | 534 |
This study shows that 75% of newborns between 22
The main admission diagnoses for the
One of the largest studies researching ACS in very preterm infants concluded
that even ACS given only hours before delivery may be effective. The EPICE
research group published data from 4594 infants born between 24 and 31
gestational weeks. Approximately 40.7% of the women received ACS within the
optimal time frame of 24 hours to seven days before delivery [10]. Our
percentages of surfactant use were lower than those reported in the EPICE cohort
(
The original dosing regimen of betamethasone (12 mg injections intramuscularly, 24 hours apart) leads to a maternal plasma concentration of approximately 100 ng/mL 1 hour after treatment and a fetal concentration of 20 ng/mL 2 hours after administration. The half-life in fetal plasma was estimated to be 12 hours [21, 22]. Our data confirmed a protective effect when administered under 24 hours.
While it is known that corticosteroids support surfactant production, leading to
decreased respiratory distress in fetal lungs (in vivo and in animal
models), it is important to note that surfactant is not the sole factor in
preventing RDS [22, 23, 24]. There are other molecular mechanisms triggered by ACS
that aid in fetal lung processes. BPD, for instance, is a complex pulmonary
complication that may be reduced in newborns with optimal ACS timing. In our
cohort the highest BPD incidences were in the
Our study features several strengths, including a large cohort size, long-term
follow-up (including MDI and PDI), and a low gestational age (beginning at
22
We are limited in prevention of preterm delivery and have seen, in spite of technological advances, that the rate of preterm delivery is not decreasing. Optimal timed ACS is effective in prevention of numerous adverse outcomes. Gestational age at delivery plays a substantial role in short- and long-term outcomes, such as BPD and IVH. Although more studies are needed, the current study showed that the rate of neonatal outcomes, such as NEC, neurodevelopment at 2 years of age, and ROP, are not negatively influenced by shorter ACS intervals.
ACS, antenatal corticosteroids administration; BPD, bronchopulmonary dysplasia; ROP, retinopathy of prematurity; NEC, necrotizing enterocolitis; IVH, intraventricular hemorrhage; MDI, Mental Development Index; PDI, Psychomotor Development Index; EPICE, Effective Perinatal Intensive Care in Europe.
Available upon written request through the corresponding author.
KK was responsible for conceptualization, data curation, formal analysis, writing—original draft, review, and editing. LS was responsible for conceptualization, data curation, writing—review and editing. TF was responsible for formal analysis, writing—critical review and editing. JE, MD, AP, HB, SC, WJ, PS and BH were responsible for acquisition and interpretation of data, writing—review and editing. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the University of Ulm (Record number 445/18, accepted March 2019). Informed consent was waived because of the retrospective nature of the study and the analysis used anonymous clinical data.
The authors would like to thank Prof. Dr. Frank Reister for his support and input for this study.
This research received no external funding.
The authors declare no conflict of interest.
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