Clinical Opinion
org
Antenatal corticosteroids: an assessment of
anticipated benefits and potential risks
Alan H. Jobe, MD, PhD; Robert L. Goldenberg, MD
A ntenatal corticosteroids (ACS) are
standard of care in high-income
and many middle-income countries to
improve the outcomes of infants born
prematurely. However, the knowledge
bases for benefits and risks for the
different populations presently being
considered for treatment are less secure
than generally appreciated. We provide
our perspective on the clinical studies for
the current and expanding populations
being considered for ACS treatment. We
will supplement the discussion with
results from animal models that frame
the biology of ACS effects on the fetus
relevant to benefits and risks of ACS in
human beings. Although the body of
clinical and research information is vast,
much of the information is dated for at-
risk populations today. Recent random-
ized controlled trials (RCTs) tested ACS
in populations that are at low risk of
adverse outcomes. Large cohorts and
epidemiology reports may over-
emphasize the benefits and underesti-
mate the risks of ACS for very preterm
infants. In experimental models, ACS are
potent mediators of lifelong health
captured by the concepts of the Devel-
opmental Origins of Health and Dis-
eases. These risks of developmental
From the Division of Neonatology, Perinatal and
Pulmonary Biology, Cincinnati Children’s
Hospital Medical Center, University of Cincinnati
School of Medicine, Cincinnati, OH (Dr Jobe);
and Department of Obstetrics and Gynecology,
Columbia University Medical Center, New York,
NY (Dr Goldenberg).
Received Feb. 21, 2018; revised March 30,
2018; accepted April 2, 2018.
Dr Jobe was supported in part by the Bill and
Melinda Gates Foundation.
The authors report no conflict of interest.
Corresponding author: Alan H. Jobe, MD, PhD.
alan.jobe@cchmc.org
0002-9378/$36.00
ª 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2018.04.007
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ajog.
Antenatal corticosteroids are standard of care for pregnancies at risk of preterm delivery
between 24-34 weeks’ gestational age. Recent trials demonstrate modest benefits from
antenatal corticosteroids for late preterm and elective cesarean deliveries, and antenatal
corticosteroids for periviable deliveries should be considered with family discussion.
However, many women with threatened preterm deliveries receive antenatal cortico-
steroids but do not deliver until >34 weeks or at term. The net effect is that a substantial
fraction of the delivery population will be exposed to antenatal corticosteroids. There are
gaps in accurate assessments of benefits of antenatal corticosteroids because the
randomized controlled trials were performed prior to about 1990 in pregnancies
generally >28 weeks. The care practices for the mother and infant survival were
different than today. The randomized controlled trial data also do not strongly support the
optimal interval from antenatal corticosteroid treatment to delivery of 1-7 days.
Epidemiology-based studies using large cohorts with >85% of at-risk pregnancies
treated with antenatal corticosteroids probably overestimate the benefits of antenatal
corticosteroids. Although most of the prematurity-associated mortality is in low-resource
environments, the efficacy and safety of antenatal corticosteroids in those environments
remain to be evaluated. The short-term benefits of antenatal corticosteroids for high-risk
pregnancies in high-resource environments certainly justify antenatal corticosteroids as
few risks have been identified over many years. However, cardiovascular and metabolic
abnormalities have been identified in large animal models and cohorts of children
exposed to antenatal corticosteroids that are consistent with fetal programming for adult
diseases. These late effects of antenatal corticosteroids suggest caution for the
expanded use of antenatal corticosteroids beyond at-risk pregnancies at 24-34 weeks. A
way forward is to develop noninvasive fetal assessments to identify pregnancies across a
wider gestational age that could benefit from antenatal corticosteroids.
Key words: antenatal corticosteroids, intraventricular hemorrhage, necrotizing
enterocolitis, neonatal death, neonatal morbidities, neurodevelopment, prematurity,
respiratory distress syndrome
programming cannot be easily inte- weeks’ gestation pregnancies at risk of
grated into clinical decisions about ACS. preterm delivery within 1-7 days after
The combination of the poorly under- initiation of treatment.2 A single course
stood and complex biology of ACS ef- of two 12-mg doses of a 1:1 mixture
fects on the fetus, the clinical of betamethasone (Beta)-phosphate (P)
abnormalities associated with prematu- and Beta-acetate (Ac) separated by 24
rity, and the limitations of the clinical hours or four 6-mg doses of dexameth-
data will continue to plague decision asone (Dex)-P given at 12-hour intervals
making about who should be treated are the recommended treatment
with ACS. options. The World Health Organization
(WHO) supports the use of Dex-P,
Standard of care for ACS which is on their list of essential drugs,
Since the 1994 Consensus Conference is inexpensive, and is widely available.3
recommendations,1 the standard of care These recommendations are based pri-
for the use of ACS in the United States marily on the influential meta-analyses
and, with small variations, in the rest of by Crowley4 in 1995, Roberts and
the high medicaleresource world has Dalziel5 in 2006, and the updated anal-
been the treatment of virtually all 24-34 ysis in 2017.6 There are limitations to
MONTH 2018 American Journal of Obstetrics & Gynecology 1
Clinical Opinion
TABLE 1
Comparison of antenatal factors for populations exposed and not
exposed to antenatal corticosteroids: a cohort of 4594 infants 24e31
weeks’ gestation
Maternal variables
Preeclampsia
Preterm premature rupture of membrane
Delivery at level-3 unit
Deliveryeday of admission
Data abstracted from Norman et al. 16
ACS, antenatal corticosteroids.
Jobe. Antenatal corticosteroids. Am J Obstet Gynecol 2018.
generalization from these excellent ana-
lyses to current practice: the age of the
RCTs and the entrenched concept that
the benefit of ACS is for a 1- to 7-day
treatment to delivery interval.
ACS for 24-28 weeks’ pregnancies
During studies of the mechanisms of
labor in sheep, Liggins7 recognized that
fetal subjects exposed to ACS caused
early lung maturation in 1969. Liggins
and Howie8 completed the RCTreport in
1972 demonstrating the benefits of ACS.
The logo of the Cochrane Systematic
Reviews is a forest plot of 7 RCTs from
the initial meta-analysis by Crowley4 in
1995. In all, 21 RCTs of 4269 infants were
included in the 2006 meta-analysis.5 The
majority of the trials were completed
prior to 1990, and only about 100 preg-
nancies randomized to ACS delivered at
<28 weeks’ gestational age. In that era,
extremely low birthweight infants with
very low survival rates were not the focus
of concern that they are today. As new
trials for infants <34 weeks’ gestation
were viewed as unethical, there are no
recent RCTs for ACS for extremely pre-
mature fetuses. Further, these fetuses are
now also routinely exposed to maternal
antibiotics, tocolytics and magnesium
sulfate, and modern neonatal care, in-
terventions that may interact with ACS
responses.
Recently very large data sets from
research networks and clinical care
groups have been used to evaluate ACS
treatments for extremely preterm
pregnancies at risk of preterm delivery as
alternatives to RCTs. The initial ACS trials
2 American Journal of Obstetrics & Gynecology MONTH 2018
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ACS (84.6%) No ACS (14.4%)
21% 11%
29% 9%
79% 57%
18% 67%
had primary outcomes of decreased res-
piratory distress syndrome (RDS) and
mortality. However, for infants born at
<28 weeks’ gestation, the diagnosis of
RDS is imprecise with virtually all infants
coded as having RDS.9,10 Further, sur-
factant treatment soon after delivery
confounds diagnostic precision related to
lung disease. The epidemiologic research
has used primarily death and neuro-
developmental outcomes to evaluate ACS
for at-risk very preterm pregnancies. And
the apparent benefits of ACS are striking.
As examples, Carlo et al11 reported
decreased death, decreased intraventric-
ular hemorrhage (IVH), and improved
neurodevelopmental outcomes for
10,541 infants treated in the Eunice
Kennedy Shriver National Institute of
Child Health and Human Development
(NICHD) Neonatal Research Network
Centers, effects that were dose dependent
for partial relative to complete courses of
treatment.12 Travers et al13 used a Pedia-
trix database of almost 118,000 infants to
demonstrate that the number needed to
treat with ACS to decrease infant deaths
increased from 6 at 24 weeks to 798 de-
liveries at 34 weeks. An Australian cohort
study of 2549 infants at <29 weeks’
gestation reported decreased death, IVH,
and necrotizing enterocolitis for the 87%
of the population treated with ACS rela-
tive to those without treatment.14 Partial
or complete ACS treatments decreased
mortality from 41.5 to 22.7% for 11,022
infants born between 220-286 weeks in
the years 2006 through 2014 within the
NICHD Neonatal Research Network.15
These epidemiologic reports do not
ajog.org
contain much information that com-
pares the pregnancies that were or
were not given ACS. The initiatives to
achieve ACS treatments in high
medicaleresource environments as
standard of care have been remarkably
effective, with >85% of pregnancies
receiving ACS in most reports.
Our concern is that the low percent of
pregnancies not treated with ACS likely
were not comparable to the treated
population. This problem is demon-
strated in Table 1 for a European cohort
of 4594 infants with 15% of pregnancies
not exposed to ACS.16 Particularly
striking is that 67% of the no ACS pa-
tients delivered on the day of hospital
admission while only 18% of the ACS-
treated patients delivered soon after
admission. There were large differences
in the pregnancies and their manage-
ment based on ACS exposure, which
indicate that the pregnancies not treated
with ACS would be at a much higher risk
for adverse newborn outcomes. ACS
treatment is likely a very strong indicator
of the ability of the clinical team to
manage the pregnancy to the benefit of
the infant. Multivariant analyses to
compensate for pregnancy-related con-
ditions are suspect when the great ma-
jority of patients are treated with ACS.
For example, preeclampsia that requires
delivery in <24 hours at 26 weeks
without ACS differs from a managed
preeclamptic pregnancy with the same
International Statistical Classification of
Diseases, 10th Revision code that is elec-
tively delivered 5 days after ACS. There
are likely to be substantial benefits of
ACS for very preterm infants, but the
RCT data are not available to scale the
benefits. The recent results from large
databases probably overestimate death
and neurodevelopmental benefits. We
contend that the magnitude and range of
benefits of ACS at gestational ages of
23-28 weeks are not known with any
precision. There is no good solution to
the lack of contemporary information
for 24- to 34-week gestation pregnancies
as RCTs will not be performed.
Interval from treatment to benefit
Liggins and Howie8 reported in 1972
that ACS did not decrease RDS for
ajog.org
deliveries <24 or 48 hours after initia-
tion of treatment or for a treatment to
delivery interval >7 days. While many
subsequent trials did not evaluate the
treatment to delivery interval for benefit,
information from 9 trials was compiled
in the Roberts and Dalziel5 2006 meta-
analysis to support a 24-hour to 7-day
benefit interval for decreased RDS. A
secondary analysis of the same trials by
the WHO in 2015 identified that signif-
icant benefits were most consistent for
24- to 48-hour exposures with no benefit
>7-day treatment to delivery interval
(Figure 1). These assessments include
small numbers of patients and do not
provide information about very early
gestations that were not included in
these RCTs.3
There are a number of contemporary
reports about the treatment to delivery
interval for ACS. In general, the patient
numbers are low, the categorizations of
reasons for preterm delivery are incom-
plete, and convenience cohorts of at-risk
pregnancies not treated with ACS are the
comparison groups. Morales et al17
reported that ACS for pregnancies with
preterm prolonged rupture of mem-
branes improved the RDS outcome
independent of treatment to delivery
interval >7 days. The population with
ruptured membranes may be unique
because ACS interact with inflammation
to persistently augment lung maturation
in animal models.18 Sehdev et al19 also
reported no differences in neonatal
outcomes for different intervals of
treatment, but there was no comparison
to a population that did not get ACS.
Peaceman et al20 noted increased need
for respiratory support for infants
delivered >7 days compared to <7 days
after ACS, but without a no-ACS group,
attribution of the late complication to
ACS is speculative. Ring et al21 in 2007
also reported an increased risk of respi-
ratory disease for infants delivered >14
days after ACS relative to the <14-day
group, but the groups may have
differed for other reasons. Finally, Kuk
et al22 reported from Korea in 2013 that
ACS decreased RDS in twin pregnancies
only for a treatment to delivery interval
of 2-7 days. These reports and other
similar reports give varied outcomes but
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Clinical Opinion
FIGURE 1
Outcome relative to treatment to delivery intervals
Outcome Interval
Neonatal deaths <24 hr.
<48 hr.
1-7 days
>7 days
Respiratory Distress
Syndrome
<24 hr.
<48 hr.
1-7 days
>7 days
Intraventricular
<24 hr.
hemorrhage
<48 hr.
1-7 days
>7 days
0.01 0.1 1 10
ACS Benefit ACS Risk
World Health Organization (WHO) analysis of single-dose antenatal corticosteroids (ACS) for
outcomes relative to intervals from treatment to delivery. Data from WHO recommendations on
interventions to improve preterm birth outcomes, 2015.3
Jobe. Antenatal corticosteroids. Am J Obstet Gynecol 2018.
suggest lack of efficiency and the for treatment intervals for both <7 days
potential for increased risks of ACS and >7 days relative to no ACS, but
>7-14 days. again the comparison group was not
The very large perinatal databases do comparable.14
not usually contain sufficiently granular Experimental results with animals
data to address the treatment to delivery help address the question of treatment to
interval question. There generally is no response interval for ACS. Although
time identified for when ACS could have single and repeated doses of maternal
been given to the approximately 15% of corticosteroids have been evaluated in
the population not treated with ACS. rodent models, the short gestations are
Further, the no-ACS pregnancies likely not informative for treatment to delivery
had different complications and were intervals of days or weeks. Studies in
not treated with ACS for reasons that sheep were oriented toward questions
were not specified. These problems are about repetitive dosing of ACS, but they
illustrated by the comparisons of preg- do provide some information. Following
nancy and delivery variables in the fetal intramuscular (IM) treatment with
Norman et al16 report that associated a single high dose of 0.5 mg/kg of Beta-
ACS with increased survival for treat- Ac þ Beta-P, newborn lambs had the
ment to delivery intervals >3 hours same improvements in lung function 2,
(Table 1). There also was a lack of benefit 4, or 7 days after ACS compared to
>7 days using the pooled no-ACS group saline-treated controls.23 Maternal IM
for comparison. These results are not dosing with 0.5 mg/kg of Beta-Ac þ
compelling given that the comparison Beta-P at weekly intervals from 104-124
group did not include a time when ACS days’ gestation resulted in incremental
could have been given. An Australian improvements in lung function but
report with 87.5% ACS treatment decreased fetal weight.24 Germane to this
showed benefit for survival and discussion, a single dose given 3 weeks
decreased complications of prematurity before premature delivery resulted in
MONTH 2018 American Journal of Obstetrics & Gynecology 3
Clinical Opinion
TABLE 2
Estimate of delivery populations exposed to antenatal corticosteroids
Delivery populations
Population
treated
Previable deliveries, 0.5%
<24 wk
24e34 wk Deliveries 3%
34 e36 wk Deliveries
0 6
7%
Elective cesarean 15e70%
delivery >370 wk
Jobe. Antenatal corticosteroids. Am J Obstet Gynecol 2018.
modest and persistent improvements in
lung function. The residual lung matu-
rational signals could be interpreted as a
decrease in response or a gestationally
dependent decreased response. The
messenger RNA (mRNA) for the sur-
factant proteins SP-A, SP-B, and SP-C
increased after maternal Beta-Ac þ
Beta-P at 1 and 2 days but decreased over
time to 14 days, suggesting an attenua-
tion of the maturation response.25 Thus,
fetal sheep experiments with high-dose
fetal or maternal treatments do not
suggest loss of the physiological benefits
of ACS, although surfactant protein
mRNA decreased. With explants of fetal
human lung, Ballard and Ballard26
demonstrated increased SP-B and SP-C
mRNA with cortisol treatment for 24
hours, but the surfactant protein
mRNAs returned to control levels after
removal of cortisol. Continued exposure
to cortisol maintained the increased
SP-B and SP-C mRNA expression.
The RCT data from before 1994 were
arbitrarily divided into treatment to
delivery intervals of <24 hours, 1-7 days,
and >7 days. There was no granularity to
the data to further resolve the time in-
tervals. These old studies are the best
information indicating decreased effec-
tiveness >7 days. Very few infants were
delivered at <28 weeks’ gestational age
and thus the RCT data do not reflect
current high-risk patient populations.
The clinical reports are not helpful
because of poorly described populations.
The large epidemiology reports generally
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Treatments Total population
off-target potentially
exposure treated
>0.5% >1%
3% 6%
4% 11%
e 15e70%
Total deliveries 33e78%
contain no information on treatment to
delivery interval. When considered
together, the clinical results support the
effectiveness of ACS for a treatment to
delivery interval of 1-7 days. But there
are no analyses that address the period of
maximal benefit or the profile for loss of
effectivenesseis this at 5 days, 7 days, 10
days, or longer? The experimental results
in sheep do not demonstrate an attenu-
ation of efficacy >7 days, although
dosing strategies were different from
clinical reports. The question of the
optimal treatment to delivery interval
has not been adequately addressed, but
the ACS response interval is important
for considerations of timing of deliveries
and for repeat ACS treatments.
Expanding use of ACS: periviable
pregnancies
Routine use of ACS for pregnancies at
risk of preterm delivery for gestations
between 24-34 weeks is being expanded
by new clinical trials that potentially
could include a majority of deliveries. A
NICHD workshop in 2004 evaluated the
possible benefits of ACS for periviable
pregnancies at risk for delivery >20-
week gestations.27 The Obstetric Care
Consensus no. 6 for 2017 defined peri-
viable as 200-256 weeks and recom-
mended consideration of ACS in
discussion with the family.28 The reality
on the ground is that many 22- to 23-
week pregnancies are being treated,
with the percent increasing yearly. ACS
are associated with increased survival at
ajog.org
22-23 weeks in recent large data sets.
However, there likely is substantial se-
lection of which pregnancies are treated
and for the level of care offered to these
very preterm infants who have very high
probabilities of adverse outcomes. As
there are no RCT data for this popula-
tion, the magnitude of possible benefits
or risks are not known, and RCTs are
unlikely to be performed.
Experimental studies support the po-
tential for substantial benefit of ACS at
periviable gestations. Corticosteroids
will accelerate maturation in explants of
human lungs as early as 12 weeks’
gestational age.29 Maternal ACS treat-
ment of Rhesus monkeys at very early
gestational ages will alter lung structural
development toward maturation.30 A
recent report demonstrated partial
maturational responses at 60% gestation
relative to 80% gestation in sheep.31
Thus, it is biologically very likely that
ACS will have substantial developmental
effects on the preterm human fetus, but
information about those effects in the
human are lacking. About 0.5% of de-
liveries occur in the previable gestational
age range (Table 2), but an unknown
number of pregnancies will be identified
as at risk, be treated with ACS, and will
not deliver for weeks or until term.
There is no information about the out-
comes for periviable fetuses exposed to
ACS then delivered at later preterm
gestational ages or at term.
Expanding use of ACS: 34- to 37-
week gestation
Concurrently with the 1994 National
Institutes of Health (NIH) Consensus
Conference, Sinclair32 demonstrated
with RCT data that ACS probably
decreased RDS for late preterm gesta-
tions but with a number needed to treat
of about 94 at 34 weeks’ gestational age.
Based on the limited information avail-
able at the time the upper gestational age
for use of ACS was proposed as 32 or 34
weeks. However, the incidence of both
RDS and transient tachypnea increase as
gestational age at deliveries decrease
from 38 weeks.33 Over the subsequent 20
plus years, ACS have been variably used
for deliveries >32 weeks’ gestation
thought to be at risk or with amniotic
ajog.org
fluid tests indicating immaturity. Three
RCTs recently evaluated ACS treatments
for 340- to 366-week gestations for inci-
dence of RDS and for composite adverse
outcomes. With 2831 randomized
pregnancies in the NICHD-sponsored
ALPS trial, ACS decreased composite
adverse outcomes from 14.4-11.6%
(P ¼ .023) and decreased respiratory
morbidity from 12.1-8.1% (P < .001)
but without a mortality benefit.34 A risk
was increased hypoglycemia in infants
from 15-24% (P ¼ .001). The American
Congress of Obstetricians and Gynecol-
ogists (ACOG) Committee quickly rec-
ommended use of ACS in 2016 for the
majority of late preterm pregnancies,
excluding those previously receiving
ACS, with pregestational diabetes, or
clinical chorioamnionitis.35 Multiple
editorials have supported or questioned
the recommendations, primarily
because of different judgements as to the
balance between the modest benefits
relative to potential risks that include
hypoglycemia and developmental pro-
gramming.36-38 The indication of ACS
for late preterm infants expands ACS to
approximately 7% of the delivery pop-
ulation (Table 2). Souter et al39 estimated
that about 80% of late preterm infants
would be eligible for ACS, but as with
ACS use at earlier gestations, exclusions
likely will decrease with widespread use.
There is no international consensus as to
the use of ACS >34 weeks.
Expanding use of ACS: elective
cesarean delivery at term
Infants born by cesarean delivery without
labor have more respiratory symptoms
and neonatal adaptation problems than
infants born vaginally or with labor prior
to cesarean delivery.40 Stutchfield et al41
hypothesized that ACS initiated 48
hours before elective cesarean delivery
could decrease these neonatal transition
abnormalities. They demonstrated that
ACS decreased neonatal intensive care
unit admission and qualitatively
decreased respiratory findings, effects
that decreased as gestation at cesarean
delivery increased. Two other smaller
trials demonstrated similar benefits,42,43
while a more recent trial from Egypt
reported no benefit of randomizing ACS
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to 1272 cesarean delivery patients.44 A
metanalysis by Saccone and Berghella45 of
6 late preterm and term trials reported a
significant 1.7% decrease in RDS, 3.2%
decrease in transient tachypnea, and 0.9%
decrease in severe RDS with no difference
in mortality. The decreased morbidity
may save medical resources but does not
translate to substantial changes in short-
term outcomes. The routine use of ACS
for elective cesarean delivery would
greatly expand the population exposed to
ACS from about 10-20% of the delivery
population to >70% if all deliveries were
treated in environments where elective
cesarean deliveries are routine for normal
pregnancies (Table 2).
Deliveries after the treatment to
benefit interval
The (presumed) window of efficacy for
ACS exposures is 1-7 days. Deliveries >7
days after ACS may not benefit and
may be at increased risk. We define
these deliveries >7 days as off-target.
Deliveries at <24 hours after treatment
may benefit from ACS and should not be
considered off-target. For previable
pregnancies identified as being at risk,
many deliveries may occur weeks beyond
the previable window and thus ACS
treatments will be off-target. The suc-
cessful application of standard of care for
ACS to treat all at-risk pregnancies at 24-
to 34-week gestation results in many de-
liveries >7-day window or >34 weeks.
The large data sets poorly document de-
liveries beyond the degree of prematurity
of interest. Makhija et al46 retrospectively
analyzed treatment to delivery intervals
for infants treated at 24-34 weeks, and
about 15% delivered at <48 hours and
60% delivered >7 days. For RCTs of
repeated ACS, 35% of deliveries occurred
>34 weeks in the ACTORDS trial,47 70%
delivered >33-week gestation in the
MACS trial,48 and 78% delivered >32
weeks in the NICHD trial.49 Many of
these infants delivered at term. Thus, ACS
treatments are often off-target relative to
the desired treatment to delivery interval
or gestational age. These populations of
ACS-treated patients are seldom consid-
ered for risk or benefit.
Another off-target treatment variant is
treatment of women with a potential risk
MONTH 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
of preterm delivery based on a previous
pregnancy outcomeean “anticipatory”
or “prophylactic” treatment. Such usage
in women without an indication that
preterm delivery is likely has not been
recommended. However, such treat-
ments do occur in practice for women
with a history of preeclampsia for
example. Such treatments result from
the impression by the clinician that ACS
are without risks.
ACS in low-resource environments
In contrast to the effective use of
ACS for at-risk pregnancies in high
medicaleresource environments, their
use is extremely variable in low- and
middle-income countries. Generally, the
therapy is only available in the few
medical facilities that can provide higher
levels of care.50 Nevertheless, the pro-
motion of ACS use is the number 1 of 10
recommendations by the WHO to
decrease the prematurity-related mor-
tality and morbidity in low-resource
environments.3 Prematurity-related
mortality is the major contributor to
infant mortality worldwide that is not
decreasing.51 The challenges in low-
resource environments are identifica-
tion of pregnancies at risk, initiation of
therapy, and improving delivery out-
comes with basic levels of obstetric and
neonatal care. ACS have been minimally
trialed for safety and efficacy in low-
resource environments. The NICHD
Global Research Network reported the
cluster randomized ACT trial of about
100,000 pregnancies to evaluate the
ability to recognize pregnancies at risk of
preterm delivery, to give ACS treatment
with 4 doses of Dex-P, and to recom-
mend delivery in medical facilities vs
routine care in very low-resource loca-
tions in Africa, Southeast Asia, and
South and Central America.52 Many of
the women and their newborns were
cared for at home or in low-level clinics.
Because ultrasound was generally not
available and gestational age not known
with precision, the target population was
women who were believed likely to
deliver an infant weighing <5th
percentile birthweight. The primary
outcome of decreased neonatal mortality
for infants with birthweight <5th
5
Clinical Opinion
percentile was unchanged, but perinatal
mortality of larger infants was signifi-
cantly increased, an unanticipated
outcome of great concern.
The trial interventions successfully
increased ACS use for the <5th percen-
tile infants from 10-45% but also
increased the treatment of presumably
more mature fetuses because accurate
gestational age information was often
not available. Secondary analyses sug-
gested ACS contributed to the increased
mortality by increased suspected
maternal infection.53 Other factors may
have been maternal nutrition and gen-
eral health, malaria and other chronic
infections, or environmental stresses
that contribute to prematurity. Another
concern is that the late preterm infants
may be the population who would
maximally benefit because of their sub-
stantial morality in low-resource envi-
ronments. The newborn hypoglycemia
identified in the ALPS trial likely will not
be identified or treated in low-resource
environments. Further, Jolley et al54
demonstrated that the standard ACS
treatment that is not weight adjusted
caused more severe and prolonged
maternal hyperglycemia in women with
lower body mass index (BMI), suggest-
ing that ACS may cause more severe re-
flex hypoglycemia in newborns delivered
from women with low BMI in low-
resource environments.
An effective therapy in high-resource
environments may be ineffective or
harmful in low-resource environments.
We agree with the 2015 WHO recom-
mendations that ACS be used only when
gestational age can be accurately
assessed, birth is likely to be imminent
(1-7 days from treatment), there is no
clinical evidence of maternal infection,
and adequate levels of delivery and
neonatal care are available.3 However, a
caution is that the efficacy and safety of
ACS remain untested even when these
criteria are met in low-resource envi-
ronments. The need for an efficacy trial
is justified by the uncertain risks and
benefits in these environments.55 The
Bill and Melinda Gates Foundation and
WHO have initiated RCTs of ACS in
hospitals providing some level of
maternal and neonatal care to test
6 American Journal of Obstetrics & Gynecology MONTH 2018
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efficacy of ACS for deliveries <34 weeks’
gestational age and for late preterm
infants.
Benefits of ACS
The primary benefits of ACS historically
were a decrease in RDS and mortality.
But the pleotropic effects of ACS on the
developing fetus also decreased other
severe pathologies in premature infants,
including IVH, necrotizing enterocolitis,
and postnatal sepsis. The magnitudes of
the benefits were well calibrated for the
populations included in the RCT trials
prior to 1994.5 However, the target
treatment population of 24-to 34-week
gestation pregnancies at risk now
include more extremely preterm preg-
nancies. These pregnancies are managed
differently today and neonatal care with
surfactant treatment for RDS, improved
nutrition, and ventilation strategies have
greatly changed outcomes.56 There is no
current RCT information about the
benefits of ACS for the pregnancies of
most concern today. As discussed above,
the epidemiologic studies are flawed by
comparison groups that are not com-
parable to the treatment groups.
Other less well-described clinical
benefits of ACS may contribute to the
survival of very preterm infants. These
include ACS effects on neonatal
adaptationeincreased blood pressure
and cardiovascular adaptation, better
metabolic transition, improved kidney
function, and skin cornification with less
transdermal water loss.57 These effects of
ACS have been well described in animal
models. ACS decrease the large increases
in catecholamines that occur after pre-
term birth in human beings and sheep
while increasing blood pressure and
cardiac contractility in sheep.58-60
Similar effects have been reported in
preterm human beings. ACS increase
glomerular filtration rate and sodium
reabsorption by the kidney in sheep,
baboons, and human beings.61,62 ACS
also improves neuroendocrine and
endocrine responses to a postdelivery
hypoxic challenge.63 These benefits likely
interact to improve neonatal transition,
which are captured by the composite
outcomes used in ACS trials for late
preterm and term deliveries. Benefits in
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childhood from the early trials indicate
no adverse effects on postnatal growth or
lung function.5 ACS were associated with
less developmental delay and a trend
toward less cerebral palsy. Psychological
development also was comparable
between ACS-exposed and control in-
fants in a report from 1990.64 Overall,
ACS have proved to be remarkably safe
without short-term adverse effects being
identified over many years of use.
Further, ACS have not been associated
with adverse maternal or fetal effects
across multiple pregnancy-related
problems such as chorioamnionitis,
fetal growth restriction, and preeclamp-
sia.5 A caution is that the benefits were
measured in predominantly larger and
more mature infants that today have very
low mortality and few acute complica-
tions of prematurity.
Risks of ACS
Concerns about ACS can be divided into
short-term adverse effects, early child-
hood effects, and very long-term fetal/
neonatal programming within the
context of the developmental origins of
health and disease. For late preterm
pregnancies, ACS increase the risk of
hypoglycemia in newborns.34 Further,
women with a low BMI given ACS have
more severe and more prolonged hy-
perglycemia than women with a high
BMI.54 Infants born in low-resource
environments from women with low
BMI may be at substantial risk for hy-
poglycemia that likely would not be
detected or treated. In newborns in
general, neonatal hypoglycemia often
was not detected by routine monitoring
but nevertheless was associated with
poor cognitive function and motor
function at 4.5 years of age.65 It is worth
remembering that even short-term use
of corticosteroids in adults is associated
with sepsis, venous thrombosis, and
fracture.66 Corticosteroids are potent
drugs with real risks independent from
pregnancy.
To assess the delayed effects of fetal
exposures in later life, cohorts must be
followed up for decades. Prematurity
independent of ACS may contribute to
adverse outcomes. A recent report illus-
trates that even threatened preterm labor
ajog.org
may alter outcomes.67 Threatened pre-
term labor evaluated by a brief hospital
admission with antibiotics, magnesium
sulfate, tocolytic, and ACS treatments
followed by delivery at term was associ-
ated with impaired cognitive develop-
ment at 2 years relative to term deliveries
without threatened preterm labor.
Perhaps the ACS contributed to the
adverse outcome.68 Another report with
cohorts of term infants exposed or not
exposed to ACS as preterm fetuses
identified decreased IQ for both preterm
cohorts delivered at term relative to
normal-term infants, suggesting that
abnormalities identified at preterm ges-
tations and not ACS caused the injury.69
Without randomization, these cohort
studies must be cautiously interpreted.
Brain effects from ACS may be inter-
preted as injury, induced early matura-
tion, or programming effects and have
been a persistent concern, despite
decreased IVH with ACS. Uno et al70 in
1990 reported that maternal Dex caused
morphologic hippocampal injury in fetal
monkeys. Similar findings in 2012 were
identified in necropsy specimens from
neonates exposed to ACS.71 These ob-
servations are consistent with animal
studies demonstrating that ACS alter
hippocampal mRNA expression, DNA
methylation, and development that can
be detected into the third generation in
guinea pigs.72-74 Programming effects
often have a sex bias, and Rodriguez
et al75 demonstrated that clinical doses
of ACS had sex-specific effects on
learning in young baboons at about 3
years of age. Adults recruited from a
clinical cohort of very lowebirthweight
infants from 1977 through 1982 had
significantly more psychopathology at
29-36 years of age if exposed to ACS.76
Preterm infants on average have lower
IQ and motor function than infants
born at term and may be less resilient
to stress and injury.77 Multiple
interventions over many years to im-
prove outcomeseimproved postdelivery
nutrition with human milk and nutrient
supplements,78,79 decreased environ-
mental stress with developmental care,80
and decreased pain exposures with less
intensive interventions81ehave not had
substantial effects on outcomes. The
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inability to change the IQ differential of
prematurity suggests that developmental
effects from prematurity cannot be easily
altered by care strategies. A core concept
is that ACS are delivering a stress signal
to the fetus who normally is exposed to
very low levels of corticosteroids. Fetal
corticosteroid exposure normally is
greatly restricted because the placenta
limits maternal cortisol access to the
fetus and the fetal synthesis of cortisol is
low until term.82 Glucocorticoids
consistently decrease growth and pro-
mote differentiation in developing sys-
tems and are a developmental modulator
of stress responses.83 A clinical example
of ACS modulating later stress responses
was reported by Alexander et al.84 A
single off-target course of ACS given on
average at 30 weeks’ gestation with de-
livery at term was associated with
increased cortisol secretion to psycho-
logical stress in 6- to 11-year-old females
relative to normal-term controls.
Kidney function can be matured by
ACS exposure in preterm fetuses, but a
potential cost is decreased function later
in life. There is some information about
long-term kidney outcomes for preterm
infants exposed to ACS. In a cohort
study, adolescents exposed to ACS and
born prematurely had abnormal renin
angiotensin system function relative to a
preterm cohort not exposed to ACS.85 In
fetal sheep, a clinical treatment with
Beta-Ac þ Beta-P decreased glomerular
numbers by 26%,86 an effect that per-
sisted to 7 years of age for fetal exposure
to Dex.87 The 6-year-old subjects from
the Liggins trial exposed to ACS had
blood pressures similar to controls.88
However, effects of prematurity and
ACS on kidney function in later in life
remain to be evaluated in extremely
preterm infants.
Assessments of long-term cardiovas-
cular and metabolic effects of ACS from
RCTs are limited and include relatively
mature premature infants from the early
studies. Dalziel et al89 reported no dif-
ferences in growth, blood pressure,
blood lipids, or cortisol at 30-year
follow-up. Diabetes or cardiovascular
disease were not different, but a glucose
tolerance test yielded higher insulin
levels at 30 minutes for those with ACS
MONTH 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
exposure, suggesting some insulin resis-
tance for adults with mean birthweights
of 2.3 kg. Kelly et al90 also identified
altered glucose metabolism in a more
immature cohort at 23-28 years of age.
ACS treatment and preterm delivery did
not alter insulin action in adult sheep,91
but early pregnancy cortisol exposure
altered glucose homeostasis and caused
hyperinsulinemia in 4-year-old male
sheep delivered at term.92 In a cohort
study of preterm infants with birth-
weight averaging 1.1 kg, the 14-year-old
children exposed to ACS had higher
systolic and diastolic blood pressures
than unexposed children, but few of the
children were hypertensive.93 In another
recent cohort study, ACS-exposed young
adults at 23-28 years of age and with
average birthweights of 1.2 kg had
decreased aortic distensibility relative
to controls, a concern for future
cardiovascular disease.90 Functional
assessment of heart rate variability in
14-year-old females exposed to ACS was
decreased relative to controls.94 ACS
given at term increased adiposity in adult
female sheep and ACS caused pericardial
and liver fat accumulation in adult male
baboons.95 ACS effects on glucose
metabolism were modeled by fetal ACS
exposure followed by term delivery and
feeding to achieve normal or obese sheep
at 1 year. Sex and ACS interacted to cause
glucose intolerance in lean females but
not males, and obesity and ACS resulted
in worse glucose intolerance in females
and unmasked glucose tolerance in
males. The varied effects of ACS were
sex-specific and gestational age of
exposure specific in adult large animals.
These results are consistent with pro-
gramming that has been evaluated in
more detail in small animals.96 This
discussion is a sampling of multiple ob-
servations suggesting long-term adverse
effects of ACS on cardiovascular perfor-
mance, tempered by the cohort nature of
the clinical studies.
ACS decreased birthweights following
preterm delivery in multiple animal
models. The effect on birthweight was
not significant for a single course of ACS
in human beings, but growth effects
were apparent for repeated ACS treat-
ments.97,98 A cohort analysis by Braun
7
Clinical Opinion
TABLE 3
Comparison of outcomes for single vs repeated antenatal corticosteroid
treatments with betamethasone-acetate D betamethasone-phosphate
Neonatal death
Respiratory distress syndrome
Intraventricular hemorrhage
Necrotizing enterocolitis
Patent ductus arteriosus
Birthweight
Head circumference
Data abstracted from Roberts et al6 in 2017, and Crowther, et al97 in 2015.
þStatistical benefit; eno benefit.
Jobe. Antenatal corticosteroids. Am J Obstet Gynecol 2018.
et al99 identified that infants exposed
to ACS <34 weeks and delivered from
34 weeks to term were lighter than
unexposed infants. Weight differences
did not persist into childhood or adult-
hood. However, ACS effects on fetal
growth represent a pathway to adverse
outcomes as fetal growth restriction is
closely associated with increased bron-
chopulmonary dysplasia, infant mortal-
ity, and poor neurodevelopmental
outcomes.100
Repeat ACS treatments
An initial ACS treatment decreased RDS
by about 35%, but many patients
thought to be at risk for delivery within 7
days of treatment do not deliver and are
considered to be still at risk of delivery
<34 weeks’ gestational age. With con-
cerns of increased respiratory morbidity
for deliveries >7 days, the controversial
practice of retreatment 1 times at 7- to
14-day intervals became common prac-
tice resulting in a second NIH-sponsored
consensus conference in 2000 to assess
repeated treatments.101 The recommen-
dation was to not repeat treatments
outside of randomized trials. A 2011102
Cochrane library meta-analysis of RCTs
was updated in 201597 to include 10
trials of 4733 women and 5700 infants.
The repeated treatments were with the
1:1 mixture of Beta-Ac þ Beta-P in all
trials. Use of repeated doses significantly
decreased RDS (risk ratio, 0.83; confi-
dence interval, 0.75e0.91) with a
8 American Journal of Obstetrics & Gynecology MONTH 2018
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Single Repeat
þ e
þ þ
þ e
þ e
þ þ
e Decreased
e Decreased
number needed to treat for benefit of 17,
and decreased a composite of serious
infant outcomes (risk ratio, 0.84; confi-
dence interval, 0.75e94), with a number
needed to treat of 30. The pattern of
benefits differed from those achieved
with a single exposure (Table 3). There
were no benefits for mortality, IVH, or
necrotizing enterocolitis. Birthweights,
head circumferences, and lengths were
decreased in repeated treatment groups.
The authors of the meta-analysis rec-
ommended use of repeated courses of
ACS selectively. The ACOG Committee
opinion in 2016 was that a repeat course
of ACS should be considered for women
<34 weeks who were treated 14 days
previously and who were likely to deliver
within the next 7 days.103
The repeated ACS trials were per-
formed after the single treatment trials in
the more current era from 2002 through
2010 and included surfactant treat-
ments. The average delivery gestations
and birthweights were lower for at-risk
pregnancies in the gestational window
of 24-34 weeks. As the beneficial effects
were less and without a mortality benefit,
the indication for repeated treatment
was less compelling. Further, the risks
resulting from off-target treatments for
pregnancies that delivered >32-34 weeks
were substantiale36% of repeated-
dosed patients delivered at >34 weeks
in the ACTORDS trial,47 66% of patients
delivered at >33 weeks in the MACS
trial,48 and 76% of the patients delivered
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at >32 weeks in the NICHD trial.104
Thus, many pregnancies were exposed
to repeated courses of ACS and delivered
off-target at gestational ages that were at
relatively low risk for the newborn.
Reassuring results from 3 trials with
follow-up were that neurodevelop-
mental outcomes in early childhood
were comparable between a single
treatment and repeated treatments.97
Childhood outcomes at 6-8 years also
were comparable between treatment
groups for neurodevelopment, growth,
lung function, blood pressure, bone
mass, and survival free of neurosensory
disability.105-107 A caution is an analysis
by Wapner et al49 that identified a trend
toward increased cerebral palsy with
repeated ACS treatments. However, the
overall lack of early childhood toxicity
does modulate concerns that ACS
interfere substantially with neuro-
development. No outcomes in later life
are available. The general consensus is
that multiple repeated courses are not
indicated but that a single treatment >7
days and <34 weeks is reasonable when
preterm delivery is imminentedefined
generally as within the next 7 days.
Drugs, doses, and treatment interval
Most trials have evaluated the mixture
of 2 prodrugs: Beta-P, which is soluble
and rapidly dephosphorylated to Beta;
and the milled form of Beta-Ac, which
is slowly deacetylated to Beta. Beta is
the drug that crosses the placenta to
produce fetal effects. Dosing has been
as 12 mg of Beta-P þ Beta-Ac given at
recognition of a risk of preterm delivery
and a second 12-mg dose 24 hours
later. This treatment has been the most
tested drug in RCTs of single doses and
was used exclusively for RCTs of
repeated treatments.97,108 The alternate
treatment tested in RCTs is 4 doses of 6
mg of Dex-P given at 12-hour intervals.
The Dex-P is rapidly dephosphorylated
to Dex. which crosses the placenta. The
Beta and Dex treatments have been
evaluated by meta-analysis with sub-
stantially similar outcomes.108 A trial
comparing Beta-Ac þ Beta-P with 2
doses of 12 mg. Dex-P given at a 24-
hour interval should be completed
soon.109 Other dosing schemes have
ajog.org
been reported but minimally tested for
efficiency or safety. These treatment
schemes have been used empirically
without pharmacologic evaluations to
optimize treatments or to decrease
maternal and fetal exposures.
The phosphorylated steroids rapidly
reach high peak levels in the mother and
peak levels in the fetus that are about
30% of maternal values.26,110 The drugs
then are cleared rapidly from mother
and fetus with an initial half-life of about
4 hours.110 In fetal sheep models of lung
maturation, the maternal IM 2-dose
Beta-Ac þ Beta-P treatment is equiva-
lent to the 4-dose Dex-P treatment,
while a 2-dose/24-hour interval treat-
ment with Beta-P or Dex-P was less
effective, demonstrating that dose fre-
quency and interval are important.111
Further, maternal constant infusions
with Beta-P can achieve lung maturation
if fetal exposures remain in the range of
1-4 ng/mL for >24 hours.112 A single
maternal treatment with 0.125 mg/kg of
Beta-Ac maintains fetal plasma levels in
the 1-4 ng/mL for about 24 hours and
avoids the initial high maternal and fetal
Beta levels. Beta-Ac alone effectively
induces fetal lung maturation in sheep
and primate models.113 Therefore, high
peak steroid levels from IM dosing
with phosphorylated steroids are
not contributing to lung maturational
responses and may simply represent
potential toxicity. As concerns about
long-term effects are substantial and
steroid responses are dose sensitive, ACS
treatments that deliver the lowest fetal
exposure for the shortest interval should
be a goal.
The knowns and unknowns about
ACS
Our perspective on the benefits of ACS is
tempered by the current trends to view
ACS as both safe and effective for more
low-risk pregnancies. In the extreme, the
pregnant population that would not
receive ACS would be only term
nonelective cesarean deliveries and term
normal vaginal deliveries not associated
with abnormalities earlier in pregnancy
(Table 2). Kaempf and Suresh38 recently
used the framework of the knowns and
unknowns for a discussion of the
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FIGURE 2
The known and unknown risks and benefits of antenatal corticosteroids
Known – Known
Benefits
24-34 weeks – decreased RDS, IVH, NEC,
death
Late Preterm and Elecve C-secon: Less
respiratory morbidity.
Risks
24-34 weeks – none idenfied
Late Preterm: Hypoglycemia
Known – Unknowns
Benefits
Improved outcomes for periviable
preterms.
Risks
Fetal programming –
neurodevelopmental, cardiovascular, and
metabolic abnormalies in later life.
Scheme for what is known and unknown about antenatal corticosteroid risks and benefits.
C-section, cesarean delivery; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; RDS, respiratory distress syndrome.
Jobe. Antenatal corticosteroids. Am J Obstet Gynecol 2018.
benefits and risks of ACS (Figure 2). The
known-knowns are the benefits of ACS
in the target populationsedecreased
respiratory morbidity, other decreased
complications of prematurity, and death.
These substantial benefits justify ACS,
acknowledging that information is
imperfect for deliveries <28 weeks’
gestation and for the optimal treatment
to delivery interval. Benefits from ACS
for the 7% late preterm deliveries and
elective cesarean deliveries are modest
but the net benefit to health care systems
are substantial because of large patient
numbers (Table 2). The short-term risk
of hypoglycemia in the newborn can be
easily managed in high-care environ-
ments but could be substantial in low-
resource environments.
The known-unknowns are injury
and fetal programming effects on
neurodevelopment, cardiovascular, and
metabolic outcomes, which may vary
across gestational age of exposure to
ACS. Much literature demonstrates
MONTH 2018 American Journal of Obstetrics & Gynecology
Clinical Opinion
Unknown – Knowns
Benefits
None
Risks
Effects on growth.
Off-target treatment effects with delivery
at term
Unknown – Unknowns
Benefits
Possibly
Risks
There may be surprises.
programming effects in animal models
with corticosteroids and an entire field of
epidemiology is exploring develop-
mental origins of health and diseases in
human populations. Human cohort
studies demonstrate modest effects on
cardiovascular and metabolic variables,
but we do not know if those effects have
long-term consequences. We ignore in-
formation about programming effects at
unknown risks. Treatment of a large
percent of the delivery population could
result in some large surprises in 50 years.
But without randomized cohorts to
follow up, population-based adverse ef-
fects may not be attributable to ACS.
The unknown-knowns category has
no identified benefits. We include as
known adverse effects decreased fetal
growth from animal models and the
repeat dose ACS trials. Fetal/neonatal
growth arrest from ACS is known, but it
is unknown if that arrest increases
adverse outcomes, particularly for
off-target treated infants delivered at
9
Clinical Opinion
term. The unknown-unknown category
is simply supposition that there may be
completely unanticipated risks or bene-
fits of ACS.
These considerations of what we
know and do not know must be further
tempered by the potential for in-
teractions. All preterm deliveries are
abnormal eventseresulting from multi-
ple maternal and/or fetal pathologies. At
early gestations, ACS are used with
multiple drugs such as antenatal antibi-
otics, magnesium sulfate, and tocolytics
to treat the pregnancy. There is no in-
formation on interactions with ACS. The
prototypic hormonal response to stress
is an increase in cortisol in the newborn
(eg, pain, fetal growth restriction), which
is associated with prolonged sensitiza-
tions to pain and stress in childhood.81
Why should ACS not contribute to
these phenomena?
Ways forward for ACS
We must accept that clinical decision
making for ACS is imperfect because
risks to benefits change with gestational
age and the potential for the life-
changing risks from programming are
essentially unknown in the human.
High-risk patients certainly benefit and
the accepted gestational age for treat-
ment are for deliveries at 24-34 weeks.
Treatments at earlier or later gestations
are less secure as to benefits or risks, and
parents need to be aware of the un-
certainties. Better targeting of treatments
would results from selection filters for
ACS to identify pregnancies that would
benefit from ACS. Routine amniocen-
tesis for maturational assessments are
seldom used today. There are opportu-
nities to develop new screening tools to
identify at-risk patients. Ultrasound of
the fetal lung can predict fetal lung
maturation comparably to amniotic
fluid testing.114,115 Amniotic fluid or
maternal plasma could be used for omic
profiling of mRNA, proteins, or metab-
olites to assess lung and other organ
maturation.116 The 24- to 34-week
treatment recommendation could be
revisited to avoid the treatment of the
majority of 30- to 34-week deliveries that
do not develop RDS and may not benefit
from ACS. These infants have minimal
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morbidity and essentially no mortality
with modern neonatal care. Another way
forward is to improve dosing strategies
to avoid excessive fetal exposure to ACS.
Fetal exposure to inflammation is a more
consistent and more potent stimulus to
pleotropic maturational effects than ACS
in animal models, and the combination
of ACS and inflammation further
enhance fetal maturation.117 The mo-
lecular pathways to maturation medi-
ated by both antiinflammation (steroids)
and inflammation should be explored by
omics biology to identify targets for
drugs to achieve more of the desired
elements of maturation without effects
associated with fetal programming if
possible.
Our view is that ACS is a remarkable
old therapy that needs to be reassessed
and further developed to be a better
targeted therapy designed to minimize
the long-term risks that will remain
largely undefined. ACS treatments
should be selectively used for targeted
goals to improve short-term neonatal
outcomes. A research agenda to identify
better ways of fetal assessment is clearly
justifiable as a substantial percent of the
population of tomorrow will have been
exposed to ACS. - e1-13.
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