DISCUSSION
Main findings:
Our population-based study demonstrated that publication of APLS trial
in 2016 resulted in a significant rise in the rates of any ACS
administration among infants delivered at 35-36 weeks of gestation
between 2017 and 2020 in both Nova Scotia, Canada and the United States.
Although rates of any ACS administration in each gestational age
category were lower in the United States compared with Nova Scotia,
there was a substantial temporal increase in the rates of ACS
administration from 2007 to 2020 in the United States. Among live births
delivered between 24 and 34 weeks’ gestation in Nova Scotia in 2020,
32% received the optimal dose and appropriately timed ACS, while 47%
received ACS with suboptimal timing. There was a significant reduction
in the proportion of infants born at ≥37 weeks’ gestation who received
any ACS in Nova Scotia between 2016 and 2020, while in the United
States, there was an increase in any ACS use in infants born at ≥37
weeks gestation. Approximately, 34% of infants born in Canada and 20%
in the United States, whose mothers received ACS in 2020 were born at
term gestation.
Strength and limitations:
The strengths of our study include the use of the previously validated
and clinically-focused Nova Scotia database that included detailed
information on ACS administration14. The
population-based nature of our study, with less than 2% missing
information on gestational age, is also a significant strength, and this
increases the likelihood that our findings are generalizable to a wide
range of settings. Limitations of our study include the lack of data on
the indication for steroids use and the dosage of antenatal
corticosteroid administered. Also, our data source only captured the
timing of the earliest dose of the first course of ACS administered in
relation to delivery.
Interpretation:
Our results show that publication of the ALPS trial in 2016 influenced
clinical practice in Canada and the United States, despite conflicting
recommendations regarding ACS use at late preterm gestation in the two
countries. There was a steady increase in ACS use among infants born at
35 weeks’ gestation in Nova Scotia and this increase was mainly observed
among women who delivered by planned cesarean delivery. In line with our
findings, a recent study from the United States reported that the
publication of ALPS study was associated with an immediate increase in
the rates of ACS administration in late preterm births across the United
States.19
Consistent with our findings, Kearsey et al.19observed an increase in the proportion of babies born at term who had
received ACS in the United States between 2016 and 2018, whereas in the
Canadian setting, we observed a significant reduction in the
administration of ACS in infants born at term gestation since 2016.
Nevertheless, our study and previous research show that about 20-35% of
infants whose mothers received ACS ultimately deliver at term
gestation.4 7 11 This highlights the challenge of
accurately diagnosing preterm labour, an ongoing impediment to optimal
ACS use.20 Conversely, our findings and others have
revealed that the opportunity for optimal ACS use, between 24 hours and
less than 7 days prior to delivery, is missed in approximately 60% of
preterm deliveries and nearly 50% of infants delivering preterm receive
suboptimal ACS at <24 hours or >7 days prior to
delivery.4 11 21 22 The rate of optimal administration
of ACS has not improved in the past 14 years in Nova Scotia and if
labour is short, it is likely that ACS administration will be missed.
Suboptimal administration of ACS is associated with reduced efficacy
with regard to neonatal respiratory complications and neonatal brain
injury.22 23 Nevertheless, ACS therapy is partially
effective in reducing infant mortality even if it is given only hours
before delivery.23 With the potential for harm from
unnecessary steroid therapy, and long term adverse impacts being
increasingly recognized,24 25 it is necessary to
improve methods of preterm birth prediction, so that ACS can be
administered within the ideal time frame.12 26-28
The current Canadian guideline recommends a single course of ACS for all
pregnant women at risk of preterm delivery between “…..24 and 34
weeks gestation”, i.e., including women between 24 + 0 and 34 + 6 weeks
gestation. However, rates of ACS administration have always been
significantly higher among infants born at 33 weeks’ gestation compared
with those born at 34 weeks’ gestation for various
reasons.6 In our study, 72% of live births at 33
weeks’ gestation received ACS, whereas only 56% of live births at 34
weeks’ gestation received ACS in Nova Scotia. Although the care of
preterm infants has undergone significant changes since the introduction
of ACS prophylaxis more than four decades ago, the magnitude of the
reduction in neonatal mortality and severe neurological injury following
ACS treatment among preterm infants has remained stable in the past few
decades.29 This highlights the critical and continuing
role of ACS therapy in the current era of neonatal care.
The reduction in rate of ACS administration among live births delivered
between 28 and 32 weeks’ gestation in Nova Scotia was unexpected and may
be due to recent concerns regarding the current double dose of ACS
administration.30 A few animal and human randomized
trials have suggested that administration of a single dose of
betamethasone might be equally beneficial in inducing fetal lung
maturation compared with two doses at an interval of 24
hours.31-34 Given the concerns about long-term effects
of ACS, more definitive randomized controlled trials are urgently needed
to determine the effect of lower doses of ACS in comparison to the
standard double dose ACS.35
Conclusion:
In summary, our study showed that publication of the ALPS trial resulted
in an increased rate of ACS administration among late preterm infants.
ALPS trial findings influenced clinical practice in Canada and the
United States, although in Canada the extent of the change in ACS use at
late preterm gestation may have been moderated by the 2018 Canadian
guideline which did not recommend routine ACS use at late preterm
gestation. A significant proportion of the women receiving ACS delivered
at ≥37 weeks gestation in both Canada and the United States. Future
research should be directed at developing and validating prognostic
models that accurately predict impending delivery among women at preterm
gestation in order to optimize ACS use. Studies on the dose and
long-term effects of ACS are also needed to address the long-term
developmental effects of ACS and to resolve the existing conflict
between clinical guidelines.
Acknowledgment: This study was funded by the Canadian
Institutes of Health Research (grant number PJT-173329). NR is supported
by a grant from the Swedish Research Council for Health, Working Life
and Welfare (grant number 4-2702/2019). KSJ is supported by an
Investigator award from the BC Children’s Hospital Research Institute.
Conflict of interest: The authors report no conflict of
interest.
Financial disclosure: The authors have no financial
relationships relevant to this article to disclose.