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.