Preterm birth, defined as delivery before 37 weeks of gestation, is the leading cause of death in new-borns and young children worldwide. This phenomenon accounts for a significant proportion of neonatal mortality, with complications from immature organ systems posing the greatest risks to survival. For decades, antenatal corticosteroids (ACS) have been a key intervention to address these challenges. By accelerating foetal organ maturation, particularly the development of the lungs, ACS drastically reduce the risks of respiratory distress syndrome, intraventricular haemorrhage, and other complications associated with prematurity.
ACS are routinely administered to pregnant individuals at increased risk of preterm birth, typically between 24 and 34 weeks+6 days of gestation. This treatment has consistently demonstrated its ability to improve outcomes for preterm infants, saving lives and preventing severe morbidity. However, the broad adoption of this intervention has raised significant questions about its use beyond the context of imminent preterm birth. In particular, there is growing concern about its application in pregnancies that ultimately result in term or late preterm deliveries, where the benefits are uncertain, and the potential for harm becomes a critical consideration.
Problem of Unnecessary ACS Exposure
One of the most significant challenges associated with ACS is the difficulty in accurately predicting preterm birth. As a result, many foetuses exposed to ACS are born at term (≥37 weeks) or during the late preterm period (34-36 weeks). For these infants, the benefits of ACS are limited or non-existent, yet they are still subjected to the risks associated with the intervention.
The issue of unnecessary ACS exposure is not new. In fact, concerns were raised as early as 1972, when a randomised controlled trial showed that 30% of infants exposed to ACS were born at term. Despite this early warning, the practice of administering ACS broadly and “just in case” has persisted for more than five decades. More recent data indicate that approximately 40% of infants exposed to ACS are born at term, while over 50% are born either at term or in the late preterm period. These statistics highlight the need for improved predictive tools and more stringent guidelines to ensure that ACS are reserved for pregnancies with a high likelihood of preterm delivery.
In 2016, the United States adopted the practice of administering ACS during the late preterm period, but this approach has been less commonly embraced in Canada and Europe. Current guidelines in the UK and North America now recommend tracking the proportion of pregnancies with unnecessary ACS exposure, particularly those resulting in term births. The UK guideline, in particular, emphasises that the proportion of term births after ACS exposure should ideally be zero. This recommendation reflects a broader effort to discourage the overuse of ACS and to promote more critical assessment of which pregnancies are most likely to benefit from the intervention.
Short and Long-Term Risks of Early ACS Exposure
While the benefits of ACS for infants born very prematurely are well-documented, the same cannot be said for those born at term or in the late preterm period. For these infants, the risks associated with early ACS exposure can outweigh any potential benefits. Short-term adverse outcomes include increased rates of neonatal intensive care unit (NICU) admissions, intubation, and hypoglycaemia requiring treatment. Additionally, infants exposed to ACS at term often exhibit reduced head circumference, a surrogate marker for impaired brain growth.
The long-term consequences of ACS exposure are even more concerning. Research has shown that ACS can disrupt normal foetal brain development, with animal studies providing critical insights into the underlying mechanisms. For instance, ACS exposure has been linked to reduced cortical surface area, a decrease in hippocampal neurons, and impaired neuronal plasticity. These changes are consistent with findings in human studies, which have documented an increased risk of neurodevelopmental impairments, including reduced intellectual capacity and altered stress regulation via the hypothalamic-pituitary-adrenal axis.
Beyond neurodevelopmental impacts, ACS exposure has also been associated with long-term cardiovascular, renal, and metabolic risks. For example, elevated glucose and insulin levels resulting from ACS exposure increase the risk of neonatal hypoglycaemia, which can have cascading effects on metabolic health later in life. These findings highlight the significance of weighing the potential risks and benefits of ACS administration, particularly as pregnancies progress toward term.
Evidence from Research
A comprehensive systematic review and meta-analysis of over 1.6 million infants provides valuable insights into the risks associated with ACS exposure. The study found that approximately 40% of infants exposed to early ACS were born at term, while more than half were born either at term or in the late preterm period. These infants exhibited a range of adverse outcomes, including reduced anthropometric measurements such as head circumference and birth length. Observational studies further demonstrated consistent associations between ACS exposure and adverse neurodevelopmental and metabolic outcomes.
While randomised controlled trials (RCTs) are often considered the gold standard for evaluating medical interventions, they have limitations in this context. For instance, RCTs often exclude term or late preterm births from their analyses, focusing instead on outcomes for extremely premature infants. As a result, population-based observational studies have become a critical source of data for understanding the broader implications of ACS exposure. These studies, despite their susceptibility to bias, provide valuable insights into real-world outcomes and highlight the need for more targeted use of ACS.
Animal studies have also played a crucial role in elucidating the biological mechanisms underlying the risks associated with ACS. For example, research has shown that ACS doses comparable to those used clinically in humans can affect up to 20% of the transcriptome, altering foetal development and programming. These findings reinforce concerns about the potential toxicity of current ACS dosing protocols and highlight the need to explore alternative approaches.
Addressing Overuse and Charting a Path Forward
The high proportion of term and late preterm births after early ACS exposure accentuates the challenges in predicting preterm birth and the need for more precise clinical guidelines. To address these challenges, researchers and clinicians are exploring strategies to reduce unnecessary ACS exposure while maintaining its life-saving benefits for those who truly need it. One potential approach is to lower the doses of ACS, which could help mitigate the risks of toxicity without compromising efficacy.
Another strategy involves adopting more stringent inclusion criteria for ACS administration. For example, limiting the use of ACS to pregnancies with imminent risk of preterm birth, as defined by specific clinical markers, could significantly reduce unnecessary exposure. Studies have shown that stricter inclusion criteria can lower the proportion of term births after ACS exposure to as little as 7-10%, compared to the 40% observed in less selective practices.
Tracking outcomes is another critical step in addressing the overuse of ACS. By monitoring the proportion of term births after ACS exposure, clinicians can better assess the appropriateness of their interventions and identify areas for improvement. Population-based studies have demonstrated that restricting ACS use to pregnancies at high risk of preterm birth can reduce unnecessary exposures without compromising neonatal outcomes, providing a valuable model for improving clinical practice.
Long-Term Research and Individualised Care
Despite significant advances in our understanding of ACS, many questions remain unanswered. For instance, it is unclear whether specific clinical indications for ACS are more likely to result in term births. Additionally, the long-term outcomes of ACS exposure remain underexplored, particularly in the context of randomised controlled trials with extended follow-up periods. One study that assessed children at 12 years of age found a doubling in the risk of being in the lower quartile of academic performance for those exposed to ACS at term, emphasising the need for further research.
Another critical area for future investigation is the impact of ACS on maternal outcomes. While much of the existing research has focused on neonatal and paediatric outcomes, little is known about the potential effects of ACS on pregnant individuals. Addressing this gap in knowledge will be essential for providing comprehensive care and ensuring that the benefits of ACS outweigh any potential risks.
In the meantime, a cautious and individualised approach to ACS administration is warranted. Clinicians must carefully weigh the potential benefits and risks of ACS for each pregnancy, taking into account factors such as gestational age, clinical indications, and the likelihood of preterm birth. By adopting a more personalised approach, clinicians can optimise outcomes for both mothers and infants while minimising unnecessary exposure to ACS.
Conclusion
Antenatal corticosteroids remain one of the most powerful tools for improving outcomes in preterm infants, but their overuse represents a significant clinical challenge. As the evidence mounts regarding the risks associated with unnecessary ACS exposure, particularly for infants born at term or late preterm, the medical community must reassess its approach to this intervention. By reducing overuse, refining dosing protocols, and prioritising long-term research, clinicians can ensure that ACS continue to save lives while minimising unintended harm.
The path forward requires a collaborative effort among researchers, clinicians, and policymakers to develop more precise predictive tools, refine clinical guidelines, and expand our understanding of the long-term effects of ACS. Through these efforts, the medical community can strike a balance between the life-saving potential of ACS and the imperative to minimise harm, ensuring that this critical intervention is used responsibly and effectively.
Reference
Yao, T.-C., Chang, S.-M., Wu, C.-S., Tsai, Y.-F., Sheen, K.-H., Hong, X., Chen, H.-Y., Wu, A. C., & Tsai, H.-J. (2023). Association between antenatal corticosteroids and risk of serious infection in children: nationwide cohort study. BMJ (Clinical Research Ed.), 382, e075835. https://doi.org/10.1136/bmj-2023-075835