Abstract
Being born before 37 weeks’ gestation, or preterm birth, is a leading cause of early childhood death and life-long disability. Antenatal steroids (ANS) are recommended for women judged at risk of imminent preterm delivery. The primary intent of ANS treatment is to rapidly mature the fetal lungs to reduce the risk of mortality and lasting morbidity. Despite being used clinically for some 50 years, a large number of uncertainties remain surrounding the use of ANS. In particular, the choice of agent, dose/regimen, and appropriate gestational age range for ANS therapy all remain unclear. Unresolved concerns regarding the potential risk of harms from ANS treatment, especially in light of the modest benefits seen with expanding latepreterm administration, make it increasingly important to optimize the dosing and application of this important and widely used treatment. This review will serve to summarize past data, provide an update on recent developments, and chart a way forward to maximize the overall benefit of this important therapy.
Introduction
Being born preterm (before 37 weeks’ completed gestation) is a leading cause of early childhood mortality and directly results in one million deaths each year (Blencowe et al. 2013). Preterm infants are at increased risk of lung injury and disease (seen clinically as respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH)), each contributing to acute risk and potential lifelong morbidity (Crowther et al. 2006, Jobe & Goldenberg 2018). Broadly speaking, the risk of death and lasting morbidity is proportional to the degree of prematurity. Although comparatively small in number, babies born extremely preterm (<28 weeks) have the highest prevalence of serious disease and perinatal death (Stoll et al. 2015, Roberts et al. 2017, Travers et al. 2018, WHO 2022). Similarly, the risk of adulthood diseases, including chronic obstructive pulmonary disease and heart failure, is heightened with preterm birth (Carr et al. 2017, Bui et al. 2022). Although preterm birth is a multifactorial syndrome, and many of the antecedents of prematurity also predispose the infant to injury or death (e.g. intrauterine infection/inflammation), a significant percentage of preterm injury derives from the immature fetal lungs being insufficiently developed to safely support the transition to ex-utero life. Up to one-half of babies born <28 weeks and one-third of babies born <32 weeks have difficulty breathing (Roberts & Dalziel 2006, McGoldrick et al. 2020).
Endogenous glucocorticoids are essential for normal fetal development, and a surge of circulating glucocorticoids in late pregnancy facilitates normal maturation of the fetal lungs, heart, brain, and kidneys (Moisiadis & Matthews 2014). Antenatal steroids (ANSs) exert a multitude of effects, the best understood of which (at least in terms of outcome) is the rapid maturation of the preterm fetal lung, manifesting as improved lung compliance and enhanced gas exchange and resulting in a reduction in the risk of morbidity (principally RDS) and mortality (in infants below born 32 weeks’ gestation) associated with preterm birth (Ballard & Ballard 1995, Kemp et al. 2018). A single-course ANS treatment is now recommended for women judged to be at imminent risk of preterm birth prior to 34+6 weeks’ gestation (Antenatal Corticosteroid Clinical Practice Guidelines Panel 2015). Recently released guidance from the WHO recommends a single course of ANS in at-risk women up to 34 weeks’ gestation (WHO 2022).
Following the first human trial published by Liggins and Howie in 1972, the antenatal administration of synthetic glucocorticoids, or ANS therapy, has become one of the most widely used treatments in pregnancy (Liggins & Howie 1972). However, in assessing the importance of their findings, Liggins and Howie opined that ‘In view of the present trial’s empirical basis of selection of the glucocorticoid and its dosage and duration of treatment, it would be surprising if there were no scope for improved results from therapeutic regimens’ (Liggins & Howie 1972). Fifty years and many clinical trials later, ANS use remains largely un-optimized with the choice of agent, dose/regimen, and reasonable gestational age (GA) range for ANS therapy remaining contentious.
Significant uncertainty remains regarding the optimal dose of ANS necessary for balancing the maturation of the preterm lung with unwanted off-target effects. Recent data from animal studies show that current dosing regimens see both mother and fetus exposed to unnecessarily high doses of steroids, with no further lung benefit to the preterm fetus (Kemp et al. 2018). Elevated steroid exposures may disrupt (suppress) the maternal hypothalamic pituitary axis (HPA) axis (Duthie & Reynolds 2013) and increase the risk of placental dysfunction (Audette et al. 2014), reducing transport capacity and negatively impacting fetal growth. It is known that ANS exposure can increase the risk of short-term effects including neonatal hyperglycemia; however, long-term data have linked ANS exposure to potential developmental delays in childhood, with concerns that these could remain in adulthood (Murphy et al. 2008, Stutchfield et al. 2013, Raikkonen et al. 2020, Tao et al. 2022).
There is clear evidence that a single course of ANS therapy saves lives and improves health outcomes for babies delivered between 24+0 and 34+6 weeks’ gestation; however, there are less data to inform ANS use outside this range. Babies born <28 weeks, or extremely preterm, are at the greatest risk of death and lasting morbidity (Stoll et al. 2015). There are data to support ANS use in extremely preterm infants, with treatment associated with improvements in IVH risk and overall survival, although not RDS, as a binary outcome (Mori et al. 2011). One particular challenge in ANS use in this population relates to difficulties in accurately predicting imminent preterm delivery. Accordingly, many pregnancies treated with ANS early in gestation continue to term, with no treatment benefit but potential for disruption of normal growth and development (McLaughlin et al. 2003, Battarbee et al. 2020).
ANS therapy is of low cost, readily available, and easily administered in a range of resource settings. As such, the optimization of ANS therapy is of particular importance given that global rates of preterm birth are not decreasing and the regions with the most preterm deliveries are generally those with the least resources to intervene and to manage a high-need preterm population (Blencowe et al. 2013, Walani 2020). Although there are active efforts underway to improve the prediction of preterm birth risk, effective interventions to reduce the risk of preterm birth remain scarce (Newnham et al. 2017, Medley et al. 2018).
More recent trials have focused on assessments of ANS benefits at later preterm gestations, with increasing interest in ANS use prior to late preterm delivery (34+0–36+6 weeks) and in the setting of elective cesarean section (CS) at term (Stutchfield et al. 2005, Gyamfi-Bannerman 2016, Sotiriadis et al. 2018, WHO ACTION Trials Collaborators 2022b). Although infants born late preterm are at increased risk of neonatal relative morbidity than infants born at term (McIntire & Leveno 2008, Kitsommart et al. 2009), reported benefits of ANS in these groups are somewhat modest and the numbers needed to treat (NNT) are high. The aims and desired benefits of ANS therapy in the late preterm period and prior to elective CS at term are less defined and require articulation. A key question to be debated is the basis on which these modest benefits can be reasonably justified against an evolving background of developmental risk, the very large NNT, and evidence of increased risk of harm.
These factors will be addressed in the present review, along with a brief primer into the agents in general use and the various dosing regimens in which they are employed.
Antenatal steroids: agent, dose, and treatment regimen
The fluorinated steroids betamethasone and dexamethasone are the most commonly used synthetic glucocorticoids for maternal ANS treatment. Dexamethasone and betamethasone both cross the placenta in their active form and act by altering gene expression, resulting in glucocorticoid effects to accelerate fetal organ maturation and reflect changes seen in a more mature fetus (Ballard & Ballard 1995, Roberts & Dalziel 2006). Betamethasone and dexamethasone have significantly higher affinities for the glucocorticoid receptor (GR) than that of cortisol. The GR affinity of dexamethasone is slightly higher than that of betamethasone (Ballard & Ballard 1995).
A range of dosing regimens and agents are employed in different regions. Australia, Europe, and the US use a combined preparation of betamethasone phosphate (Beta-PO4) and betamethasone acetate (Beta-Ac) (2 × 12 mg doses, 24 h apart). Beta-PO4 alone is used in Japan and UK (2 × 12 mg doses, 24 h apart) and dexamethasone is predominantly used in Singapore (2 × 12 mg doses, 12–24 h apart) and in many low- and middle-resource environments (4 × 6 mg doses, 12 h apart) (Ministry of Health 2001, Brownfoot et al. 2013, Jobe & Goldenberg 2018, McGoldrick et al. 2020). The World Health Organization (WHO) includes dexamethasone phosphate (Dex-PO4) on the list of essential medicines as it is inexpensive and readily available and does not require refrigeration (unlike betamethasone), making it the preferred option for low-income countries (WHO 2022).
Betamethasone is used clinically in two forms, Beta-PO4 or a combination drug consisting of equal parts betamethasone Beta-PO4 and Beta-Ac (Samtani et al. 2005). Beta-PO4 is freely soluble and has a shorter half-life, while Beta-Ac is a slow-release suspension with a relatively long half-life (Jobe & Soll 2004, Jobe et al. 2020). Dosing using combination Beta-PO4 + Beta-Ac, based on the protocol used in the Liggins & Howie (1972) clinical trial, consists of two doses of a combination drug containing 11.4 mg of betamethasone (7.8 mg Beta-PO4 and 6 mg Beta-Ac) given by maternal intramuscular injection (i.m.) 24 h apart (Liggins & Howie 1972, McGoldrick et al. 2020). Dex-PO4 has the shortest half-life (5.2 ± 0.4 h, compared to 10.2 ± 2.5 h for Beta-PO4 in non-pregnant females (Jobe et al. 2020)) and is rapidly cleared from circulation. Dexamethasone is commonly administered as four 6 mg doses of Dex-PO4 given by maternal i.m. at 12-h intervals and is predominantly used in low-income environments, as it is inexpensive and widely available (WHO 2015).
Several human trials and animal studies have compared the effectiveness of betamethasone and dexamethasone to reduce neonatal mortality and neonatal morbidity, including RDS and IVH. An indirect comparison of betamethasone and dexamethasone in the 2013 Cochrane systemic review by Brownfoot et al. reported no difference in perinatal morbidity and mortality between the two steroids (Brownfoot et al. 2013). The 2019 Australian-based ASTEROID trial compared maternal i.m. betamethasone (2 × 11.4 mg, 24 h apart; Beta-PO4 + Beta-Ac) and Dex-PO4 (2 × 12 mg, 24 h apart), assessing a primary outcome of death or neurosensory disability at age 2 years. Neonatal outcomes for the two groups found no significant difference for neonatal death, RDS or IVH (Crowther et al. 2019). It is important to note that Dex-PO4 and a combined Beta-PO4 + Beta-Ac preparation have very different maximal concentrations (Cmax) and treatment half-lives, making it difficult to meaningfully compare treatment efficacy and safety of these particular regimens from a pharmacokinetic perspective. An additional consideration when interpreting these data is that the betamethasone treatment, which generates a lower maternofetal maximum plasma concentration than that of the dexamethasone arm, is itself already supra-pharmacological for both lung benefit and very likely so for risk threshold.
A 2006 cohort study by Lee et al. compared fetal outcomes in very low birth weight infants (401–1500 g) following exposure to betamethasone (2 × 12 mg, 24 h apart; combination drug of equal parts phosphate + acetate) or Dex-PO4 (4 × 6 mg given at 12 h apart). The study found that both dexamethasone and betamethasone reduced periventricular leukomalacia, IVH, and severe IVH when compared to placebo. However, it was reported that betamethasone reduced the risk of neonatal death, while dexamethasone was associated with an increased risk of fetal death and a non-significant trend of greater risk for IVH and severe retinopathy of prematurity when compared to the betamethasone group (Lee et al. 2006). A follow-up of this study, comparing the development of adverse neurodevelopmental outcomes at the corrected age of 18–22 months, found that betamethasone exposure was associated with an increased likelihood of unimpaired neurodevelopmental status (defined as the absence of cerebral palsy, deafness, and blindness, mental development index of ≥85, and psychomotor development index of ≥85) and reduced risk of hearing impairment compared with the dexamethasone or no steroid groups (Lee et al. 2008). As there are limited follow-up data for dexamethasone, it is difficult to conclude which drug is more efficacious for long-term health outcomes. However, given recent data supporting the importance of low-amplitude, extended fetal steroid exposures in driving lung maturation, it is interesting to note that the comparably improved outcomes in the betamethasone group are consistent with the superior pharmacokinetic properties of that drug.
Recent data from sheep show that, with regard to acute respiratory function, current dosing regimens result in both mother and fetus being exposed to unnecessarily high doses of steroids. Excessive steroid exposures increase the disruption of the maternal HPA, alter placental size and transport capacity, and impact fetal growth (Audette et al. 2014, Kemp et al. 2018, Tetro et al. 2018). The doses of betamethasone employed in present dosing regimens result in steroids rapidly reaching high peak levels in the mother and fetus, with ~37% traveling across the human placenta to the fetus (Ballard & Ballard 1995). The plasma betamethasone is then rapidly cleared from the maternal and fetal circulation (Samtani et al. 2005). A 2018 study by Kemp et al. using an ovine model of pregnancy reported that a constant, low-concentration exposure to steroids was sufficient to generate fetal lung maturation equivalent to that of higher dose clinical regimens, suggesting comparable elevated exposures given with current dosing regimens do not contribute to fetal lung development (Kemp et al. 2018). This study found that optimal lung maturation could be achieved using a steroid dose 70% less than the current clinical treatment (Kemp et al. 2018). A subsequent study by Fee et al. using the same model found that by removing maternal exposure and directly treating the fetus a dose of approximately 1% of the current clinical dose could achieve fetal lung maturation (Fee et al. 2022). This report also highlighted the prodigious rate (at least in the sheep) of retrograde transport of betamethasone from the fetal to the maternal compartment. A 2022 study by Takahashi et al. using a similar model found that the durability of ANS response at extended treatment to delivery intervals, primarily measured by fetal lung maturation, was dependent on an unbroken low-concentration steroid exposure (Takahashi et al. 2022a). An additional study by Usuda et al. reported that a low-dose treatment of 8 mg Beta-PO4 promoted equivalent lung maturation to the clinically used 24 mg Dex-PO4 regimen (Usuda 2022). This study also found that the lower dose approach reduced – but did not eliminate – the disruption of both the maternofetal HPA axis and immunocyte populations.
ANS are recommended in the setting of imminent preterm delivery, with the presumed optimal window of treatment efficacy being 1–7 days (WHO 2022). However, predicting preterm delivery is often difficult, and a large number of ANS-treated fetuses go on to be born at term (Gyamfi-Bannerman et al. 2016, Rodriguez et al. 2019). Evidence also suggests that, in some centers, ANSs are often administered on a precautionary basis, before imminent preterm delivery risk is adequately assessed (Takahashi et al. 2022b). Both dexamethasone and betamethasone equivalently reduce perinatal death, but data suggest that betamethasone is associated with fewer neurological outcomes at 18–22 months of age (Lee et al. 2008, Brownfoot et al. 2013, Crowther et al. 2019). Furthermore, results from recent human and animal trials indicate that there might be a dose-dependent association with fetal growth restriction and ANS exposure (Moss et al. 2001, Murphy et al. 2008, Davis et al. 2009). Data suggest that lowering the dose could still achieve optimal fetal lung maturation while reducing adverse effects associated with high levels of steroid exposure.
Antenatal steroids for extremely early preterm birth
Extreme preterm term birth, or delivery before 28 weeks’ gestation, accounts for ~0.5% of total births (Morgan et al. 2022). Babies born 20+0–25+6 weeks’ gestation are considered to be at the lower limit of survival, characterized as the periviable period as defined by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine Obstetric Care Consensus statement (American College of Obstetricians and Gynecologists et al. 2016). Despite improvements in extremely preterm survival rates, babies born <28 weeks’ gestation are still vulnerable to a substantially increased risk of complications after birth (Stoll et al. 2015, Johnson & Marlow 2017). In particular, babies born in the periviable period (<26 weeks’ gestation) have the highest risk of neonatal mortality or developing lifelong disability associated with preterm birth, including cerebral palsy, significant intellectual impairment, and sensory loss (Mactier et al. 2020).
Comparably limited data exist for ANS use for extreme preterm birth. Trials completed before 1995 included very few extremely preterm babies; largely this is due to the lower survival rate of babies born <28 weeks’ gestation in this era. Additionally, previous studies used RDS as a primary outcome to evaluate ACS for extreme preterm babies. However, due to the extremely underdeveloped lungs of babies born <28 weeks’ gestation, the majority of these infants will suffer from RDS regardless of antenatal treatment (Stoll et al. 2015). More recent studies now use neonatal death and neurodevelopmental outcomes to discriminate the effectiveness of ANS treatment for extreme preterm neonates (Bancalari & Jobe 2012).
Studies have found that ANS exposure reduces the risk of neonatal death in infants born <28 weeks (especially in the first 48 h of life); however, the ability to reduce respiratory injury and disease, including bronchopulmonary dysplasia (BPD), is less clear (Mori et al. 2011, Travers et al. 2018). Studies assessing neonatal morbidity following ANS treatment in infants born <28 weeks suggest ANS treatment is less effective for reducing respiratory complications in younger gestations. A study of 11,022 infants born <28+6 weeks by Travers et al. showed that infants exposed to ANS had a lower mortality (22.7%), compared to infants who did not receive ANS (41.5%) (P < 0.0001) (Travers et al. 2018). The reduction in mortality rate remained significant (P < 0.0001) for infants who only received a partial course of ANS (26% mortality rate) (Travers et al. 2018). A 2017 study by Norman et al. found that the treatment to the delivery window was less important in extremely preterm gestations, suggesting that exposure to ANS even 3 h before delivery could reduce neonatal mortality (Norman et al. 2017). This observation highlights the potential for non-genomic signaling responses to contribute to ANS treatment benefit (Oakley & Cidlowski 2013) and also that benefits from treatment may extend beyond easily identified improvements in lung function.
Recent literature from high-resource settings supports the use of ANS for women at risk of preterm birth at 24+0–28+6 weeks (Roberts & Dalziel 2006). A retrospective analysis by Mori et al. evaluated the effectiveness of ANS to improve neonatal outcomes in infants born as early as 22 weeks’ gestation and found that exposure to ANS significantly reduced overall neonatal mortality up to hospital discharge (P < 0.001), including in the 22–23 weeks’ gestation group (P = 0.03) (Mori et al. 2011). When assessing respiratory morbidity (including RDS, surfactant use, and duration of O2 use) and IVH, ANS exposure did not alter these factors in 22–23 weeks’ gestation group. Respiratory outcomes, decreased RDS and IVH, were only reported in infants born later than 24 weeks’ gestation (Mori et al. 2011). A study by Carlo et al. found that steroid exposure was associated with a reduction in neonatal death and in neurodevelopmental impairment at 18–22 months for infants born between 22 and 25 weeks’ gestation (Carlo et al. 2011).
Due to improvement in obstetric and neonatal care over the past few decades, the GA at which extremely preterm infants are considered viable has moved well into the second trimester. As a result, the periviable period has expanded to include infants born as early as 200 weeks’ gestation (American College of Obstetricians and Gynecologists et al. 2016) and treatment recommendations have shifted from palliative or comfort care to active perinatal intervention (where resuscitation is considered ethically mandatory) for infants born after 220 weeks (Di Stefano et al. 2021), with survival dependent on higher quality care with more aggressive interventions (Petrou et al. 2006). The importance of optimizing ANS treatments for this particular population is clear; in England and Wales, the total cost of preterm birth in the public sector was estimated to be £2.946 billion and the average cost of surviving babies born extremely preterm up to the age of 18 years was 3.24 times that of an infant born at term (£135,779 vs £41,907) (Mangham et al. 2009). Although further studies are required to improve outcomes for extremely preterm babies, data support the use of ANS to reduce neonatal death and IVH associated with extreme preterm birth.
Antenatal steroids for late preterm birth
Late preterm infants (34+0–36+6 weeks’ gestation) have higher rates of neonatal morbidity, including poorer respiratory outcomes, and a higher need for respiratory support when compared to babies born at term (McIntire & Leveno 2008, Kitsommart et al. 2009). As such, there is justifiable interest in improving outcomes for these infants. Additionally, late preterm births make up a large percentage (>70%) of the preterm population, posing significant social, financial, and economic costs (Gyamfi-Bannerman et al. 2016, Office for National Statistics 2020, Osterman et al. 2021). In 2019, the preterm birth rate in England and Wales was 7.8%, with a large percentage of these babies (~84%) being born between 32 and 36 weeks’ gestation (moderate–late preterm) (Office for National Statistics 2020). A 2020 US birth report found that 10.09% of babies were born preterm, with ~73% of preterm babies born between 34+0 and 36+6 weeks’ gestation (Osterman et al. 2021). A 2006 review including data from babies born late preterm found that babies born between 35 and 36 weeks’ gestation were three times more likely to require supplemental oxygen support for at least 1 h than babies born >37 weeks and were much more likely to be re-hospitalized than infants born at term (6.8–7.3% for babies born 35–36 weeks vs 3.6–4.4% for babies born 38–40 weeks to >41 weeks) (Escobar et al. 2006).
The 2016 Antenatal Late Preterm Steroids (ALPS) trial aimed to determine if ANS treatment would decrease the risk of neonatal morbidities in late preterm infants (Gyamfi-Bannerman et al. 2016). This large, multicenter, randomized control trial (RCT), conducted in the US recruited women with a singleton pregnancy between 34+0 and 36+5 weeks’ gestation with a high probability of preterm birth in the late preterm period (defined as (i) preterm labor with intact membranes and >3 cm dilation or 75% cervical effacement, or (ii) spontaneous rupture of membranes, or (iii) planned preterm delivery via induction or cesarean within 24 h–7 days). Subjects were randomized to receive two i.m. injections of 12 mg betamethasone or placebo 24 h apart. The primary outcomes included the need for neonatal composite treatment in the first 72 h (including continuous positive airway pressure (CPAP) or high flow nasal cannula ≥ 2 h, supplemental oxygen of at least 30% ≥ 4 h, extracorporeal membrane oxygenation or mechanical ventilation) or stillbirth or neonatal death before 72 h. Secondary outcomes included severe respiratory morbidity, surfactant administration, need for resuscitation at birth, or neonatal morbidity, including transient tachypnea of the newborn (TTN), RDS, apnea, BPD, NEC, and IVH).
Assessment of primary outcome found that exposure to betamethasone reduced the need for respiratory support in the first 72 h of life (11.6 vs 14.4%, P = 0.02), with the number needed to treat to prevent one case being 35. Secondary outcomes showed that the betamethasone group had a significant reduction in severe respiratory complications (7.9 vs 12.1%, P < 0.001), surfactant use (1.8 vs 3.1%, P = 0.03), immediate need for resuscitation (14.5 vs 18.7%, P = 0.003), TTN (6.7 vs 9.9%, P < 0.01), BPD (0.1 vs 0.6%, P = 0.04), and neonatal intensive care unit (NICU) stays ≥ 3 days (32.0 vs 37%, P = 0.03) when compared to the placebo group; however, there was no significant difference in overall admissions to intermediate/NICU between the two groups (41.6 vs 44.8%, P = 0.08), and no significant difference in the interval between birth and discharge.
Following the ALPS trial, updates to US guidelines included recommendations for ANS use for threatened preterm delivery at 34+0–36+6 weeks’ gestation without follow-up data. Nine months after the trial dissemination, steroid use for late preterm infants in the US increased from 5 to 11.7%, with the use of any assisted ventilation in these infants decreasing by 9% (Clapp et al. 2022, Kearsey et al. 2022). However, ANS use in the late preterm population may come with long-term risks. The ALPS trial found that babies exposed to betamethasone were significantly more likely to have neonatal hypoglycemia (glucose < 40 mg/dL) than those not exposed (24.0 vs 15.0%, P < 0.001) (Gyamfi-Bannerman et al. 2016). A Finnish population-based retrospective cohort study by Räikkönen found that infants exposed to ANS at 340–366 weeks’ gestation and delivered at term, totaling 45.3% of ANS-exposed infants in this study, may result in increased psychiatric and behavioral diagnoses in childhood (Raikkonen et al. 2020); this figure was less significant in the ALPS trial, with ~17% of exposed infants delivering at term. A cohort study from Taiwan similarly identified a significant association between any ANS use and increased risk of childhood mental disease (Lin et al. 2023). However, recently published follow-up data from the ALPS study assessing childhood neurodevelopment at ≥6 years of age found that administration of late preterm betamethasone did not affect neurodevelopment outcomes (Gyamfi-Bannerman 2023), including cognitive function, gross motor function, social responsiveness, and childhood behavior.
Recommendations for ANS use in late preterm gestations are inconsistent. Clinical recommendations in the UK, US, and Canada recommend a single cycle of ANS up until 34+0 weeks’ gestation, with the inclusion to ‘consider’ administering a single cycle of ANS for suspected late preterm delivery after 34 weeks (Committee on Obstetric Practice 2017, Skoll et al. 2018, Stock et al. 2022b ). Recommendations in the Guideline of the German, Austrian, and Swiss Societies of Gynecology and Obstetrics state no ANS after 34+0 weeks’ gestation (Berger et al. 2019). The WHO recommends ANS for women with a high likelihood of delivery between 24 and 34 weeks but does not recommend ANS after 340 weeks including for women undergoing planned CS before 366 weeks’ gestation (WHO 2022). It is unclear if the benefits surpass the risks associated with ANS use in late preterm gestations. Additional larger definitive trials with long-term follow-up need to be conducted further before ANS use can be safely recommended for late preterm deliveries.
ANS use in low- and middle-resource environments
The majority of ANS research has taken place in middle- and high-resource countries, with insufficient evidence to inform of the use of ANS treatment in low-resource countries. Between 2011 and 2014, the Antenatal Corticosteroids Trial, a cluster-randomized trial, was conducted in six middle- and low-resource countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) (Althabe et al. 2015). The trial aimed to assess the feasibility and efficacy of implementing a multifaceted intervention aimed to increase ANS use in low-resource environments with the primary outcome to reduce neonatal mortality, more specifically the death of low birthweight infants. Rural and semi-urban clusters were randomly assigned to standard care (control) or a multifaceted intervention including improved identification of women at risk of delivering preterm to facilitate appropriate use of ANS treatment. A single course of four doses of 6 mg of Dex-PO4 (administered 12 h apart) was given to women at risk of preterm delivery between 24 and 36+0 weeks’ gestation. ANS administration did not decrease neonatal mortality in low birth weight infants and across the total treatment group. Mortality was found to be significantly increased in association with ANS use; the risk of still birth (26.8 vs 24.3 per 1000 births, P = 0.0181), neonatal death (27.4 vs 23.9 per 1000 live births, P = 0.0127), and perinatal mortality (48.0 vs 42.9 per 1000 births, P = 0.0031) were all increased when compared to the control group. Following the publication of this trial in 2015, the WHO recommended that ANS treatment should only be used for preterm birth between 24 and 34 weeks’ gestation, in a setting where certain clinical conditions can be met (including imminent preterm birth, accurate GA assessment, adequate childbirth, and preterm newborn care) and that further trials in low-resource settings were required to assess the efficacy of ANS use in both early and late preterm populations (WHO 2015).
To further assess the safety and efficacy of ANSs for women in low-resource countries, the WHO conducted a series of trials, formally known as the ACTION (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns) Trials. The first, ACTION I, aimed to determine if administration of dexamethasone for early preterm birth (for women at risk of preterm delivery between 24+0 and 33+6 weeks’ gestation) could reduce neonatal death in low-income countries. The trial was a multicountry, randomized trial that took place in 29 secondary and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan. Participating facilities were required to meet certain criteria to be eligible, including accurate GA assessment, ability to diagnose imminent preterm birth, and ability to provide minimum obstetric and neonatal standard care. To further assist with standardized care and to allow a more accurate comparison to ANS trials conducted in middle- and high-resource countries, selected hospitals were provided with diagnostic equipment (including ultrasound machines, CPAP machines, and pulse oximeters) and hospital staff were offered equipment training. Participants were randomized to receive either a single course of Dex-PO4 (4 × 6 mg, 12 h apart) or an identical placebo. Results showed treatment with dexamethasone significantly decreased neonatal death when compared to the placebo group (25.7 vs 29.2%; relative risk, 0.88; 95% CI, 0.78 to 0.99; P = 0.04). The trial concluded that, where minimum resource needs were met and imminent preterm birth could be accurately predicted, antenatal dexamethasone significantly reduced neonatal death in low-resource countries.
The ACTION II trial was a multi-center, two-arm, parallel, double-blind, randomized study undertaken in four hospitals in India and recruited women 34+0–36+0 weeks’ gestation at imminent risk of preterm birth (WHO ACTION Trials Collaborators 2022b ). Women were randomized to receive a course of 6 mg of Dex-PO4 (every 12 h to a maximum of four doses) or a placebo. Primary outcomes were neonatal death (death of liveborn neonate < 28 days of life), any baby death (including stillbirth and death of liveborn neonate < 28 days of life), or severe neonatal respiratory distress and possible maternal bacterial infection (defined as maternal fever ≥38°C or clinically confirmed infection treated with antibiotics, during hospital stay).
Secondary outcomes included maternal and infant mortality and morbidities and process of care outcomes, including major resuscitation at birth, oxygen therapy, CPAP mechanical ventilation, and admission to the special care unit.
The ACTION II trial found no significant difference between the dexamethasone group and placebo group for neonatal death (2.7 vs 2.8%), any baby death (3.8 vs 4.4%), maternal infection (2.3 vs 3.8%) and severe respiratory distress considered low in both groups (0.8 vs 0.5%). Dexamethasone was found to significantly reduce major resuscitation at birth (positive pressure ventilation for more than 1 min) (1.5 vs 3.8%) compared to the placebo group; however, other secondary outcomes were comparable between groups. The trial was stopped ahead of schedule due to lower than expected prevalence of primary outcomes and slow recruitment. It was concluded that antenatal dexamethasone did not reduce fetal or neonatal death, severe respiratory distress, or maternal infection in this trial and that further trials were required.
The planned ACTION III trial is a multi-country, multi-center, three-arm, parallel group, three-arm, individually randomized, double-blind, placebo-controlled trial and will take place across 24 hospitals in Bangladesh, India, Kenya, Nigeria, and Pakistan. The trial will include women in low-resource settings perceived to be at risk of delivery late preterm, between 34+0 to 36+5 weeks gestation. Women will be randomized to one of three groups: (i) clinical dexamethasone regimen of four doses 6 mg dexamethasone, 12 hourly; (ii) a lower dose regimen of four doses 2 mg betamethasone, 12 hourly; or (iii) placebo. The trial will access primary outcomes of stillbirth, neonatal death, or use of respiratory support within 72 h of life to build evidence of ANS use in low-resource settings and improve newborn outcomes for babies born in the late preterm period (WHO ACTION Trials Collaborators 2022a ).
Antenatal steroids for elective caesarean section (CS) at term
Over the last 20 years, CS rates have increased substantially, and in 2020, delivery by CS accounted for 21% of all births worldwide (Betran et al. 2016, Betran et al. 2021). However, there is significant variation worldwide, with the highest CS rates seen in Latin America and the Caribbean at 42.8% (highest CS rates, Dominican Republic 58.1%, Brazil 55.7%, and Cyprus 55.3%) and the lowest rates in Sub-Saharan Africa accounting for just 5% of births (lowest CS rates, Chad 1.4%, Niger 1.4%, and Ethiopia 1.9%) (Betran et al. 2021). In the US, CS rates have increased from 20% in 1996 to 31.8% in 2020, while in the UK, CS rates have increased from 19.7% in 2000 to >30% in 2020, with Scotland showing the biggest increase, with CS totaling 34.5% of all births (Wise 2018, Scottish Government 2021, Osterman et al. 2021). The reason for the increase in CS is not well known and likely multifaceted, potentially resulting from evolving medical practices including pregnancy following previous CS and breech delivery, increased clinical pressure, and social, cultural, and economic pressures leading to elective CS without medical complications (Boerma et al. 2018).
Babies delivered by CS are at a higher risk of neonatal morbidity, including respiratory complications, than those born vaginally or with labor prior to CS delivery (Levine et al. 2001, Yoder et al. 2008, Sandall et al. 2018, Sotiriadis et al. 2018). A cohort study by Hansen et al. found that babies born by planned CS at 37 weeks were significantly more likely to have respiratory complications (including RDS and TTN) compared to those delivered vaginally (10 vs 2.6%) (Hansen et al. 2008).
A small number of studies have reported the use of ANS in infants born by CS to reduce adverse respiratory outcomes (Sotiriadis et al. 2018). A 2005 RCT reported by Stutchfield et al., the antenatal betamethasone for term cesarean section (ASTECS) trial, aimed to determine if ANS prior to CS at term could reduce respiratory distress (Sotiriadis et al. 2018). The trial recruited mothers booked for planned elective CS at 37 weeks or later and 48 h before delivery scheduled them to receive either two i.m. doses of betamethasone 24 h apart or treatment as usual without ANS (not placebo controlled). The primary outcome for this study was admission to a special care unit with respiratory distress and the secondary outcomes were severity of respiratory distress (defined by tachypnoea with grunting, recession, or nasal flaring and graded by arterial gases and oximetry measurements and radiograph) and level of care needed. The trial found that infants exposed to betamethasone prior to delivery were significantly less likely to develop respiratory distress and be admitted to the special care unit than babies who were not exposed (P = 0.02) (Stutchfield et al. 2005); NNT was 37 to prevent one admission to neonatal intensive care. A long-term follow-up of the 2005 Stutchfield et al. study cohort found that children exposed to steroids were twice as likely to be in the bottom quartile of academic ability as those who did not receive steroids (17.7 vs 8.5%) (Stutchfield et al. 2005, 2013). This finding was consistent with a 2022 study by Tao et al. assessing neurodevelopment in infants at 1 year of age following exposure to ANS, which found that children exposed to steroids were significantly more likely to be noncompetent in the cognitive development domain than children not exposed (P = 0.017) (Tao et al. 2022).
Despite potential improvements in neonatal outcomes following ANS use for CS at term, it should be noted that study sizes were small and overall significance was low. Including infants born by elective CS at term in ANS recommendations would significantly expand the ANS exposure population, potentially unnecessarily exposing a large number of infants to ANS for modest benefits with the number needed to treat extremely high (NNT 37, to prevent one admission to NICU for respiratory complications (Stutchfield et al. 2005)). Results remain unclear and further investigation is required. Two trials currently underway include the Australian and New Zealand-based C*Steroid trial using ANS prior to planned CS at 35+0– 39+6 to reduce respiratory morbidity (Groom et al. 2022) and the Scotland-based STOPPIT-3 trial (Stock et al. 2022a ) which aims to administer ANS for planned birth in twins to reduce the need for respiratory support in twins born after planned late preterm or early term birth.
Antenatal steroids: potential risks and long-term follow-up
Recent studies have raised increasing concern about the potential harm caused by ANS exposure on the mother and developing fetus, in particular, that treatment with ANS may alter fetal growth and program the fetus increased risk of adulthood disease (Jobe & Goldenberg 2018). Studies have assessed the immediate risk of ANS on the fetus, including the impact on placental programming, fetal growth, and neonatal hyperglycemia (Murphy et al. 2008, Audette et al. 2014, Gyamfi-Bannerman et al. 2016). Further long-term follow-up of earlier ANS trials have identified potential adverse effects in school-aged children including cognitive challenges and behavioral disorders with concerns that developmental delays may be lifelong (Stutchfield et al. 2005, Raikkonen et al. 2020).
Some animal- and human-based studies have shown that infants exposed to exogenous steroids have lower birth weights, smaller head circumference, and shorter overall length than those not exposed to steroids (Jobe et al. 1998, Newnham et al. 1999, Davis et al. 2009). The MACS trial (multiple courses of antenatal corticosteroids for preterm birth) found that this effect was further exacerbated by the use of repeat courses of steroids, showing that infants exposed to multiple courses of ACS (every 14 days) were significantly smaller at birth (P = 0.0026), weighing an average of 113 g less, with significantly smaller head circumference (P < 0.001) and overall length (P < 0.001) (Murphy et al. 2008). When used for late preterm pregnancies, ANS exposure was associated with increased risk of neonatal hyperglycemia (Gyamfi-Bannerman et al. 2016). Perhaps more concerning, neonatal hypoglycemia has been found to have potential links to a child’s longer-term risk of development delay, including poor cognitive and motor function and continuation in adverse health outcomes into adulthood (Kerstjens et al. 2012, McKinlay et al. 2017). However, findings on fetal growth restriction as a result of ANS exposure are inconsistent, and the 2020 Cochrane review of 19 RCTs found that reductions in birthweight were only minor and not significantly different from age-matched infants who did not receive ANS, with differences in weight resolved by discharge (McGoldrick et al. 2020).
Several studies have assessed the effect of synthetic glucocorticoids on fetal programming and the HPA axis, with potential cognitive and behavioral consequences later in life (Raikkonen et al. 2020). Fetal endogenous glucocorticoids (cortisol) and regulation of the HPA axis play a vital role in fetal growth and brain development, including subcellular reorganization to neuron–neuron and neuron–glial interaction (Harris & Seckl 2011, Tijsseling et al. 2012, Waffarn & Davis 2012). The fetal HPA axis is highly sensitive to excessive levels of glucocorticoids, and exposure to high levels of exogenous glucocorticoids, namely antenatal corticosteroids including betamethasone or dexamethasone, alter the regulation of the HPA axis (suppressing the production of cortisol) disrupting normal fetal brain development and can permanently modify brain structure and function with potential long-term consequences (Matthews 2000, Waffarn & Davis 2012). A 2022 study by Usuda et al. using a sheep model of pregnancy concluded that even low doses of betamethasone (4 × 2 mg, 12 h apart) significantly suppressed fetal cortisol and ACTH production when compared to control animals that received saline (P < 0.001) (Usuda 2022). There was also no significant difference between the suppression of cortisol and ACTH in the low-dose betamethasone group compared to a higher-dose dexamethasone group which received the clinically used regimen of 4 × 6 mg, 12 h apart. These data suggest that any dose of exogenous steroids that delivers adequate fetal exposure for lung maturation will be suprapharmacological for HPA suppression.
In addition to endocrine disruption, a number of animal and human studies have investigated the potential impacts of ANS therapy on the developing fetal brain. A 2001 study using an ovine model of pregnancy found that exposure to repeat courses of ANS was associated with decreased fetal brain growth and myelination in sheep (Huang et al. 2001). A study by Uno et al. using rhesus macaques reported hippocampal injuries associated with exposure to dexamethasone, including dose-dependent brain injury with more severe degeneration seen in fetuses that received multiple doses (Uno et al. 1990). Consistent with the finding of other primate studies, a 2012 human study by Tijsseling assessed the effects of steroids on the hippocampus of 10 preterm infants and found a significantly lower density of neurons in infants treated with glucocorticoids (P = 0.01) (Tijsseling et al. 2012).
Raikkonen et al. (2020) conducted an observational study to determine if ANS exposure was associated with behavioral and mental disorders in school-aged children. The study found that exposure to steroids was associated with the diagnosis of any mental and behavioral disorder (12.01 vs 6.45%, P < 0.001) (Raikkonen et al. 2020). This figure remained significant when assessing individual disorders including intellectual disability (P < 0.001); psychological development disorders (P < 0.001); autism spectrum disorders (P < 0.001); attention-deficit/hyperactivity disorders (P < 0.001); and psychotic, mood, neurotic, stress-related, or somatization disorders (P = 0.005).
Studies by McKinlay et al. assessed childhood neurodevelopment following ANS-induced neonatal hypoglycemia. The study found that neonatal hypoglycemia was not associated with the primary outcome of increased risk of combined neurosensory impairment at 4.5 years; however, data supported dose-dependent increased risk of poor executive function and visual motor function with potential influence in later learning (McKinlay et al. 2017, Shah et al. 2019). Similarly, a 30-year follow-up of the inaugural Liggins trial found no difference in the primary outcomes of cognitive function, working memory, or attention associated with exposure to antenatal betamethasone; however, ANS exposure was found to result in adult insulin resistance, potentially increasing the potential risk of developing diabetes and cardiovascular disease in later life (Liggins & Howie 1972, Dalziel et al. 2005a, b ).
Despite emerging evidence of possible adverse outcomes following fetal ANS exposure, previous studies focused on acute short-term outcomes and were not designed for long-term follow-up. Studies show that ANS exposure conveys modest benefits for infants born late preterm and in the setting of elective caesarean at term. With late preterm birth accounting for ~70% of the preterm population (Office for National Statistics 2020, Osterman et al. 2021) and caesarean rates continuing to rise (~21% worldwide (Betran et al. 2016, Betran et al. 2021) and >30% in the US and UK (Wise 2018, Scottish Government 2021, Osterman et al. 2021)), a growing proportion of the total population is likely to be in scope for ANS therapy. The wisdom of this practice without further treatment optimization and little consensus on desired treatment benefits is ethically questionable.
In addition to important efforts to optimize ANS dosing based on pharmacokinetic and pharmacodynamic data, we also now need a broad discussion as to whether the benefits of ANS therapy warrant the potential associated risks, with particular reference to late preterm and term ANS use; an important question here is whether we may be more prudent in managing these comparably low-risk populations (noting that ANS exposure in the ALPS study did not alter the duration of maternal or infant hospital stay) with modest oxygen supplementation or even surfactant treatment (interventions that do not have long-run risk profiles) to minimize the risk of long-term harm. Moreover, we need to clearly and comprehensively articulate this information to both care providers and to patients, especially those now being recruited to late preterm and term treatment trials.
Conclusion
Fifty years on from the inaugural clinical trial by Liggins and Howie and countless clinical and animal trials later, there is still considerable variation in ANS treatment use, with little uniformity worldwide (Liggins & Howie 1972). There is robust evidence to support the use of a single course of ANS prior to anticipated preterm delivery (within 7 days of treatment) to reduce perinatal death, RDS, and IVH associated with preterm birth (McGoldrick et al. 2020). However, many areas of ANS treatment remain unresolved including ANS dose and regimen, benefit vs risk in later gestations including late preterm and for infants born by elective CS at term and the long-term health effects.
Despite the lack of dose optimization and evaluation of treatment efficacy, the current focus has shifted to expanding the treatment gestational range to include later gestation (>34 weeks), comparably low-risk pregnancies including late preterm birth and infants delivered by elective CS at term. Before expanding the recommended gestational range for ANS treatment, further studies need to focus on dose optimization to improving treatment regimens and reducing dose-dependent adverse effects. Secondly, further clarification around treatment objectives is required; specifically, is the aim of ANS treatment to minimize the risk of serious neonatal mortality and mortality, or is a reduction in a generally self-limiting neonatal morbidity (e.g. TTN) sufficient to justify potential risk.
Declaration of interest
SJS has received honoraria (paid to institution) for research talks from Hologic, and consultancy fees (paid to institution) from Natera. MWK has received royalties from Chiesi S.p.A (paid to institution). SJS receives research funding from Wellcome Trust (209560/Z/17/Z), National Institute of Healthcare Research, Medical Research Council and Chief Scientist Office Scotland. SJS is the Wellcome Leap In Utero program director. MWK receives research funding from the National Health and Medical Research Council (Australia) and the Ministry of Education, Government of the Republic of Singapore.
Funding
This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
References
Althabe F, Belizan JM, Mcclure EM, Hemingway-Foday J, Berrueta M, Mazzoni A, Ciganda A, Goudar SS, Kodkany BS, et al.2015 A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in lowincome and middle-income countries: the ACT cluster-randomised trial. Lancet 385 629–639. (https://doi.org/10.1016/S0140-6736(1461651-2)
American College of Obstetricians and Gynecologists , The Society for Maternal-Fetal Medicine, Ecker JL, , Kaimal A, , Mercer BM, , Blackwell SC, , Deregnier RA, , Farrell RM, , Grobman WA, , Resnik JL, & Sciscione AC2016 Periviable birth: Interim update. American Journal of Obstetrics and Gynecology 215 B2–B12.e1. (https://doi.org/10.1016/j.ajog.2016.04.017)
Antenatal Corticosteroid Clinical Practice Guidelines Panel 2015 Antenatal Corticosteroids Given to Women Prior to Birth to Improve Fetal, Infant, Child and Adult Health: Clinical Practice Guidelines. Auckland. New Zealand: Liggins Institute, The University of Auckland. (available at: https://www.ligginstrials.org/ANC_CPG/downloads/Antenatal_Corticosteroid_Clinical_Practice_Guidelines.pdf)
Audette MC, Challis JR, Jones RL, Sibley CP & & Matthews SG 2014 Synthetic glucocorticoid reduces human placental system a transport in women treated with antenatal therapy. Journal of Clinical Endocrinology and Metabolism 99 E2226–E2233. (https://doi.org/10.1210/jc.2014-2157)
Ballard PL & & Ballard RA 1995 Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. American Journal of Obstetrics and Gynecology 173 254–262. (https://doi.org/10.1016/0002-9378(9590210-4)
Bancalari EH & & Jobe AH 2012 The respiratory course of extremely preterm infants: a dilemma for diagnosis and terminology. Journal of Pediatrics 161 585–588. (https://doi.org/10.1016/j.jpeds.2012.05.054)
Battarbee AN, Ros ST, Esplin MS, Biggio J, Bukowski R, Parry S, Zhang H, Huang H, Andrews W, Saade G, et al.2020 Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes. American Journal of Obstetrics & Gynecology MFM 2 100077. (https://doi.org/10.1016/j.ajogmf.2019.100077)
Berger R, Abele H, Bahlmann F, Bedei I, Doubek K, Felderhoffmuser U, Fluhr H, Garnier Y, Grylka-Baeschlin S, Helmer H, et al.2019 Prevention and therapy of preterm birth. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/025, February 2019) – Part 2 with Recommendations on the Tertiary Prevention of Preterm Birth and the Management of Preterm Premature Rupture of Membranes. Zeitschrift fur Geburtshilfe und Neonatologie 223 373–394. (https://doi.org/10.1055/a-1008-8730)
Betran AP, Ye J, Moller AB, Souza JP & & Zhang J 2021 Trends and projections of caesarean section rates: global and regional estimates. BMJ Global Health 6. (https://doi.org/10.1136/bmjgh-2021-005671)
Betran AP, Ye J, Moller AB, Zhang J, Gulmezoglu AM & & Torloni MR 2016 The increasing trend in Caesarean section rates: global, regional and national estimates: 1990–2014. PLOS ONE 11 e0148343. (https://doi.org/10.1371/journal.pone.0148343)
Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J & Born Too Soon Preterm Birth Action Group 2013 Born Too Soon: the global epidemiology of 15 million preterm births. Reproductive Health 10(Supplement 1) S2. (https://doi.org/10.1186/1742-4755-10-S1-S2)
Boerma T, Ronsmans C, Melesse DY, Barros AJD, Barros FC, Juan L, Moller AB, Say L, Hosseinpoor AR, Yi M, et al.2018 Global epidemiology of use of and disparities in caesarean sections. Lancet 392 1341–1348. (https://doi.org/10.1016/S0140-6736(1831928-7)
Brownfoot FC, Gagliardi DI, Bain E, Middleton P & & Crowther CA 2013 Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 8 CD006764. (https://doi.org/10.1002/14651858.CD006764.pub3)
Bui DS, Perret JL, Walters EH, Lodge CJ, Bowatte G, Hamilton GS, Thompson BR, Frith P, Erbas B, Thomas PS, et al.2022 Association between very to moderate preterm births, lung function deficits, and COPD at age 53 years: analysis of a prospective cohort study. Lancet. Respiratory Medicine 10 478–484. (https://doi.org/10.1016/S2213-2600(2100508-7)
Carlo WA, Mcdonald SA, Fanaroff AA, Vohr BR, Stoll BJ, Ehrenkranz RA, Andrews WW, Wallace D, Das A, Bell EF, et al.2011 Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22 to 25 weeks' gestation. JAMA 306 2348–2358. (https://doi.org/10.1001/jama.2011.1752)
Carr H, Cnattingius S, Granath F, Ludvigsson JF & & Bonamy AKE 2017 Preterm birth and risk of heart failure up to early adulthood. Journal of the American College of Cardiology 69 2634–2642. (https://doi.org/10.1016/j.jacc.2017.03.572)
Clapp MA, Melamed A, Freret TS, James KE, Gyamfi-Bannerman C & & Kaimal AJ 2022 Effect of the ALPS trial on steroid and assisted ventilation use in late preterm infants. American Journal of Obstetrics and Gynecology 226(Supplement27) S26–S27. (https://doi.org/10.1016/j.ajog.2021.11.087)
Committee on Obstetric Practice 2017 Committee Opinion No. 713: Antenatal Corticosteroid Therapy for Fetal Maturation. Obstetrics and Gynecology 130 e102–e109. (https://doi.org/10.1097/aog.0000000000002237)
Crowther CA, Ashwood P, Andersen CC, Middleton PF, Tran T, Doyle LW, Robinson JS, Harding JE & ASTEROID Study Group 2019 Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial. Lancet. Child and Adolescent Health 3 769–780. (https://doi.org/10.1016/S2352-4642(1930292-5)
Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS & Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group 2006 Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 367 1913–1919. (https://doi.org/10.1016/S0140-6736(0668846-6)
Dalziel SR, Lim VK, Lambert A, Mccarthy D, Parag V, Rodgers A & & Harding JE 2005a Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial. BMJ 331 665. (https://doi.org/10.1136/bmj.38576.494363.E0)
Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A & & Harding JE 2005b Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 365 1856–1862. (https://doi.org/10.1016/S0140-6736(0566617-2)
Davis EP, Waffarn F, Uy C, Hobel CJ, Glynn LM & & Sandman CA 2009 Effect of prenatal glucocorticoid treatment on size at birth among infants born at term gestation. Journal of Perinatology 29 731–737. (https://doi.org/10.1038/jp.2009.85)
Di Stefano LM, Wood K, Mactier H, Bates SE & & Wilkinson D 2021 Viability and thresholds for treatment of extremely preterm infants: survey of UK neonatal professionals. Archives of Disease in Childhood. Fetal and Neonatal Edition 106 596–602. (https://doi.org/10.1136/archdischild-2020-321273)
Duthie L & & Reynolds RM 2013 Changes in the maternal hypothalamic-PituitaryAdrenal axis in pregnancy and postpartum: influences on maternal and fetal outcomes. Neuroendocrinology 98 106–115. (https://doi.org/10.1159/000354702)
Escobar GJ, Clark RH & & Greene JD 2006 Short-term outcomes of infants born at 35 and 36 weeks gestation: we need to ask more questions. Seminars in Perinatology 30 28–33. (https://doi.org/10.1053/j.semperi.2006.01.005)
Fee EL, Takahashi T, Takahashi Y, Carter S, Furfaro L, Clarke MW, Milad MA, Usuda H, Newnham JP, Saito M, et al.2022 One percent of the clinical dose used for antenatal steroid therapy is sufficient to induce lung maturation when administered directly to the preterm ovine fetus. American Journal of Physiology. Lung Cellular and Molecular Physiology 322 L853–L865. (https://doi.org/10.1152/ajplung.00058.2022)
Groom K, Crowther C, Bloomfield F, Lee A, Morris J & & Grobman W 2022 The C*STEROID Trial. Antenatal Corticosteroids Prior to Planned Caesarean Section Delivery from 35+0 to 39+6 Weeks Gestation; a Randomised Controlled Trial Assessing the Effects on Neonatal Respiratory Morbidity and Glycaemic Control. (available at: https://cdn.auckland.ac.nz/assets/liggins/docs/CSTEROID_Protocol_V2_9Sept2020.pdf)
Gyamfi-Bannerman C 2016 1: Antenatal Late Preterm Steroids (ALPS): a randomized trial to reduce neonatal respiratory morbidity. American Journal of Obstetrics and Gynecology 214 S2–S2. (https://doi.org/10.1016/j.ajog.2015.10.022)
Gyamfi-Bannerman C 2023 Neurodevelopmental outcomes after late preterm antenatal corticosteroids: the alps follow-up study. American Journal of Obstetrics and Gynecology 228 S764–S765. (https://doi.org/10.1016/j.ajog.2022.11.1305)
Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita ATN, Reddy UM, Saade GR, Rouse DJ, Mckenna DS, Clark EAS, Thorp JM, et al.2016 Antenatal betamethasone for women at risk for late preterm delivery. New England Journal of Medicine 374 1311–1320. (https://doi.org/10.1056/NEJMoa1516783)
Hansen AK, Wisborg K, Uldbjerg N & & Henriksen TB 2008 Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study. BMJ 336 85–87. (https://doi.org/10.1136/bmj.39405.539282.BE)
Harris A & & Seckl J 2011 Glucocorticoids, prenatal stress and the programming of disease. Hormones and Behavior 59 279–289. (https://doi.org/10.1016/j.yhbeh.2010.06.007)
Huang WL, Harper CG, Evans SF, Newnham JP & & Dunlop SA 2001 Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep. International Journal of Developmental Neuroscience 19 415–425. (https://doi.org/10.1016/s0736-5748(0100026-0)
Jobe AH & & Goldenberg RL 2018 Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. American Journal of Obstetrics and Gynecology 219 62–74. (https://doi.org/10.1016/j.ajog.2018.04.007)
Jobe AH, Milad MA, Peppard T & & Jusko WJ 2020 Pharmacokinetics and pharmacodynamics of intramuscular and oral betamethasone and dexamethasone in reproductive age women in India. Clinical and Translational Science 13 391–399. (https://doi.org/10.1111/cts.12724)
Jobe AH, Newnham J, Willet K, Sly P & & Ikegami M 1998 Fetal versus maternal and gestational age effects of repetitive antenatal glucocorticoids. Pediatrics 102 1116–1125. (https://doi.org/10.1542/peds.102.5.1116)
Jobe AH & & Soll RF 2004 Choice and dose of corticosteroid for antenatal treatments. American Journal of Obstetrics and Gynecology 190 878–881. (https://doi.org/10.1016/j.ajog.2004.01.044)
Johnson S & & Marlow N 2017 Early and long-term outcome of infants born extremely preterm. Archives of Disease in Childhood 102 97–102. (https://doi.org/10.1136/archdischild-2015-309581)
Kearsey EOR, Been JV, Souter VL & & Stock SJ 2022 The impact of the Antenatal Late preterm Steroids trial on the administration of antenatal corticosteroids. American Journal of Obstetrics and Gynecology 227 280.e1–280.e15. (https://doi.org/10.1016/j.ajog.2022.03.037)
Kemp MW, Saito M, Usuda H, Watanabe S, Sato S, Hanita T, Kumagai Y, Molloy TJ, Clarke M, Eddershaw PJ, et al.2018 The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy. American Journal of Obstetrics and Gynecology 219 301.e1–301.e16. (https://doi.org/10.1016/j.ajog.2018.05.007)
Kerstjens JM, Bocca-Tjeertes IF, De Winter AF, Reijneveld SA & & Bos AF 2012 Neonatal morbidities and developmental delay in moderately preterm-born children. Pediatrics 130 e265–e272. (https://doi.org/10.1542/peds.2012-0079)
Kitsommart R, Janes M, Mahajan V, Rahman A, Seidlitz W, Wilson J & & Paes B 2009 Outcomes of late-preterm infants: a retrospective, single-center, Canadian study. Clinical Pediatrics (Phila) 48 844–850. (https://doi.org/10.1177/0009922809340432)
Lee BH, Stoll BJ, Mcdonald SA, Higgins RD & National Institute of Child Health and Human Development Neonatal Research Network 2006 Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics 117 1503–1510. (https://doi.org/10.1542/peds.2005-1749)
Lee BH, Stoll BJ, Mcdonald SA, Higgins RD & National Institute of Child Health and Human Development Neonatal Research Network 2008 Neurodevelopmental outcomes of extremely low birth weight infants exposed prenatally to dexamethasone versus betamethasone. Pediatrics 121 289–296. (https://doi.org/10.1542/peds.2007-1103)
Levine EM, Ghai V, Barton JJ & & Strom CM 2001 Mode of delivery and risk of respiratory diseases in newborns. Obstetrics and Gynecology 97 439–442. (https://doi.org/10.1016/s0029-7844(0001150-9)
Liggins GC & & Howie RN 1972 A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 50 515–525. (https://doi.org/10.1542/peds.50.4.515)
Lin YH, Lin CH, Lin MC, Hsu YC & & Hsu CT 2023 Antenatal corticosteroid exposure is associated with childhood mental disorders in late preterm and term infants. Journal of Pediatrics 253 245–251.e2. (https://doi.org/10.1016/j.jpeds.2022.09.050)
Mactier H, Bates SE, Johnston T, Lee-Davey C, Marlow N, Mulley K, Smith LK, To M, Wilkinson D, GRP, et al.2020 Perinatal management of extreme preterm birth before 27 weeks of gestation: a framework for practice. Archives of Disease in Childhood. Fetal and Neonatal Edition 105 232–239. (https://doi.org/10.1136/archdischild-2019-318402)
Mangham LJ, Petrou S, Doyle LW, Draper ES & & Marlow N 2009 The cost of preterm birth throughout childhood in England and Wales. Pediatrics 123 e312–e327. (https://doi.org/10.1542/peds.2008-1827)
Matthews SG 2000 Antenatal glucocorticoids and programming of the developing CNS. Pediatric Research 47 291–300. (https://doi.org/10.1203/00006450-200003000-00003)
McGoldrick E, Stewart F, Parker R & & Dalzie SR 2020 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 12 CD004454. (https://doi.org/10.1002/14651858.CD004454.pub4)
McIntire DD & & Leveno KJ 2008 Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstetrics and Gynecology 111 35–41. (https://doi.org/10.1097/01.AOG.0000297311.33046.73)
McKinlay CJD, Alsweiler JM, Anstice NS, Burakevych N, Chakraborty A, Chase JG, Gamble GD, Harris DL, Jacobs RJ, Jiang YN, et al.2017 Association of neonatal glycemia with neurodevelopmental outcomes at 4.5 years. JAMA Pediatrics 171 972–983. (https://doi.org/10.1001/jamapediatrics.2017.1579)
McLaughlin KJ, Crowther CA, Walker N & & Harding JE 2003 Effects of a single course of corticosteroids given more than 7 days before birth: a systematic review. Australian and New Zealand Journal of Obstetrics and Gynaecology 43 101–106. (https://doi.org/10.1046/j.0004-8666.2003.00052.x)
Medley N, Vogel JP, Care A & & Alfirevic Z 2018 Interventions during pregnancy to prevent preterm birth: an overview of Cochrane systematic reviews. Cochrane Database of Systematic Reviews 11 CD012505. (https://doi.org/10.1002/14651858.CD012505.pub2)
Ministry of Health 2001 Management of Preterm Labour: Clinical Practice Guidelines Singapore 3. (available at: https://www.moh.gov.sg/docs/librariesprovider4/guidelines/cpg_management-of-preterm-labour-may-2001.pdf)
Moisiadis VG & & Matthews SG 2014 Glucocorticoids and fetal programming part 2: mechanisms. Nature Reviews. Endocrinology 10 403–411. (https://doi.org/10.1038/nrendo.2014.74)
Morgan AS, Mendonca M, Thiele N & & David AL 2022 Management and outcomes of extreme preterm birth. BMJ 376 e055924. (https://doi.org/10.1136/bmj-2021-055924)
Mori R, Kusuda S, Fujimura M & & Japan NRN 2011 Antenatal corticosteroids promote survival of extremely preterm infants born at 22 to 23 weeks of gestation. Journal of Pediatrics 159 110–114.e1. (https://doi.org/10.1016/j.jpeds.2010.12.039)
Moss TJ, Sloboda DM, Gurrin LC, Harding R, Challis JR & & Newnham JP 2001 Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 281 R960–R970. (https://doi.org/10.1152/ajpregu.2001.281.3.R960)
Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly EN, Matthews SG, Saigal S, Asztalos E, Ross S, et al.2008 Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 372 2143–2151. (https://doi.org/10.1016/S0140-6736(0861929-7)
Newnham JP, Evans SF, Godfrey M, Huang W, Ikegami M & & Jobe A 1999 Maternal, but not fetal, administration of corticosteroids restricts fetal growth. Journal of Maternal-Fetal Medicine 8 81–87. (https://doi.org/10.1002/(SICI)1520-6661(199905/06)8:3<81::AID-MFM3>3.0.CO;2-N)
Newnham JP, White SW, Meharry S, Lee HS, Pedretti MK, Arrese CA, Keelan JA, Kemp MW, Dickinson JE & & Doherty DA 2017 Reducing preterm birth by a statewide multifaceted program: an implementation study. American Journal of Obstetrics and Gynecology 216 434–442. (https://doi.org/10.1016/j.ajog.2016.11.1037)
Norman M, Piedvache A, Borch K, Huusom LD, Bonamy AE, Howell EA, Jarreau PH, Maier RF, Pryds O, Toome L, et al.2017 Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals with Survival and Morbidity among very preterm infants: results from the EPICE Cohort. JAMA Pediatrics 171 678–686. (https://doi.org/10.1001/jamapediatrics.2017.0602)
Oakley RH & & Cidlowski JA 2013 The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. Journal of Allergy and Clinical Immunology 132 1033–1044. (https://doi.org/10.1016/j.jaci.2013.09.007)
Office for National Statistics 2020 Birth characteristics in England and Wales. (available at: https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/bulletins/birthcharacteristicsinenglandandwales/2020)
Osterman M, Hamilton B, Martin JA, Driscoll AK & & Valenzuela CP 2021 Births: final data for 2020. National Vital Statistics Reports 70 1–50. (available at: https://www.cdc.gov/nchs/data/nvsr/nvsr70/nvsr70-17.pdf)
Petrou S, Henderson J, Bracewell M, Hockley C, Wolke D, Marlow N & EPICure Study Group 2006 Pushing the boundaries of viability: the economic impact of extreme preterm birth. Early Human Development 82 77–84. (https://doi.org/10.1016/j.earlhumdev.2006.01.002)
Raikkonen K, Gissler M & & Kajantie E 2020 Associations between maternal antenatal corticosteroid treatment and mental and behavioral disorders in children. JAMA 323 1924–1933. (https://doi.org/10.1001/jama.2020.3937)
Roberts D, Brown J, Medley N & & Dalziel SR 2017 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 3 CD004454. (https://doi.org/10.1002/14651858.CD004454.pub3)
Roberts D & & Dalziel S 2006 Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews. (https://doi.org/10.1002/14651858.CD004454.pub2)
Rodriguez A, Wang YB, Khan AA, Cartwright R, Gissler M & & Jarvelin MR 2019 Antenatal corticosteroid therapy (ACT) and size at birth: a population-based analysis using the Finnish Medical Birth Register. PLOS Medicine 16 e1002746. (https://doi.org/10.1371/journal.pmed.1002746)
Samtani MN, Lohle M, Grant A, Nathanielsz PW & & Jusko WJ 2005 Betamethasone pharmacokinetics after two prodrug formulations in sheep: implications for antenatal corticosteroid use. Drug Metabolism and Disposition 33 1124–1130. (https://doi.org/10.1124/dmd.105.004309)
Sandall J, Tribe RM, Avery L, Mola G, Visser GH, Homer CS, Gibbons D, Kelly NM, Kennedy HP, Kidanto H, et al.2018 Short-term and long-term effects of caesarean section on the health of women and children. Lancet 392 1349–1357. (https://doi.org/10.1016/S0140-6736(1831930-5)
Scottish Government 2021 The Best Start - Caesarean Section Rates: Review Report. (available at: https://www.gov.scot/publications/best-start-review-caesarean-section-rates-scotland/)
Shah R, Harding J, Brown J & & McKinlay C 2019 Neonatal glycaemia and neurodevelopmental outcomes: a systematic review and meta-analysis. Neonatology 115 116–126. (https://doi.org/10.1159/000492859)
Skoll A, Boutin A, Bujold E, Burrows J, Crane J, Geary M, Jain V, Lacaze-Masmonteil T, Liauw J, Mundle W, et al.2018 No. 364-Antenatal Corticosteroid Therapy for Improving Neonatal Outcomes. Journal of Obstetrics and Gynaecology Canada 40 1219–1239. (https://doi.org/10.1016/j.jogc.2018.04.018)
Sotiriadis A, Makrydimas G, Papatheodorou S, Ioannidis JPA & & McGoldrick E 2018 Corticosteroids for preventing neonatal respiratory morbidity after elective caesarean section at term. Cochrane Database of Systematic Reviews 8 CD006614. (https://doi.org/10.1002/14651858.CD006614.pub3)
Stock SJ, Murray S, Luyt K, Boyd K, Deidda M, Bick D, Boardman J, Norman J, Norrie J & & Reynolds R 2020a A Rando mised Placebo-Controlled Trial of Antenatal Corticosteroids for Planned Birth in Twins: STOPPIT-3. (available at: https://twinstrust.org/who-we-are/what-we-do/research/clinical-research/stoppit-3.html)
Stock SJ, Thomson AJ, Papworth S & Royal College of Gynaecologists 2022b Antenatal corticosteroids to reduce neonatal morbidity and mortality: Green-top Guideline No. 74. BJOG 129 e35–e60. (https://doi.org/10.1111/1471-0528.17027)
Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S, Laptook AR, Sánchez PJ, Van Meurs KP, Wyckoff M, et al.2015 Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA 314 1039–1051. (https://doi.org/10.1001/jama.2015.10244)
Stutchfield P, Whitaker R, Russell I & Antenatal Steroids for Term Elective Caesarean Section Research 2005 Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ 331 662.
Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S & & Doull IJ 2013 Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Archives of Disease in Childhood. Fetal and Neonatal Edition 98 F195–F200. (https://doi.org/10.1136/archdischild-2012-303157)
Takahashi T, Fee E, Takahashi Y, Usuda H, Jobe A & & Kemp M 2022a Continuous but not pulsed steroid exposures extend the durability of antenatal steroid therapy in a sheep model of pregnancy. Reproductive Sciences 29 43–53.
Takahashi T, Jobe AH, Fee EL, Newnham JP, Schmidt AF, Usuda H & & Kemp MW 2022b The complex challenge of antenatal steroid therapy nonresponsiveness. American Journal of Obstetrics and Gynecology. (https://doi.org/10.1016/j.ajog.2022.07.030)
Tao S, Du J, Chi X, Zhu Y, Wang X, Meng Q, Ling X, Diao F, Song C, Jiang Y, et al.2022 Associations between antenatal corticosteroid exposure and neurodevelopment in infants. American Journal of Obstetrics and Gynecology. (https://doi.org/10.1016/j.ajog.2022.05.060)
Tetro N, Moushaev S, Rubinchik-Stern M & & Eyal S 2018 The placental barrier: the gate and the fate in drug distribution. Pharmaceutical Research 35 71. (https://doi.org/10.1007/s11095-017-2286-0)
Tijsseling D, Wijnberger LD, Derks JB, Van Velthoven CT, De Vries WB, Van Bel F, Nikkels PG & & Visser GH 2012 Effects of antenatal glucocorticoid therapy on hippocampal histology of preterm infants. PLoS One 7 e33369. (https://doi.org/10.1371/journal.pone.0033369)
Travers CP, Carlo WA, Mcdonald Das SA, A, Bell EF, Ambalavanan N, Jobe AH, Goldberg RN, D'angio CT, Stoll BJ, et al.2018 Mortality and pulmonary outcomes of extremely preterm infants exposed to antenatal corticosteroids. American Journal of Obstetrics and Gynecology 218 130.e1–130.e13. (https://doi.org/10.1016/j.ajog.2017.11.554)
Uno H, Lohmiller L, Thieme C, Kemnitz JW, Engle MJ, Roecker EB & & Farrell PM 1990 Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Research. Developmental Brain Research 53 157–167. (https://doi.org/10.1016/0165-3806(9090002-g)
Usuda HF, EL, Carter S, Furfaro L, Takahashi T, Takahashi Y, Newnham JP, Milad MA, Saito M, Jobe AH, et al.2022 Low-dose antenatal betamethasone treatment achieves preterm lung maturation equivalent to that of the WHO dexamethasone regimen but with reduced endocrine disruption in a sheep model of pregnancy. American Journal of Obstetrics and Gynecology 227 903.e1–903.e16.
Waffarn F & & Davis EP 2012 Effects of antenatal corticosteroids on the hypothalamicpituitary-adrenocortical axis of the fetus and newborn: experimental findings and clinical considerations. American Journal of Obstetrics and Gynecology 207 446–454. (https://doi.org/10.1016/j.ajog.2012.06.012)
Walani SR 2020 Global burden of preterm birth. International Journal of Gynaecology and Obstetrics 150 31–33. (https://doi.org/10.1002/ijgo.13195)
WHO 2015 WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva, Switzerland: World Health Organization. (available at: https://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988_eng.pdf)
WHO 2022 WHO Recommendations on Antenatal Corticosteroids for Improving Preterm Birth Outcomes. Geneva, Switzerland: World Health Organization. (available: https://www.who.int/publications/i/item/9789240057296)
WHO ACTION Trials Collaborators 2022a Action III: A Multi-country, Multi-centre, Three-Arm, Parallel Group, Double-Blind, Placebo-Controlled, Randomized Trial of Two Doses of Antenatal Corticosteroids for Women with a High Probability of Birth in the Late Preterm Period in Hospitals in Low-Resource Countries to Improve Newborn Outcomes. (available at: https://www.who.int/publications/m/item/action-iii-a-multi-country-multi-centre-three-arm-parallelgroup)
WHO ACTION Trials Collaborators 2022b Antenatal dexamethasone for late preterm birth: A multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial. EClinicalmedicine 44 101285. (https://doi.org/10.1016/j.eclinm.2022.101285)
Wise J 2018 Alarming global rise in caesarean births, figures show. BMJ 363 k4319. (https://doi.org/10.1136/bmj.k4319)
Yoder BA, Gordon MC & & Barth WH 2008 Late-preterm birth - Does the changing obstetric paradigm alter the epidemiology of respiratory complications? Obstetrics and Gynecology 111 814–822. (https://doi.org/10.1097/AOG.0b013e31816499f4)