Antenatal corticosteroids

#Background

The effect of corticosteroids on improved fetal lung maturity after preterm birth was first identified by the pioneering New Zealand scientist and obstetrician, Professor Sir Graham ‘Mont’ Liggins, in the late 1960s.¹ This finding was quickly followed by the world’s first-ever randomised placebo-controlled trial of the administration of corticosteroids prior to preterm birth at National Women’s Hospital, Auckland in the early 1970s.² This trial demonstrated significant benefit on neonatal respiratory morbidity and pēpi survival, findings which have consistently been demonstrated in subsequent trials. Multiple meta-analyses, including the most recent Cochrane Review, show clear benefit in reducing perinatal death (RR 0.85, 95% CI 0.77-0.93); neonatal death (RR 0.78, 95% CI 0.70-0.87); respiratory distress syndrome (RR 0.71, 95% CI 0.65-0.78); intraventricular haemorrhage (RR 0.58, 95% CI 0.45-0.75) and developmental delay in childhood (RR 0.51, 95% CI 0.27-0.97), with no adverse effect on birthweight, chorioamnionitis and endometritis.³

The use of corticosteroids prior to early preterm birth is considered an international standard of practice^4-8 and recommended in the bi-national Australian and New Zealand guidelines.⁸ Despite this, and widespread knowledge on the benefits corticosteroids prior to preterm birth, only 51% of pēpi born <35 weeks and admitted to a Level 2 or Level 3 neonatal unit in Aotearoa in 2020 received a complete course of corticosteroids within seven days of birth.⁹ Furthermore, a 2017 survey of Australian and New Zealand obstetricians demonstrated significant variation in practice including use when preterm birth was expected beyond seven days and after 35 weeks gestation.¹⁰

More extended use of corticosteroids prior to birth, e.g. in late preterm birth or as repeat doses, and in particular subgroups, e.g. wāhine/people with diabetes, continues to create discussion. Limited, and sometimes conflicting, evidence contributes to significant variation in practice.

Concerns have been raised about longer-term, potentially harmful effects of corticosteroids which may contribute to hesitation in their use, even at preterm gestations. These concerns are often identified and inferred from animal studies and poorly controlled population-based studies. Follow-up studies of the 30-year-old offspring from the original Liggins randomised trial provided very reassuring data in support of short-term benefits without long-term harm of corticosteroid use prior to preterm birth including on cardiac, respiratory, metabolic and psychological wellbeing.^11-14 More recently further follow-up of the offspring from the same original trial has demonstrated that corticosteroid exposure in utero has no impact on the prevalence of cardiovascular risk factors or events up to the age of 50 years¹⁵ or on other aspects of wellbeing such as obstructive airways disease, mental health, educational achievement, employment status and criminal convictions.¹⁶

There are several mechanisms by which corticosteroids accelerate fetal lung maturity, including increased surfactant production, improved antioxidant activity resulting in reduced damage from oxygen free radicals, and decreased pro-inflammatory cytokine production.¹⁷ Corticosteroids also promote the maturation of many other fetal organs by similar pathways. This includes maintenance of intestinal barrier function and reduction of pro-inflammatory cytokines, reducing the risk of necrotising enterocolitis^18,19 and stabilisation of the germinal matrix vasculature, reducing the risk of intraventricular haemorrhage.²⁰

#Recommendations and Practice

Assessment, indications and timing for antenatal corticosteroid use

There are a wide variety of indications where corticosteroid use should be considered, these broadly include consideration of gestational age, likelihood of preterm birth and reason for preterm birth. Evidence has been assimilated in multiple meta-analyses and systematic reviews to inform clinical practice guidelines.

Optimal use and timing of corticosteroid administration is essential to maximise benefit and minimise harm. Increased perinatal survival is only seen when corticosteroids are given within 24 and 48 hours of preterm birth, there is no effect on survival when birth occurs more than 48 hours after administration.^5,8,24 The benefit on perinatal morbidity (reduced incidence of respiratory distress syndrome) is seen when corticosteroids are given within 48 hours and up to seven days before preterm birth.^5,8,24

Beyond seven days after administration, the benefit of corticosteroids is no longer significant and so if wāhine/people remain pregnant and are assessed to still be at risk of preterm birth, repeat corticosteroid doses should be considered. Any benefit of repeat doses appears to be limited to perinatal morbidity and not survival. The most recent evidence to demonstrate this includes a 2019 individual participant data meta-analysis of 11 trials (4857 wāhine/people and their 5915 pēpi), in which repeat corticosteroid doses were associated with a reduction in the use of respiratory support in pēpi (RR 0.91, 95% CI 0.85-0.97).²⁶ The 2022 Cochrane Review update has a similar size of effect on the incidence of respiratory distress syndrome (RR 0.82, 95% CI 0.74-0.90) and a significant effect on a composite of serious infant outcomes (RR 0.88, 95% CI 0.80-0.97).²⁷ Despite these positive effects, concern exists that multiple repeat doses may impact on birthweight.^28,29 Furthermore, evidence from population-based studies suggests children whose māmā/person received antenatal corticosteroids but are born at term may have an increased risk of mental health and behavioural disorders in early childhood,³⁰ although differences have not been demonstrated in childhood follow-up of randomised trials in this field.^31,32

Careful risk assessment should be undertaken to achieve corticosteroid use only in those at highest risk of preterm birth and where there is reasonable expectation of birth within seven days, ideally within 48 hours. Focusing on this narrow window of efficacy will maximise healthy outcomes for those that deliver preterm and limit risk for those that do not.

Antenatal corticosteroid drug type and dosing prior to preterm birth

Betamethasone and dexamethasone are fluorinated synthetic corticosteroids. They have a similar molecular structure and share the ability to cross the human placenta from māmā/parent to pēpi. High-quality evidence has been established on the short-term comparable effectiveness of these two preparations with recommendations included in the New Zealand and Australian Clinical Practice Guidelines 2015. Since that time further evidence on the longer-term comparable effectiveness has been reported. The Australian/New Zealand ASTEROID Trial published in 2019, was a multicentre, double-blind, randomised controlled trial comparing two intramuscular doses of either 12 mg dexamethasone or 11.4 mg betamethasone, 24 hours apart including 1346 wāhine/people and their 1509 pēpi.³³ There was no difference in the primary outcome of death or neurosensory disability at age 2 years (adjRR 0.97, 95% CI 0.83-1.13) between dexamethasone and betamethasone and the effects on neonatal health, including respiratory and neurological outcomes were similar.³³

The optimal dose and dose interval for a single course of corticosteroids has been assessed, with similar efficacy between studied regimens for a reduction in neonatal death and respiratory distress syndrome, and in risk of chorioamnionitis and sepsis.^8,34 The 2022 French multicentre, randomised controlled, BETADOSE trial including 3141 pēpi has explored the benefits of a single (half) dose compared to the standard two dose corticosteroid course. ³⁵ The risk difference in the primary outcome of the need for exogenous intratracheal surfactant within 48 hours of birth did not meet the trial’s criteria to demonstrate non-inferiority (20.0% in half dose group and 17.5% in full dose group, risk difference 2.4%, 95% CI -0.3 to 5.2).³⁵ Thus, there is no recommendation to change current dosing regime, although results of ongoing trials are awaited, including 5 year follow-up of the children from the BETADOSE trial.

Repeat and rescue antenatal corticosteroid treatment

With careful risk assessment, corticosteroids should be given within seven days, and ideally within 48 hours of birth. However, despite best risk assessment some wāhine/people will remain pregnant after seven days and the beneficial effect of corticosteroids will no longer be significant. In this scenario, the benefits and risks of any further corticosteroid administration must be considered.

‘Repeat’ doses may be considered for wāhine/people at significant ongoing risk of preterm birth within the next seven days, if seven to 14 days from the initial course. For wāhine/people who re-present at risk of preterm birth following a longer interval from an initial course, there are no randomised trials to guide practice, but ‘rescue’ doses are often considered.

Clinical trial evidence on the benefits and risks of repeat doses of corticosteroids compared to placebo is focussed on betamethasone only. However, secondary analysis of wāhine/people receiving repeat doses of corticosteroid in the ASTEROID Trial, show no difference in infant, childhood, and maternal health outcomes with repeat betamethasone or dexamethasone use.³⁶

Additonal considerations for corticosteroid use

Diabetes in Pregnancy

Pēpi born to wāhine/people with diabetes are at increased risk of neonatal respiratory morbidity, and hence, corticosteroids prior to preterm birth may provide additional benefit for these pēpi. However, corticosteroids temporarily induce hyperglycaemia for the māmā/person and for wāhine/people with diabetes in pregnancy, this may necessitate a short-term increase in their diabetes medication as well as potentially exacerbating the existing risk of hypoglycaemia in the pēpi. Concern has also been raised about the risk of infection with corticosteroid use in wāhine/people with diabetes.

To date very few wāhine/people with diabetes have been included in clinical trials of corticosteroid use and therefore there is insufficient evidence to make specific recommendations.

#Auditable standards

To be added

Standards should be considered across your population and by ethnic group to allow objective assessment of equity in practice.

#Included guidelines

The search identified five clinical practice guidelines relevant to corticosteroid use that met criteria for high-quality and/or were recommended for use.8,18-21 Three of these were assessed to be high-quality in Rigour of Development (score >60%) and in Overall Assessment (score >60%) and were recommended for use in clinical practice by the Review Panel.8,18,21 One of these guidelines, prepared by a single district health board,18 clearly documented that evidence and recommendations were adopted from one of the other identified guideline, the ‘Antenatal corticosteroids given to women prior to birth to improve fetal, infant, child and adult health: New Zealand and Australian Clinical Practice Guidelines 2015’ (New Zealand and Australian Clinical Practice Guidelines 2015).8 The remaining two guidelines did not meet high-quality criteria but were recommended for use with modifications by the Review Panel.19,20 Both of these guidelines made specific reference to the 2015 bi-national guideline in their recommendations.

Recommendations in this section are based on the New Zealand and Australian Clinical Practice Guidelines 2015.8 This bi-national guideline was developed by a multidisciplinary guideline development panel with systematic review of all relevant evidence to provide evidence-based recommendations to guide clinical decision-making on antenatal corticosteroid use in Australasia. However, as these guidelines were released in 2015 and the planned three-year review and update has not occurred (unfunded), additional evidence from high-quality clinical trials and systematic reviews published since 2015 has been considered and included where appropriate.

#Impact on equity

Aotearoa specific data supplied by the Australian and New Zealand Neonatal Network (ANZNN) for births <35⁺⁰ weeks in 2020, demonstrate an overall rate of 51.2% of pēpi were born to māmā/people who had received a complete course of corticosteroids <7 days prior to birth; but only 46.3% for pēpi born to wāhine Māori (ANZNN data only report maternal ethnicity).²⁵ National data on antenatal corticosteroid use by ethnic group, region of residence, socioeconomic status and other equity factors are not routinely reported. It is likely that differences in use by these factors may occur and contribute to differences seen in perinatal outcomes.

Review Panel assessments identified that the recommendations in all five antenatal corticosteroid clinical practice guidelines^8,21-24 had potential to reduce differences by ethnicity and other equity factors in preterm birth outcomes. Note was made that this would be dependent on access to pregnancy care and targeted implementation to those most likely to benefit.

#Research in progress that may inform future practice recommendations

A follow-up study of the ACTORDS Trial is using national, routinely-collected data on education, employment and use of health services to assess the effect of exposure to repeat doses of antenatal betamethasone in young adults. Results are awaited.

The Single Dose of Antenatal Corticosteroids for Pregnancies at Risk of Preterm Delivery (SNACS) study is a multi-centre, blinded, two arm non-inferiority randomised controlled trial assessing whether half the usual dose of betamethasone (a single dose of 11.4 mg in Australia, 12 mg in Canada) is equivalent to the standard two dose course regime. The trial is currently recruiting in Canada and Australia with an estimated recruitment end date of 2025, with results anticipated by 2028.

The C*STEROID Trial is a randomised placebo-controlled trial of betamethasone in wāhine/people without diabetes undergoing planned caesarean section at 35⁺⁰ to 39⁺⁶ weeks gestation. It has co-primary outcomes relating to neonatal respiratory support and neonatal hypoglycaemia. It is funded by the Health Research Council of New Zealand and the Australian Medical Research Futures Fund and available at sites across Aotearoa and Australia. Wāhine/people without diabetes undergoing a planned caesarean section at late preterm gestations (35⁺⁰ to 36⁺⁶ weeks) are eligible. Sites participating in the trial should offer inclusion to all wāhine/people as the standard of care.

The PRECeDE Trial is a randomised placebo-controlled trial of betamethasone in wāhine/people with diabetes undergoing planned caesarean section at 35⁺⁰ to 39⁺⁶ weeks gestation. This trial is very similar in design to the C*STEROID Trial but particularly focussed on wāhine/people with diabetes (type 1, type 2 and gestational) as the risks of both benefit (neonatal respiratory morbidity) and harm (neonatal hypoglycaemia) are increased for pēpi born to wāhine/people with diabetes in pregnancy. It is funded by the Australian National Health and Medical Research Council and available at sites across Aotearoa and Australia. Wāhine/people with diabetes in pregnancy undergoing a planned caesarean section at late preterm gestations (35⁺⁰ to 36⁺⁶ weeks) will be eligible. Sites participating in the trial should offer inclusion to all wāhine/people as the standard of care.

#Statement on rationale for any differing recommendations from the high-quality guidelines

The New Zealand and Australian Clinical Practice Guidelines 2015 recommendation on type and dose of corticosteroid to use for a single course is either betamethasone 24 mg in divided doses completed between 12 and 36 hours (Celestone Chronodose 11.4 mg two doses, 24 hours apart) or dexamethasone 24 mg in divided doses completed between 24 and 40 hours (dexamethasone phosphate 6 mg four doses, 12 hours apart).⁸ In the ASTEROID Trial, two doses of 12 mg dexamethasone was compared to two doses of 11.4 mg betamethasone, 24 hours apart.³³ Using these two sources of evidence, this Guide initially proposed three options for the first course of corticosteroid (betamethasone 11.4 mg as two doses 24 hours apart, dexamethasone 12 mg as two doses 24 hours apart or dexamethasone 6 mg as four doses 12 hours apart). A recommendation from those attending the December 2022 Taonga Tuku Iho Stakeholder Hui was to remove the option of four doses of dexamethasone option. This decision was made to optimise the chance of women receiving the complete course of corticosteroid as prescribed (practical implications of administering two rather than four doses in a 24 hour period).

The World Health Organization (WHO) recommendations on interventions to improve preterm birth outcomes includes ten recommendations on corticosteroid use.²⁴ These are consistent with the recommendations from the New Zealand and Australian Clinical Practice Guidelines 2015,⁸ which are used in this guide, with the exception of their recommendation on repeat use of corticosteroids. The WHO recommendation is for only a ‘single repeat dose if preterm birth does not occur within seven days after the initial dose, and subsequent clinical assessment demonstrates a high risk of preterm birth in the next seven days’.

#References

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21. Auckland District Health Board. Antenatal Corticosteroids to Improve Neonatal Outcomes. Auckland: Auckland District Health Board; 2021. Available from: https://www.nationalwomenshealth.adhb.govt.nz/assets/Womens-health/Documents/Policies-and-guidelines/Antenatal-Corticosteroids-to-Improve-Neonatal-Outcomes-3.2017.pdf.

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26. Crowther CA, Middleton PF, Voysey M, Askie L, Zhang S, Martlow TK, et al. Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis. PLoS Med. 2019;16(4):e1002771. DOI: 10.1371/journal.pmed.1002771.

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29. Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly EN, et al. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet. 2008;372(9656):2143-51. DOI: 10.1016/S0140-6736(08)61929-7.

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31. Crowther CA, Anderson PJ, McKinlay CJD, Harding JE, Ashwood PJ, Haslam RR, et al. Mid-childhood outcomes of repeat antenatal corticosteroids: A randomized controlled trial. J Pediatr. 2016;138(4):e20160947. DOI:10.1542/peds.2016-0947.

32. Asztalos EV, Murphy KE, Willan AR, Matthews SG, Ohlsson A, Saigal S, et al. Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5). JAMA Pediatr. 2013;167(12):1102-10. DOI: 10.1001/jamapediatrics.2013.2764.

33. Crowther CA, Ashwood P, Anderson CC, Middleton PF, Tran T, Doyle LW, et al. Maternal intramuscular dexamethasone versus betamethasone before preterm birth (ASTEROID): a multicentre, double-blind, randomised controlled trial. Lancet Child Adolesc Health. 2019;3(11):769-80. DOI: 10.1016/S2352-4642(19)30292-5.

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non-inferiority trial. Lancet. 2022;400:592-604. DOI: 10.1016/S0140-6736(22)01535-5.

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42. Ehret DEY, Edwards EM, Greenberg LT, Bernstein IM, Buzas JS, Soll RF, et al. Association of Antenatal Steroid Exposure With Survival Among Infants Receiving Postnatal Life Support at 22 to 25 Weeks' Gestation. JAMA Netw Open. 2018;1(6):e183235. DOI: 10.1001/jamanetworkopen.2018.3235.

43. Newborn Clinical Network. New Zealand Consensus Statement on the Care of Mother and Baby(ies) at Periviable Gestations: Newborn Clinical Network; 2019. Available from: https://www.starship.org.nz/guidelines/new-zealand-consensus-statement-on-the-care-of-mother-and-baby-ies-at/.

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47. McKinlay CJD, Alsweiler JM, Anstice NS, Burakevych N, Chakraborty A, Chase JG, et al. Association of Neonatal Glycemia With Neurodevelopmental Outcomes at 4.5 Years. JAMA Pediatr. 2017;171(10):972-83. DOI: 10.1001/jamapediatrics.2017.1579.

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