Antenatal corticosteroids to reduce neonatal morbidity and mortality

This guideline will supplement NICE guideline [NG25] Preterm labour and birth (November 2015, updated 2019) and the archived RCOG Green-top Guideline No. 7 Antenatal corticosteroids to reduce neonatal morbidity and mortality (October 2010). Maternal administration of antenatal corticosteroids before anticipated preterm birth is one of the most important interventions to improve neonatal outcomes.1 They are effective in reducing neonatal respiratory morbidity and other complications of prematurity. The aim of this guideline is to provide evidence-based recommendations on the use of antenatal corticosteroids in women at risk of preterm birth or undergoing caesarean birth at term. Within this document we use the terms woman and women's health. However, it is important to acknowledge that it is not only people who identify as women for whom it is necessary to access women's health and reproductive services in order to maintain their gynaecological health and reproductive wellbeing. Gynaecological and obstetric services and delivery of care must therefore be appropriate, inclusive and sensitive to the needs of those individuals whose gender identity does not align with the sex they were assigned at birth. The Cochrane Library and electronic databases (DARE, EMBASE, Trip, MEDLINE and PubMed) were searched looking for the following terms in the title or abstract ‘corticosteroids’, ‘glucocorticoids’, ‘pregnancy’, ‘obstetrics’, ‘antenatal’ and ‘fetal’. The search was restricted to articles published until January 2021. The full search strategy is available to view online as supporting information (Appendix S1 and S2). This guideline was developed using the standard methodology for developing Green-top Guidelines. The recommendations have been graded according to the SIGN hierarchy of evidence.8 No studies were identified that showed direct beneficial effects of antenatal corticosteroids for the woman. There is a paucity of evidence on the balance of benefits versus harms when corticosteroids are administered in late pregnancy. Antenatal corticosteroids may increase the risk of neonatal hypoglycaemia in term neonates (extrapolating data from trials of corticosteroids in the late preterm period15 and observational data16, 17) and there is some evidence that they may be associated with developmental delay (based on limited and incomplete trial follow-up18 and observational studies;19 see section 9.2). As the risk of respiratory distress at term is low (~5%), and it is usually mild and transient, and there is low certainty of benefit, clinicians should discuss these factors with the woman when considering the administration of corticosteroids prior to caesarean birth at term (See Table 1). 22+0* to 34+6 weeks (*when the woman, in discussion with the perinatal care team, has made an informed decision that active care for the baby is appropriate) Highly likely to reduce: NNT 43.5 (95% CI 27.8–100) NNT 38.5 (95% CI 27.8–62.5) NNT 23.3 (95% CI 19.2–30.3) Likely to reduce: NNT 71.4 (95% CI 55.6–125) NNT 27 (95% CI 17.9–500) Reductions in the above conditions are most likely to be seen if birth is 24–48 hours after starting treatment.1 A reduction in respiratory morbidity (but not mortality or interventricular haemorrhage) likely to be seen if birth is within 7 days of starting treatment.1 Likely to affect maternal glucose tolerance for up to 5 days after administration (with higher risk in diabetic women).28 Likely to reduce birthweight if birth more than 7 days after steroids (MD −147.01 g, 95% CI −291.97 to −2.05).1 No benefits are likely to be seen if birth is more than 7 days after starting treatment.1 May increase psychiatric and behavioural diagnoses if children born at term NNH 38.8 (95% CI 30–52.4) 19 There is less evidence for women with multiple pregnancy.9 Effects of unnecessary antenatal corticosteroids (i.e. if birth more than 7 days after steroids) are not well described. While no long term harms have been proven, large scale observational studies necessary for pharmacovigilance are lacking Likely to reduce: NNT 33.3 (95% CI 21.5–76.9) Likely to increase neonatal hypoglycaemia (150/1000 to 240/1000, RR 1.60 [1.37–1.87])**** Figures include women 34–36+5 weeks’ gestation. ‘Highly likely’ indicates high certainty evidence; ‘Likely’ indicates moderate certainty evidence and ‘May’ indicates low certainty evidence. Certainty of evidence was aligned to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system.75 .15 NNH 11.1 (95% CI 8.8–14.7) May increase psychiatric and behavioural diagnoses if children born at term. NNH 38.8 (95% CI 30.5–52.4) 19 While no long term harms have been proven, large scale observational studies necessary for pharmacovigilance are lacking. Benefits seem unlikely if birth is more than 7 days after starting treatment, but this has not been studied in women at this gestation May decrease: NNT 35.7 (95% CI 25.1–196.1) There is uncertainty as to whether there is any reduction in RDS, TTN or NNU admission overall. Risk of bias in the single centre study means there is low certainty around estimates. Short term complications such as hypoglycaemia have not been rigorously studied, but are likely to also apply at these gestational ages16 as well as at late preterm gestations. Benefits seem unlikely if birth is more than 7 days after starting treatment, but this has not been studied in women at this gestation. While no long term harms have been proven, large scale observational studies necessary for pharmacovigilance are lacking Likely to reduce need for respiratory support (reduction from 395 per 1000 to 311 per 1000 RR 0.91 [0.85–0.97]). NNT 11.9 (95% CI 9.9–14.9) 64 There are currently insufficient data to assess on long-term effects of late preterm antenatal corticosteroids for the child.9 Women with diabetes mellitus have been excluded from most randomised controlled trials of antenatal corticosteroids because of concerns about their potential effects on glycaemic control. Maternal blood glucose levels rise shortly after administration of corticosteroids and can remain elevated for up to 5 days.28, 29 One systematic review and meta-analysis identified no eligible studies on preterm birth outcomes following corticosteroid therapy in pregnancies complicated by diabetes.30 Ideally the risks and benefits of corticosteroids, and the potential adverse effects of a variable rate intravenous insulin infusion if required, should be discussed with the woman (and her family members or carers as appropriate) prior to the administration of steroids. Trials of antenatal corticosteroids include a diverse number of sub-populations of women whose response to corticosteroids may vary. However, in general sub-group analyses have been underpowered to provide precise estimates of the benefits and risks of antenatal corticosteroids for specific indications. NICE NG25 recommendations for antenatal corticosteroid administration were thus made regardless of any specific indication for preterm birth.2 The administration of a repeat course of corticosteroids is addressed in section 10. In women with PPROM, concerns have been raised that multiple courses of corticosteroids may increase the risk of chorioamnionitis and neonatal sepsis.40-42 Antenatal corticosteroids are designed to cross the placenta. They are given at high doses that have been unchanged since Liggins’ and Howie’s original experiments in the 1970s and have not been optimised for human pregnancy.46 Two types of antenatal corticosteroid have been widely tested and used in clinical practice – betamethasone and dexamethasone. These are synthetic fluorinated corticosteroids, with similar activities.46 However, caution should be exercised in the interpretation of the data due to the limitations and potential bias of the subgroup analyses in the original 2006 review. The question as to whether the effects of antenatal corticosteroids change with time to delivery would require re-analysis of individual patient data to clarify whether the association is real.54 This re-analysis was not undertaken in the 2017 or 2020 updates of the Cochrane review and therefore the need for caution remains.9, 55 AJ and SP have declared no conflicts of interest. SJS has received grant funding from the Welcome trust for research into antenatal corticosteroids, paid to their institution, grant funding from the National Institute for Health Research, the Chief Scientist Office Scotland, Tommy's and HDR UK, paid to their institution and honoraria for a research talk from Hologic, paid to their institution. Full disclosure of interests are available to view online as supporting information. All those involved in the development of the Green-top Guidelines, including the Guidelines Committee, Guidelines Committee co-chairs, guideline developers, peer reviewers and other reviewers, are unpaid volunteers and receive no direct funding for their work in producing the guideline. The exception to this are the RCOG staff involved who are salaried employees of the College and Guidelines Committee members who receive reimbursement for expenses for attending Guidelines Committee meetings. Please see more information on travel expense rules on the RCOG website. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. This guideline was produced on behalf of the Royal College of Obstetricians and Gynaecologists by: Dr SJ Stock FRCOG, Edinburgh; Dr A J Thomson MRCOG, Paisley and Dr S Papworth FRCPCH, Newport. and peer reviewed by: Professor DA Giussani FRCOG, Cambridge; Mr D Fraser FRCOG, Norwich; Dr T Watts MBBS, MD, FRCPCH, London; Dr G Ng FRCPCH, London; Professor JE Norman FRCOG, Bristol; Dr HS Salama MRCOG, Benghazi, Libya; Dr F S Malik MRCOG, Lincoln; British Intrapartum Care Society; UK National Screening Committee; Dr EA Bonney MD MRCOG, Leeds; Dr R Curry MRCOG, Oxford. Committee lead reviewers were: Dr A McKelvey MRCOG, Norwich and Dr S Karavolos MRCOG, Manchester The Co-Chairs of the Guidelines Committee were: Dr MA Ledingham FRCOG, Glasgow and Dr B Magowan FRCOG, Melrose All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts of interest for this guideline is available from: https://www.rcog.org.uk/en/guidelinesresearch-services/guidelines/gtg74 The final version is the responsibility of the Guidelines Committee of the RCOG. The guideline will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication. The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient’s case notes at the time the relevant decision is taken.