NIHR DC Discover

NIHR Signal A dose of corticosteroids benefits most women anticipating a preterm delivery

Published on 16 May 2017

doi: 10.3310/signal-000415

Giving corticosteroids to most women who are anticipating labour before completing 37 weeks of pregnancy helps reduce immediate health problems in the baby compared with placebo or no intervention. Deaths around the time of birth were reduced by 28% and babies were a third (34%) less likely to develop respiratory distress syndrome.

A corticosteroid dose is already used for women who go into labour or if waters break before 37 weeks or where delivery is planned for other reasons. The drug accelerates the development of the baby’s lungs and reduces breathing difficulties at birth. This recommendation followed decades of research.

This review supports current practice of using a dose of corticosteroids in high-income settings and was designed to include more recent research and to look in more depth at new questions, such as the risk of infection. Evidence is still lacking in low-income settings and some very high-risk groups, like twins. There is also remaining uncertainty about the best corticosteroid, its dose and timing.

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Why was this study needed?

About one in every 13 babies in the UK is preterm, which means born before 37 weeks of pregnancy. Preterm babies are at higher risk for complications due to a lack of full development of several organs. This can lead to disability and death. Breathing difficulties such as respiratory distress syndrome are among preterm babies’ serious complications.

The benefits of corticosteroids in prevention of respiratory distress syndrome has been investigated since 1972. A recent review found that corticosteroids in late preterm babies, at 34 to 37 weeks of pregnancy, reduce the risk of respiratory distress syndrome.

This review and meta-analyses focuses on the use of corticosteroids in women at risk of preterm birth from 24 weeks. The authors aimed to include findings from new trials, to summarise the impact of corticosteroids on new outcomes such as infections and to define needs for future research.

What did this study do?

This systematic review compared the use of corticosteroids with placebo or no intervention in women at 24 to 37 weeks pregnancy at risk of birth. It included 30 randomised controlled trials with a total of 7774 women and 8158 babies. Nine new trials were added since the previous review in 2006.  The drugs used were betamethasone, dexamethasone or hydrocortisone. Most women received a single dose of corticosteroid, and in nine studies women received weekly doses.

The main outcomes for babies included respiratory distress syndrome, bleeding in the brain, perinatal death (stillbirth or death within the first week) and neonatal death (within the first 28 days of life).

A bias present in the conduction of some studies where participants and health professionals were aware of whether the intervention was given or not is unlikely to have affected confidence in the results. Outcome assessment was blinded. All studies except one were conducted in high-income countries.

What did it find?

  • Antenatal corticosteroids reduced respiratory distress syndrome by 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.56 to 0.77). Specifically, the risk reduced from 17.6% to 11.6% (95% CI 9.8% to 13.5%). Six studies looked into moderate/severe respiratory difficulties and showed similar findings (RR 0.59, 95% CI 0.38 to 0.91).
  • Based on 15 studies and 6729 participants, corticosteroids reduced perinatal death rate from 10.2% to 7.3% (RR 0.72, 95% CI 0.58 to 0.89).
  • Corticosteroids also reduced neonatal deaths (RR 0.69, 95% CI 0.59 to 0.81) and necrotising enterocolitis - severe inflammation of the intestines (RR 0.50, 95% CI 0.32 to 0.78).
  • Corticosteroids had no effect on maternal death (RR 0.98, 95% CI 0.06 to 15.50). This result was based on few events (one trial with two deaths, four trials with no deaths).

What does current guidance say on this issue?

The NICE 2015 guideline on preterm labour and birth recommends offering corticosteroids between 26 and 33 weeks plus six days of pregnancy to women who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have ruptured membranes. It recommends considering corticosteroids for women in the same situation between 23 to 25 weeks plus six days and 34 to 35 weeks plus six days.

The Royal College of Obstetricians and Gynaecologists has a more detailed guideline on antenatal corticosteroids issued in 2010.

What are the implications?

The findings of this study support the practice of giving corticosteroids to women at risk of labour, which became mainstream advice by 2000.

The authors note a need to improve other aspects the antenatal corticosteroid practice and research. Evidence is lacking in low-income settings, multiple pregnancies and high-risk groups, such as women with high blood pressure or ruptured membranes.

It is also important to determine the optimal corticosteroid, dose-to-delivery interval and long-term effects into adulthood.

The advice to use steroids for most women where preterm delivery is anticipated seems secure, without further research.

Citation and Funding

Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3:CD004454.

This project was funded by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth.

Bibliography

Dickson MJ. Why did it take so long for antenatal steroid use to become mainstream. BMJ. 2017.

NHS Choices. Premature labour and birth. London: Department of Health; 2015.

NIHR DC. Antenatal corticosteroids reduce breathing problems in late preterm babies. National Institute for Health Research Dissemination Centre. 2017

NICE. Preterm labour and birth. NG25. London: National Institute for Health and Clinical Excellence; 2015.

RCOG. Antenatal corticosteroids to reduce neonatal morbidity and mortality. London: Royal College of Obstetricians and Gynaecologists; 2010.

WHO. Maternal and perinatal health. Geneva: World health Organization; 2017.

Why was this study needed?

About one in every 13 babies in the UK is preterm, which means born before 37 weeks of pregnancy. Preterm babies are at higher risk for complications due to a lack of full development of several organs. This can lead to disability and death. Breathing difficulties such as respiratory distress syndrome are among preterm babies’ serious complications.

The benefits of corticosteroids in prevention of respiratory distress syndrome has been investigated since 1972. A recent review found that corticosteroids in late preterm babies, at 34 to 37 weeks of pregnancy, reduce the risk of respiratory distress syndrome.

This review and meta-analyses focuses on the use of corticosteroids in women at risk of preterm birth from 24 weeks. The authors aimed to include findings from new trials, to summarise the impact of corticosteroids on new outcomes such as infections and to define needs for future research.

What did this study do?

This systematic review compared the use of corticosteroids with placebo or no intervention in women at 24 to 37 weeks pregnancy at risk of birth. It included 30 randomised controlled trials with a total of 7774 women and 8158 babies. Nine new trials were added since the previous review in 2006.  The drugs used were betamethasone, dexamethasone or hydrocortisone. Most women received a single dose of corticosteroid, and in nine studies women received weekly doses.

The main outcomes for babies included respiratory distress syndrome, bleeding in the brain, perinatal death (stillbirth or death within the first week) and neonatal death (within the first 28 days of life).

A bias present in the conduction of some studies where participants and health professionals were aware of whether the intervention was given or not is unlikely to have affected confidence in the results. Outcome assessment was blinded. All studies except one were conducted in high-income countries.

What did it find?

  • Antenatal corticosteroids reduced respiratory distress syndrome by 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.56 to 0.77). Specifically, the risk reduced from 17.6% to 11.6% (95% CI 9.8% to 13.5%). Six studies looked into moderate/severe respiratory difficulties and showed similar findings (RR 0.59, 95% CI 0.38 to 0.91).
  • Based on 15 studies and 6729 participants, corticosteroids reduced perinatal death rate from 10.2% to 7.3% (RR 0.72, 95% CI 0.58 to 0.89).
  • Corticosteroids also reduced neonatal deaths (RR 0.69, 95% CI 0.59 to 0.81) and necrotising enterocolitis - severe inflammation of the intestines (RR 0.50, 95% CI 0.32 to 0.78).
  • Corticosteroids had no effect on maternal death (RR 0.98, 95% CI 0.06 to 15.50). This result was based on few events (one trial with two deaths, four trials with no deaths).

What does current guidance say on this issue?

The NICE 2015 guideline on preterm labour and birth recommends offering corticosteroids between 26 and 33 weeks plus six days of pregnancy to women who are in suspected, diagnosed or established preterm labour, are having a planned preterm birth or have ruptured membranes. It recommends considering corticosteroids for women in the same situation between 23 to 25 weeks plus six days and 34 to 35 weeks plus six days.

The Royal College of Obstetricians and Gynaecologists has a more detailed guideline on antenatal corticosteroids issued in 2010.

What are the implications?

The findings of this study support the practice of giving corticosteroids to women at risk of labour, which became mainstream advice by 2000.

The authors note a need to improve other aspects the antenatal corticosteroid practice and research. Evidence is lacking in low-income settings, multiple pregnancies and high-risk groups, such as women with high blood pressure or ruptured membranes.

It is also important to determine the optimal corticosteroid, dose-to-delivery interval and long-term effects into adulthood.

The advice to use steroids for most women where preterm delivery is anticipated seems secure, without further research.

Citation and Funding

Roberts D, Brown J, Medley N, et al. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3:CD004454.

This project was funded by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth.

Bibliography

Dickson MJ. Why did it take so long for antenatal steroid use to become mainstream. BMJ. 2017.

NHS Choices. Premature labour and birth. London: Department of Health; 2015.

NIHR DC. Antenatal corticosteroids reduce breathing problems in late preterm babies. National Institute for Health Research Dissemination Centre. 2017

NICE. Preterm labour and birth. NG25. London: National Institute for Health and Clinical Excellence; 2015.

RCOG. Antenatal corticosteroids to reduce neonatal morbidity and mortality. London: Royal College of Obstetricians and Gynaecologists; 2010.

WHO. Maternal and perinatal health. Geneva: World health Organization; 2017.

Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth

Published on 21 March 2017

D Roberts, J Brown, N Medley, S Dalziel

Cochrane Library , 2017

Background Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless. Liggins and Howie published the first randomised controlled trial in humans in 1972 and many others followed. Objectives To assess the effects of administering a course of corticosteroids to the mother prior to anticipated preterm birth on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. Search methods We searched Cochrane Pregnancy and Childbirth's Trials Register (17 February 2016) and reference lists of retrieved studies. Selection criteria We considered all randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co-morbidity, for inclusion in this review. Most women in this review received a single course of steroids; however, nine of the included trials allowed for women to have weekly repeats. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. Main results This update includes 30 studies (7774 women and 8158 infants). Most studies are of low or unclear risk for most bias domains. An assessment of high risk usually meant a trial had potential for performance bias due to lack of blinding. Two trials had low risks of bias for all risk of bias domains. Treatment with antenatal corticosteroids (compared with placebo or no treatment) is associated with a reduction in the most serious adverse outcomes related to prematurity, including: perinatal death (average risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.89; participants = 6729; studies = 15; Tau² = 0.05, I² = 34%; moderate-quality); neonatal death (RR 0.69, 95% CI 0.59 to 0.81; participants = 7188; studies = 22), RDS (average RR 0.66, 95% CI 0.56 to 0.77; participants = 7764; studies = 28; Tau² = 0.06, I² = 48%; moderate-quality); moderate/severe RDS (average RR 0.59, 95% CI 0.38 to 0.91; participants = 1686; studies = 6; Tau² = 0.14, I² = 52%); intraventricular haemorrhage (IVH) (average RR 0.55, 95% CI 0.40 to 0.76; participants = 6093; studies = 16; Tau² = 0.10, I² = 33%; moderate-quality), necrotising enterocolitis (RR 0.50, 95% CI 0.32 to 0.78; participants = 4702; studies = 10); need for mechanical ventilation (RR 0.68, 95% CI 0.56 to 0.84; participants = 1368; studies = 9); and systemic infections in the first 48 hours of life (RR 0.60, 95% CI 0.41 to 0.88; participants = 1753; studies = 8). There was no obvious benefit for: chronic lung disease (average RR 0.86, 95% CI 0.42 to 1.79; participants = 818; studies = 6; Tau² = 0.38 I² = 65%); mean birthweight (g) (MD -18.47, 95% CI -40.83 to 3.90; participants = 6182; studies = 16; moderate-quality); death in childhood (RR 0.68, 95% CI 0.36 to 1.27; participants = 1010; studies = 4); neurodevelopment delay in childhood (RR 0.64, 95% CI 0.14 to 2.98; participants = 82; studies = 1); or death into adulthood (RR 1.00, 95% CI 0.56 to 1.81; participants = 988; studies = 1). Treatment with antenatal corticosteroids does not increase the risk of chorioamnionitis (RR 0.83, 95% CI 0.66 to 1.06; participants = 5546; studies = 15; moderate-quality evidence) or endometritis (RR 1.20, 95% CI 0.87 to 1.63; participants = 4030; studies = 10; Tau² = 0.11, I² = 28%; moderate-quality). No increased risk in maternal death was observed. However, the data on maternal death is based on data from a single trial with two deaths; four other trials reporting maternal death had zero events (participants = 3392; studies = 5; moderate-quality). There is no definitive evidence to suggest that antenatal corticosteroids work differently in any pre-specified subgroups (singleton versus multiple pregnancy; membrane status; presence of hypertension) or for different study protocols (type of corticosteroid; single course or weekly repeats). GRADE outcomes were downgraded to moderate-quality. Downgrading decisions (for perinatal death, RDS, IVH, and mean birthweight) were due to limitations in study design or concerns regarding precision (chorioamnionitis, endometritis). Maternal death was downgraded for imprecision due to few events. Authors' conclusions Evidence from this update supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids could be considered routine for preterm delivery. It is important to note that most of the evidence comes from high income countries and hospital settings; therefore, the results may not be applicable to low-resource settings with high rates of infections. There is little need for further trials of a single course of antenatal corticosteroids versus placebo in singleton pregnancies in higher income countries and hospital settings. However, data are sparse in lower income settings. There are also few data regarding risks and benefits of antenatal corticosteroids in multiple pregnancies and other high-risk obstetric groups. Further information is also required concerning the optimal dose-to-delivery interval, and the optimal corticosteroid to use. We encourage authors of previous studies to provide further information, which may answer any remaining questions about the use of antenatal corticosteroids in such pregnancies without the need for further randomised controlled trials. Individual patient data meta-analysis from published trials is likely to answer some of the evidence gaps. Follow-up studies into childhood and adulthood, particularly in the late preterm gestation and repeat courses groups, are needed. We have not examined the possible harmful effects of antenatal corticosteroids in low-resource settings in this review. It would be particularly relevant to explore this finding in adequately powered prospective trials.

Participants were women, with a singleton or multiple pregnancies, expected to deliver preterm (before the 37th week of pregnancy) as a result of either spontaneous preterm labour, preterm prelabour rupture of the membranes or planned preterm delivery.

Expert commentary

This is an important reiteration of the benefits of antenatal corticosteroids, for those not old enough to remember the pre-steroid era. However, it should be noted that there is a place for steroids in planned preterm delivery and that there is a gradient of benefit across the gestations, these points are not noted in “main message” of the review.

The conclusion that more research is needed into optimal timing and dosing is welcome, and for the more mature babies for whom the benefit is less, unintended consequences should be studied.

We hope that in future benefits of antenatal magnesium are equally well described.

Dr J M Hawdon, Responsible Officer, Consultant Neonatologist, Royal Free London NHS Foundation Trust