WHO recommendation on antenatal corticosteroid administration when preterm birth is considered imminent within 7 days of starting treatment, including within the first 24 hours

A midfwife with a pregnant woman during a prenatal visit, Cambodia

WHO recommendation on antenatal corticosteroid administration when preterm birth is considered imminent within 7 days of starting treatment, including within the first 24 hours

 

Recommendation

For eligible women, antenatal corticosteroid should be administered when preterm birth is considered imminent within 7 days of starting treatment, including within the first 24 hours.

 

(Strong recommendation, low-quality evidence)

 

Publication history

First published: November 2015

Updated: No update planned

Assessed as up-to-date: November 2015

 

Remarks

  • Antenatal corticosteroid therapy should be started even when the completion of a full course before preterm birth is uncertain.
  • Tocolysis may be considered as an intervention to gain time to complete a single course of antenatal corticosteroids (see also Recommendation on tocolytic treatment).
  • The GDG acknowledged the limitations and potential bias of evidence derived from the subgroup analyses according to interval between steroid administration and preterm birth, which led to rating of the quality of evidence as “low”. Nevertheless, the group made a strong recommendation on the basis of the balance being in favour of the benefits of antenatal corticosteroids (in terms of reducing respiratory morbidity and mortality for babies born within 24 hours and up to 7 days of starting treatment), the low resource requirements, and the feasibility of implementing the intervention.

 

Background

Preterm birth, defined as birth before 37 weeks of gestation, is the single most important determinant of adverse infant outcomes, in terms of survival and quality of life. (1)  Globally, it is the leading cause of perinatal and neonatal mortality and morbidity. (2) Preterm infants are particularly vulnerable to complications due to impaired respiration, difficulty in feeding, poor body temperature regulation and high risk of infection. (3-5) With the increasing contribution of neonatal deaths to overall child mortality, it is critical to address the determinants of poor outcomes related to preterm birth to achieve further reductions in child mortality. (6-8)

Infant mortality and morbidity from preterm birth can be reduced through interventions delivered to the mother before or during pregnancy, and to the preterm infant after birth. (9) Interventions can be directed at all women for primary prevention and reduction of the risk of preterm birth (e.g. smoking cessation programme) or aimed at minimizing the risk in women with known risk factors (e.g. progestational agents, cervical cerclage). (10) However, the most beneficial set of maternal interventions are those that are aimed at improving outcomes for preterm infants when preterm birth is inevitable (e.g. antenatal corticosteroids, magnesium sulfate and antibiotic prophylaxis). (9) Special care of the preterm newborn to prevent and treat complications of prematurity is also critical to newborn survival. In high-income countries, reductions in mortality rates in infants that were born preterm have been driven largely by improved care and, more importantly, by appropriate policy changes.

 

Methods

The recommendations were developed using standard operating procedures in accordance with the process described in the WHO handbook for guideline development (11). Briefly, these included (i) identification of priority questions and critical outcomes, (ii) retrieval of the evidence, (iii) assessment and synthesis of evidence, (iv) formulation of recommendations, and (v) planning for the dissemination, implementation, impact evaluation and updating of the guideline.

The scientific evidence underpinning the recommendations was synthesized using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (12). Up-to-date systematic reviews were used to prepare evidence profiles for the priority questions. WHO then convened a Technical Consultation in May 2014 where an international group of experts – the Guideline Development Group (GDG) – formulated and approved the recommendations based on the evidence profiles.

In November 2014, an online consultation of the GDG was conducted to review and revise the recommendations in the light of the findings of a large implementation trial of antenatal corticosteroids in low-resource countries.

 

Further information on procedures for developing this recommendation are available here.

 

Recommendation question

For this recommendation, we aimed to answer the following questions:

  • Among pregnant women at risk of imminent preterm birth (P), is antenatal corticosteroid therapy (I), compared with no antenatal corticosteroid therapy (C), effective in reducing adverse newborn outcomes (O)?

 

  • Which population of pregnant women should be offered antenatal corticosteroids? (considering the gestational age at presentation or birth; interval between presentation and anticipated birth; single and multiple birth; status of amniotic membranes; and women undergoing elective caesarean section in late preterm )
  • Which population of pregnant women should not be offered antenatal corticosteroids? (considering conditions where there are concerns that associated risks may outweigh benefits: women with diabetes mellitus, hypertensive disorders, chorioamnionitis and growth-restricted babies )
  • Which corticosteroids (and regimens) should be used for eligible women?
  • Should repeat course(s) of corticosteroids be offered to a woman who has completed a course of corticosteroid but remains at risk of preterm birth 7 days or more after the initial treatment?

 

Evidence summary

 

Antenatal corticosteroids versus placebo or no treatment (interval between corticosteroid therapy and birth: < 24 hours, < 48 hours, 1-7 days, >7 days)

 In the Cochrane review that showed overall benefits of antenatal corticosteroids compared with placebo (13), subgroup analyses were performed according to the interval between corticosteroid treatment and birth of the preterm infant. Only one to four trials could be included for most of the critical outcomes reported with the exception of RDS, which had eight to nine trials providing evidence for the  < 24 hours, < 48 hours, 1-7 days,  >7 days categories.

Maternal outcomes

Maternal infectious morbidity: No significant differences were observed in the occurrence of chorioamnionitis across all the subgroups.

Infant outcomes

Fetal and neonatal death: There was a significant reduction in combined fetal and neonatal deaths for infants born within 24 hours (RR 0.60, 95% CI 0.39–0.94; 3 studies, 293 infants) and within 48 hours (RR 0.59, 95% CI 0.41–0.86; 1 study, 373 infants) of corticosteroid therapy, but not those born between 1 and 7 days (RR 0.81, 95% CI 0.60–1.09; 3 studies, 606 infants) or those born after 7 days (RR 1.42, 95% CI 0.91–2.23; 3 studies, 598 infants). This pattern was consistent across the subgroup for neonatal deaths alone but no differences were observed for fetal deaths.

Severe neonatal morbidity: There were significantly fewer cases of RDS among babies born before 48 hours (RR 0.67, 95% CI 0.49–0.93; 3 studies, 374 infants) and between 1 and 7 days (RR 0.46, 95% CI 0.35–0.60; 9 studies, 1110 infants), but not among those born before 24 hours (RR 0.87, 95% CI 0.66– 1.15; 9 studies, 517 infants) or those born more than 7 days after the first dose (RR 0.82, 95% CI 0.53–1.28; 8 studies, 988 infants). Significant reductions were also observed in cases of cerebroventricular haemorrhage among infants born within 48 hours of the first dose of steroids (RR 0.26, 95% CI 0.09–0.75; 1 study, 339 infants) but not in any of the other subgroups. While there were no significant differences demonstrated in the birth weights of babies born before 24 hours, 48 hours, and between 1 and 7 days, there was a trend towards a reduction in birth weight among infants exposed to corticosteroid treatment who were born more than 7 days after the first dose (MD -147.01 g, 95% CI -291.97 to -2.05; 1 study, 486 infants).

 

Further information and considerations related to this recommendation can be found in the WHO guidelines, available at:

http://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988_eng.pdf?sequence=1

http://apps.who.int/iris/bitstream/handle/10665/183038/WHO_RHR_15.17_eng.pdf?sequence=1

 

Implementation considerations

  • The successful introduction of this recommendation into national programmes and health-care services depends on well-planned and participatory consensus-driven processes of adaptation and implementation. The adaptation and implementation processes may include the development or revision of existing national guidelines or protocols based on this recommendation.
  • The recommendation should be adapted into a locally appropriate document that can meet the specific needs of each country and health service. Any changes should be made in an explicit and transparent manner.
  • A set of interventions should be established to ensure that an enabling environment is created for the use of the recommendations, and that the behaviour of the healthcare practitioner changes towards the use of this evidence-based practice.
  • In this process, the role of local professional societies is important and an all-inclusive and participatory process should be encouraged.

 

Research implications

The GDG identified these priority questions related to this recommendation:

  • What are the long-term outcomes of all infants exposed to antenatal corticosteroids (including term infants)?
  • What strategies can effectively and safely increase the use of corticosteroids in low- and middle-income country (LMIC) settings to improve outcomes?
  • What are the effects of antenatal corticosteroid at different gestational ages at birth (using independent patient data analysis)?
  • Assessment of coverage of antenatal corticosteroids before and after guideline implementation (and associated reduction in neonatal mortality).
  • Assessment of implementation strategies and monitoring of adverse events (in LMIC settings).
  • What are the effects of task shifting in the context of antenatal corticosteroid administration (e.g. using the first dose in the community followed by referral to a health-care facility)?
  • Are there differences in the pharmacokinetic properties of betamethasone acetate versus betamethasone phosphate (consider using available data in settings where they are routinely used)?
  • What is the impact of antenatal corticosteroid administration among mothers with evidence of infection who also receive appropriate antibiotic therapy on both maternal and neonatal outcomes?
  • What is the minimum effective dose of corticosteroids to achieve fetal lung maturation and other improved outcomes?
  • What is the minimum effective dose required for repeat courses of antenatal corticosteroids?
  • What is the most effective regimen and dose for antenatal corticosteroids?
  • In what contexts can antenatal corticosteroids be used safely and effectively in low-income countries?

 

Related links

WHO recommendations on interventions to improve preterm birth outcomes (2015) –full document and evidence tables

Managing Complications in Pregnancy and Childbirth: A guide for midwives and doctors

Pregnancy, Childbirth, Postpartum and Newborn Care: A guide for essential practice

WHO Programmes: Sexual and Reproductive health

Maternal Health

Infant, Newborn Health

 

Supporting systematic review:

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. The Cochrane database of systematic reviews. 2006(3):CD004454.

 

References

  1. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. The New England journal of medicine. 1985;312(2):82-90.
  2. Kinney MV, Lawn JE, Howson CP, Belizan J. 15 million preterm births annually: what has changed this year? Reproductive Health. 2012;9:28.
  3. Escobar GJ, McCormick MC, Zupancic JAF, Coleman‐Phox K, Armstrong MA, Greene JD, et al. Unstudied infants: outcomes of moderately premature infants in the neonatal intensive care unit. Archives of Disease in Childhood Fetal and Neonatal Edition. 2006;91(4):F238-44.
  4. Kinney HC. The near-term (late preterm) human brain and risk for periventricular leukomalacia: a review. Seminars in perinatology. 2006;30(2):81-8.
  5. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics. 2004;114(2):372-6.
  6. Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet (London, England). 2010;375(9730):1969-87.
  7. Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? Where? Why? Lancet (London, England). 2005;365(9462):891-900.
  8. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet (London, England). 2012;379(9832):2151-61.
  9. Iams JD, Romero R, Culhane JF, Goldenberg RL. Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth. Lancet (London, England). 2008;371(9607):164-75.
  10. Burguet A, Kaminski M, Abraham-Lerat L, Schaal JP, Cambonie G, Fresson J, et al. The complex relationship between smoking in pregnancy and very preterm delivery. Results of the Epipage study. BJOG : an international journal of obstetrics and gynaecology. 2004;111(3):258-65.
  11. WHO handbook for guideline development, 2nd edition. Geneva: World Health Organization; 2014 (http://www.who.int/kms/handbook_2nd_ ed.pdf, accessed 6 October 2016).
  12. GRADE [website]. The GRADE Working Group; 2016 (http://gradeworkinggroup.org/, accessed 27 October 2016).
  13. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. The Cochrane database of systematic reviews. 2006(3):Cd004454.

 

Citation: WHO Reproductive Health Library. WHO recommendation on antenatal corticosteroid administration when preterm birth is considered imminent within 7 days of starting treatment, including within the first 24 hours (November 2015). The WHO Reproductive Health Library; Geneva: World Health Organization.