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Meta-Analysis
. 2011 Jun 15:(6):CD003935.
doi: 10.1002/14651858.CD003935.pub3.

Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes

Caroline A Crowther  1 , Christopher Jd McKinlay, Philippa Middleton, Jane E Harding
Affiliations
Meta-Analysis

Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes

Caroline A Crowther et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial.

Objectives: To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids.

Search strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2011), searched reference lists of retrieved studies and contacted authors for further data.

Selection criteria: Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth.

Data collection and analysis: We assessed trial quality and extracted data independently.

Main results: We included 10 trials (more than 4730 women and 5650 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNT 30, 95% CI 19 to 79).Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) -75.79 g, 95% CI -117.63 to -33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small-for-gestational age) did not differ between treatment groups.At early childhood follow-up no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or serious outcome) or in the secondary outcome growth assessments.

Authors' conclusions: The short-term benefits for babies of less respiratory distress and fewer serious health problems in the first few weeks after birth support the use of repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. These benefits were associated with a small reduction in size at birth. The current available evidence reassuringly shows no significant harm in early childhood, although no benefit.Further research is needed on the long-term benefits and risks for the woman and baby. Individual patient data meta-analysis may clarify how to maximise benefit and minimise harm.

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Update of

References

References to studies included in this review

    1. Aghajafari F, Murphy K, Ohlsson A, Amankwah K, Matthews S, Hannah M. Multiple versus single courses of antenatal corticosteroids for preterm birth: a pilot study. Journal of Obstetrics and Gynaecology Canada: JOGC. 2002;24(4):321–9. - PubMed
    1. Ashwood PJ, Crowther CA, Willson KJ, Haslam RR, Kennaway DK, Hiller JE, et al. Neonatal adrenal function after repeat dose prenatal corticosteroids: a randomized controlled trial. American Journal of Obstetrics and Gynecology. 2006;194:861–7. - PubMed
    2. Battin M, Bevan C, Harding J. Repeat doses of antenatal steroids and hypothalamic-pituitary-adrenal axis (HPA) function. American Journal of Obstetrics and Gynecology. 2007;197:40.e1–40.e6. - PubMed
    3. Battin MR, Bevan C, Morton SM, Harding JE. Repeat courses of antenatal corticosteroids do not alter hypothalamic-pituitary-adrenal axis function after birth; results of a randomised controlled trial. Pediatric Academic Societies Annual Meeting; San Francisco, USA. 2004 May 1-4.2004.
    4. Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS, et al. Outcome at 2 years of age after repeat doses of antenatal corticosteroids. New England Journal of Medicine. 2007;357:1179–89. - PubMed
    5. Crowther CA, Haslam RR, Doyle LW, Harding JE, Hiller JE, Robinson JS, for the ACTORDS Study Group Repeat doses of prenatal corticosteroids for women at risk of preterm birth: follow-up of children at 2 years corrected age in the ACTORDS trial. Journal of Paediatrics and Child Health. 2007;43(Suppl 1):A76.

    6. *

    7. Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS, for the Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet. 2006;367:1913–9. - PubMed
    8. Crowther CA, Hiller JE, Haslam RR, Doyle LW, Robinson JS. Repeat doses of prenatal corticosteroids for women at risk of preterm birth: the ACTORDS Trial 12 month follow up. Perinatal Society of Australia and New Zealand 10th Annual Congress; Perth, Australia. 2006 April 3-6.2006. p. 179.
    9. Mildenhall L, Battin M, Bevan C, Kuschel C, Harding J. Repeat prenatal corticosteroid doses do not alter neonatal blood pressure or myocardial thickness: randomized, controlled trial. Pediatrics. 2009;123(4):e646–e652. - PubMed
    10. Mildenhall L, Battin M, Morton S, Bevan C, Kuschel C, Harding J. Exposure to repeat doses of antenatal glucocorticoids is associated with altered cardiovascular status after birth. Archives of Disease in Childhood. Fetal and Neonatal Edition. 2006;91:F56–F60. - PMC - PubMed
    11. Mildenhall LFJ, Battin MR, Bevan C, Kuschel CA, Harding JE. Repeat doses of antenatal corticosteroids do not alter neonatal cardiovascular status after birth; a randomised controlled trial. Perinatal Society of Australia and New Zealand 10th Annual Congress; Perth, Australia. 2006 April 3-6.2006. p. 55.

    1. *

    2. Garite T, Kurtzman J, Maurel K, Clark R, for the Obstetrix Collaborative Research Network Impact of a ’rescue course’ of antenatal corticosteroids: a multicenter randomized placebo-controlled trial. American Journal of Obstetrics and Gynecology. 2009;200:248.e1–248.e9. - PubMed
    3. Kurtzman J, Garite T, Clark R, Maurel K. The Obstetrix Collaborative Research Network. Impact of a “rescue course” of antenatal corticosteroids (ACS): a multicenter randomized placebo controlled trial. American Journal of Obstetrics and Gynecology. 2008;199(6 Suppl 1):S2. - PubMed
    4. Obstetrix Medical Group [accessed 20 February 2008];A randomized trial comparing the impact of one versus two courses of ACS on neonatal outcome. ClinicalTrials.gov. www.clinicaltrials.gov.
    1. Guinn D, Atkinson M, Sullivan L, Lee M, MacGregor S, Parilla B, et al. Single versus weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial. Obstetrics & Gynecology. 2003;101(1):195. - PubMed
    2. Guinn D, BMZ Study Group Multicenter randomized trial of single versus weekly courses of antenatal corticosteroids (ACS) American Journal of Obstetrics and Gynecology. 2001;184(1):S6.

    3. *

    4. Guinn DA, Atkinson MW, Sullivan L, Lee M, MacGregor S, Parilla B, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery. JAMA. 2001;286(13):1581–7. - PubMed
    5. Guinn DA, BMZ Study Group Multicenter randomized trial of single versus weekly courses of antenatal corticosteroids (ACS): interim analysis. American Journal of Obstetrics and Gynecology. 2000;182(1 Pt 2):S12. - PubMed
    6. Lee M, Davies J, Atkinson MW, Guinn D, BMZ Study Group Efficacy of weekly courses of antenatal corticosteroids (ACS) in preterm premature rupture of the membranes. American Journal of Obstetrics and Gynecology. 2001;184(1):S8. - PubMed
    7. Lee MJ, Davies J, Guinn D, Sullivan L, Atkinson MW, McGregor S, et al. Single versus weekly courses of antenatal corticosteroids in preterm premature rupture of membranes. Obstetrics & Gynecology. 2004;103(2):274–81. - PubMed
    1. Mazumder P, Dutta S, Kaur J, Narang A. Single versus multiple courses of antenatal betamethasone and neonatal outcome: a randomized controlled trial. Indian Pediatrics. 2008;45:650–2. - PubMed

References to studies excluded from this review

    1. Mercer B, Egerman R, Beazley D, Sibai B, Carr T, Sepesi J. Steroids reduce fetal growth: analysis of a prospective trial. American Journal of Obstetrics and Gynecology. 2001;184(1):S7.

    2. *

    3. Mercer B, Egerman R, Beazley D, Sibai B, Carr T, Sepesi J. Weekly antenatal steroids trial in women at risk of preterm birth: a randomized trial. American Journal of Obstetrics and Gynecology. 2001;184(1):S6.
    4. Sawady J, Mercer B. Impact of repeated doses of antenatal corticosteroids on placental growth and histology. American Journal of Obstetrics and Gynecology. 2006;195(6 Suppl 1):S73. - PubMed
    1. Thorp JA, Yeast JD, Cohen GR, Wickstrom EA, D’ Angelo. LJ. Repeated antenatal betamethasone and perinatal outcome. American Journal of Obstetrics and Gynecology. 2000;182(1 Pt 2):S21.

References to ongoing studies

    1. Ataroud Z. [accessed 6 December 2010];Single versus multiple courses of antenatal betamethasone: evaluation of preterm infant’s outcome. Iranian Clinical Trials Registry. http://www.irct.ir/searchresult.php?keyword=neonates&id=1689&number=1&fi....
    1. Sohrabvand F, Behbahani B, Kazeminejad A. Effects of single versus multiple courses of corticosteroid therapy on pregnancy results in women with PPROM. Journal of Perinatal Medicine. 2001;29(Suppl 1(Pt 2)):528. - PubMed
    1. Adams H. [accessed 4 November 2003];Trial of the effects of antenatal multiple courses of steroids versus a single course (TEAMS): pilot study. Current Controlled Trials. http://www.controlled-trials.com/ISRCTN46614711.
    2. Brocklehurst P, Gates S, Johnson A. Effects of multiple courses of antenatal steroids are uncertain [letter] BMJ. 2000;321:47. - PMC - PubMed

Additional references

    1. Ashwood PJ, Crowther CA, Willson KJ, Haslam RR, Kennaway DJ, Hiller JE, et al. Neonatal adrenal function after repeat dose prenatal corticosteroids: a randomized controlled trial. American Journal of Obstetrics and Gynecology. 2006;194:861–7. - PubMed
    1. Benediktsson R, Lindsay RS, Noble J, Secki JR, Edwards CRW. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet. 1993;341:339–41. - PubMed
    1. Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet. 2005;365(9474):1856–62. - PubMed
    1. Dalziel SR, Lim VK, Lambert A, McCarthy D, Parag V, Rodgers A, et al. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial. BMJ. 2005;331(7518):665. - PMC - PubMed
    1. Dunlop SA, Archer MA, Quinlivan JA, Beazley LD, Newnham JP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. Journal of Maternal-Fetal Medicine. 1997;6:309–13. - PubMed

References to other published versions of this review

    1. Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database of Systematic Reviews. 2007;(Issue 3) [DOI: 10.1002/14651858.CD003935.pub2] - PubMed

    1. * Indicates the major publication for the study

MeSH terms