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Meta-Analysis
. 2015 Jul 5;2015(7):CD003935.
doi: 10.1002/14651858.CD003935.pub4.

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

Caroline A Crowther  1 , Christopher J D 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 methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 January 2015), 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 (a total of 4733 women and 5700 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, number needed to treat to benefit (NNTB) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNTB 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. In women, for the two primary outcomes, there was no increase in infectious morbidity of chorioamnionitis or puerperal sepsis, and the likelihood of a caesarean birth was unchanged.

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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Conflict of interest statement

CAC and JEH are investigators in the Australasian Collaborative Trial of Repeat Doses of Corticosteroid for the Prevention of Neonatal Respiratory Disease (Crowther 2006).

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 1 Respiratory distress syndrome.
1.2
1.2. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 2 Severe lung disease.
1.3
1.3. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 3 Composite serious outcome (variously defined).
1.4
1.4. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 4 Mean birthweight (g).
1.5
1.5. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 5 Birthweight Z scores.
1.6
1.6. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 6 Birthweight multiples of the median.
1.7
1.7. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 7 Small‐for‐gestational age at birth.
1.8
1.8. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 8 Fetal and neonatal mortality.
1.9
1.9. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 9 Fetal death.
1.10
1.10. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 10 Neonatal death.
1.11
1.11. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 11 Chronic lung disease.
1.12
1.12. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 12 Intraventricular haemorrhage.
1.13
1.13. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 13 Intraventricular haemorrhage grade 3/4.
1.14
1.14. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 14 Periventricular leukomalacia.
1.15
1.15. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 15 Chorioamnionitis.
1.16
1.16. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 16 Puerperal sepsis.
1.17
1.17. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 17 Mean gestational age at birth (weeks).
1.18
1.18. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 18 Preterm birth before 37 weeks.
1.19
1.19. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 19 Very preterm birth before 34 weeks.
1.20
1.20. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 20 Extremely preterm birth before 28 weeks.
1.21
1.21. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 21 Mean head circumference at birth (cm).
1.22
1.22. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 22 Head circumference Z scores at birth.
1.23
1.23. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 23 Mean length at birth (cm).
1.24
1.24. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 24 Length Z scores at birth.
1.25
1.25. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 25 Length multiples of the median at birth.
1.26
1.26. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 26 Apgar score less than 7 at 5 minutes.
1.27
1.27. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 27 Use of mechanical ventilation.
1.28
1.28. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 28 Duration of respiratory support in days.
1.29
1.29. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 29 Use of oxygen supplementation.
1.30
1.30. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 30 Duration of oxygen supplementation in days.
1.31
1.31. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 31 Use of surfactant.
1.32
1.32. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 32 Use of inotropic support.
1.33
1.33. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 33 Use of nitric oxide for respiratory support.
1.34
1.34. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 34 Early systemic neonatal infection (variously defined).
1.35
1.35. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 35 Proven infection while in the neonatal intensive care unit.
1.36
1.36. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 36 Admission to the neonatal intensive care unit.
1.37
1.37. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 37 Air leak syndrome.
1.38
1.38. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 38 Necrotising enterocolitis.
1.39
1.39. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 39 Patent ductus arteriosus.
1.40
1.40. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 40 Retinopathy of prematurity.
1.41
1.41. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 41 Use of postnatal steroids.
1.42
1.42. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 42 Mean neonatal blood pressure on first day after birth.
1.43
1.43. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 43 Mean neonatal blood pressure 6 weeks after birth.
1.44
1.44. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 44 Neonatal cardiac hypertrophy as measured by interventricular septal thickness (IVSd).
1.45
1.45. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 45 Neonatal cardiac hypertrophy as measured by left ventricular wall thickness in diastole.
1.46
1.46. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 46 Mean basal cortisol concentrations (nmol/L) at birth.
1.47
1.47. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 47 Mean weight (g) at primary hospital discharge.
1.48
1.48. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 48 Weight Z scores at primary hospital discharge.
1.49
1.49. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 49 Mean head circumference (cm) at primary hospital discharge.
1.50
1.50. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 50 Head circumference Z scores at primary hospital discharge.
1.51
1.51. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 51 Mean length (cm) at primary hospital discharge.
1.52
1.52. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 52 Length Z score at primary hospital discharge.
1.53
1.53. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 53 Prelabour rupture of membranes after trial entry.
1.54
1.54. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 54 Maternal Hypertension (variously defined by the authors).
1.55
1.55. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 55 Vaginal birth.
1.56
1.56. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 56 Caesarean section.
1.57
1.57. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 57 Postpartum haemorrhage.
1.58
1.58. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 58 Postnatal pyrexia (variously defined by authors).
1.59
1.59. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 59 Length of postnatal hospitalisation (days).
1.60
1.60. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 60 Any maternal side effects of therapy.
1.61
1.61. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 61 Maternal hyperglycaemia (variously defined by authors).
1.62
1.62. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 62 Insomnia.
1.63
1.63. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 63 Pain at injection site.
1.64
1.64. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 64 Bruising at injection site.
1.65
1.65. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 65 Total mortality up to early childhood follow up.
1.66
1.66. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 66 Survival free of any disability to early childhood follow up.
1.67
1.67. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 67 Survival free of major neurosensory disability to early childhood follow up.
1.68
1.68. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 68 Major neurosensory disablity at early childhood follow‐up.
1.69
1.69. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 69 Disability at early childhood follow‐up.
1.70
1.70. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 70 Composite serious outcome at early childhood follow‐up (however defined by authors).
1.71
1.71. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 71 Weight small for age at early childhood follow‐up.
1.72
1.72. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 72 Head circumference small for age at early childhood follow‐up.
1.73
1.73. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 73 Height small for age at early childhood follow‐up.
1.74
1.74. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 74 Mean weight at early childhood follow‐up.
1.75
1.75. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 75 Mean head circumference at early childhood follow‐up.
1.76
1.76. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 76 Mean height at early childhood follow‐up.
1.77
1.77. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 77 Weight Z score at early childhood follow‐up.
1.78
1.78. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 78 Head circumference Z score at early childhood follow‐up.
1.79
1.79. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 79 Height Z score at early childhood follow‐up.
1.80
1.80. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 80 Developmental delay at early childhood follow‐up.
1.81
1.81. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 81 Mental Developmental Index at early childhood follow‐up.
1.82
1.82. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 82 Psychomotor Developmental Index at early childhood follow‐up.
1.83
1.83. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 83 Bindness at early childhood follow‐up.
1.84
1.84. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 84 Deafness at early childhood follow‐up.
1.85
1.85. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 85 Cerebral palsy at early childhood follow‐up.
1.86
1.86. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 86 Behaviour score at early childhood follow‐up within clinical range.
1.87
1.87. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 87 Asthma/Wheezing at early childhood follow‐up.
1.88
1.88. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 88 Hypertensive at early childhood follow‐up.
1.89
1.89. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 89 Mean systolic blood pressure at early childhood follow‐up.
1.90
1.90. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 90 Mean diasystolic blood pressure at early childhood follow‐up.
1.91
1.91. Analysis
Comparison 1 Repeat doses of corticosteroids versus single course, Outcome 91 Hospital re‐admission by early childhood follow‐up.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Aghajafari 2002 {published data only}
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Crowther 2006 {published data only}
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Guinn 2002 {published data only}
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Mazumder 2008 {published data only}
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McEvoy 2002 {published data only}
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Murphy 2008 {published and unpublished data}
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    1. Maternal Infant and Reproductive Health Research Unit. Multiple courses of antenatal steroids for preterm birth (MACS). Center for Mother, Infant, and Child Research (www.utoronto.ca/miru/macs/protocol02.htm) 2002.
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Peltoniemi 2007 {published data only}
    1. Janer C, Helve O, Pitkänen OM, Kari MA, Peltoniemi OM, Hallman M, et al. Expression of airway epithelial sodium channel in the preterm infant is related to respiratory distress syndrome but unaffected by repeat antenatal beta‐methasone. Neonatology 2010;97(2):132‐8. - PubMed
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Wapner 2006 {published data only}
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References to studies excluded from this review

Bontis 2011 {published data only}
    1. Bontis N, Vavilis D, Tsolakidis D, Goulis DG, Tzevelekis P, Kellartzis D, et al. Comparison of single versus multiple courses of antenatal betamethasone in patients with threatened preterm labor. Clinical and Experimental Obstetrics and Gynecology 2011;38(2):165‐7. - PubMed
Mercer 2001 {published data only}
    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.
    1. 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.
    1. 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
Romejko‐Wolniewicz 2013 {published data only}
    1. Romejko‐Wolniewicz E, Oleszczuk L, Zareba‐Szczudlik J, Czajkowski K. Dosage regimen of antenatal steroids prior to preterm delivery and effects on maternal and neonatal outcomes. Journal of Maternal‐Fetal and Neonatal Medicine 2013;26(3):237‐41. - PubMed
Thorp 2000 {published data only}
    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 studies awaiting assessment

Atarod 2014 {published data only}
    1. Atarod Z, Taghipour M, Roohanizadeh H, Fadavi S, Taghavipour M. Effects of single course and multicourse betamethasone prior to birth in the prognosis of the preterm neonates: a randomized, double‐blind placebo‐control clinical trial study. Journal of Research in Medical Sciences 2014;19(8):715‐9. - PMC - PubMed
    1. Ataroud Z. Single versus multiple courses of antenatal betamethasone: evaluation of preterm infant's outcome. IRCT Iranian Registry of Clinical Trials (www.irct.ir) (accessed 6 December 2010). IRCT138711261689N1 2010.
Crowther 2011 {published data only}
    1. Crowther C, Doyle LW, Anderson P, Harding JE, Haslam RR, Hiller JE. Repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth: early school‐age outcomes (6 to 8 years) for the ACTORDS trial. Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; 2011 April 30‐May 3; Denver, Colorado, USA. 2011:3123.6.
    1. Crowther CA, Doyle LW, Anderson P, Harding JE, Haslam RR, Hiller JE, et al. Repeat dose(s) of prenatal corticosteroids for women at risk of preterm birth: Early school‐age outcomes (6 to 8 years) for children in the ACTORDS trial. Journal of Paediatrics and Child Health 2011;47(Suppl 1):52‐3.
    1. McKinlay CJ, Cutfield WS, Battin MR, Dalziel SR, Crowther CA, Harding JE. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT. Pediatrics 2015;135(2):e405‐e415. - PubMed
    1. McKinlay CJD, Cutfield WS, Battin MR, Dalziel SR, Crowther CA. Cardiovascular risk factors after exposure to repeat antenatal betamethasone: early school‐age follow‐up of a randomised trial (ACTORDS). Journal of Paediatrics and Child Health 2011;47(Suppl 1):20.
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Murphy 2012 {published data only}
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References to other published versions of this review

Crowther 2000
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