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. 2022 Apr 4;4(4):CD003935.
doi: 10.1002/14651858.CD003935.pub5.

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

Anthony Walters  1 , Christopher McKinlay  1 , Philippa Middleton  2 , Jane E Harding  1 , Caroline A Crowther  1
Affiliations

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

Anthony Walters et al. Cochrane Database Syst Rev. .

Abstract

Background: Infants born preterm (before 37 weeks' gestation) are at risk of respiratory distress syndrome (RDS) and need for respiratory support due to lung immaturity. One course of prenatal corticosteroids, administered to women at risk of preterm birth, reduces the risk of respiratory morbidity and improves survival of their infants, but these benefits do not extend beyond seven days. Repeat doses of prenatal corticosteroids have been used for women at ongoing risk of preterm birth more than seven days after their first course of corticosteroids, with improvements in respiratory outcomes, but uncertainty remains about any long-term benefits and harms. This is an update of a review last published in 2015.

Objectives: To assess the effectiveness and safety, using the best available evidence, of a repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with the primary aim of reducing fetal and neonatal mortality and morbidity.

Search methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies.

Selection criteria: Randomised controlled trials, including cluster-randomised trials, of women who had already received one course of corticosteroids seven or more days previously and were still at risk of preterm birth, randomised to further dose(s) or no repeat doses, with or without placebo. Quasi-randomised trials were excluded. Abstracts were accepted if they met specific criteria. All trials had to meet criteria for trustworthiness, including a search of the Retraction Watch database for retractions or expressions of concern about the trials or their publications.

Data collection and analysis: We used standard Cochrane Pregnancy and Childbirth methods. Two review authors independently selected trials, extracted data, and assessed trial quality and scientific integrity. We chose primary outcomes based on clinical importance as measures of effectiveness and safety, including serious outcomes, for the women and their fetuses/infants, infants in early childhood (age two to less than five years), the infant in mid- to late childhood (age five to less than 18 years) and the infant as an adult. We assessed risk of bias at the outcome level using the RoB 2 tool and assessed certainty of evidence using GRADE.

Main results: We included 11 trials (4895 women and 5975 babies). High-certainty evidence from these trials indicated that 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) of corticosteroids, compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary infant outcome of RDS (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.90; 3540 babies; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 11 to 29) and had little or no effect on chronic lung disease (RR 1.00, 95% CI 0.83 to 1.22; 5661 babies). Moderate-certainty evidence indicated that the composite of serious infant outcomes was probably reduced with repeat dose(s) of corticosteroids (RR 0.88, 95% CI 0.80 to 0.97; 9 trials, 5736 babies; NNTB 39, 95% CI 24 to 158), as was severe lung disease (RR 0.83, 95% CI 0.72 to 0.97; NNTB 45, 95% CI 27 to 256; 4955 babies). Moderate-certainty evidence could not exclude benefit or harm for fetal or neonatal or infant death less than one year of age (RR 0.95, 95% CI 0.73 to 1.24; 5849 babies), severe intraventricular haemorrhage (RR 1.13, 95% CI 0.69 to 1.86; 5066 babies) and necrotising enterocolitis (RR 0.84, 95% CI 0.59 to 1.22; 5736 babies). In women, moderate-certainty evidence found little or no effect on the likelihood of a caesarean birth (RR 1.03, 95% CI 0.98 to 1.09; 4266 mothers). Benefit or harm could not be excluded for maternal death (RR 0.32, 95% 0.01 to 7.81; 437 women) and maternal sepsis (RR 1.13, 95% CI 0.93 to 1.39; 4666 mothers). The evidence was unclear for risk of adverse effects and discontinuation of therapy due to maternal adverse effects. No trials reported breastfeeding status at hospital discharge or risk of admission to the intensive care unit. At early childhood follow-up, moderate- to high-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids for primary outcomes relating to neurodevelopment (neurodevelopmental impairment: RR 0.97, 95% CI 0.85 to 1.10; 3616 children), survival without neurodevelopmental impairment (RR 1.01, 95% CI 0.98 to 1.04; 3845 children) and survival without major neurodevelopmental impairment (RR 1.02, 95% CI 0.98 to 1.05; 1816 children). An increase or decrease in the risk of death since randomisation could not be excluded (RR 1.06, 95% CI 0.81 to 1.40; 5 trials, 4565 babies randomised). At mid-childhood follow-up, moderate-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids on survival free of neurocognitive impairment (RR 1.01, 95% CI 0.95 to 1.08; 963 children) or survival free of major neurocognitive impairment (RR 1.00, 95% CI 0.97 to 1.04; 2682 children). Benefit or harm could not be excluded for death since randomisation (RR 0.93, 95% CI 0.69 to 1.26; 2874 babies randomised) and any neurocognitive impairment (RR 0.96, 95% CI 0.72 to 1.29; 897 children). No trials reported data for follow-up into adolescence or adulthood. Risk of bias across outcomes was generally low although there were some concerns of bias. For childhood follow-up, most outcomes had some concerns of risk of bias due to missing data from loss to follow-up.

Authors' conclusions: The short-term benefits for babies included less respiratory distress and fewer serious health problems in the first few weeks after birth with repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. The current available evidence reassuringly shows no significant harm for the women or child in early and mid-childhood, although no benefit. Further research is needed on the long-term benefits and risks for the baby into adulthood.

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Conflict of interest statement

AW: reports working as a health professional but in an unrelated area (as an Endocrinology advanced trainee).

CM: reports previously publishing on repeat prenatal corticosteroids, being an investigator in the six‐ to eight‐year follow‐up studies of the Australasian Collaborative Trial of Repeat Doses of Corticosteroid for the Prevention of Neonatal Respiratory Disease (Crowther 2006), and working as a health professional for Counties Manukau Health.

PM: reports being an Editor for Cochrane Pregnancy and Childbirth, but was not involved in the editorial process for this review.

JH: reports giving multiple lectures and publishing review articles which relate to the material included in this review, none directly reporting the contents of the review. Investigator in the two‐year and six‐ to eight‐year follow‐up studies of the Australasian Collaborative Trial of Repeat Doses of Corticosteroid for the Prevention of Neonatal Respiratory Disease (Crowther 2006). Funding for the ACTORDS follow‐up studies was updated received from: the National Health and Medical Research Council of Australia; Channel 7 Research Foundation, South Australia; the Women's and Children's Research Foundation, Adelaide, South Australia; Discipline of Obstetrics and Gynaecology, University of Adelaide, South Australia; Health Research Council of New Zealand; Auckland Medical Research Foundation, New Zealand. None of the funding bodies had any role in the conduct of the study, analysis or decision to publish.

CAC: reports being the lead investigator for the Australasian Collaborative Trial of Repeat Doses of Corticosteroid for the Prevention of Neonatal Respiratory Disease and subsequent follow‐up studies (Crowther 2006).

Figures

1
1
Applying the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool.
2
2
Study flow diagram.
3
3
4
4
5
5
6
6
1.1
1.1. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 1: A1: Fetal or neonatal or infant death (< 1 year of age)
1.2
1.2. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 2: A2: Fetal death
1.3
1.3. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 3: A3: Neonatal death
1.4
1.4. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 4: A5: Respiratory distress syndrome
1.5
1.5. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 5: A6: Severe respiratory distress syndrome
1.6
1.6. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 6: A7: Severe lung disease
1.7
1.7. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 7: A8: Chronic lung disease
1.8
1.8. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 8: A9: Severe intraventricular haemorrhage (grade 3/4)
1.9
1.9. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 9: A10: Intraventricular haemorrhage
1.10
1.10. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 10: A11: Necrotising enterocolitis
1.11
1.11. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 11: A12: Composite of serious outcomes
1.12
1.12. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 12: F1i: Term birth ≥ 37 weeks
1.13
1.13. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 13: F1ii: Preterm birth before 37 weeks
1.14
1.14. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 14: F1iii: Very preterm birth before 34 weeks
1.15
1.15. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 15: F1iv: Extremely preterm birth before 28 weeks
1.16
1.16. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 16: F1v: Mean gestational age at birth (weeks)
1.17
1.17. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 17: F2: Small‐for‐gestational age at birth
1.18
1.18. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 18: F3: Admission to the neonatal intensive care unit
1.19
1.19. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 19: F4: Proven neonatal infection while in the neonatal intensive care unit
1.20
1.20. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 20: F5: Early systemic neonatal infection
1.21
1.21. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 21: F6: Late systemic neonatal infection
1.22
1.22. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 22: F7: Retinopathy of prematurity
1.23
1.23. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 23: F8: Periventricular leukomalacia
1.24
1.24. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 24: F9: Neonatal encephalopathy
1.25
1.25. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 25: F10: Patent ductus arteriosus
1.26
1.26. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 26: F11: Use of respiratory support
1.27
1.27. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 27: F12: Use of invasive respiratory support
1.28
1.28. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 28: F13: Use of non‐invasive respiratory support
1.29
1.29. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 29: F14: Use of oxygen supplementation
1.30
1.30. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 30: F15: Use of surfactant
1.31
1.31. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 31: F17: Use of postnatal corticosteroids
1.32
1.32. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 32: F16: Use of nitric oxide for respiratory support
1.33
1.33. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 33: F20: Use of inotropic support
1.34
1.34. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 34: F18: Air leak syndrome
1.35
1.35. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 35: F21: Apgar score < 7 at 5 minutes
1.36
1.36. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 36: F22: Neonatal cardiac hypertrophy as measured by interventricular septal thickness (IVS in mm)
1.37
1.37. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 37: F22: Neonatal cardiac hypertrophy as measured by left ventricular wall thickness in diastole (mm)
1.38
1.38. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 38: L1: Mean birthweight (g)
1.39
1.39. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 39: L1: Mean birthweight Z score
1.40
1.40. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 40: L1: Birthweight multiples of the median
1.41
1.41. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 41: L1: Birthweight adjusted for gestation (standardised mean difference)
1.42
1.42. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 42: L2: Interval between trial entry and birth (days)
1.43
1.43. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 43: L3: Mean head circumference at birth (cm)
1.44
1.44. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 44: L3: Mean head circumference Z score at birth
1.45
1.45. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 45: L4: Mean length at birth (cm)
1.46
1.46. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 46: L4: Mean length Z score at birth
1.47
1.47. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 47: L4: Length multiples of the mean at birth
1.48
1.48. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 48: L4: Length at birth adjusted for gestation (standardised mean difference)
1.49
1.49. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 49: L5i: Mean weight (g) at primary hospital discharge
1.50
1.50. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 50: L5i: Mean weight Z score at primary hospital discharge
1.51
1.51. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 51: L5ii: Mean head circumference (cm) at primary hospital discharge
1.52
1.52. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 52: L5ii: Mean head circumference Z score at primary hospital discharge
1.53
1.53. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 53: L5iii: Mean length (cm) at primary hospital discharge
1.54
1.54. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 54: L5iii: Mean length Z score at primary hospital discharge
1.55
1.55. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 55: L6i: Mean weight at infant follow‐up (kg)
1.56
1.56. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 56: L6i: Mean weight Z score at infant follow‐up
1.57
1.57. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 57: L6ii: Mean head circumference at infant follow‐up (cm)
1.58
1.58. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 58: L6ii: Mean head circumference Z score at infant follow‐up
1.59
1.59. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 59: L6iii: Mean length at infant follow‐up (cm)
1.60
1.60. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 60: L6iii: Mean length Z score at infant follow‐up
1.61
1.61. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 61: L8: Mean duration of invasive respiratory support (days)
1.62
1.62. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 62: L9: Mean duration of non‐invasive respiratory support (days)
1.63
1.63. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 63: L10: Mean duration of oxygen supplementation (days)
1.64
1.64. Analysis
Comparison 1: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the fetus/neonate/infant, Outcome 64: L14: Mean cord cortisol concentrations at birth (nmol/L)
2.1
2.1. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 1: B1: Maternal death
2.2
2.2. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 2: B2: Maternal sepsis
2.3
2.3. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 3: B3: Caesarean section
2.4
2.4. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 4: B4: Discontinuation of therapy due to maternal adverse effects
2.5
2.5. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 5: G1: Puerperal sepsis
2.6
2.6. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 6: G2: Chorioamnionitis during labour
2.7
2.7. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 7: G3: Endometritis
2.8
2.8. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 8: G4: Pyrexia after trial entry requiring the use of antibiotics
2.9
2.9. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 9: G6: Postpartum haemorrhage
2.10
2.10. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 10: G7: Postnatal pyrexia
2.11
2.11. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 11: G8: Prelabour rupture of membranes after trial entry
2.12
2.12. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 12: G9: Mode of birth: vaginal birth
2.13
2.13. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 13: G10: Hypertension
2.14
2.14. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 14: G12: Glucose intolerance
2.15
2.15. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 15: G13: Postnatal depression
2.16
2.16. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 16: G14: Local injection site adverse effects
2.17
2.17. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 17: G15: Insomnia after treatment
2.18
2.18. Analysis
Comparison 2: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the woman, Outcome 18: G16: Gastrointestinal adverse effects of treatment
3.1
3.1. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 1: C1: Total deaths (after randomisation) up to early childhood follow‐up
3.2
3.2. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 2: C2: Neurodevelopmental impairment at early childhood follow‐up
3.3
3.3. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 3: C3: Survival free of neurodevelopmental impairment at early childhood follow‐up
3.4
3.4. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 4: C4: Survival free of major neurodevelopmental impairment at early childhood follow‐up
3.5
3.5. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 5: C5: Cerebral palsy at early childhood follow‐up
3.6
3.6. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 6: C6: Developmental delay or intellectual impairment at early childhood follow‐up (any)
3.7
3.7. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 7: Mental Developmental Index at early childhood follow‐up
3.8
3.8. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 8: H1: Child behaviour at early childhood follow‐up, Child Behaviour Checklist total score in the clinical range
3.9
3.9. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 9: H1: Child behaviour: Behaviour rating scale in the clinical range (BSID‐II)
3.10
3.10. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 10: H1: Child behaviour at early childhood follow‐up as assessed by Early Child Behaviour Questionnaire Extraversion summary scale
3.11
3.11. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 11: H1: Child behaviour at early childhood follow‐up assessed by Early Child Behaviour questionnaire Negative affectivity summary scale
3.12
3.12. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 12: H1: Child behaviour at early childhood follow‐up assessed by Early Child Behaviour questionnaire Effortful control summary scale
3.13
3.13. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 13: H2: Psychomotor Developmental Index at early childhood follow‐up
3.14
3.14. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 14: H3: Deafness/hearing impairment at early childhood follow‐up
3.15
3.15. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 15: H4: Blindness/visual impairment at early childhood follow‐up
3.16
3.16. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 16: H5: Hypertension at early childhood follow‐up
3.17
3.17. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 17: H8: Asthma or recurrent wheeze at early childhood follow‐up
3.18
3.18. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 18: H9: Any respiratory disease at early childhood follow‐up
3.19
3.19. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 19: N1i: Mean weight at early childhood follow‐up (kg)
3.20
3.20. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 20: N1i: Mean weight Z score at early childhood follow‐up
3.21
3.21. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 21: N1i: Mean weight adjusted for age at early childhood follow‐up (standardised mean difference)
3.22
3.22. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 22: N1i: Weight small for age  at early childhood follow‐up
3.23
3.23. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 23: N1ii: Mean head circumference at early childhood follow‐up (cm)
3.24
3.24. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 24: N1ii: Mean head circumference Z score at early childhood follow‐up
3.25
3.25. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 25: N1ii: Mean head circumference adjusted for age at early childhood follow‐up (standardised mean difference)
3.26
3.26. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 26: N1ii: Head circumference small for age at early childhood follow‐up
3.27
3.27. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 27: N1iii: Mean height at early childhood follow‐up (cm)
3.28
3.28. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 28: N1iii: Height Z score at early childhood follow‐up
3.29
3.29. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 29: N1iii: Mean height adjusted for age at early childhood follow‐up (standardised mean difference)
3.30
3.30. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 30: N1iii: Height small for age at early childhood follow‐up
3.31
3.31. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 31: N3: Mean systolic blood pressure at early childhood follow‐up (mmHg)
3.32
3.32. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 32: N3: Mean systolic blood pressure Z score at early childhood follow‐up
3.33
3.33. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 33: N3: Mean diastolic blood pressure at early childhood follow‐up (mmHg)
3.34
3.34. Analysis
Comparison 3: Repeat dose(s) of corticosteroids versus single course: outcomes for the child in early childhood (2 to < 5 years of age), Outcome 34: N3: Mean diastolic blood pressure Z score at early childhood follow‐up
4.1
4.1. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 1: D1: Total deaths (after randomisation) up to mid‐ to later childhood follow‐up
4.2
4.2. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 2: D2: Neurocognitive impairment at mid‐ to later childhood follow‐up
4.3
4.3. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 3: D3: Survival free of neurocognitive impairment at mid‐ to later childhood follow‐up
4.4
4.4. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 4: D4: Survival free of major neurocognitive impairment at mid‐ to later childhood follow‐up
4.5
4.5. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 5: D6: Cognitive impairment at mid‐ to later childhood follow‐up
4.6
4.6. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 6: D8: Cerebral palsy at mid‐ to later childhood follow‐up
4.7
4.7. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 7: I2: Blindness/visual impairment at mid‐ to later childhood follow‐up
4.8
4.8. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 8: I3: Deafness/hearing impairment at mid‐ to later childhood follow‐up
4.9
4.9. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 9: I4: Abnormal child behaviour at mid‐ to later childhood follow‐up
4.10
4.10. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 10: I4: Child behaviour at mid‐ to later childhood follow‐up (standardised mean difference)
4.11
4.11. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 11: I5: Asthma or recurrent wheeze at mid‐ to later childhood follow‐up
4.12
4.12. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 12: I6: Any respiratory disease at mid‐ to later childhood follow‐up
4.13
4.13. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 13: O1i: Mean weight at mid‐ to later childhood follow‐up (kg)
4.14
4.14. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 14: O1i: Mean weight Z score at mid‐ to later childhood follow‐up
4.15
4.15. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 15: O1ii: Mean head circumference at mid‐ to later childhood follow‐up (cm)
4.16
4.16. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 16: O1ii: Head circumference Z score at mid‐ to later childhood follow‐up
4.17
4.17. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 17: O1iii: Mean height at mid‐ to later childhood follow‐up (cm)
4.18
4.18. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 18: O1iii: Mean height Z score at mid‐ to later childhood follow‐up
4.19
4.19. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 19: O2: BMI Z scores at mid‐ to later childhood follow‐up
4.20
4.20. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 20: O4: Body composition: total body fat‐free mass at mid‐ to later childhood follow‐up (kg)
4.21
4.21. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 21: O5: Body composition: total body fat mass at mid‐ to later childhood follow‐up (kg)
4.22
4.22. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 22: O6: Mean systolic blood pressure at mid‐ to later childhood follow‐up (mmHg)
4.23
4.23. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 23: O6: Mean diastolic blood pressure at mid‐ to later childhood follow‐up (mmHg)
4.24
4.24. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 24: O6: Mean systolic blood pressure Z score at mid‐ to later childhood follow‐up
4.25
4.25. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 25: O6: Mean diastolic blood pressure Z score at mid‐ to later childhood follow‐up
4.26
4.26. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 26: O8: Measures of lung function at mid‐ to later childhood follow‐up: mean FEV1 Z score
4.27
4.27. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 27: O8: Measures of lung function at mid‐ to later childhood follow‐up: mean FVC Z score
4.28
4.28. Analysis
Comparison 4: Repeat dose(s) of prenatal corticosteroids versus single course: outcomes for the child in mid‐ to later childhood (5 to < 18 years of age), Outcome 28: O8: Measures of lung function at mid‐ to later childhood follow‐up: mean FEV1/FVC Z score
6.1
6.1. Analysis
Comparison 6: Repeat dose(s) of corticosteroids versus single course: outcomes for health services, Outcome 1: K1: Hospital re‐admission by early childhood follow‐up
6.2
6.2. Analysis
Comparison 6: Repeat dose(s) of corticosteroids versus single course: outcomes for health services, Outcome 2: K1: Hospital re‐admission by mid to later childhood follow‐up
6.3
6.3. Analysis
Comparison 6: Repeat dose(s) of corticosteroids versus single course: outcomes for health services, Outcome 3: Q2: Length of postnatal hospitalisation for the woman (days)
6.4
6.4. Analysis
Comparison 6: Repeat dose(s) of corticosteroids versus single course: outcomes for health services, Outcome 4: Q4: Length of infant hospitalisation (days)
7.1
7.1. Analysis
Comparison 7: Subgroup analysis for the number of babies in utero, Outcome 1: A12: Composite serious outcome (variously defined)
7.2
7.2. Analysis
Comparison 7: Subgroup analysis for the number of babies in utero, Outcome 2: C3: Survival free of neurodevelopmental impairment at early childhood follow‐up
8.1
8.1. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 1: A1: Fetal or neonatal or infant death (< 1 year of age)
8.2
8.2. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 2: A2: Fetal death
8.3
8.3. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 3: A3: Neonatal death
8.4
8.4. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 4: A5: Respiratory distress syndrome
8.5
8.5. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 5: A6: Severe respiratory distress syndrome
8.6
8.6. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 6: A7: Severe lung disease
8.7
8.7. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 7: A8: Chronic lung disease
8.8
8.8. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 8: A9: Severe Intraventricular haemorrhage (grade 3 or 4)
8.9
8.9. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 9: A10: Intraventricular haemorrhage
8.10
8.10. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 10: A11: Necrotising enterocolitis
8.11
8.11. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 11: A12: Composite serious outcome (variously defined)
8.12
8.12. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 12: B2: Maternal sepsis
8.13
8.13. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 13: B3: Caesarean section
8.14
8.14. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 14: C1: Total deaths (after randomisation) up to early childhood follow‐up
8.15
8.15. Analysis
Comparison 8: Subgroup analysis for the planned number of repeat courses of corticosteroids to be given, Outcome 15: C4: Survival free of major neurodevelopmental impairment at early childhood follow‐up
9.1
9.1. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 1: A1: Fetal or neonatal or infant death (< 1 year of age)
9.2
9.2. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 2: A2: Fetal death
9.3
9.3. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 3: A3: Neonatal death
9.4
9.4. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 4: A5: Respiratory distress syndrome
9.5
9.5. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 5: A6: Severe respiratory distress syndrome
9.6
9.6. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 6: A7: Severe lung disease
9.7
9.7. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 7: A8: Chronic lung disease
9.8
9.8. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 8: A9: Severe intraventricular haemorrhage (grade 3 or 4)
9.9
9.9. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 9: A10: Intraventricular haemorrhage
9.10
9.10. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 10: A11: Necrotising enterocolitis
9.11
9.11. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 11: A12: Composite serious outcome (variously defined)
9.12
9.12. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 12: B2: Maternal sepsis
9.13
9.13. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 13: B3: Caesarean section
9.14
9.14. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 14: C1: Total deaths after randomisation up to early childhood follow‐up
9.15
9.15. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 15: C2: Neurodevelopmental impairment at early childhood follow‐up
9.16
9.16. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 16: C3: Survival free of neurodevelopmental impairment at early childhood follow‐up
9.17
9.17. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 17: C5: Cerebral palsy at early childhood follow‐up
9.18
9.18. Analysis
Comparison 9: Subgroup analysis for planned interval between corticosteroid treatments, Outcome 18: C6: Developmental delay or intellectual impairment at early childhood follow‐up (any)
10.1
10.1. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 1: A1: Fetal or neonatal or infant death (< 1 year of age)
10.2
10.2. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 2: A2: Fetal death
10.3
10.3. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 3: A3: Neonatal death
10.4
10.4. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 4: A5: Respiratory distress syndrome
10.5
10.5. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 5: A6: Severe respiratory distress syndrome
10.6
10.6. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 6: A7: Severe lung disease
10.7
10.7. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 7: A8: Chronic lung disease
10.8
10.8. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 8: A9: Severe intraventricular haemorrhage (grade 3 or 4)
10.9
10.9. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 9: A10: Intraventricular haemorrhage
10.10
10.10. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 10: A11: Necrotising enterocolitis
10.11
10.11. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 11: A12: Composite serious outcome (variously defined)
10.12
10.12. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 12: B2: Maternal sepsis
10.13
10.13. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 13: B3: Caesarean section
10.14
10.14. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 14: C1: Total deaths after randomisation up to early childhood follow‐up
10.15
10.15. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 15: C2: Neurodevelopmental impairment at early childhood follow‐up
10.16
10.16. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 16: C3: Survival free of neurodevelopmental impairment at early childhood follow‐up
10.17
10.17. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 17: C4: Survival free of major neurodevelopmental impairment at early childhood follow‐up
10.18
10.18. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 18: C5: Cerebral palsy at early childhood follow‐up
10.19
10.19. Analysis
Comparison 10: Subgroup analysis for the planned dose of corticosteroid given per treatment , Outcome 19: C6: Developmental delay or intellectual impairment at early childhood follow‐up (any)
11.1
11.1. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 1: A1: Fetal or neonatal or infant death (< 1 year of age)
11.2
11.2. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 2: A2: Fetal death
11.3
11.3. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 3: A3: Neonatal death
11.4
11.4. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 4: A5: Respiratory distress syndrome
11.5
11.5. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 5: A6: Severe respiratory distress syndrome
11.6
11.6. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 6: A7: Severe lung disease
11.7
11.7. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 7: A8: Chronic lung disease
11.8
11.8. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 8: A9: Severe intraventricular haemorrhage (grade 3 or 4)
11.9
11.9. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 9: A10: Intraventricular haemorrhage
11.10
11.10. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 10: A11: Necrotising enterocolitis
11.11
11.11. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 11: A12: Composite serious outcome (variously defined)
11.12
11.12. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 12: B2: Maternal sepsis
11.13
11.13. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 13: B3: Caesarean section
11.14
11.14. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 14: C1: Total deaths after randomisation up to early childhood follow‐up
11.15
11.15. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 15: C2: Neurodevelopmental impairment at early childhood follow‐up
11.16
11.16. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 16: C3: Survival free of neurodevelopmental impairment at early childhood follow‐up
11.17
11.17. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 17: C4: Survival free of major neurodevelopmental impairment at early childhood follow‐up
11.18
11.18. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 18: C5: Cerebral palsy at early childhood follow‐up
11.19
11.19. Analysis
Comparison 11: Subgroup analysis for the planned dose of repeat dose of corticosteroid drug exposure/week, Outcome 19: C6: Developmental delay or intellectual impairment at early childhood follow‐up (any)
12.1
12.1. Analysis
Comparison 12: Subgroup analysis for the gestational age at which the first repeat treatment was given, Outcome 1: A12: Composite serious outcome (variously defined)
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References

References to studies included in this review

Aghajafari 2002 {published data only}
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Guinn 2001 {published data only}
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Mazumder 2008 {published data only}
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McEvoy 2010 {published data only}
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Murphy 2008 {published and unpublished data}
    1. Asztalos E, Murphy K, Hannah M, Willan A, MACS Collaborative Group.Outcomes of children at two years after multiple courses of antenatal corticosteroids for threatened preterm birth: the Multiple Antenatal Corticosteroids study (MACS). Pediatric Academic Societies' 2010 Annual Meeting; 2010 May 1-4; Vancouver, Canada.
    1. Asztalos E, Willan A, Murphy K, Matthews S, Ohlsson A, Saigal S, et al.Association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years: multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5). BMC Pregnancy and Childbirth 2014;14(1):272. - PMC - PubMed
    1. Asztalos E, Willan A, Murphy K, Matthews S, Ohlsson A, Saigal S, et al.Multiple courses of antenatal corticosteroids for preterm birth study at 5 years of age (MACS-5): association between gestational age at birth, antenatal corticosteroids, and outcomes at 5 years of age (MACS-5). American Journal of Obstetrics and Gynecology 2014;210(1 Suppl):S321-2.
    1. Asztalos EV, Murphy KE, Hannah ME, Willan AR, Matthews SG, Ohlsson A, et al.Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. Pediatrics 2010;126:e1045-55. - PubMed
    1. Asztalos EV, Murphy KE, Willan AR, Matthews SG, Ohlsson A, Saigal S, et al, for the MACS-5 Collaborative Group.Multiple courses of antenatal corticosteroids for preterm birth study: outcomes in children at 5 years of age (MACS-5). Journal of the American Medical Association Pediatrics 2013;167(12):1102-10. - PubMed
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 betamethasone. Neonatology 2010;97(2):132-8. - PubMed
    1. Koivisto M, Peltoniemi OM, Saarela T, Tammela O, Jouppila P, Hallman M.Blood glucose level in preterm infants after antenatal exposure to glucocorticoid. Acta Paediatrica 2007;96(5):664-8. - PubMed
    1. NCT00295464.Antenatal rescue course of glucocorticoids in threatened premature birth [Randomized trial on efficacy and safety of the antenatal rescue course of glucocorticoids in threatened premature birth (ACG Trial)]. clinicaltrials.gov/show/NCT00295464 (first received 21 February 2006).
    1. Peltoniemi O, Kari M, Lano A, Yliherva A, Puosi R, Lehtonen L, et al.Two-year follow-up of a randomized trial with repeated antenatal betamethasone. Archives of Disease in Childhood. Fetal and Neonatal Edition 2009;94(6):F402-6. - PubMed
    1. Peltoniemi OM, Kari MA, Halmesmaki E, Raudaskoski T, Tammela O, Uotila J, et al.The effect of second course of antenatal betamethasone (BM) on neonatal morbidity in preterm infants: a randomised trial. Pediatric Research 2005;58(2):404.
TEAMS 1999 {unpublished data only}ISRCTN46614711
    1. Brocklehurst P, Gates S, Johnson A.Effects of multiple courses of antenatal steroids are uncertain [letter]. BMJ 2000;321:47. - PMC - PubMed
    1. ISRCTN46614711.Trial of the effects of antenatal multiple courses of steroids versus a single course (TEAMS): pilot study. www.isrctn.com/ISRCTN46614711 (first received 1 March 2001).
Wapner 2006 {published data only}
    1. Borowski KS, Clark EA, Lai Y, Wapner RJ, Sorokin Y, Peaceman AM, et al.Neonatal genetic variation in steroid metabolism and key respiratory function genes and perinatal outcomes in single and multiple courses of corticosteroids. American Journal of Perinatology 2015;32(12):1126-32. [CENTRAL: CN-01169539] [PMID: ] - PMC - PubMed
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    1. Church M.Auditory brainstem responses (ABRs) in neonates exposed to repeated courses of antenatal corticosteroids. In: Program of the Twenty Eighth Annual Midwinter Research Meeting of the Association for Research in Otolaryngology; 2005 Feb 19-24; New Orleans (LA). 2005:669.
    1. Church MW, Wapner RJ, Mele LM, Johnson F, Dudley DJ, Spong CY, et al.Repeated courses of antenatal corticosteroids: are there effects on the infant's auditory brainstem responses? Neurotoxicology and Teratology 2010;32(6):605-10. - PMC - PubMed
    1. Dude C, Dude A, Gilner J, Swamy G, Grotegut C.Predicting preterm delivery: using the MFMU BEARS trial data to optimize corticosteroid use in women at risk for preterm delivery. Reproductive Sciences (Thousand Oaks, Calif.) 2016;23(Suppl 1):188A-9A. [CENTRAL: CN-02011932]

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
CTRI/2017/04/008326 {published data only}
    1. CTRI/2017/04/008326.Improving newborn survival in preterm birth [A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial of antenatal corticosteroids for women at risk of imminent birth in the early preterm period in hospitals in low-resource countries to improve newborn outcomes – Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns (ACTION-I TRIAL)]. www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2017/04/008326 (first received 10 April 2017).
CTRI/2017/05/008721 {published data only}
    1. CTRI/2017/05/008721.Improving newborn survival in late preterm birth [A multi-country, multi-centre, two-arm, parallel, double-blind, placebo-controlled, randomized trial of antenatal corticosteroids for women at risk of imminent birth in the late preterm period in hospitals in low-resource countries to improve newborn outcomes – Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns (ACTION-II TRIAL)]. www.who.int/trialsearch/Trial2.aspx?TrialID=CTRI/2017/05/008721 (first received 31 May 2017). [CENTRAL: CN-01884324]
Ernawati 2016 {published data only}
    1. Ernawati, Gumilar E, Kuntoro, Soeroso J, Dekker G.Expectant management of preterm preeclampsia in Indonesia and the role of steroids. Journal of Maternal-fetal & Neonatal Medicine 2016;29(11):1736-40. [CENTRAL: CN-01141034] [EMBASE: 2015249052] [PMID: ] - PubMed
EUCTR2009‐010759‐29‐BE {published data only}
    1. EUCTR2009-010759-29-BE.Etude clinique sur l'administration de 3 doses de betamethasone (12mg) a 18 heures d'intervalle lors d'une menace d'accouchement premature dans les grossesses gemellaires traitees par Atosiban, plutot que 2 doses de betamethasone (12mg) a 24 heures d'intervalle; afin de diminuer le risque de syndrome de detresse respiratoire chez les nouveau-nes – CORTGEM. www.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2009-010759-29-BE (first received 30 March 2009).
Gyamfi‐Bannerman 2016 {published data only}
    1. Viteri OA, Doty MS, Alrais MA, Sibai BM.471: intended administration of antenatal late preterm steroids: is a single dose enough? American Journal of Obstetrics and Gynecology 2019;220(1):S315. [CENTRAL: CN-01710606] [EMBASE: 2001405752]
IRCT2014090912789N6 {published data only}
    1. IRCT2014090912789N6.Impact of betamethasone on preterm infants outcomes [Comparing the impact of one versus two doses of betamethasone on preterm infants outcomes: a clinical trial study]. www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT2014090912789N6 (first received 20 October 2014). [CENTRAL: CN-01862384]
IRCT2015120415634N2 {published data only}
    1. IRCT2015120415634N2.The effect of antenatal intramuscular administration of two doses of betamethasone every 12 hours on acute pulmonary complications in preterm infants born [Comparing of antenatal intramuscular administration of two doses of betamethasone every 12 hours with standard method every 24 hours on acute neonatal pulmonary complications in preterm infants born from women with preterm premature of membrane]. www.who.int/trialsearch/Trial2.aspx?TrialID=IRCT2015120415634N2 (first received 27 September 2017). [CENTRAL: CN-01886227]
IRCT20191202045571N1 {published data only}
    1. IRCT20191202045571N1.The effect of betamethasone injection on maternal and neonatal outcomes in pregnant women with gestational age 34–37 weeks exposed to preterm labor in Sayyad Shirazi Hospital, Gorgan. www.irct.ir/trial/44053 (first received 17 July 2020). [CENTRAL: CN-02148336]
Kashanian 2018 {published data only}
    1. Kashanian M, Eshraghi N, Sheikhansari N, Bordbar A, Khatami E.Comparison between two doses of betamethasone administration with 12 hours vs. 24 hours intervals on prevention of respiratory distress syndrome: a randomised trial. Journal of Obstetrics and Gynaecology 2018;38(6):770-6. [CENTRAL: CN-01665275] [EMBASE: 621208178] [PMID: ] - 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
NCT03446937 {published data only}
    1. NCT03446937.Effect of antenatal corticosteroids on neonatal morbidity. clinicaltrials.gov/show/NCT03446937 (first received 5 February 2018). [CENTRAL: CN-01483469]
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
Schmitz 2019 {published data only}
    1. Schmitz T, Alberti C, Ursino M, Baud O, Aupiais C.Full versus half dose of antenatal betamethasone to prevent severe neonatal respiratory distress syndrome associated with preterm birth: study protocol for a randomised, multicenter, double blind, placebo-controlled, non-inferiority trial (BETADOSE). BMC Pregnancy and Childbirth 2019;19(1):67. [CENTRAL: CN-01787973] [EMBASE: 626359019] [PMID: ] - PMC - PubMed
Sohrabvand 2001 {published data only}
    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.
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. Atarod Z.Single versus multiple courses of antenatal betamethasone: evaluation of preterm infant's outcome. www.irct.ir/trial/1175 (first received 16 May 2009).

References to ongoing studies

NCT02469519 {published data only}
    1. NCT02469519.Impact of a booster course of antenatal steroids on neonatal outcome in patients with premature rupture of the membranes [A randomized double-blinded trial comparing the impact of one versus two courses of antenatal steroids on neonatal outcome in the patient with prelabor premature rupture of the membranes]. clinicaltrials.gov/show/NCT02469519 (first received 5 June 2015). [CENTRAL: CN-01552815]
NCT02939742 {published data only}
    1. NCT02939742.Does a rescue course of betamethasone in pregnant women with PPROM decrease neonatal morbidity? [Does a repeat course of antenatal corticosteroids in pregnant women with preterm premature rupture of membranes decrease neonatal morbidity?]. clinicaltrials.gov/show/nct02939742 (first received 23 September 2016). [CENTRAL: CN-01583154]

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Crowther 2000
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