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Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth

  1. Fiona C Brownfoot1,*,
  2. Daniela I Gagliardi2,
  3. Emily Bain2,
  4. Philippa Middleton2,
  5. Caroline A Crowther2,3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 29 AUG 2013

Assessed as up-to-date: 1 MAY 2013

DOI: 10.1002/14651858.CD006764.pub3


How to Cite

Brownfoot FC, Gagliardi DI, Bain E, Middleton P, Crowther CA. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD006764. DOI: 10.1002/14651858.CD006764.pub3.

Author Information

  1. 1

    Mercy Hospital for Women, Heidelberg, Australia

  2. 2

    The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, The Robinson Institute, Discipline of Obstetrics and Gynaecology, Adelaide, Australia

  3. 3

    The University of Auckland, Liggins Institute, Auckland, New Zealand

*Fiona C Brownfoot, Mercy Hospital for Women, Heidelberg, Australia. fiona.brownfoot@gmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 29 AUG 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Chen 2005

MethodsRandomised controlled trial.


Participants168 women "received antenatal corticosteroids" so we have assumed 168 was the number randomised.

After exclusions 140 women, who gave birth to 157 infants (17 sets of twins), were included.

Setting: Mackay Memorial Hospital, Taiwan (from December 2001 to September 2003).

Inclusion criteria: preterm prelabour rupture of membranes between 24 and 32 weeks and preterm labour between 24 and 34 weeks.


InterventionsDexamethasone group (n = 76 infants)

24 mg: 4 x 6 mg doses IM 12 hours apart.
Betamethasone group (n = 81 infants)

24 mg: 2 x 12 mg doses IM 24 hours apart.


OutcomesInfant:
RDS; IVH (grade 3 to 4); PVL; birthweight; Apgar score < 7 at 5 mins; head circumference; neonatal sepsis; NEC; ROP.

Mother:

Caesarean birth.


NotesFunding source was not detailed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "These women were randomly divided into two groups,"

Allocation concealment (selection bias)Unclear riskAs above, no further detail provided.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear, not reported.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear, not reported.

Incomplete outcome data (attrition bias)
All outcomes
High riskData were excluded for 28/168 (16%) women (1 intrauterine fetal death, 15 women gave birth after 37 weeks' gestation, 4 neonates died immediately after delivery, 8 women gave birth at another hospital); it was not reported in which groups (dexamethasone or betamethasone) the losses occurred.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement (while a number of important outcomes were reported, no protocol was available, and thus it was difficult to assess selective reporting).

Other biasUnclear riskWhile groups were comparable at baseline, women in the betamethasone group were approximately 3 years older compared to women in the dexamethasone group.

Danesh 2012

MethodsRandomised controlled trial.


Participants240 women randomised.

Setting: Isfahan University of Medical Sciences Obstetrics Department, Iran (from February to November 2011).

Inclusion criteria: pregnant women of low parity; 16 to 45 years of age; between 24 and 34 weeks gestation; hospitalised because of high risk of preterm birth that justified preventative corticosteroid therapy; with or without intact membranes; low Bishop score ≤ 5; non-smokers; singleton pregnancy; residence in Isfahan; hospitalisation planned to last at least 3 days.

Preterm rupture of membranes was diagnosed in the presence of a gush of fluid from the vagina, followed by persistent, uncontrolled leakage, or pooling of fluid on speculum examination, with positive nitrazine and Fern testing. Preterm labour was diagnosed in the presence of uterine contractions of 4 in 20 minutes or 8 in 60 minutes, plus progressive change in the cervix, cervical dilatation greater than 1 cm and cervical effacement 80% or greater.

Exclusion criteria: women were excluded if they had evidence of fetal distress, substantial abnormalities in neurological, psychiatric, cardiac, endocrinological, haematologic, hepatic, renal or metabolic function; had signs of infection; positive urine culture; vaginal bleeding due to placental praevia or abruption.


InterventionsBetamethasone group (n = 120)

2 IM injections of 12 mg betamethasone sodium at 24-hour intervals.

Dexamethasone group (n = 120) 

4 IM injections of 6 mg dexamethasone phosphate at 12-hour intervals.


OutcomesInfant:

Fetal plasma glucose; Apgar scores (1 minute and 5 minute); NICU stay.

Mother:

Maternal WBC and differential count; ESR; maternal fasting plasma glucose; length of admission to birth; preterm birth; gestational age at birth.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: “women were randomised with a list of computer-generated numbers".

Allocation concealment (selection bias)Low riskGroup assignments were concealed in an opaque sealed envelope until just before entry into the study. It was not stated whether the envelopes were consecutively numbered.

Blinding of participants and personnel (performance bias)
All outcomes
High riskQuote: "due to the different injection frequency and treatment period of dexamethasone and betamethasone, it was not possible to ensure patients were blinded".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear, not reported.

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "all 240 women who completed treatment were available for follow-up at delivery". It was assumed that there was no attrition nor were there any exclusions.

Selective reporting (reporting bias)Unclear riskWith no access to a trial protocol, the review authors cannot confidently assess selective reporting. In regards to NICU admission, it is unclear as to whether the values in the table represents all admissions, or only those due to RDS (the text suggests it represents only those due to RDS). In regards to adverse events, data is not reported, quote "Both, dexamethasone and betamethasone treatment was tolerated well and most of the adverse events reported were mild in severity".

Other biasLow riskThe study appears to be free of other sources of bias. Groups were comparable at baseline.

Egerman 1998

MethodsRandomised controlled trial.


Participants170 women randomised.

Setting: Tennessee, USA (from July 1996 to July 2007).

Inclusion criteria: preterm birth between 24 to 33 weeks' gestation, preterm labour, preterm rupture of membranes, medical indication for delivery.

Exclusion criteria: received corticosteroids during the pregnancy (except immediately before transfer), anticonvulsant therapy, rifampin, infection other than cystitis or cervicitis, advanced cervical dilatation, fetal pulmonary maturity.


InterventionsOral dexamethasone group (n = 92 women; 99 infants)

32 mg oral dexamethasone: 4 x 8 mg, 12 hourly.

IV dexamethasone group (n = 78 women; 84 infants)
24 mg IM dexamethasone: 4 x 6 mg IM, 12 hourly.

Repeated weekly until 34 weeks' gestation if birth had not yet occurred.


OutcomesInfant:
Death; RDS; IVH; birthweight; sepsis; NEC; gestational age at birth.

Mother:
Gestational age at entry (weeks); dilatation (cm); latency; caesarean birth; antibiotic use.


NotesThe study was discontinued at 39% enrolment (170 women) after a blinded review of available outcomes.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were randomly assigned by computer-generated numbers (placed in sealed envelopes).

Allocation concealment (selection bias)Unclear riskSealed envelopes were used; no further details provided.

Blinding of participants and personnel (performance bias)
All outcomes
High riskDue to the nature of the intervention, it is considered unlikely that participants and personnel were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAn investigator not involved in recruitment or patient care performed the analysis.

Incomplete outcome data (attrition bias)
All outcomes
Low risk5/170 (3%) women were unavailable for follow-up.

Selective reporting (reporting bias)Unclear riskWhile the pre-specified primary and secondary outcomes from the methods were reported, no protocol was available to assess selective reporting, and furthermore, clinical outcomes were reported incompletely, for example quote "No differences in Apgar scores at 1 and at 5 minutes were noted between the oral and intramuscular groups".

Other biasLow riskNo other obvious sources of bias identified. Groups were comparable at baseline.

Elimian 2007

MethodsRandomised controlled trial.


Participants299 women randomised.
Setting: Stony Brook University Hospital, New York, USA (from August 2002 to July 2004).

Inclusion criteria: risk of preterm birth between 24 to 33 weeks' gestation.
Exclusion criteria: clinical chorioamnionitis, major fetal structural abnormalities, major fetal chromosomal abnormalities, prior antenatal corticosteroid exposure, use of betamethasone or dexamethasone for other medical indications and quadruplets.


InterventionsDexamethasone group (n = 149 women; 178 infants)

24 mg dexamethasone: 4 x 6 mg doses of dexamethasone IM 12 hours apart.

Betamethasone group (n = 150 women; 181 infants).
24 mg betamethasone: 2 x 12 mg doses of betamethasone IM 24 hours apart (placebo 2 doses given at 12-hour intervals).


OutcomesInfant:
Death; IVH (diagnosed by ultrasound, diagnosed by autopsy); RDS; PVL; birthweight; BPD; NEC; neonatal sepsis; surfactant use; ROP; neonatal blood pressure; need for inotropic support; mean duration of inotropic support (days); PDA; need for a vasopressor.

Women:
Chorioamnionitis; fever after trial entry requiring the use of antibiotics; intrapartum fever requiring the use of antibiotics.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated random numbers were used.

Allocation concealment (selection bias)Low riskAllocation was conducted by pharmacy.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and health care providers were reported as being blind. Syringes were covered with "opaque material". A placebo was used to ensure that the regimens for administration did not differ.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors were blind to group assignment.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo loss to follow-up; however only 105/178 infants in the dexamethasone group and 100/181 in the betamethasone group were assessed for IVH and PVL.

Selective reporting (reporting bias)Low riskData for all pre-specified outcomes (from the methods) and many of the expected outcomes were reported.

Other biasLow riskGroups were comparable at baseline. The study appears to be free of other sources of bias.

Khandelwal 2012

MethodsRandomised controlled trial.


Participants228 mothers, 260 fetuses were randomised.

Setting: Cooper University Hospital, Camden, New Jersey, USA (from July 2006 to May 2009).

Inclusion criteria: steroids administered for any indication between 23 to 34 weeks. gestation

Exclusion criteria: < 23 or > 34 weeks' gestation; elapsed time > 12 hours since administration of the first dose of betamethasone; known drug allergy to betamethasone; given steroids other than betamethasone for lung maturation; any contraindication to steroid therapy were excluded.


Interventions12 hourly group (n = 161 women; 180 fetuses)

24 mg betamethasone: 2 x 12 mg doses, 12 hourly.

24 hourly group (n = 67 women; 80 fetuses)

24 mg betamethasone: 2 x 12 mg doses; 24 hourly.

No rescue steroid doses were offered in this trial.


OutcomesFor the fetus/neonate:

Death (fetal/neonatal); RDS; neonatal sepsis; antibiotic use; admission to NICU; mean birthweight; mode of delivery LUSCS; SGA; NEC; ROP; IVH; CLD.

For the mother: 

Maternal fever; maternal postpartum length of stay.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskParticipants were allocated into four groups stratified by 3 gestational age categories:

Group A: 23.1 to 26.0 weeks;

Group B: 26.1 to 29.0 weeks;

Group C: 29.1 to 32.0 weeks;

Group D: 32.1 to 34.0 weeks.

The participants in each group were randomly assigned to either the 12-hour arm or 24-hour arm. Randomisation sequence was generated in Excel using its 'random function' in 4 groups of 50 each. Randomisation was performed in 2:1 ratio (for 12:24-hour dosing interval).

Allocation concealment (selection bias)Low riskStudy assignments placed in sealed opaque envelopes with a study number and group number on each envelope.

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and personnel were not blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors were blinded; neonatologists were informed if women received steroids and whether 1 or 2 doses, but not informed of the dosing interval.

Incomplete outcome data (attrition bias)
All outcomes
Low risk7 infants 3% (7/260) were lost to follow-up: incomplete information was available for 4 neonates in the 12-hour dosing group and 3 in the 24-hour dosing group (7/260: 3%).

Selective reporting (reporting bias)Low riskOutcome data for all pre-specified outcomes (from the methods and trial registration) were reported.

Other biasUnclear riskThere were some baseline imbalances between groups: approximately 70% (161/228 mothers; 180/260 fetuses) were assigned to the 12-hour arm and only 30% (67/228 mothers; 80/260 fetuses) were assigned to the 24-hour arm.

Women in the 24-hour arm were about 2 years older than in the 12-hour arm; In the 24-hour cohort, there were more African American women at risk for delivery 26 weeks and more Caucasians at risk in the 32 to 34 week group.

Magee 1997

MethodsRandomised controlled trial.


Participants59 women were randomised.

Setting: John Radcliffe Hospital, Oxford, UK (from April 1995 to March 1996).

Inclusion criteria: women with singleton pregnancies at risk of birth between 26 to 34 weeks' gestation inclusive, who had not received steroids in the preceding week.


InterventionsDexamethasone group (n = 29)

24 mg dexamethasone: 2 x 12 mg IM; 12 hourly.

Betamethasone group (n = 29)
24 mg betamethasone: 2 x 12 mg IM; 12 hourly.


OutcomesInfant:
Biophysical parameters (day 0, 1, 2); FHR; LTV/STV; number of movements/hour; number of accelerations; number of decelerations; Apgar score at 5 mins; caesarean birth.


NotesFunding source not mentioned.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom number table was used to generate the random sequence.

Allocation concealment (selection bias)Low riskConsecutively numbered, sealed, opaque envelopes were used. The IM vials were labelled by the hospital pharmacy with A or B.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipant and clinicians were blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskData were analysed in "a blinded fashion".

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up: > 20% in total: 1/30 post-randomisation exclusion in the betamethasone group (a woman with a twin pregnancy was enrolled in error); then 9/29 losses from the betamethasone group at day 2 (1 transfer, 3 early births, 5 early discharges); 7/29 losses from the dexamethasone group (1 self-discharge, 3 early births, 3 early discharges).

Selective reporting (reporting bias)Unclear riskThe trial focused on the effects of steroids on FHR, and very few clinical outcomes were reported. With no access to a trial protocol it is difficult to assess selective reporting.

Other biasLow riskThe study appears to be free of other sources of bias. Groups were comparable at baseline.

Mulder 1997

MethodsRandomised controlled trial.


Participants60 women were randomised.

Setting: University Hospital, Utrecht, The Netherlands.

Inclusion criteria: women with premature contractions or at risk of preterm labour, between 26 to 33 weeks' gestation, SGA (estimated fetal size < 5th centile), premature contractions, placenta praevia or other cause of vaginal blood loss, preterm rupture of membranes without evidence of intrauterine infection, pre-eclampsia, essential hypertension, poor obstetrical history, or leiomyoma.

Exclusion criteria: cervical dilatation > 5 cm, signs of intrauterine infection, ritodrine hydrochloride treatment for < 4 days at the start of the study.


InterventionsDexamethasone group (n = 24)
24 mg dexamethasone: 2 x 12 mg IM, 12 hourly.

Betamethasone group (n = 26)
24 mg betamethasone: 2 x 12 mg IM, 24 hourly.


OutcomesInfant:
Birthweight; biophysical parameters - FHR, LTV/STV, breathing movement, breathing bout length, number of breaths, breath-to-breath interval, body movement incidence, body movement number of bursts, body movement burst length; Apgar score less than 7 at 5 mins; mode of birth.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "eligible women were randomised (sealed envelope method)". No further detail provided.

Allocation concealment (selection bias)Unclear riskAs above.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear, not reported; however considered unlikely in view of the intervention (12-hourly dexamethasone versus 24-hourly betamethasone).

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear, not reported.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk17%; 6 of 30 from the dexamethasone group and 4 of 30 from the betamethasone group were lost to follow-up.

Selective reporting (reporting bias)Unclear riskThe trial focused on the effects of steroids on FHR and behaviour and clinical outcomes were not reported. With no access to a trial protocol it is difficult to assess selective reporting.

Other biasLow riskThe study appears to be free of other sources of bias. Groups were comparable at baseline.

Mushkat 2001

MethodsQuasi-randomised controlled trial.


Participants33 women were randomised.

Setting: Israel.

Inclusion criteria: women with preterm labour between 26 to 33 weeks' gestation.
Exclusion criteria: chronic or acute hypertension, gestational diabetes, vaginal bleeding due to placenta praevia or abruption placenta, IUGR, fetal distress.


InterventionsDexamethasone group (n = 16)
24 mg dexamethasone: 2 x 12 mg IM, 12 hourly.

Betamethasone group (n = 17)
24 mg betamethasone: 12 mg betamethasone sodium and 12 mg betamethasone acetate IM, divided into 2 doses 12 hours apart.


OutcomesInfant:
Biophysical parameters (0, 6, 12, 18, 36 hours): maternal perception of fetal movements, body movement, breathing movements; gestational age.


NotesFunding source not documented.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe participants were randomly assigned to 2 groups according to computer-generated randomisation schedule.

Allocation concealment (selection bias)High riskQuasi-randomised design "each consecutive candidate got an even or an uneven number drawn out of performed random computer-generated list. Even numbers were assigned to betamethasone treatment, while uneven numbers were assigned to dexamethasone treatment".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and clinicians were blinded, with treatment regimens being similar, and both drugs being "identical in appearance".

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskWhile the study was described as "double blind" it was not made clear as to whether outcome assessment was performed blind.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were unclear.

Selective reporting (reporting bias)Unclear riskWhile the trial focused on fetal biophysical parameters, it also reported a number of clinical outcomes incompletely, example: "gestational age, birthweight and Agpar score at 5 min did not differ between the 2 groups".

Other biasLow riskGroups were comparable at baseline for age, parity and gestational age. The study appears to be free of other sources of bias.

Rotmensch 1999

MethodsRandomised controlled trial.


Participants46 women were randomised.

Setting: Israel and Italy (from June 1995 to March 1997).

Inclusion criteria: women with preterm birth at 27 to 34 weeks' gestation, preterm premature rupture of membranes with no clinical evidence of infection, pregnancy-induced hypertension syndromes, IUGR, third trimester bleeding due to placenta praevia.


InterventionsDexamethasone group (n = 24)
24 mg dexamethasone: 2 x 12 mg IM, 24 hourly.

Betamethasone group (n = 22)
24 mg betamethasone: 2 x 12 mg IM, 24 hourly.


OutcomesInfant:
Birthweight; biophysical parameters (0, 2 ,4 days): FHR, acceleration > 10 bpm, deceleration > 10 bpm, LTV/STV, breathing time (sec in 30 mins), movement in 30 mins.


NotesFunding source not documented.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised by "computer-generated randomisation tables".

Allocation concealment (selection bias)Unclear riskUnclear, details were not reported.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUnclear if participants were blinded. "Examiners were blinded to the administered drugs."

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above; unclear if outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAttrition or exclusions were not documented.

Selective reporting (reporting bias)Unclear riskThe trial focused on the effects of steroids on FHR and biophysical activities and clinical outcomes were not reported. With no access to a trial protocol it is difficult to assess selective reporting.

Other biasLow riskGroups were comparable at baseline.The study appears to be free of other sources of bias.

Senat 1998

MethodsRandomised controlled trial.


Participants82 women were randomised.

Setting: Clamart, France (between October 1994 to October 1995).

Inclusion criteria: women with preterm labour < 34 weeks' gestation.

Exclusion criteria: uncertain pregnancy history, clinical infection in women, vaginal bleeding, suspicion of premature rupture of membranes.


InterventionsDexamethasone group (n = 40 women, 44 babies - 39 babies analysed)
16 mg dexamethasone: 4 x 4 mg IM, 12 hourly.

Betamethasone group (n = 42 women, 53 babies - 42 babies analysed).
24 mg betamethasone: 4 x 3 mg betamethasone sodium and 3 mg betamethasone acetate IM, 12 hourly.


OutcomesInfant:
Death; RDS; IVH; PVL; birthweight; NEC; biophysical parameters (0, 24-48 hours, 4-7 days): FHR, LTV/STV, high/low variation, acceleration > 10 bpm; deceleration > 10 bpm; uterine contractions; gestational age; CTG.


NotesIn the case of multiple pregnancy, one fetus was randomly selected for analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA table of random numbers was used.

Allocation concealment (selection bias)Unclear riskThe table of random numbers was "held by an independent investigator. " Women were allocated to either one of two different corticosteroid regiments in a "non blinded fashion."

Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and clinicians were not blinded.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskUnclear if outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk1 neonate from the dexamethasone group died; this case was excluded from the study and statistics were therefore derived from the analysis of 39 pregnancies.

Selective reporting (reporting bias)Unclear riskThe trial focused on the effects of steroids on FHR variability in preterm labour; while some clinical outcomes were reported in addition, with no access to a trial protocol it is difficult to assess selective reporting.

Other biasUnclear riskIn the case of multiple pregnancy, one fetus was randomly selected for analysis.

Subtil 2003

MethodsRandomised controlled trial.


Participants105 women were randomised.

Setting: Lille, France (from November 1997 to February 1999).

Inclusion criteria: women at high risk of preterm birth, recruited at 27 to 35 weeks' gestation, with singleton pregnancies.

Exclusion criteria: imminent birth, multiple pregnancy, previously participated in the protocol, received corticosteroid therapy < 10 days prior.


InterventionsBetamethasone acetate and phosphate group (n = 35)
24 mg betamethasone acetate and phosphate: 2 x 12 mg IM, 24 hourly.

Betamethasone phosphate group (n = 34)
24 mg betamethasone phosphate: 4 x 6 mg IM, 12 hourly.

Dexamethasone phosphate group (n = 36)

24mg dexamethasone phosphate: 4 x 6 mg IM, 12 hourly.


OutcomesInfant:
Death; RDS; BPD; IVH (grade 1 and 2); severe IVH (grade 3 and 4); hyperechoic > 10 days; PVL; birthweight; NICU admission; GA at delivery; biophysical parameters: duration of tracing; STV/LTV; FHR; acceleration/deceleration number per hr; movement number per hr.
For the child (18 months):
Neurodevelopmental disability at follow-up.

Other:

Tests of the specific drug effect, time effect, and interaction by analysis of variance.


NotesFunding source not mentioned.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA random number table was used.

Allocation concealment (selection bias)Unclear riskWomen were allocated randomly to treatment groups through a "system of envelopes" that had been numbered from 1 to 105. The randomisation was performed with a random number table, by random distribution of the 3 formulations.

Blinding of participants and personnel (performance bias)
All outcomes
High riskThe midwives and participants were not blinded. The manuscript details that physicians were blinded, however it is unclear as to whether this would have been successfully achieved, quote "physicians were blinded to the product; both midwives and patients were instructed that no physician was to be informed of the rhythm of injections or of the product that was being administered".

Blinding of outcome assessment (detection bias)
All outcomes
High riskOutcome assessment was not blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskHigh numbers lost to follow-up for FHR (due to discharge and birth): none at day 0; 1 of 105 (1%) at day 1; 16 (15%) at day 2, 44 (42%) at day 3; and 57 (54%) at day 4 (due to discharge and birth). The percentage of missing recordings for the relevant time period averaged 8.6% and remained stable from day 0 through to day 4. The percentage of women who went home or gave birth before day 4 (and were lost to follow-up) did not differ significantly between groups.

Selective reporting (reporting bias)Low riskWhile this trial focused on the effects of steroids on FHR, the manuscript also reports the pre-specified and expected clinical outcomes.

Other biasLow riskGroups were comparable at baseline. The study appears to be free of other sources of bias.

Urban 2005

MethodsRandomised controlled trial.


Participants67 women were randomised.

Setting: Medical Academy of Bialystok, Poland.

Inclusion criteria: preterm contractions of the uterus, preterm premature rupture of membranes, cervical length less than 20 mm, placenta praevia before 34 weeks, singleton pregnancy.

Exclusion criteria: fetal major structural malformations or abnormal karyotype.


InterventionsDexamethasone group (n = 34)
24 mg dexamethasone: 4 x 6 mg IM, 12 hourly.

Betamethasone group (n = 33)
24 mg betamethasone: 2 x 12 mg IM, 24 hourly.


OutcomesInfant:
Birthweight; UA PI; MCA PI; abnormal FHR patterns (at 0, 24 and 72 hours); Apgar score at 1 and 5 minutes; umbilical cord artery pH; base deficit.


NotesFunding sources not mentioned.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated randomisation table was used.

Allocation concealment (selection bias)Low risk"Consecutively numbered and sealed opaque envelopes" were used.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding not stated; considered unlikely for participants and personnel in view of the different timings of administration of the dexamethasone versus betamethasone.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessors was not detailed.

Incomplete outcome data (attrition bias)
All outcomes
Low riskIt was assumed that there were no exclusions or attrition.

Selective reporting (reporting bias)Unclear riskThe trial focused on the effects of steroids on fetal Doppler flow velocity waveforms; while some important clinical outcomes were reported in addition, with no access to a trial protocol it is difficult to assess selective reporting.

Other biasLow riskThe study appears to be free of other sources of bias. The groups were comparable at baseline for maternal age and gestational age.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Egerman 1997Assessed bioavailability of dexamethasone post oral or IM administration; parallel cross-over trial.

Kurz 1993L-carnitine was added to betamethasone and compared against betamethasone alone to assess the effect it had on RDS.

Liu 2006Vitamin K was added to dexamethasone and compared with dexamethasone injection alone, vitamin K injection alone or no treatment to determine which treatment was most effective in reducing the incidence of IVH.

Romaguera 1997Intra-amniotic thyroxine and intramuscular betamethasone versus betamethasone alone to assess the effect it had on maturity.

Salzer 1982Carnitine and dexamethasone versus dexamethasone to assess the effect it had on lung maturity.

Shanks 2010Corticosteroids (either betamethasone or dexamethasone) were compared with placebo.

Vytiska 1985Carnitine and betamethasone versus betamethasone to assess the effects on RDS prophylaxis.

Whitt 1976Trial not randomised.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Romejko-Wolniewicz 2013

MethodsRandomised controlled trial.

Participants121 women who gave birth by gestational week 35 and within 7 days after the completion of a full course of steroid treatment (24 mg).

Interventions6 4 mg doses of betamethasone every 8 hours was compared with 2 12 mg doses of betamethasone separated by 24 hours.

OutcomesMaternal rheological parameters and C-reactive protein concentrations; leucocyte blood counts; gestational age; method of delivery; neonatal birthweight, status, and complications.

NotesRandomisation unclear: "The dosage regimen was chosen in a randomized manner"; awaiting contract from trialists.

 
Characteristics of ongoing studies [ordered by study ID]
Crowther 2010

Trial name or titleAustralasian Antenatal Study To Evaluate the Role of Intramuscular Dexamethasone versus Betamethasone prior to preterm birth to increase survival free of childhood neurosensory disability- a randomised controlled trial (A*STEROID).

MethodsThe randomised schedule will use balanced variable blocks and will be created using computer software (computerised sequence generation) by researchers not involved in clinical care. Assignment to either group will be stratified for collaborating centre, gestational age (< 28 weeks, > 28 weeks' gestation), and number of fetuses (1 or 2).

ParticipantsWomen at risk of preterm birth at less than 34 weeks' gestation, who have a singleton or twin pregnancy, have no contraindications to the use of antenatal corticosteroids and give informed consent.

InterventionsIntervention:

Dexamethasone (antenatal corticosteroid),

2 syringes of 12 mg dexamethasone sodium phosphate- a non-sulphite containing preparation

Administered as 2 intramuscular injections, 24 hours apart.

Control:

Betamethasone (antenatal corticosteroid),

2 syringes of 11.4mg betamethasone (as Clestone Chronodose 11.4 mg)

Administered as 2 intramuscular injections, 24 hours apart.

OutcomesPrimary outcome:

Composite of incidence of death (defined as stillbirths, deaths from live born infants before and after hospital discharge) or any neurosensory disability in the children (includes cerebral palsy, blindness, deafness and any developmental delay defined as a standardised score more than 1 SD below the mean (< -1 SD).

Secondary outcomes:

Neonatal outcomes:

IVH; severe IVH; PVL; ROP requiring treatment; PDA requiring treatment; use of inotropes; RDS; Severity of any neonatal lung disease; CLD; use of mechanical ventilation; confirmed infection within the first 48 hours; infection after the first 48 hours; birthweight.

Childhood outcomes:

Developmental domains as measured by Ages & Stages Questionnaire; body size; general health (including use of health services since primary hospitalisation; childhood respiratory morbidity; blood pressure z scores and proportions in hypertensive ranges and behaviour.

Maternal outcomes:

Maternal perinatal infectious morbidity (defined as clinical chorioamnionitis requiring intrapartum antibiotics, use of postpartum antibiotics).

Starting date1/12/2008

Contact informationProfessor Caroline Crowther

Australian Research Centre for Health of Women and Babies (ARCH)

Discipline of Obstetrics and Gynaecology

The University of Adelaide

Women's and children's Hospital

King William Road

North Adelaide

South Australia 5006

Australia

Tel: +61 8 8161 7747

Fax: +61 8 8161 7652

Notes

 
Comparison 1. Dexamethasone versus betamethasone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal death4596Risk Ratio (M-H, Fixed, 95% CI)1.41 [0.54, 3.67]

    1.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
2464Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.38, 3.33]

    1.2 Dexamethasone (16 mg - 4 x 4 mg; 12 hourly) v betamethasone (24 mg - 4 x 6 mg; 12 hourly)
182Risk Ratio (M-H, Fixed, 95% CI)3.15 [0.13, 75.05]

    1.3 Dexamethasone (24 mg - 2 x 12 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
150Risk Ratio (M-H, Fixed, 95% CI)3.24 [0.14, 75.91]

 2 Respiratory distress syndrome5753Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.88, 1.27]

    2.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
3621Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.89, 1.30]

    2.2 Dexamethasone (16 mg - 4 x 4 mg; 12 hourly) v betamethasone (24 mg - 4 x 6 mg; 12 hourly)
182Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.01, 8.34]

    2.3 Dexamethasone (24 mg - 2 x 12 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
150Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.02, 8.43]

 3 Intraventricular haemorrhage4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Intraventricular haemorrhage (any dose)
4549Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.21, 0.92]

    3.2 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
3467Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.21, 0.92]

    3.3 Dexamethasone (16 mg - 4 x 4 mg; 12 hourly) v betamethasone (24 mg - 4 x 6 mg; 12 hourly)
182Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Neurosensory disability as a child (18 months)112Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.08, 33.75]

    4.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
112Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.08, 33.75]

 5 Apgar score < 7 at 5 minutes2207Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.43, 2.18]

    5.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
1157Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.45, 2.54]

    5.2 Dexamethasone (24 mg - 2 x 12 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
150Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.05, 5.60]

 6 Apgar score at 5 minutes2307Mean Difference (IV, Random, 95% CI)0.23 [-0.23, 0.70]

    6.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
167Mean Difference (IV, Random, 95% CI)-0.20 [-0.89, 0.49]

    6.2 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); intact membranes
1120Mean Difference (IV, Random, 95% CI)0.60 [0.26, 0.94]

    6.3 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); ruptured membranes
1120Mean Difference (IV, Random, 95% CI)0.10 [-0.37, 0.57]

 7 Apgar score at 5 minutesOther dataNo numeric data

 8 Birthweight (kg)5734Mean Difference (IV, Fixed, 95% CI)0.01 [-0.11, 0.12]

    8.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
5734Mean Difference (IV, Fixed, 95% CI)0.01 [-0.11, 0.12]

 9 Birthweight (kg)Other dataNo numeric data

 10 Low birthweight1105Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.65, 1.24]

    10.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
1105Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.65, 1.24]

 11 Head circumference (cm)1157Mean Difference (IV, Fixed, 95% CI)-0.5 [-1.55, 0.55]

    11.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
1157Mean Difference (IV, Fixed, 95% CI)-0.5 [-1.55, 0.55]

 12 Neonatal intensive care unit admission2345Risk Ratio (M-H, Random, 95% CI)1.72 [0.44, 6.72]

    12.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
2345Risk Ratio (M-H, Random, 95% CI)1.72 [0.44, 6.72]

 13 Vasopressor use1359Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.17, 1.11]

    13.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
1359Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.17, 1.11]

 14 Bronchopulmonary dysplasia2464Risk Ratio (M-H, Random, 95% CI)2.50 [0.10, 61.34]

    14.1 Dexamethasone (24 mg - 4 x 6 mg, 12 hourly) v betamethasone (24 mg - 2 x 12 mg, 24 hourly)
2464Risk Ratio (M-H, Random, 95% CI)2.50 [0.10, 61.34]

 15 Severe intraventricular haemorrhage4549Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.13, 1.24]

    15.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
3467Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.13, 1.24]

    15.2 Dexamethasone (16 mg - 4 x 4 mg; 12 hourly) v betamethasone (24 mg - 4 x 6 mg; 12 hourly)
182Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 16 Periventricular leukomalacia4703Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.23, 3.03]

    16.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
3621Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.23, 3.03]

    16.2 Dexamethasone (16 mg - 4 x 4 mg; 12 hourly) v betamethasone (24 mg - 4 x 6 mg; 12 hourly)
182Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 17 Neonatal sepsis2516Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.78, 2.19]

    17.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
2516Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.78, 2.19]

 18 Necrotising enterocolitis3598Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.38, 4.40]

    18.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
2516Risk Ratio (M-H, Fixed, 95% CI)1.29 [0.38, 4.40]

    18.2 Dexamethasone (16 mg - 4 x 4 mg; 12 hourly) v betamethasone (24 mg - 4 x 6 mg; 12 hourly)
182Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 19 Retinopathy of prematurity2516Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.59, 1.47]

    19.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
2516Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.59, 1.47]

 20 Patent ductus arteriosus1359Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.56, 2.49]

    20.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
1359Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.56, 2.49]

 21 Fetal heart rate, bpm (day 2)146Mean Difference (IV, Fixed, 95% CI)-4.20 [-7.17, -1.23]

    21.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
146Mean Difference (IV, Fixed, 95% CI)-4.20 [-7.17, -1.23]

 22 Fetal heart rate (day 2)Other dataNo numeric data

 23 Accelerations per hour146Mean Difference (IV, Fixed, 95% CI)2.80 [-0.15, 5.75]

    23.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg, 24 hourly)
146Mean Difference (IV, Fixed, 95% CI)2.80 [-0.15, 5.75]

 24 Accelerations per hourOther dataNo numeric data

 25 Fetal movements in 30 minutes146Mean Difference (IV, Fixed, 95% CI)2.3 [-0.74, 5.34]

    25.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
146Mean Difference (IV, Fixed, 95% CI)2.3 [-0.74, 5.34]

 26 Fetal movements per hour (maternal perception)133Mean Difference (IV, Fixed, 95% CI)3.0 [-3.20, 9.20]

    26.1 Dexamethasone (24 mg - 2 x 12 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 12 hourly)
133Mean Difference (IV, Fixed, 95% CI)3.0 [-3.20, 9.20]

 27 Fetal movements per hour (ultrasound)133Mean Difference (IV, Fixed, 95% CI)7.00 [2.15, 11.85]

    27.1 Dexamethasone (24 mg - 2 x 12 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 12 hourly)
133Mean Difference (IV, Fixed, 95% CI)7.00 [2.15, 11.85]

 28 Fetal movements per hourOther dataNo numeric data

 29 Fetal breathing movements per hour133Mean Difference (IV, Fixed, 95% CI)0.0 [-2.05, 2.05]

    29.1 Dexamethasone (24 mg - 2 x 12 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 12 hourly)
133Mean Difference (IV, Fixed, 95% CI)0.0 [-2.05, 2.05]

 30 Duration of breathing time at 2 days (seconds in 30 minutes)146Mean Difference (IV, Fixed, 95% CI)32.0 [4.37, 59.63]

    30.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly)
146Mean Difference (IV, Fixed, 95% CI)32.0 [4.37, 59.63]

 31 Length of admission to birth (days)1240Mean Difference (IV, Random, 95% CI)3.48 [-3.38, 10.34]

    31.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); intact membranes
1120Mean Difference (IV, Random, 95% CI)7.0 [5.56, 8.44]

    31.2 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); ruptured membranes
1120Mean Difference (IV, Random, 95% CI)0.0 [-0.99, 0.99]

 32 Neonatal intensive care unit stay (days)170Mean Difference (IV, Fixed, 95% CI)-0.91 [-1.77, -0.05]

    32.1 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); intact membranes
121Mean Difference (IV, Fixed, 95% CI)-2.2 [-4.52, 0.12]

    32.2 Dexamethasone (24 mg - 4 x 6 mg; 12 hourly) v betamethasone (24 mg - 2 x 12 mg; 24 hourly); ruptured membranes
149Mean Difference (IV, Fixed, 95% CI)-0.70 [-1.63, 0.23]

 
Analysis 1.7 Comparison 1 Dexamethasone versus betamethasone, Outcome 7 Apgar score at 5 minutes.
Apgar score at 5 minutes

StudyDexamethasoneBetamethasone

Magee 199724 mg - 2 x 12 mg; 12 hourly24 mg - 2 x 12 mg; 12 hourly

Magee 1997median 10: IQR 8.8 to 10 (n = 22)median 10: IQR 10 to 10 (n = 20)

 
Analysis 1.9 Comparison 1 Dexamethasone versus betamethasone, Outcome 9 Birthweight (kg).
Birthweight (kg)

StudyDexamethasoneBetamethasone

Magee 199724 mg - 2 x 12 mg; 12 hourly24 mg - 2 x 12 mg; 12 hourly

Magee 1997median 1.843 IQR 1.211 to 3.363 (n = 20)median 2.001 IQR 1.150 to 3.121 (n = 22)

Mulder 199724 mg - 2 x 12 mg; 12 hourly24 mg - 2 x 12 mg; 24 hourly

Mulder 1997median 2.02 IQR 0.75 to 3.5 (n = 24)median 1.79 IQR 0.84 to 3.75 (n = 26)

Senat 199816 mg - 4 x 4 mg; 12 hourly24 mg - 4 x 6 mg; 12 hourly

Senat 1998median 2.55 IQR 1.13 to 3.91 (n = 40)median 2.5 IQR 0.98 to 3.84 (n = 42)

 
Analysis 1.22 Comparison 1 Dexamethasone versus betamethasone, Outcome 22 Fetal heart rate (day 2).
Fetal heart rate (day 2)

StudyDexamethasoneBetamethasonep-value

Magee 199724 mg - 2 x 12 mg; 12 hourly24 mg - 2 x 12 mg; 12 hourly

Magee 1997median change from baseline (bpm) 1.5: IQR -5.9 to 9.0 (n=22)median change from baseline (bpm) -2.0: IQR -6.0 to 5.0 (n=20)pns

Senat 199816 mg - 4 x 4 mg; 12 hourly24 mg - 4 x 6 mg; 12 hourly

Senat 1998median bpm 142 IQR 137 to 149 (n=40)median bpm 147 IQR 141 to 154 (n=42)p=0.01 (for change data)

 
Analysis 1.24 Comparison 1 Dexamethasone versus betamethasone, Outcome 24 Accelerations per hour.
Accelerations per hour

StudyDexamethasoneBetamethasone

Magee 199724 mg - 2 x 12 mg; 12 hourly24 mg - 2 x 12 mg, 12 hourly

Magee 1997median change -1.0 IQR -4.0 to 0 (n=22)median change 0.5 IQR -2.5 to 2.5 (n=20)

Senat 199816 mg - 4 x 4 mg; 12 hourly24 mg - 4 x 6 mg; 12 hourly

Senat 1998median 5.0 IQR 2.2 to 10 (n=40)median 7.0 IQR 3.0 to 10 (n=42)

 
Analysis 1.28 Comparison 1 Dexamethasone versus betamethasone, Outcome 28 Fetal movements per hour.
Fetal movements per hour

StudyDexamethasoneBetamethasone

Magee 199724 mg - 2 x 12 mg; 12 hourly24 mg - 2 x 12 mg; 12 hourly

Magee 1997median 2.5 IQR -27.0 to 32.0 (n=22)median 4.0 IQR -15.0 to 18.5 (n=20)

 
Comparison 2. Dexamethasone: oral versus intramuscular

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)
1183Risk Ratio (M-H, Fixed, 95% CI)1.48 [0.45, 4.90]

    1.2 < 34 weeks' gestation
1125Risk Ratio (M-H, Fixed, 95% CI)1.72 [0.53, 5.59]

 2 Respiratory distress syndrome1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)
1183Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.75, 1.77]

    2.2 < 34 weeks' gestation
1125Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.85, 1.86]

 3 Intraventricular haemorrhage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)
1183Risk Ratio (M-H, Fixed, 95% CI)4.24 [0.96, 18.83]

    3.2 < 34 weeks' gestation
1125Risk Ratio (M-H, Fixed, 95% CI)4.92 [1.12, 21.55]

 4 Birthweight (kg)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    4.1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)
1183Mean Difference (IV, Fixed, 95% CI)0.05 [-0.17, 0.27]

 5 Neonatal sepsis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)
1183Risk Ratio (M-H, Fixed, 95% CI)8.48 [1.11, 64.93]

    5.2 < 34 weeks' gestation
1125Risk Ratio (M-H, Fixed, 95% CI)9.84 [1.30, 74.60]

 6 Necrotising enterocolitis1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Dexamethasone: oral (32 mg - 4 x 8 mg, 12 hourly) v IM (24 mg - 4 x 6 mg, 12 hourly)
1183Risk Ratio (M-H, Fixed, 95% CI)5.09 [0.63, 41.45]

    6.2 < 34 weeks' gestation
1125Risk Ratio (M-H, Fixed, 95% CI)4.92 [0.59, 40.92]

 
Comparison 3. Betamethasone acetate + phosphate versus betamethasone phosphate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Neonatal death169Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.69]

    1.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.69]

 2 Respiratory distress syndrome169Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.01, 3.91]

    2.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.01, 3.91]

 3 Intraventricular haemorrhage169Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.69]

    3.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.32 [0.01, 7.69]

 4 Neurodevelopmental disability169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Birthweight (kg)169Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.44, 0.24]

    5.1 beta a+p (2 x 12 mg, 24hrly) and beta p (4 x 6 mg,12hrly)
169Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.44, 0.24]

 6 Low birthweight169Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.86, 1.72]

    6.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.86, 1.72]

 7 Neonatal intensive care unit admission169Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.93]

    7.1 24 mg beta a+p (2 x 12 mg, 24 hourly) x 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.93]

 8 Bronchopulmonary dysplasia169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    8.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Periventricular leukomalacia169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    9.1 24 mg beta a+p (2 x 12 mg, 24 hourly) v 24 mg beta p (4 x 6 mg, 12 hourly)
169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. Betamethasone 12 hour versus 24 hour dosing

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perinatal death1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1255Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.46, 1.87]

    1.2 23+1 to 26+0 weeks at trial entry
156Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.43, 1.50]

    1.3 26+1 to 29+0 weeks at trial entry
143Risk Ratio (M-H, Fixed, 95% CI)1.93 [0.24, 15.71]

    1.4 29+1 to 32+0 weeks at trial entry
181Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.06, 34.35]

    1.5 32+1 to 34+0 weeks at trial entry
175Risk Ratio (M-H, Fixed, 95% CI)1.75 [0.09, 35.00]

 2 Respiratory distress syndrome1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1242Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.69, 1.40]

    2.2 23+1 to 26+0 weeks at trial entry
149Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.69, 0.99]

    2.3 26+1 to 29+0 weeks at trial entry
140Risk Ratio (M-H, Fixed, 95% CI)2.73 [0.97, 7.67]

    2.4 29+1 to 32+0 weeks at trial entry
181Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.43, 2.06]

    2.5 32+1 to 34+0 weeks at trial entry
172Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.17, 12.04]

 3 Intraventricular hemorrhage1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1135Risk Ratio (M-H, Fixed, 95% CI)1.40 [0.76, 2.56]

    3.2 23+1 to 26+0 weeks at trial entry
138Risk Ratio (M-H, Fixed, 95% CI)1.57 [0.76, 3.24]

    3.3 26+1 to 32+0 weeks at trial entry
131Risk Ratio (M-H, Fixed, 95% CI)3.27 [0.48, 22.52]

    3.4 29+1 to 32+0 weeks at trial entry
145Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.29, 3.45]

    3.5 32+1 to 34+0 weeks at trial entry
121Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.02, 4.14]

 4 Maternal fever > 100.4 F1213Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.25, 2.02]

    4.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1213Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.25, 2.02]

 5 Birthweight (g)1255Mean Difference (IV, Fixed, 95% CI)84.0 [-144.63, 312.63]

    5.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1255Mean Difference (IV, Fixed, 95% CI)84.0 [-144.63, 312.63]

 6 Small-for-gestational age1255Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.36, 1.05]

    6.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1255Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.36, 1.05]

 7 Neonatal intensive care unit admission1247Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.79, 1.00]

    7.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1247Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.79, 1.00]

 8 Chronic lung disease1230Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.49, 1.26]

    8.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1230Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.49, 1.26]

 9 Neonatal sepsis1236Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.47, 2.81]

    9.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1236Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.47, 2.81]

 10 Neonatal antibiotic use (> 5 days)1236Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.61, 1.46]

    10.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1236Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.61, 1.46]

 11 Necrotising enterocolitis1231Risk Ratio (M-H, Fixed, 95% CI)9.20 [0.55, 154.92]

    11.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1231Risk Ratio (M-H, Fixed, 95% CI)9.20 [0.55, 154.92]

 12 Retinopathy of prematurity1109Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.53, 1.66]

    12.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1109Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.53, 1.66]

 13 Postpartum maternal length of stay (days)1215Mean Difference (IV, Fixed, 95% CI)-0.73 [-1.28, -0.18]

    13.1 Betamethasone: 12 mg 12 hourly v 12 mg 24 hourly
1215Mean Difference (IV, Fixed, 95% CI)-0.73 [-1.28, -0.18]

 
Table 1. Comparison of direct and indirect estimates and interaction tests

OutcomeDirect comparisonIndirect comparisonDiscrepancyInteraction test

Fetal/neonatal deathDirect comparison from this review: dexamethasone v betamethasone RR 1.41, 95% CI 0.54 to 3.67 (4 trials, 596 infants).Indirect comparison from Roberts 2006 Cochrane review: RR 0.92, 95% CI 0.57 to 1.49.Nonsignificant discrepancy between direct and indirect results (MD 0.42, 95% CI -0.65 to 1.49).Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.00 and P value: 0.98, I² value: 0%).

RDSDirect comparison from this review: dexamethasone v betamethasone: RR 1.06, 95% CI 0.88 to 1.27 (5 trials, 753 infants).Indirect comparison from Roberts 2006 Cochrane review: RR 1.40, 95% CI 1.02 to 1.90.Nonsignificant discrepancy between direct and indirect results (MD -0.28, 95% CI -0.64 to 0.08).Test for subgroup differences in trials in Roberts 2006 Cochrane review was significant (Chi² statistic: 4.68 and P value 0.03, I² value: 78.6%).

IVH (any)Direct comparison from this review: dexamethasone v betamethasone: RR 0.44, 95% CI 0.21 to 0.92 (4 trials, 549 infants).Indirect comparison from Roberts 2006 Cochrane review: RR 0.96, 95% CI 0.35 to 2.66.Nonsignificant discrepancy between direct and indirect results (MD -0.78, 95% CI -2.04 to 0.48).Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.78 and P value: 0.38, I² value: 0%).

ChorioamnionitisNo direct comparison (outcome not reported in any trials included in this review).Indirect comparison from Roberts 2006 Cochrane review: RR 1.90, 95% CI 1.10 to 3.28.NA.Test for subgroup differences in trials in Roberts 2006 Cochrane review was significant (Chi² statistic: 5.41 and P value 0.02, I² value: 81.5%).

Puerperal sepsisNo direct comparison (outcome not reported in any trials included in this review).Indirect comparison from Roberts 2006 Cochrane review: RR 1.68, 95% CI 0.60 to 4.66.NA.Test for subgroup differences in trials in Roberts 2006 Cochrane review was non significant (Chi² statistic: 0.99 and P value: 0.32, I² value: 0%).

 CI: confidence interval
IVH: intraventricular haemorrhage
MD: mean difference
NA: not applicable
RDS: respiratory distress syndrome
RR: risk ratio
v: versus