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Thyrotropin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease

  1. Caroline A Crowther1,2,*,
  2. Zarko Alfirevic3,
  3. Shanshan Han2,
  4. Ross R Haslam4

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 21 NOV 2013

Assessed as up-to-date: 17 JUL 2013

DOI: 10.1002/14651858.CD000019.pub3


How to Cite

Crowther CA, Alfirevic Z, Han S, Haslam RR. Thyrotropin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD000019. DOI: 10.1002/14651858.CD000019.pub3.

Author Information

  1. 1

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

  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, South Australia, Australia

  3. 3

    The University of Liverpool, Department of Women's and Children's Health, Liverpool, UK

  4. 4

    The University of Adelaide, Department of Perinatal Medicine, Adelaide, South Australia, Australia

*Caroline A Crowther, Liggins Institute, The University of Auckland, Private Bag 92019, 85 Park Road, Auckland, New Zealand. caroline.crowther@adelaide.edu.au.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 21 NOV 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Abuhamad 1999

MethodsRandomised controlled trial.


ParticipantsSetting: 1 centre in Norfolk, East Virginia, USA.

103 women with a singleton pregnancy with PPROM at 24 to 34 weeks' gestation (55 in the TRH group vs 48 in the placebo group). Gestational age range: 24 to 34 weeks. Exclusions: preterm labour, chorioamnionitis or multiple pregnancy.


Interventions500 μg of TRH or placebo x 4 every 8 hours (total 2000 μg). Treatment was completed weekly for a maximum of 4 weeks or until delivery. Betamethasone was given to all women (12 mg IM every 24 hours for 2 doses).


OutcomesPrimary outcome: length of stay in neonatal intensive care unit. Secondary outcomes: length of ventilation; RDS; bronchopulmonary dysplasia.


NotesNo sample size calculation given.

Source of funding: not stated.

Use of surfactant not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from abstract "103 pregnancies were blindly randomized [random # list]".

Allocation concealment (selection bias)Low riskCentral allocation by using a random list in pharmacy. Patients were allocated to study groups by using sealed envelopes.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used; TRH and placebo packs were prepared by pharmacy; patients and treating physicians were blinded.

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

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up. No data excluded. Intention-to-treat analysis performed.

Selective reporting (reporting bias)Unclear riskInsufficent information to make a judgement.

Other biasUnclear riskInsufficent information to make a judgement.

ACTOBAT 1995

MethodsRandomised controlled trial.


ParticipantsSetting: 18 centres in Australia from 1990 to 1993.
1234 women with a singleton or twin pregnancy at sufficient risk of preterm birth to warrant prenatal corticosteroid treatment (616 in the TRH group vs 618 in the placebo group). Gestational age range: 24 to less than 32 weeks. Not eligible if heart disease in the mother or the fetus, maternal hypertension, maternal hyperthyroidism, intrauterine growth restriction with cardiotocographic abnormalities, high likelihood of imminent delivery (< 6 hours), chorioamnionitis, or evidence of lung maturity.


Interventions200 μg of TRH or placebo in 50 mL saline over 20 minutes x 4 every 12 hours (total 800 μg). Only 1 course of TRH was given. Betamethasone was given to all women.


OutcomesPrimary outcomes: frequency and severity of RDS; need for and duration of oxygen therapy; need for and duration of ventilatory support; chronic lung disease (defined as need for oxygen at 28 days of life); need for oxygen therapy or death at 28 days and duration of stay on the neonatal unit. Secondary outcomes: stillbirths and neonatal deaths; gestational age at delivery; birthweight; air leak syndrome; patent ductus arteriosus; pulmonary haemorrhage; intraventricular haemorrhage; maternal events after randomisation; childhood outcomes.


NotesSample size calculation.

Source of funding: National Health and Medical Research Council, Australia; Queen Victoria Hospital Foundation; Channel 7 Children's Research Foundation; SIDS Foundation SA.

Placebo not available for the first 220 women enrolled.
Surfactant became available during the time course of the trial and was given as needed for respiratory distress. Surfactant was given to 81 (12%) babies in the TRH group and 69 (10%) babies in the placebo group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random number generator; stratification by centre and gestational age.

Allocation concealment (selection bias)Low riskCentral telephone randomisation service.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used except for the first 198 recruits (16%).

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "assessment of neonatal outcomes was masked throughout the study period".

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up at hospital discharge 3/1234 (< 1%), 1 in TRH group and 2 in placebo group. Losses to follow-up at 1 year 145/1234 (11%). Analyses were based on intention-to-treat.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes reported.

Other biasLow riskNo obvious risk of other bias.

Ballard 1992b

MethodsRandomised controlled trial.


ParticipantsSetting: 4 centres in the USA between 1986 to 1989.

850 women with threatened preterm delivery (404 in the TRH group and 446 in the placebo group). Gestational age range: less than 32 weeks. Not eligible if evidence of lung maturity.


Interventions400 μg of TRH or placebo in 50 mL saline as a 20-minute infusion x 4 every 8 hours (total 1600 μg). Only 1 course of TRH was given. Betamethasone was given to all women.


OutcomesApgar scores; resuscitation measures; respiratory morbidity (RDS, chronic lung disease); other complications of prematurity (patent ductus arteriosus, necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity).


NotesSample size calculation.

Source of funding: March of Dimes - National Foundation; Mount Zion General Research Support; National Heart, Lung, and Blood Institute; Perinatal Associates Inc.; Yale Children's Clinical Research Center; Harbor-UCLA project. Abbott Laboratories provided the TRH.

Surfactant not given to any baby in the trial.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "treatment groups were assigned centrally (Yale) with a table of random numbers". Stratification by centre.

Allocation concealment (selection bias)Low riskCentral allocation by pharmacy.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as a "blinded" trial with a placebo used.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All analyses and assays were performed in a blinded manner."

Incomplete outcome data (attrition bias)
All outcomes
High riskNot an intention-to-treat analysis. Analysis restricted to fully treated infants (at least 3 doses) who delivered 1-10 days from entry (114 infants delivered to 99 women in the TRH group and 117 babies delivered to 105 women in the placebo group). Losses to follow-up to hospital discharge 103/404 (23%).

Selective reporting (reporting bias)High riskAnalysis restricted to fully treated infants (at least 3 doses) who delivered 1-10 days from entry.

Other biasLow riskNo obvious risk of other bias.

Ballard 1998

MethodsRandomised controlled trial.


ParticipantsSetting: 13 North American centres between 1992 to 1996.
981 women in active labour with gestational age range 24 to less than 30 weeks, delivering 1134 liveborn infants. Data available for 1101 infants only for timing outcomes, since infusion times were missing in 33 cases. Not eligible if bleeding, infection, hypertension, fetus with hydrops, life-threatening fetal anomaly, or 1 dead fetus in a multiple pregnancy.


Interventions400 μg of TRH or placebo in 50 mL saline as a 20 minute infusion x 4 every 8 hours (total 1600 μg). Only 1 course of TRH was given. Betamethasone was given to all women.


OutcomesPrimary outcomes: infant death on or before 28th day after delivery or chronic lung disease (need for oxygen therapy for 21 of the first 28 days of life, including day 28). Secondary outcomes: chronic lung disease or death at 36 weeks postmenstrual age or less; complications of prematurity (patent ductus arteriosus, necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity).


NotesSample size calculation.

Source of funding: National Institutes of Health, USA, Perinatal Associates Inc., Hospital for Sick Children, Toronto, Children's Hospital of Eastern Ontario Research Institution. Ferring and Abbott Laboratories provided the TRH.

Infants weighing 800 g or less were treated at birth with surfactant. Infants weighing more than 800 g were treated with surfactant as needed for respiratory distress.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskThe randomisation schedule was only kept in pharmacies at the participating centres. Stratification by centre. Unclear how the schedule was generated.

Allocation concealment (selection bias)Low riskCentral allocation: pharmacy-controlled randomisation.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as "double-blinded trial"; placebo used.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"All analyses and assays were performed in a blinded fashion."

Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalyses were based on intention-to-treat; losses to follow-up at hospital discharge 15/996 (1.5%) women.

Selective reporting (reporting bias)Low riskAll pre-specified outcomes reported.

Other biasLow riskNo other obvious risk of bias.

Campos 1993

MethodsRandomised controlled trial.


ParticipantsSetting: Chile. Women at risk of preterm birth with a gestational age between 24 to 32 weeks (number of women not stated; 135 infants).


Interventions400 μg of TRH x 4 every 8 hours (total 1600 μg) or no TRH (not clear if placebo). Betamethasone to all women.


OutcomesMortality and respiratory morbidity.


NotesUse of surfactant unclear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescribed as "prospectively randomised trial"; no other information available.

Allocation concealment (selection bias)Unclear riskInsufficent information to make the judgement, "sealed envelopes" were used.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPlacebo used; no further information was available.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
High riskNot based on an intention-to-treat analysis. Analysis restricted to 135 infants who received all doses and who delivered within 48 hours of the last hormonal dose.

Selective reporting (reporting bias)High riskAnalysis restricted to 135 infants who received all doses and who delivered within 48 hours of the last hormonal dose.

Other biasLow riskInsufficent information to make the judgement.

Carlan 1991

MethodsRandomised controlled trial.


ParticipantsSetting: Tampa, Florida.

44 women with preterm prelabour rupture of the membranes between 24 to 34 weeks' gestation.


Interventions3 study groups. Group 1 (n = 13) given 400 μg of TRH intravenously x 6 every 8 hours (total 2400 μg) and betamethasone, Group 2 (n = 11) given only betamethasone and Group 3 (n = 13) given nothing for pulmonary maturity. [This last group was not analysed in the review, as study inclusion criteria specified that all women must have received corticosteroids.]
Treatment was repeated weekly until delivery or 34 weeks' gestation.


OutcomesRDS; duration of ventilation; length of stay in neonatal intensive care.


NotesSample size calculation not given.

Funding source not stated.

Use of surfactant not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskWithin this abstract, reported as "prospectively randomised"; no information was available on randomisation methods.

Allocation concealment (selection bias)Unclear riskNo details were given on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo placebo used; no other information given on blinding.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
High riskLosses to follow-up at hospital discharge 7/44 (15.9%) (excluded 5 patients who "sealed" and 2 with evidence of pulmonary maturity). Analysis was based on 37 patients.

Selective reporting (reporting bias)Unclear riskInsufficent information to make the judgement.

Other biasUnclear riskInsufficent information to make the judgement.

Ceriani 1992

MethodsRandomised controlled trial.


ParticipantsSetting: Buenos Aires, Argentina.

52 women at a gestational age between 26 to less than 31 weeks who delivered 57 infants within 10 days of treatment. No exclusion criteria reported.


Interventions200 μg of TRH or placebo x 2 every 12 hours (total 400 μg). Betamethasone was given to all women.


OutcomesRDS; need for and duration of oxygen; duration of ventilation; bronchopulmonary dysplasia.


NotesSample size calculation not given.

Source of funding not stated.

Use of surfactant not reported. Final report not available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskWithin the abstract, described as "randomised trial"; no information was available on randomisation methods.

Allocation concealment (selection bias)Unclear riskNo information was available on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as "double blind"; placebo used.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlind outcome assessment not detailed (trial described as "double blind" only).

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details was given on loss to follow-up (unclear); probably an intention-to-treat analysis. Analysis of 57 premature infants from 52 mothers treated for 10 days prior to labour (26 babies in the TRH group and 31 babies in the placebo group).

Selective reporting (reporting bias)Unclear riskInsufficent information to make the judgement.

Other biasUnclear riskInsufficent information to make the judgement.

Chile 1998

MethodsRandomised controlled trial.


ParticipantsSetting: 7 maternity centres in Chile between 1993 to 1996.

370 women with a singleton gestation between 24 to less than 33 weeks' gestation at risk of preterm delivery were eligible. Not eligible if insulin-dependent diabetes, prenatal diagnosis of a major fetal anomaly, Rhesus isoimmunisation, eclampsia, significant heart disease, chorioamnionitis, imminent delivery or contraindications to the use of corticosteroids or TRH.


Interventions400 μg of TRH or placebo in 50 mL saline as a 30-minute infusion x 4 every 8 hours (total 1600 μg). Only 1 course of TRH was given. Betamethasone was given to all women.


OutcomesPrimary outcomes: RDS; need for oxygen therapy at 28 days; neonatal mortality.
Secondary outcomes: need for and duration of mechanical ventilation; air leaks; intracranial haemorrhage; patent ductus arteriosus; pulmonary haemorrhage; necrotising enterocolitis; infectious complications. For the follow-up study: developmental scores using the Bayley Infant Scales II (MDI: Mental Developmental Index; PDI: Psychomotor Developmental Index; BRS: Behavioural Rating Scale; LDA; Language Developmental Age; CDA: Cognitive Developmental Age); ophthalmological and hearing abnormalities; serious neurological abnormalities.


NotesSample size calculation.

Source of funding: Fondo Nacional de Ciencia Tecnologia grant no. 193-0854.

Surfactant was given after birth to all infants weighing < 1 kg and to other infants if signs of respiratory distress were present.

For the follow-up: of the 134 infants born during the study period, 66 came for follow-up (including 4 pairs of twins). Only twin 1 was included in the analysis. Therefore, 60 infants who reached 18 months during the period July 1997 to December 1998 were contacted and invited for medical and neurodevelopmental follow-up evaluations.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation: computerised randomisation program. Stratification by centre.

Allocation concealment (selection bias)Low riskQuote: "use of a computerised randomisation program including stratification by centre".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: 'the content of these vials remained blinded for all patients, investigators, and clinicians until the trial was finalized'; placebo used.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above; members of the group of investigators collected data. Follow-up was conducted by a neonatologist/neonatal fellow who was blind to group allocation.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIntention-to-treat analyses. Losses to follow-up at hospital discharge 21/370 (5.7%; 8 in the TRH group and 13 in the placebo group, due to either delivered elsewhere or lost to follow-up). For the follow-up 49% of infants were recruited (those turning 1 between July 1997 and December 1998).

Selective reporting (reporting bias)Low riskNo obvious risk of selective reporting.

Other biasLow riskNo obvious risk of other bias.

Crowther 1995

MethodsRandomised controlled trial.


ParticipantsSetting: Australia.

26 women (8 in the 200 ug TRH group, 9 in the 400 ug TRH group, 9 in the control group) expected to deliver within 1 to 4 hours with a gestational age between 24 weeks and 33+6 weeks, who had received at least 1 dose of betamethasone at least 12 hours before entry. Women were excluded who had contraindications to TRH treatment.


Interventions3 treatment groups: 200 μg TRH or 400 μg TRH intravenously mixed with 50 mL of 0.9% sodium chloride in water infused over 30 minutes, compared with control (no detail of a placebo).


OutcomesMaternal pulse rates, systolic and diastolic blood pressures (10 minutes and end of infusion), maternal side effects of treatment, cord blood: TSH, T4, T3, PRL (and 2-hour, 24-hour, 48-hour neonatal blood).


NotesThe sample size was determined by the number of women recruited during the 6 months of the study.

Funding: Women's and Children's Hospital Foundation.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote "women were randomly assigned to one of the three treatment groups...by opening the next in a series of study envelopes".

Allocation concealment (selection bias)Unclear riskAs above.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo placebo; blinding not detailed.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses/exclusions.

Selective reporting (reporting bias)Unclear riskOutcomes not all clearly pre-specified, and with no access to a trial protocol it is difficult to assess selective reporting. Some incomplete reporting "The neonatal outcome was similar between the three treatment groups".

Other biasLow riskNo other obvious sources of bias identified.

Europe 1999

MethodsRandomised controlled trial.


ParticipantsSetting: 31 centres in Europe between 1996 to 1997.

225 women where the risk of preterm delivery was sufficient to prescribe prenatal corticosteroids, at a gestational age between 25 to 30 weeks for the Thyroneth trial and less than 32 weeks for the Antenatal TRH trial. Not eligible if uncontrolled hypertension, persistent cardiac arrhythmia, intrauterine growth restriction with cardiotocographic abnormality, severe maternal disease such as cardiac disease, current thyroid disease, prolactinoma, intrauterine infection and insulin-dependent diabetes.


Interventions400 μg of TRH or placebo in 50 mL saline as a 20-minute infusion (Thyroneth trial) and a 30-minute infusion (Antenatal TRH trial) x 4 every 8 hours (total 1600 μg). Only 1 course of TRH was given. Betamethasone to all women.


OutcomesPrimary outcomes: death or oxygen dependency at 28 days after birth. For the Thyroneth trial the proportion of infants who developed RDS or died within 72 hours of birth. Secondary outcomes: need to stop the infusion because of side effects; major neonatal morbidity.


NotesSample size calculation.

Source of funding: Medical Research Council, UK; The European Union and UCB Pharm. The drugs were supplied by UCB Pharm.

Surfactant was used for babies in the Thyroneth trial if respiratory distress present. In the Antenatal TRH trial many centres used prophylactic surfactant for all preterm babies.

Trial was stopped early due to new information becoming available from two other trials shortly after the start of recruitment to the trial.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation: a central telephone randomisation service.

Allocation concealment (selection bias)Low riskCentral randomisation service used.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe caregivers, the women, pregnancy outcome assessors were all blinded (placebo used).

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Low riskLosses to follow-up at hospital discharge 1/225 (< 1%); intention-to-treat analyses.

Selective reporting (reporting bias)Low riskNo obvious risk of selective reporting.

Other biasLow riskNo other obvious risk of bias.

Jikihara 1990

MethodsRandomised controlled trial.


ParticipantsSetting: single-centre study from Osaka, Japan between 1988 to 1990.

80 women with threatened preterm labour with or without ruptured membranes between 23 to less than 30 weeks' gestation, (63 infants in the TRH group and 61 in the control group). Exclusion criteria not stated.


Interventions400 μg of TRH iv x 4 every 8 hours (total 1600 μg) compared with no treatment. Betamethasone was given to all women.


OutcomesRespiratory morbidity; need for ventilation; need for oxygen at 28 days; death; intraventricular haemorrhage; patent ductus arteriosus; maternal side effects of treatment.


NotesSample size calculation not stated.

Source of funding not stated.

Surfactant used for some babies. Final report not available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskWithin this abstract, described as "randomly assigned"; no other details given.

Allocation concealment (selection bias)Unclear riskInsufficent information to make the judgement.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPlacebo not used; no other information was available.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskProbably an intention-to-treat analysis. Losses to follow-up at hospital discharge not stated.

Selective reporting (reporting bias)Unclear riskInsufficent information to make the judgement.

Other biasUnclear riskInsufficent information to make the judgement.

Kim 2000

MethodsRandomised controlled trial.


ParticipantsSetting: single-centre study from Seoul, Korea.

61 women with preterm labour at 26 to 34 weeks' gestation (30 in the TRH and dexamethasone group vs 31 in the dexamethasone alone group.


Interventions400 μg of TRH every 8 hours intravenously (maximum 6 doses) along with 6 mg dexamethasone at 12 hour intervals intravenously (maximum 4 doses) or control group receiving same regimen of dexamethasone.


OutcomesPrimary outcomes: RDS. Other outcomes: changes of surfactant synthesis; and various neonatal outcomes.


NotesNo sample size calculation given.

Use of surfactant not stated.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskWithin this abstract, described as "participants were randomised into a study group or a control group". No details was given on randomisation methods. No stratification stated.

Allocation concealment (selection bias)Unclear riskNo information was given on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo details on blinding; placebo not used.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information given on losses to follow-up. Probably an intention-to-treat analysis.

Selective reporting (reporting bias)Unclear riskInsufficent information to make the judgement.

Other biasUnclear riskInsufficent information to make the judgement.

Knight 1994

MethodsRandomised controlled trial.


ParticipantsSettomg: single-centre study from Auckland, New Zealand between 1985 to 1990.

378 women at risk of preterm delivery sufficient to use prenatal corticosteroids between 24 to 33 weeks' gestation (183 in the TRH group vs 195 in the placebo group). These women delivered 418 infants (405 liveborn).


Interventions400 μg of TRH or placebo as iv bolus (1 minute) x 4 every 12 hours (total 1600 μg). Betamethasone was given to all women.


OutcomesPrimary outcomes: RDS; chronic lung disease. Secondary outcomes: death; other complications of prematurity (intraventricular haemorrhage, patent ductus arteriosus, necrotising enterocolitis, retinopathy of prematurity). Maternal side effects.


NotesSample size calculation.

Source of funding: not stated.

Surfactant was not available.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskWomen were randomised from random number tables in blocks of 100 to receive either TRH or placebo.

Allocation concealment (selection bias)Low riskDrugs prepared by hospital pharmacist in sets of identical, serially numbered vials.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskInvestigators, patients and clinicians were blinded. Placebo used.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above. The identify of the vials was not known until all data collection was complete.

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analyses. Losses to follow-up at hospital discharge 9/418 babies (2.2%, with 4 from the TRH group and 5 from the placebo group).

Selective reporting (reporting bias)Low riskNo obvious risk of selective reporting.

Other biasLow riskNo obvious risk of other bias.

Morales 1989

MethodsRandomised controlled trial.


ParticipantsSetting: single-centre study from Tampa, Florida, USA between 1986 to 1987.

248 women (119 in the TRH group vs 129 in the control group) at risk of preterm delivery at less than 34 weeks.
No exclusion criteria stated.


Interventions400 μg of TRH iv x 6 every 8 hours (total 2400 μg) compared with no treatment. Betamethasone was given to all women.


OutcomesRespiratory morbidity; intraventricular haemorrhage; fetal lung maturity on L/S ratio after 1 week of therapy; cord blood thyroid function tests.


NotesSample size calculation not given.

Source of funding: not stated.

Surfactant not available for use.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "'randomised into two groups by means of sealed envelopes blocked for gestational age".

Allocation concealment (selection bias)Unclear riskNo detail was given on allocation concealment.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPlacebo not used (therefore unclear for women and personnel).

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe perinatal research nurse who recorded the clinical course of the neonate during its stay in the intensive care unit was blinded. 2 investigators who graded the neonatal respiratory distress were blinded.

Incomplete outcome data (attrition bias)
All outcomes
High riskNot an intention-to-treat analysis. Post randomisation exclusions of pregnancies complicated by lethal anomalies or L/S ratios of 2 or more. Losses to follow-up at hospital discharge 148/248 (59.7%). Infant outcomes restricted to 100 infants (50 in the TRH group and 50 in the control group) delivered by 1 week from the start of therapy.

Selective reporting (reporting bias)High riskNo separate information reported about neonates morbidity for those delivered after 1 week of therapy. Post randomisation exclusions of pregnancies complicated by lethal anomalies or L/S ratios of 2 or more.

Other biasLow riskNo other obvious risk of bias.

Voto 1998

MethodsRandomised controlled trial.


ParticipantsSetting: Juan A Fernandez Hospital, University of Buenos Aires from October 1994 to July 1995.

35 women (18 in the TRH group and 17 in the placebo group) with singleton pregnancies affected with fetal haemolytic disease due to Rh-isoimmunisation, with an indication for their first cordocentesis and induction of fetal lung maturation.

No exclusion criteria were stated.


Interventions400 μg of TRH iv x 4 every 6 hours compared with a normal saline placebo (administered with the same treatment regimen). All women received 2 doses of betamethasone (12 mg intramuscularly 24 hours apart), the first administered at entry.


OutcomesFetal and maternal serum prolactin, TSH and iodothyronine concentrations.


NotesSample size calculation not given.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskA computer-generated randomised sequence was used, with a block design with permuting blocks of 4.

Allocation concealment (selection bias)Low riskPacks were prepared and numbered by an independent statistician. Once an entry form was completed, a consecutive number corresponding to a sealed treatment pack was assigned.

Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe trial was described as "double-blind" with the use of a matching placebo.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Low riskCordocentesis was not successful in 3 cases in the TRH group and 1 in the placebo group, and therefore data were analysed for 15/18 women in the TRH group and 16/17 women in the placebo group.

Selective reporting (reporting bias)Unclear riskNo clinical outcome data reported.

Other biasLow riskNo other obvious risk of bias.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Devlieger 1997The aim of the trial was to evaluate the effects of TRH on uterine contractility, blood pressure and maternal heart rate. 30 women were recruited. It is unclear as to whether all women received corticosteroids, and the trial has a cross-over design.

Dola 1997The placebo group did not appear to have received corticosteroids.

Roti 1990Trial comparing thyroid hormone and prolactin levels in neonatal blood following TRH administration. It is unclear as to whether all women included in the trial received corticosteroids.

Torres 1994Comparison of neonatal T4 levels in 112 infants either exposed to 400 μg TRH doses x 6 or not. It is unclear if this was a randomised trial.

Torres 1995The aim of the trial was to compare TSH and thyroid hormone levels in the cord blood of 21 infants whose mothers had received either 100 μg, 200 μg, 400 μg of TRH or saline placebo. It is unclear whether all women received corticosteroids.

Yoder 1997Trial stopped without enrolling any women due to the infeasibility of having a placebo controlled group.

 
Characteristics of ongoing studies [ordered by study ID]
Pearlman 1997

Trial name or titleTrial to compare corticosteroids vs corticosteroids + TRH to mothers at 23 to 28 weeks with PROM.

MethodsNo information.

ParticipantsNo information.

InterventionsNo information.

OutcomesNo information.

Starting dateNo information.

Contact informationNo information.

NotesPersonal communication.

 
Comparison 1. TRH + steroids versus steroids alone (intention-to-treat)

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

 1 Death prior to hospital discharge63694Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.86, 1.27]

 2 Chronic lung disease52511Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.85, 1.19]

 3 Respiratory distress syndrome93833Risk Ratio (M-H, Random, 95% CI)1.05 [0.91, 1.22]

 4 Chronic lung disease or death63694Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.95, 1.18]

 5 Need for oxygen therapy42387Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.97, 1.13]

 6 Severe respiratory distress syndrome32119Risk Ratio (M-H, Random, 95% CI)0.88 [0.57, 1.36]

 7 Use of respiratory support31969Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.03, 1.29]

 8 Admission to neonatal intensive care unit21637Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.98, 1.11]

 9 Intraventricular haemorrhage63645Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.93, 1.26]

 10 Severe intraventricular haemorrhage53313Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.82, 1.57]

 11 Air leak syndrome43103Risk Ratio (M-H, Random, 95% CI)1.14 [0.71, 1.83]

 12 Pulmonary haemorrhage31969Risk Ratio (M-H, Random, 95% CI)0.83 [0.25, 2.80]

 13 Necrotising enterocolitis43103Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.64, 1.30]

 14 Patent ductus arteriosus63645Risk Ratio (M-H, Random, 95% CI)1.00 [0.79, 1.28]

 15 Low Apgar score at 5 minutes31969Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.14, 1.92]

 16 Use of surfactant43103Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.98, 1.25]

 17 Gestational age at birth21563Mean Difference (IV, Fixed, 95% CI)-0.43 [-0.86, 0.01]

 18 Motor delay at follow-up1971Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.09, 1.56]

 19 Motor impairment at follow-up1972Risk Ratio (M-H, Fixed, 95% CI)1.51 [1.01, 2.24]

 20 Fine motor delay at follow-up1926Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.91, 1.32]

 21 Sensory impairment at follow-up11004Risk Ratio (M-H, Fixed, 95% CI)1.97 [1.10, 3.53]

 22 Language delay at follow-up11004Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.93, 1.54]

 23 Social delay at follow-up1966Risk Ratio (M-H, Fixed, 95% CI)1.25 [1.03, 1.51]

 24 Any neurodevelopmental abnormality at follow-up139Risk Ratio (M-H, Fixed, 95% CI)4.75 [0.61, 37.01]

 25 Bayley Mental Developmental Index299Mean Difference (IV, Random, 95% CI)-6.52 [-21.69, 8.64]

    25.1 24 months
139Mean Difference (IV, Random, 95% CI)-15.70 [-30.86, -0.54]

    25.2 18 months
160Mean Difference (IV, Random, 95% CI)0.0 [-8.36, 8.36]

 26 Bayley Psychomotor Developmental Index299Mean Difference (IV, Fixed, 95% CI)-2.73 [-8.58, 3.12]

    26.1 24 months
139Mean Difference (IV, Fixed, 95% CI)-5.0 [-13.90, 3.90]

    26.2 18 months
160Mean Difference (IV, Fixed, 95% CI)-1.0 [-8.77, 6.77]

 27 Bayley Behavioural Rating Scales (18 months)160Mean Difference (IV, Fixed, 95% CI)9.0 [-4.88, 22.88]

 28 Bayley Language Developmental Age (18 months)160Mean Difference (IV, Fixed, 95% CI)2.0 [-0.36, 4.36]

 29 Bayley Cognitive Developmental Age (18 months)160Mean Difference (IV, Fixed, 95% CI)1.70 [-0.64, 4.04]

 30 Serious neurological abnormality at follow-up160Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.06, 13.35]

 31 Opthalmological or hearing abnormalities at follow-up160Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 32 Maternal nausea32370Risk Ratio (M-H, Fixed, 95% CI)3.92 [3.13, 4.92]

 33 Maternal vomiting11011Risk Ratio (M-H, Fixed, 95% CI)2.35 [1.35, 4.09]

 34 Maternal light headedness11011Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.36, 2.22]

 35 Urgency of micturition11011Risk Ratio (M-H, Fixed, 95% CI)2.39 [1.75, 3.27]

 36 Maternal facial flushing32523Risk Ratio (M-H, Fixed, 95% CI)2.67 [2.26, 3.16]

 37 Maternal systolic blood pressure rise >= 25 mmHg11011Risk Ratio (M-H, Fixed, 95% CI)1.80 [1.05, 3.06]

 38 Maternal diastolic blood pressure rise >= 15 mmHg11011Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.24, 2.12]

 
Comparison 2. TRH + steroids versus steroids alone (dose of TRH subgroups)

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

 1 Death prior to hospital discharge63694Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.86, 1.27]

    1.1 200 μg (x 4 every 12 hours)
11397Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.87, 1.75]

    1.2 400 μg (x 4 every 8-12 hours)
52297Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.77, 1.23]

 2 Chronic lung disease52511Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.85, 1.19]

    2.1 200 μg (x 4 every 12 hours)
11369Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.84, 1.30]

    2.2 400 μg (x 4 every 8-12 hours)
41142Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.73, 1.23]

 3 Respiratory distress syndrome93833Risk Ratio (M-H, Random, 95% CI)1.05 [0.91, 1.22]

    3.1 200 μg (x 4 every 12 hours)
11369Risk Ratio (M-H, Random, 95% CI)1.17 [1.00, 1.36]

    3.2 400 μg (x 4 every 8-12 hours)
52276Risk Ratio (M-H, Random, 95% CI)0.97 [0.78, 1.20]

    3.3 400 μg (x 6 every 8 hours)
285Risk Ratio (M-H, Random, 95% CI)1.67 [0.87, 3.19]

    3.4 500 μg (x 4 every 8 hours)
1103Risk Ratio (M-H, Random, 95% CI)1.12 [0.69, 1.80]

 4 Chronic lung disease or death63694Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.95, 1.18]

    4.1 200 μg (x 4 every 12 hours)
11397Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.91, 1.30]

    4.2 400 μg (x 4 every 8-12 hours)
52297Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.92, 1.19]

 5 Need for oxygen therapy42387Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.97, 1.13]

    5.1 200 μg (x 4 every 12 hours)
11369Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.95, 1.16]

    5.2 400 μg (x 4 every 8-12 hours)
31018Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.93, 1.18]

 6 Severe respiratory distress syndrome32119Risk Ratio (M-H, Random, 95% CI)0.88 [0.57, 1.36]

    6.1 200 μg (x 4 every 12 hours)
11369Risk Ratio (M-H, Random, 95% CI)0.87 [0.66, 1.14]

    6.2 400 μg (x 4 every 8-12 hours)
2750Risk Ratio (M-H, Random, 95% CI)0.91 [0.37, 2.26]

 7 Use of respiratory support31969Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.03, 1.29]

    7.1 200 μg (x 4 every 12 hours)
11369Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.01, 1.31]

    7.2 400 μg (x 4 every 8-12 hours)
2600Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.95, 1.46]

 
Comparison 3. TRH + steroids versus steroids alone (timing of delivery subgroups)

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

 1 Death prior to hospital discharge52538Risk Ratio (M-H, Random, 95% CI)0.94 [0.70, 1.26]

    1.1 Birth < 24 hours after first dose
4245Risk Ratio (M-H, Random, 95% CI)0.89 [0.50, 1.59]

    1.2 Birth ≥ 24 hours to ≤ 10 days after first dose
51164Risk Ratio (M-H, Random, 95% CI)0.87 [0.59, 1.27]

    1.3 Birth > 10 days after first dose
41129Risk Ratio (M-H, Random, 95% CI)1.25 [0.47, 3.34]

 2 Chronic lung disease52574Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.81, 1.10]

    2.1 Birth < 24 hours after first dose
5306Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.54, 1.13]

    2.2 Birth ≥ 24 hours to ≤ 10 days after first dose
51152Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.77, 1.12]

    2.3 Birth > 10 days after first dose
41116Risk Ratio (M-H, Fixed, 95% CI)1.30 [0.81, 2.10]

 3 Respiratory distress syndrome63535Risk Ratio (M-H, Random, 95% CI)1.00 [0.91, 1.10]

    3.1 Birth < 24 hours after first dose
5495Risk Ratio (M-H, Random, 95% CI)0.97 [0.87, 1.08]

    3.2 Birth ≥ 24 hours to ≤ 10 days after first dose
61485Risk Ratio (M-H, Random, 95% CI)0.94 [0.81, 1.10]

    3.3 Birth > 10 days after first dose
41555Risk Ratio (M-H, Random, 95% CI)1.33 [1.05, 1.68]

 4 Chronic lung disease or death53459Risk Ratio (M-H, Random, 95% CI)0.97 [0.84, 1.11]

    4.1 Birth < 24 hours after first dose
5457Risk Ratio (M-H, Random, 95% CI)0.90 [0.75, 1.08]

    4.2 Birth ≥ 24 hours to ≤ 10 days after first dose
51317Risk Ratio (M-H, Random, 95% CI)0.92 [0.77, 1.11]

    4.3 Birth > 10 days after first dose
51685Risk Ratio (M-H, Random, 95% CI)1.30 [0.92, 1.83]

 5 Need for oxygen therapy21440Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.10]

    5.1 Birth < 24 hours after first dose
1155Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.85, 1.07]

    5.2 Birth ≥ 24 hours to ≤ 10 days after first dose
2577Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.92, 1.08]

    5.3 Birth > 10 days after first dose
1708Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.88, 1.42]

 6 Severe respiratory distress syndrome32031Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.61, 0.93]

    6.1 Birth < 24 hours after first dose
3270Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.57, 1.30]

    6.2 Birth ≥ 24 hours to ≤ 10 days after first dose
3874Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.49, 0.85]

    6.3 Birth > 10 days after first dose
2887Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.62, 1.82]

 7 Use of respiratory support21440Risk Ratio (M-H, Random, 95% CI)1.04 [0.92, 1.17]

    7.1 Birth < 24 hours after first dose
1155Risk Ratio (M-H, Random, 95% CI)0.99 [0.82, 1.19]

    7.2 Birth ≥ 24 hours to ≤ 10 days after first dose
2577Risk Ratio (M-H, Random, 95% CI)1.02 [0.87, 1.19]

    7.3 Birth > 10 days after first dose
1708Risk Ratio (M-H, Random, 95% CI)1.34 [0.94, 1.91]

 
Comparison 4. TRH + steroids versus steroids alone (optimally treated variously defined)

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

 1 Death prior to hospital discharge10Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Optimally treated infants
91465Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.67, 1.14]

    1.2 All treated infants
63694Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.86, 1.27]

 2 Chronic lung disease8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Optimally treated infants
81318Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.04]

    2.2 All treated infants
52511Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.85, 1.19]

 3 Respiratory distress syndrome13Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Optimally treated infants
101786Risk Ratio (M-H, Random, 95% CI)0.89 [0.77, 1.03]

    3.2 All treated infants
93833Risk Ratio (M-H, Random, 95% CI)1.05 [0.91, 1.22]

 4 Chronic lung disease or death6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Optimally treated infants
51317Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.84, 1.09]

    4.2 All treated infants
63694Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.95, 1.18]

 5 Need for oxygen therapy4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    5.1 Optimally treated infants
1506Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.91, 1.09]

    5.2 All treated infants
42387Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.97, 1.13]

 6 Severe respiratory distress syndrome3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    6.1 Optimally treated infants
2694Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.49, 0.86]

    6.2 All treated infants
32119Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.69, 1.04]

 7 Use of respiratory support3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Optimally treated infants
1506Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.94, 1.22]

    7.2 All treated infants
31969Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.03, 1.29]

 
Comparison 5. TRH + steroids versus steroids alone (high-quality trials)

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

 1 Death prior to hospital discharge53570Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.84, 1.25]

 2 Chronic lung disease42387Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.84, 1.18]

 3 Respiratory distress syndrome53521Risk Ratio (M-H, Random, 95% CI)1.06 [0.91, 1.24]

 4 Chronic lung disease or death53570Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.17]

 5 Need for oxygen therapy42387Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.97, 1.13]

 6 Severe respiratory distress syndrome32119Risk Ratio (M-H, Random, 95% CI)0.88 [0.57, 1.36]

 7 Use of respiratory support31969Risk Ratio (M-H, Fixed, 95% CI)1.16 [1.03, 1.29]