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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, 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

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Preterm birth remains the leading cause of early neonatal death and infant mortality, often from respiratory distress syndrome as a consequence of immature lung development (Nassar 2001). Between 5% and 9% of pregnant women will give birth before 37 weeks' gestation, with higher rates in developing countries (Li 2012). Preterm babies who survive the early weeks of life are at risk of long-term neurological disability (Moore 2012; Saigal 2008; Serenius 2013). Parents are understandably worried and distressed when their baby is born preterm. Strategies to reduce the risk of preterm birth and, in particular, neonatal respiratory disease receive considerable attention (Crowther 2011; Roberts 2006; Stevens 2007).

The first report of a trial of prenatal thyrotropin-releasing hormone (TRH) given with antenatal corticosteroids to women threatening to give birth preterm with the aim of enhancing lung development was presented, in abstract form, by Liggins and his co-workers in 1988 (Liggins 1988). The rationale for the use of TRH was based on previous research by Liggins' group (Schellenberg 1988). In an elegant series of experiments in preterm lambs they showed both an increase in lung fluid phospholipids and an increase in lung distensibility when thyroid hormones were used in combination with corticosteroids. TRH and glucocorticoids showed similar synergism (Liggins 1988).

Thyroid hormones (T3 and T4) given antenatally to the mother do not readily reach the fetal circulation due to metabolism by the placenta and membranes. However, TRH given to the mother elevates thyroid stimulating hormone (TSH) and thyroid hormones concentrations in the fetus (Roti 1981). The exact action of TRH on the fetal lung is not known and it is possible that any action may be mediated via non-hormonal pathways.

In adults, intravenous TRH administration is associated with side effects, which are often transient, of nausea, vomiting, light headedness, facial flushing, metallic taste, and a rise in blood pressure (Jackson 1982).

Since the initial abstract reported by Liggins 1988, the use of prenatal TRH as an intervention strategy to reduce the risk of neonatal lung disease and its sequelae has been evaluated in several randomised trials.

This review updates a previously published Cochrane review on TRH added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease (Crowther 2004). The previous version of this review was able to include 13 trials, and concluded that prenatal TRH in addition to corticosteroids does not improve infants outcomes, and can be associated with maternal side effects.

This review assesses the current available evidence regarding the effectiveness and safety of prenatal TRH given in addition to corticosteroids to women at risk of preterm birth.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

To assess the effects of TRH administered in addition to corticosteroids to women at risk of preterm birth on fetal and infant mortality and morbidity, and on maternal side effects.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All published, unpublished and ongoing randomised controlled trials and quasi-randomised controlled trials with reported data that compare outcomes in women and babies exposed to prenatal thyrotropin-releasing hormone (TRH) and corticosteroids with outcomes in controls receiving corticosteroids alone, with or without placebo. We planned to include cluster-randomised trials, and exclude cross-over trials. We planned to include studies published as abstracts only.

 

Types of participants

Women at sufficiently high risk of preterm birth to warrant administration of prenatal corticosteroids to promote fetal lung maturity. High-risk groups were those women showing signs of threatening to give birth preterm, or needing early delivery because of maternal or fetal complications.

 

Types of interventions

TRH (any dosage) administered to the women intravenously and corticosteroids, compared with corticosteroids with either placebo or no placebo.

 

Types of outcome measures

Pre-specified clinical measures of outcome related to fetal and neonatal mortality, neonatal morbidity, childhood development and maternal morbidity.

 

Primary outcomes

Primary outcomes were chosen to be most representative of the clinically important measures of effectiveness and safety for the infants.

  1. Death prior to hospital discharge;
  2. chronic lung disease (variously defined by authors);
  3. respiratory distress syndrome (RDS).

 

Secondary outcomes

Secondary outcomes included other measures of effectiveness, complications and health services use.

 
For the infant

  1. Chronic lung disease (variously defined by authors) or death;
  2. need for oxygen therapy;
  3. severe RDS (variously defined by authors);
  4. use of respiratory support (mechanical ventilation or continuous positive airway pressure, or both);
  5. admission to neonatal intensive care unit;
  6. intraventricular haemorrhage;
  7. intraventricular haemorrhage grade three or four;
  8. periventricular leucomalacia;
  9. air leak syndrome;
  10. pulmonary haemorrhage;
  11. necrotising enterocolitis;
  12. patent ductus arteriosus;
  13. low Apgar score at five minutes;
  14. gestational age at birth;
  15. use of surfactant;
  16. neurodevelopmental abnormality at follow-up (variously defined by authors);
  17. visual impairment at follow-up (variously defined by authors);
  18. hearing impairment at follow-up (variously defined by authors);
  19. motor delay at follow-up (variously defined by authors);
  20. motor impairment at follow-up (variously defined by authors);
  21. fine motor delay at follow-up (variously defined by authors);
  22. sensory impairment at follow-up (variously defined by authors);
  23. language development delay at follow-up (variously defined by authors);
  24. social delay at follow-up (variously defined by authors);
  25. Bayley Mental Development Index (variously defined by authors);
  26. Bayley Psychomotor Developmental Index (variously defined by authors).

 
For the mother

  1. Nausea;
  2. vomiting;
  3. light headedness;
  4. urgency of micturition;
  5. facial flushing;
  6. systolic blood pressure rise during treatment (variously defined by authors);
  7. diastolic blood pressure rise during treatment (variously defined by authors).

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (30 June 2013). 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from: 

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
  2. weekly searches of MEDLINE;
  3. weekly searches of Embase;
  4. handsearches of 30 journals and the proceedings of major conferences;
  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.  

[For details of additional searching carried out in the previous version of the review (Crowther 2004), please see: Appendix 1.]

 

Searching other resources

We searched reference lists of trials and other review articles and contacted researchers. We contacted authors of Pearlman 1997 and Yoder 1997 for further information.

We did not apply any language restrictions.

 

Data collection and analysis

The following methods were used for this update.

Please see Crowther 2004 for methods used in the previous version of this review.

 

Selection of studies

Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion, or if required we consulted a third review author.

 

Data extraction and management

We designed a form to extract data. At least two review authors extracted the data using the agreed form. We resolved discrepancies through discussion, or if required we consulted a third review author. Data were entered into Review Manager software (RevMan 2012) and checked for accuracy.

When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.

 

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving a third assessor.

 

(1) Sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);
  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
  • unclear risk of bias.

 

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal the allocation sequence and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
  • unclear risk of bias.

 

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies are at low risk of bias if they were blinded, or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

  • low, high or unclear risk of bias for participants;
  • low, high or unclear risk of bias for personnel.

 

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

 

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re-included missing data in the analyses which we undertook.

We assessed methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
  • unclear risk of bias.

 

(5) Selective reporting bias

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • low risk of bias (where it was clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review had been reported);
  • high risk of bias (where not all the study’s pre-specified outcomes had been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest were reported incompletely and so could not be used; study fails to include results of a key outcome that would have been expected to have been reported);
  • unclear risk of bias.

 

(6) Other sources of bias

We described for each included study any important concerns we had about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;
  • high risk of other bias;
  • unclear whether there is risk of other bias.

 

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

 

Measures of treatment effect

 

Dichotomous data

For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals.

 

Continuous data

For continuous data, we used the mean difference when outcomes were measured in the same way between trials. If necessary, we would have used the standardised mean difference to combine trials that measured the same outcome, but used different methods.

 

Unit of analysis issues

 

Cluster-randomised trials

We did not identify any cluster-randomised trials for inclusion. In future updates of this review, if we identify cluster-randomised trials, we plan to include them in the analyses along with individually-randomised trials. We will adjust their sample sizes using the methods described in the Cochrane Handbook using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population (Higgins 2011). If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We also plan to acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.

 

Cross-over trials

We considered cross-over trials as inappropriate for inclusion in this review.

 

Dealing with missing data

For included studies, we noted levels of attrition. We planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we carried out analyses, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

 

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. 

 

Assessment of reporting biases

In future updates of this review, if there are 10 or more studies in a meta-analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

 

Data synthesis

We carried out statistical analysis using Review Manager software (RevMan 2012). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. Where there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or where substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random-effects summary has been treated as the average range of possible treatment effects and we have discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we would not have combined trials.

Where we used random-effects analyses, we have presented the results as the average treatment effect with its 95% confidence interval, and the estimates of  Tau² and I².

 

Subgroup analysis and investigation of heterogeneity

Where we identified substantial heterogeneity, we investigated it using subgroup analyses and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, we used random-effects analysis.

We planned subgroup analyses to examine separately the primary outcomes for infants based on:

  • the reasons the women were considered at risk of preterm birth;
  • the number of infants in utero (singleton, twins or higher order multiple pregnancy);
  • the gestational age TRH treatment was given;
  • the dose of TRH given;
  • the outcome for optimally treated infants, which was variously defined by the authors.

These analyses were only possible for the dose of TRH given, and the outcome for optimally treated infants.

The greatest beneficial effect of antenatal corticosteroids was observed in the group of infants delivered 24 hours or more and 10 days or less after start of therapy (Liggins 1972). An expectation that this may be the case for the combination of prenatal TRH and corticosteroids prompted the secondary timed analysis as follows:

  1. birth less than 24 hours after first dose;
  2. birth between 24 hours and 10 days, inclusive, after first dose;
  3. birth more than 10 days after first dose.

Initial analyses were limited to the pre-specified outcomes and sensitivity and secondary analyses to the pre-specified primary outcomes, and the secondary outcomes:

  • chronic lung disease (variously defined by authors) or death;
  • need for oxygen therapy;
  • severe RDS (variously defined by authors);
  • use of respiratory support (mechanical ventilation or continuous positive airway pressure, or both).

We assessed subgroup differences by interaction tests available within RevMan (RevMan 2012). We have reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

 

Sensitivity analysis

We carried out a sensitivity analysis to explore the effects of trial quality assessed by sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting, by omitting studies rated as 'unclear risk of bias' or 'high risk of bias' for these components. The sensitivity analysis has been restricted to those pre-specified outcomes listed above.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

See Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies.

 

Results of the search

The updated search of the Pregnancy and Childbirth Group's Specialist Register identified four reports that have been added as additional references under previously included trials (Chile 1998; Kim 2000; Knight 1994). We have included two additional trials in this update that were previously excluded, due to not reporting any relevant outcome data (Crowther 1995; Voto 1998).

Therefore, of the 22 studies that were identified, 15 met our inclusion criteria (Abuhamad 1999; ACTOBAT 1995; Ballard 1992b; Ballard 1998; Campos 1993; Carlan 1991; Ceriani 1992; Chile 1998; Crowther 1995; Europe 1999; Jikihara 1990; Kim 2000; Knight 1994; Morales 1989; Voto 1998).

We excluded six trials (Devlieger 1997; Dola 1997; Roti 1990; Torres 1994; Torres 1995; Yoder 1997), and one study is classified as ongoing (reported as 'planned') (Pearlman 1997).

 

Included studies

Over 4600 women were recruited into the 15 trials that met the pre-specified criteria for inclusion in this review (Abuhamad 1999; ACTOBAT 1995; Ballard 1992b; Ballard 1998; Campos 1993; Carlan 1991; Ceriani 1992; Chile 1998; Crowther 1995; Europe 1999; Jikihara 1990; Kim 2000; Knight 1994; Morales 1989; Voto 1998).

Gestational age at trial entry varied between 24 to 33 completed weeks: 24 to 31 completed weeks in ACTOBAT 1995, Ballard 1992b and Campos 1993; 24 to less than 30 weeks in Ballard 1998; 24 to less than 33 weeks in Chile 1998 and Knight 1994; 24 to less than 34 weeks in Carlan 1991 and Crowther 1995; 24 to 34 weeks in Abuhamad 1999; less than 32 weeks in Europe 1999; less than 34 weeks in Morales 1989; 23 to 29 completed weeks in Jikihara 1990; 26 to 31 weeks in Ceriani 1992; and 26 to 34 weeks in Kim 2000.

All trials used the administration of antenatal corticosteroids as an inclusion criterion. The thyrotropin-releasing hormone (TRH) regimens varied as follows.

For further details see: Characteristics of included studies.

 

Excluded studies

We excluded six trials (Devlieger 1997; Dola 1997; Roti 1990; Torres 1994; Torres 1995; Yoder 1997) for a variety of reasons. In four trials it was unclear as to whether all women (including those in the control group) received corticosteroids (Devlieger 1997; Dola 1997; Roti 1990; Torres 1995); in one trial a cross-over design was used (Devlieger 1997); for one trial it was unclear as to whether it was randomised (Torres 1994); and one trial stopped without enrolling any women (Yoder 1997).

For further details see: Characteristics of excluded studies.

 

Risk of bias in included studies

See Characteristics of included studies, Figure 1 and Figure 2 for further information on the risk of bias in the included studies. Overall, the risk of bias in the 15 included trials was judged to be moderate.

 FigureFigure 1. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 2. 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

 

Allocation

Six of the 15 included trials used adequate methods for sequence generation. Four trials (ACTOBAT 1995; Chile 1998; Europe 1999; Voto 1998) used central telephone randomisation, and two trials (Ballard 1992b; Knight 1994) used random number tables. Sequence generation was unclear for the remaining trials (Abuhamad 1999; Ballard 1998; Campos 1993; Carlan 1991; Ceriani 1992; Crowther 1995; Jikihara 1990; Kim 2000; Morales 1989).

Eight of the 15 trials (Abuhamad 1999; ACTOBAT 1995; Ballard 1992b; Ballard 1998; Chile 1998; Europe 1999; Knight 1994; Voto 1998) reported an adequate method for concealing allocation. Four trials (Abuhamad 1999; Ballard 1992b; Ballard 1998; Knight 1994) used a central allocation (pharmacy-controlled), and three trials (ACTOBAT 1995; Chile 1998; Europe 1999) used central telephone randomisation service. Voto 1998 used sequentially numbered drug containers of identical appearance. Allocation concealment was unclear in the remaining seven trials (Campos 1993; Carlan 1991; Ceriani 1992; Crowther 1995; Jikihara 1990; Kim 2000; Morales 1989).

 

Blinding

Seven of the 15 included trials (ACTOBAT 1995; Ballard 1992b; Ballard 1998; Chile 1998; Europe 1999; Knight 1994; Voto 1998) were blinded throughout the study. In ACTOBAT 1995, assessment of neonatal outcomes was blinded, and a placebo was used except for with the first 198 women recruited. In the other six studies, all women, investigators, clinicians and pregnancy outcome assessors were blinded, and a placebo was used (Ballard 1992b; Ballard 1998; Chile 1998; Europe 1999; Knight 1994; Voto 1998).

In Abuhamad 1999, while a placebo was used and women and personnel were blinded, the blinding of outcome assessors was not detailed. Similarly, in Ceriani 1992, while a placebo was used, and the trial was described as "double-blind", no detail regarding blinding of outcome assessors was provided. In Morales 1989, neonate outcome recorders and neonatal respiratory distress assessors were blinded, however a placebo was not used (and thus women and other study personnel were not blinded).

Blinding was unclear in six trials (Campos 1993; Carlan 1991; Crowther 1995; Jikihara 1990; Kim 2000) due to limited information available.

 

Incomplete outcome data

Losses to follow-up in six trials (Abuhamad 1999; ACTOBAT 1995; Ballard 1998; Crowther 1995; Europe 1999; Knight 1994) were less than 3%. In Chile 1998, losses to follow-up were 21/370 (5.7%) for the main trial; however for the follow-up, losses were over 50%. In Voto 1998 data were missing for 4/35 (11.4%) of women; and in Carlan 1991, losses to follow-up were 7/44 (15.9%). No information was available on losses to follow-up in two trials (Jikihara 1990; Kim 2000).

In Ballard 1992b; Campos 1993; Carlan 1991 and Morales 1989, outcome data were only available for a subgroup of participants expected to benefit most from the exposure to prenatal TRH.

An intention-to-treat analysis (with data analysed from all women randomised) was reported as being used in six trials (Abuhamad 1999; ACTOBAT 1995; Ballard 1998; Chile 1998; Europe 1999; Knight 1994), was probably used in three others (Carlan 1991; Jikihara 1990; Kim 2000) and was not used in Ballard 1992b; Campos 1993 and Morales 1989.

 

Selective reporting

There was no obvious risk of selective reporting in five of the 15 trials (ACTOBAT 1995; Ballard 1998; Chile 1998; Europe 1999; Knight 1994). In six trials there was insufficient information to make a clear judgement (Abuhamad 1999; Carlan 1991; Ceriani 1992; Crowther 1995; Jikihara 1990; Kim 2000; Voto 1998).

Four trials (Ballard 1992b; Campos 1993; Ceriani 1992; Morales 1989) only presented outcomes for a subgroup of participants expected to benefit most from the exposure to prenatal TRH. This led to significant numbers of women who were randomised, being excluded from analysis in Morales 1989 (148/248; 60% excluded); Ballard 1992b (343/446; 77% infants excluded); probably Ceriani 1992 (percentage not reported); and Campos 1993 (percentage not reported). Morales 1989 gave outcome data for infants delivered within one week from the start of therapy. Ballard 1992b reported data for neonates born after full treatment, weighing less than 1500 g at birth and delivering less than 10 days after TRH treatment. Ceriani 1992 reported data for infants born within 10 days of entry who were fully treated (received all doses of TRH or corticosteroids, or both). Campos 1993 reported data on fully treated infants (received all doses of TRH or corticosteroids, or both) who were born within 48 hours of the last hormonal dose.

Neurological outcomes at childhood follow-up were reported for three trials (ACTOBAT 1995; Chile 1998; Europe 1999). ACTOBAT 1995 assessed neurological outcomes with a questionnaire completed by parents when their infants were 12 months of age. Some data were available for 1022 (81%) of the 1262 infants discharged home alive, but not all outcome data were available for all infants. A subset of 39 of 52 (75%) children recruited at a single centre in Europe 1999 (16% of the infants recruited to the trial overall and alive at end of data collection) were assessed at 12 months and 24 months using the Bayley Scales of Infant Development and by a paediatrician. Similarly, at 18 months, 66 (49%) of the 134 infants enrolled during a 12-month period (July 1997 to December 1998) of the Chile 1998 study were assessed using the Bayley Scales of Infant Development (2nd edition) by a neonatologist or neonatal fellow.

 

Other potential sources of bias

Ten of the 15 trials were judged to be at a low risk of other potential bias, with no other obvious sources of bias identified (ACTOBAT 1995; Ballard 1992b; Ballard 1998; Campos 1993; Chile 1998; Crowther 1995; Europe 1999; Knight 1994; Morales 1989; Voto 1998). For the other five trials, the risk of other potential bias was judged to be unclear, with insufficient information available to make a confident judgement (Abuhamad 1999; Carlan 1991; Ceriani 1992; Jikihara 1990; Kim 2000).

 

Effects of interventions

Fifteen trials involving over 4600 women were included, although only 13 trials contributed data to the meta-analyses. All trials used a combination of TRH and antenatal corticosteroids in the intervention group and corticosteroids alone (with or without a placebo) in the control group.

 

Comparison of TRH with corticosteroids versus corticosteroids alone

 

All eligible trials analysed by intention-to-treat

Nine trials involving 3833 women contributed data (Abuhamad 1999; ACTOBAT 1995; Ballard 1998; Carlan 1991; Chile 1998; Europe 1999; Jikihara 1990; Kim 2000; Knight 1994).

 

Primary outcomes

No beneficial effects of prenatal TRH were seen for the primary outcomes: death prior to hospital discharge (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.86 to 1.27, six trials, 3694 infants) ( Analysis 1.1), chronic lung disease (RR 1.01, 95% CI 0.85 to 1.19, five trials, 2511 infants) ( Analysis 1.2) or respiratory distress syndrome (RDS) (average RR 1.05, 95% CI 0.91 to 1.22, nine trials, 3833 infants) ( Analysis 1.3). Moderate statistical heterogeneity was found for the outcome RDS (Tau² = 0.02; I² = 48%), and thus a random-effects model was used.

 

Secondary outcomes

 
For the infant

No effects of prenatal TRH were shown on the composite outcome of death or chronic lung disease (RR 1.06, 95% CI 0.95 to 1.18, six trials, 3694 infants) ( Analysis 1.4), on the need for oxygen therapy (RR 1.05, 95% CI 0.97 to 1.13, four trials, 2387 infants) ( Analysis 1.5), or on the outcome severe RDS (average RR 0.88, 95% CI 0.57 to 1.36, three trials, 2119 infants; Tau² = 0.11; I² = 73%) ( Analysis 1.6). The need for respiratory support was significantly increased in the TRH treated group (RR 1.16, 95% CI 1.03 to 1.29, three trials, 1969 infants) ( Analysis 1.7).

No effects of prenatal TRH on gestational age at birth (mean difference (MD) -0.43 weeks, 95% CI -0.86 to 0.01, two trials, 1563 infants) ( Analysis 1.17) or on need for admission to the neonatal intensive care unit (RR 1.04, 95% CI 0.98 to 1.11, two trials, 1637 infants) ( Analysis 1.8) were discernible. Similarly, no effects were seen on the risk of intraventricular haemorrhage (RR 1.08, 95% CI 0.93 to 1.26, six trials, 3645 infants) ( Analysis 1.9), severe intraventricular haemorrhage (RR 1.13, 95% CI 0.82 to 1.57, five trials, 3313 infants) ( Analysis 1.10), air leak syndrome (average RR 1.14, 95% CI 0.71 to 1.83, four trials, 3103 infants) ( Analysis 1.11), pulmonary haemorrhage (RR 0.83, 95% CI 0.25 to 2.80, three trials 1969 infants) ( Analysis 1.12), necrotising enterocolitis (RR 0.91, 95% CI 0.64 to 1.30, four trials, 3103 infants) ( Analysis 1.13), patent ductus arteriosus (average RR 1.00, 95% CI 0.79 to 1.28, six trials, 3645 infants) ( Analysis 1.14), or use of surfactant (RR 1.10, 95% CI 0.98 to 1.25, four trials, 3103 infants) ( Analysis 1.16). A low Apgar score at five minutes was significantly more common in TRH treated infants (RR 1.48, 95% CI 1.14 to 1.92, three trials, 1969 infants) ( Analysis 1.15). Moderate statistical heterogeneity was seen for the outcomes air leak syndrome (Tau² = 0.12; I² = 55%), pulmonary haemorrhage (Tau² = 0.64; I² = 56%) and patent ductus arterious (Tau² = 0.04; I² = 44%), and thus for each outcome, a random-effects model was used.

 
For the child

Outcomes for children at 12 months of age or later were available from three trials (ACTOBAT 1995; Chile 1998; Europe 1999). As the three trials followed up infants at different ages (i.e. 18 versus 24 months) and used different methods of assessment, it was difficult to pool these data in meta-analyses.

In the ACTOBAT 1995 trial, an increased risk in the TRH treated group was shown for motor delay (RR 1.31, 95% CI 1.09 to 1.56, 971 infants) ( Analysis 1.18), motor impairment (RR 1.51, 95% CI 1.01 to 2.24, 972 infants) ( Analysis 1.19), sensory impairment (RR 1.97, 95% CI 1.10 to 3.53, 1004 infants) ( Analysis 1.21), and social delay (RR 1.25, 95% CI 1.03 to 1.51, 966 infants) ( Analysis 1.23); but not for fine motor delay (RR 1.10, 95% CI 0.91 to 1.32, 926 infants) ( Analysis 1.20), or language delay (RR 1.20, 95% CI 0.93 to 1.54, 1004 infants) ( Analysis 1.22).

While the Europe 1999 trial did not find any difference in neurological abnormality overall between the two groups (RR 4.75, 95% CI 0.61 to 37.01, 39 infants) ( Analysis 1.24), at 24 months, the mean Bayley Mental Developmental Index (MDI) was significantly lower (worse) in the TRH exposed children (MD -15.70, 95% CI -30.86 to -0.54, 39 infants). However, in the Chile 1998 trial, at 18 months, no significant difference between groups was shown in the Bayley MDI (MD 0.00, 95% CI -8.36 to 8.36, 60 infants); and when the data from the two trials were pooled, no difference was shown overall (MD -6.52, 95% CI -21.69 to 8.64; Tau² = 84.25; I² = 68%) ( Analysis 1.25). The Bayley Psychomotor Developmental Index (PDI) was not shown to be significantly different between groups at follow-up in either the Europe 1999 trial or the Chile 1998 trial (pooled MD -2.73, 95% CI -8.58 to 3.12, 99 infants) ( Analysis 1.26). The Chile 1998 trial (assessing 60 infants) also found no significant differences on follow-up between the TRH and corticosteroids and corticosteroids only group for the mean Bayley Behavioural Rating Scale (BRS) (MD 9.00, 95% CI -4.88 to 22.88) ( Analysis 1.27), the mean Language Developmental Age (LDA) (MD 2.00, 95% CI -0.36 to 4.36) ( Analysis 1.28), or for the mean Cognitive Developmental Age (CDA) (MD 1.70, 95% CI -0.64 to 4.04) ( Analysis 1.29). No ophthalmologic or hearing abnormalities were reported at follow-up for the 60 infants assessed in Chile 1998 ( Analysis 1.31), and only one serious neurological abnormality at follow-up was reported in each group ( Analysis 1.30); an infant from the TRH and corticosteroids group was reported to have congential ventriculomegaly, and one infant in the corticosteroids only group was reported to have hypotonia of congenital origin.

 
For the mother

Maternal side effects were more frequent in the TRH treated women; nausea (RR 3.92, 95% CI 3.13 to 4.92, three trials, 2370 women) ( Analysis 1.32), vomiting (RR 2.35, 95% CI 1.35 to 4.09, one trial, 1011 women) ( Analysis 1.33), light headedness (RR 1.73, 95% CI 1.36 to 2.22, one trial, 1011 women) ( Analysis 1.34), urgency of micturition (RR 2.39, 95% CI 1.75 to 3.27, one trial, 1011 women) ( Analysis 1.35), and facial flushing (RR 2.67, 95% CI 2.26 to 3.16, three trials, 2523 women) ( Analysis 1.36). In the Crowther 1995 trial, side effects of nausea, urgency of micturition, or facial flushing occurred in four (of eight) women receiving 200 μg TRH and six (of nine) receiving 400 μg; it was not detailed if any of the nine control women experienced side effects. There was a significant rise in maternal systolic blood pressure (greater than 25 mmHg) (RR 1.80, 95% CI 1.05 to 3.06, one trial, 1011 women) ( Analysis 1.37) and maternal diastolic blood pressure (greater than 15 mmHg) (RR 1.62, 95% CI 1.24 to 2.12, 1011 women) ( Analysis 1.38) in women given prenatal TRH in the ACTOBAT 1995 trial.

 

Subgroup analysis based on dose of TRH

Subgroup analyses were performed based on the dose regimen of TRH used (considering dose subgroups 200 μg (x four every 12 hours) versus 400 μg (x four every eight to 12 hours) versus 400 μg (x six every eight hours) versus 500 μg (x four every eight hours)).

The subgroup analyses revealed no subgroup differences for the outcomes death prior to hospital discharge for the infant (Chi² = 1.19, P = 0.28, I² = 15.8%) ( Analysis 2.1); chronic lung disease (variously defined) (Chi² = 0.31, P = 0.58, I² = 0%) ( Analysis 2.2); RDS (Chi² = 3.46, P = 0.33, I² = 13.2%) ( Analysis 2.3); chronic lung disease or death (Chi² = 0.11, P = 0.74, I² = 0%) ( Analysis 2.4); the need for oxygen therapy (Chi² = 0.00, P = 0.95, I² = 0%) ( Analysis 2.5); severe RDS (Chi² = 0.01, P = 0.93, I² = 0%) ( Analysis 2.6); or the use of respiratory support (Chi² = 0.05, P = 0.83, I² = 0%) ( Analysis 2.7) indicating no differential effects for these primary and other pre-specified infant outcomes according to the dose regimen administered.

 

Subgroup analysis based on timing of birth

We also performed subgroup analyses based on the timing of birth, with six trials contributing data (ACTOBAT 1995; Ballard 1992b; Ballard 1998; Chile 1998; Europe 1999; Knight 1994). Babies born less than 24 hours after trial entry made up 13% of the total population, and babies born between 24 hours and 10 days from trial entry accounted for 38% of the total population; while babies born more than 10 days after trial entry accounted for the majority of the population (49%).

Considering the timing of birth, the subgroup analyses did not reveal any significant subgroup differences for the outcomes death prior to hospital discharge for the infant (Chi² = 0.45, P = 0.80, I² = 0%) ( Analysis 3.1); chronic lung disease (variously defined) (Chi² = 2.76, P = 0.25, I² = 27.6%) ( Analysis 3.2); chronic lung disease or death (Chi² = 3.70, P = 0.16, I² = 45.9%) ( Analysis 3.4); the need for oxygen therapy (Chi² = 1.37, P = 0.50, I² = 0%) ( Analysis 3.5); severe RDS (Chi² = 3.13, P = 0.21, I² = 36.1%) ( Analysis 3.6); or the use of respiratory support (Chi² = 2.40, P = 0.30, I² = 16.6%) ( Analysis 3.7) indicating no differential effects for these infant outcomes according to timing of birth after trial entry.

Considering the outcome RDS, the subgroup interaction test indicated a significant difference (Chi² = 6.39, P = 0.04, I² = 68.7%) ( Analysis 3.3), suggesting a possible differential treatment effect based on timing of delivery in favour of corticosteroids alone (as compared with TRH and corticosteroids) for babies born more than 10 days after trial entry (RR 1.33, 95% CI 1.05 to 1.68). This difference was not seen in either of the other two timing of birth subgroups, or in the main analysis.

 

Analysis restricted to mothers and babies receiving 'optimal treatment'

A secondary analysis was performed in order to allow the additional inclusion of data from three trials (Campos 1993; Ceriani 1992; Morales 1989) in which results were reported only for a subgroup of participants regarded as optimally treated by the respective trialists. Overall, 10 trials contributed data (ACTOBAT 1995; Ballard 1992b; Ballard 1998; Campos 1993; Ceriani 1992; Chile 1998; Europe 1999; Jikihara 1990; Knight 1994; Morales 1989) to the 'optimal treatment' subgroup. Optimal treatment was described variously by different authors. Morales 1989 presented outcome data for infants delivered within one week of the start of therapy, which represented only 40% of the total number of babies in the study. Ceriani 1992 reported data for infants fully treated (received all doses of TRH or corticosteroids, or both) and born within 10 days of entry. Campos 1993 reported the data on fully treated infants (received all doses of TRH or corticosteroids, or both) who were born within 48 hours of the last hormonal dose. The included data from ACTOBAT 1995; Ballard 1992b; Ballard 1998; Chile 1998; Europe 1999; Jikihara 1990 and Knight 1994 relate to infants born between 24 hours to 10 days after entry into the trial.

No beneficial effects of prenatal TRH were seen between groups for death prior to hospital discharge (RR 0.88, 95% CI 0.67 to 1.14, nine trials, 1465 infants) ( Analysis 4.1), chronic lung disease (RR 0.87, 95% CI 0.72 to 1.04, eight trials, 1318 infants) ( Analysis 4.2), RDS (average RR 0.89, 95% CI 0.77 to 1.03, 10 trials, 1786 infants; Tau² = 0.02; I² = 40%) ( Analysis 4.3), chronic lung disease or death (RR 0.96, 95% CI 0.84 to 1.09; five trials, 1317 infants) ( Analysis 4.4), the need for oxygen therapy (RR 0.99, 95% CI 0.91 to 1.09; one trial, 506 infants) ( Analysis 4.5), or for the use of respiratory support (RR 1.07, 95% CI 0.94 to 1.22; one trial, 506 infants) ( Analysis 4.7) for the optimally treated subgroup of infants. A statistically significant reduction in severe RDS was however observed for the infants exposed to TRH as compared corticosteroids alone when considering only optimally treated infants (RR 0.65, 95% CI 0.49 to 0.86; two trials, 694 infants) ( Analysis 4.6).

When we performed subgroup interaction tests comparing all treated infants versus only those considered 'optimally treated', no significant subgroup differences were observed between the two groups for the outcomes: death (Chi² = 1.12, P = 0.29, I² = 11.0%) ( Analysis 4.1), chronic lung disease (Chi² = 1.40, P = 0.24, I² = 28.6%) ( Analysis 4.2), RDS (Chi² = 2.47, P = 0.12, I² = 59.5%) ( Analysis 4.3), chronic lung disease or death (Chi² = 1.45, P = 0.23, I² = 31.0%) ( Analysis 4.4), the need for oxygen therapy (Chi² = 0.79, P = 0.37, I² = 0%) ( Analysis 4.5), severe RDS (Chi² = 2.26, P = 0.13, I² = 55.7%) ( Analysis 4.6), or for the use of respiratory support (Chi² = 0.74, P = 0.39, I² = 0%) ( Analysis 4.7) indicating no clear differential effects based on optimal treatment for these primary and pre-specified infant outcomes.

 

Sensitivity analysis by quality rating

Five trials (ACTOBAT 1995; Ballard 1998; Chile 1998; Europe 1999; Knight 1994), considered at a low risk of bias in the domains of sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting, were included in a sensitivity analysis.

No beneficial effects of prenatal TRH were seen for any of the primary infant outcomes of death (RR 1.03, 95% CI 0.84 to 1.25, five trials, 3570 infants) ( Analysis 5.1), chronic lung disease (RR 1.00, 95% CI 0.84 to 1.18, four trials, 2387 infants) ( Analysis 5.2), and RDS (RR 1.06, 95% CI 0.91 to 1.24, five trials, 3521 infants) ( Analysis 5.3), nor for any of the other pre-specified infant outcomes, including chronic lung disease or death (RR 1.05, 95% CI 0.94 to 1.17, five trials, 3570 infants) ( Analysis 5.4), the need for oxygen therapy (RR 1.05, 95% CI 0.97 to 1.13, four trials, 2387 infants) ( Analysis 5.5), and severe RDS (average RR 0.88, 95% CI 0.57 to 1.36, three trials, 2119 infants; Tau² = 0.11; I² = 73%) ( Analysis 5.6), as in the main analysis.

The significant increase in the use of respiratory support for infants exposed to TRH as compared with corticosteroids alone persisted in the sensitivity analysis (with data from the same three trials included: ACTOBAT 1995; Chile 1998; Europe 1999) (RR 1.16, 95% CI 1.03 to 1.29, three trials, 1969 infants) ( Analysis 5.7).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

This review does not show that prenatal administration of thyrotropin-releasing hormone (TRH), in addition to corticosteroids, prior to preterm birth reduces the risk of respiratory disease in infants born preterm, or reduces other infant morbidity or mortality. Indeed the data show that this treatment may have adverse effects for women and their infants. All maternal side effects reported in the included trials (nausea, vomiting, light headedness, urgency of micturition, facial flushing) were more likely to occur in women receiving TRH, although their clinical significance and women's perceptions of their importance have not been assessed. For the infants, prenatal TRH increased the risk of infants needing respiratory support, and of having a low Apgar score at five minutes.

In one of the three trials with follow-up data, prenatal TRH was associated with adverse neurodevelopmental outcomes in childhood (such as motor and social delay, and motor and sensory impairment) (ACTOBAT 1995). However, the other two trials that assessed neurodevelopmental outcomes at follow-up using an established developmental instrument (Bayley Infant Scales) (Chile 1998; Europe 1999), did not show any significant differences between groups on follow-up, apart from a significantly lower (worse) Mental Developmental Index for infants exposed to prenatal TRH at 24-month follow-up in one trial (Europe 1999), which was not confirmed in the second trial (Chile 1998).

The first two full trial reports published showed promising therapeutic effects of prenatal TRH, but reported neonatal outcome data only in minority subgroups of babies entered into the trials (Ballard 1992b; Morales 1989). However, a significant proportion of babies in all of the studies (49%) were born more than 10 days after trial entry. The data in this review show that these babies (born more than 10 days after trial entry), if exposed to prenatal TRH in addition to corticosteroids, were more likely to develop respiratory distress syndrome (RDS) compared with babies in the control group, who received only corticosteroids. This highlights the importance of 'intention-to-treat' analyses, and subgroup analyses in this review, since many of the studies excluded categories of babies. Even where data were available for all women who were randomised, results from subgroup analyses (e.g. by timing of treatment) are less reliable than overall analyses. However, it is important to show the data by subgroups since timing of treatment appears to be an important consideration.

The expectation was that the greatest beneficial effect of prenatal TRH would be seen in infants born between 24 hours and 10 days of trial entry as shown with antenatal corticosteroids alone (Liggins 1972). Infants exposed to TRH in this timed subgroup, and a similar 'optimal' timing subgroup, did show a reduced risk of severe RDS; however, subgroup interaction tests were not significant, and therefore no firm conclusion could be made regarding this particular group of infants. Intention-to-treat data for severe RDS were only available from three earlier trials for this timed subgroup (birth more than 24 hours and less than 10 days after first dose) (ACTOBAT 1995; Ballard 1992b; Knight 1994) and thus it would be important to include any further data on severe RDS from the more recent trials if they became available.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

Implications for practice

Based on the current available evidence, TRH should not be given to pregnant women at risk of preterm birth in an attempt to prevent neonatal respiratory disease.

This review found that prenatal TRH in addition to corticosteroids given to women at risk of preterm birth does not reduce the risk or severity of neonatal lung disease, may increase the chances of the infant needing respiratory support, and is associated with adverse side effects for the mother.

 
Implications for research

In the light of the evidence reviewed, no further randomised controlled trials are warranted.

Given the trend to adverse neonatal findings in babies who were born 10 days or more after trial entry, trials should aim to provide outcome and follow-up data on all babies recruited. Those trials that reported data on only minority subgroups of babies should consider retrieving outcome data on the other babies, in particular on mortality and longer-term morbidity.

Adverse maternal side effects of therapy were significant for women receiving prenatal TRH. The duration of the adverse effects, their clinical significance and the consumers' feelings about these have not been assessed.

Five of the trials included in this review have only been reported in abstract form (Abuhamad 1999; Carlan 1991; Ceriani 1992; Jikihara 1990; Kim 2000). One trial using 400 μg TRH treatment dosage was planned in the USA in 1997 and stopped without enrolling (Yoder 1997). Another trial of TRH administration after prelabour rupture of membranes preterm was reported as planned in 1997 (Pearlman 1997).

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Professor Adrian Grant compiled the first version of this review published in 1989. We are very grateful to the people who responded to our requests for further information including Professor Yoder and Professor Abuhamad and to the investigators of all the trials who provided additional unpublished information, particularly Professor RA Ballard, Professor M Bracken, Professor JE Hiller, Dr H Jikihara, Dr DB Knight and Professor FR Moya.

We thank Emily Bain and Philippa Middleton from the Australian Research Centre for Health of Women and Babies at The University of Adelaide for assisting with this update of the review.

As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
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]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Appendix 1. Search strategy for additional author searching

For the previous version of the review (Crowther 2004), we searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2009, Issue 2), MEDLINE (1965 to 13 July 2009) and EMBASE (1988 to 13 July 2009) using the terms 'thyrotropin-releasing hormone' or 'TRH'.

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 17 July 2013.


DateEventDescription

17 July 2013New citation required but conclusions have not changedNew search for eligible studies; four reports identified, no new studies included. Follow-up data for one trial incorporated (Chile 1998). Two previously excluded trials (excluded based on no relevant outcome data) have been included (Crowther 1995; Voto 1998). Methods updated.

17 July 2013New search has been performedReview updated.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Protocol first published: Issue 2, 1995
Review first published: Issue 2, 1995


DateEventDescription

12 July 2009New search has been performedNew search for eligible studies; no new studies identified. One new report of a previously published trial added (for Ballard 1992a). 'Risk of bias' tables updated. Authors of two studies previously reported as ongoing were contacted (Pearlman 1997; Yoder 1997).

10 November 2008AmendedContact details updated.

30 October 2008AmendedConverted to new review format.

5 February 2004New citation required but conclusions have not changedTwo more trials have been included and three excluded, in this update. The review has been edited in response to editorial comments. However, the conclusions remain largely unchanged.

31 July 2003New search has been performedNew studies found and included or excluded.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

For this update, CA Crowther assessed identified studies for eligibility and prepared the new format text of the review, with assistance from SS Han. All review authors contributed to the final version of this updated review.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

CA Crowther and RR Haslam were two of the chief investigators for the Australian Collaborative Trial of thyrotropin-releasing hormone (ACTOBAT 1995) and the Crowther 1995 trial; and Z Alfirevic was one of the principal investigators for the European TRH trial (Europe 1999). Therefore, all tasks relating to these studies (assessment of eligibility for inclusion, assessment of risk of bias, and data extraction) were carried out by other members of the review team who were not directly involved in the trials.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Internal sources

  • ARCH, Robinson Institute, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Australia.
  • Division of Perinatal and Reproductive Medicine, The University of Liverpool, UK.
  • Department of Perinatal Medicine, Women's and Children's Hospital, Adelaide, Australia.

 

External sources

  • National Health and Medical Research Council, Australia.
  • Department of Health and Ageing, Australia.

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

In this update, we have reduced the number of primary infants outcomes to three (death prior to hospital discharge, chronic lung disease (variously defined by authors), and respiratory distress syndrome), and the other outcomes have been moved to 'secondary outcomes'.

We have clarified that in relation to follow-up outcomes, the definitions are 'variously defined by authors'. We have changed the wording for the outcome 'need for oxygen therapy at 28 days' to 'chronic lung disease (variously defined by authors)' to be more inclusive.

We have updated the review methods.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Abuhamad 1999 {published data only}
  • Abuhamad A, Green G, Heyl P, de Veciana M. The combined use of corticosteroids and thyrotropin releasing hormone in pregnancies with preterm rupture of membranes: a randomised double blind controlled trial. American Journal of Obstetrics and Gynecology 1999;180(1 Pt 2):S96.
ACTOBAT 1995 {published and unpublished data}
  • Crowther C, Hiller J, Haslam R, Robinson J, the ACTOBAT Study Group. Australian Collaborative Trial of Betamethasone and TRH for the prevention of neonatal respiratory disease (ACTOBAT). International Journal of Gynecology and Obstetrics 1994;46:59.
  • Crowther CA, Hiller JE, Haslam RR, Robinson JS, the ACTOBAT Study Group. Australian collaborative trial of antenatal thyrotropin-releasing hormone: Adverse effects at 12-month follow-up. Pediatrics 1997;99:311-7.
  • Hiller JE, Crowther CA, Haslam RR, Robinson JS, the ACTOBAT Study Group. Australian collaborative trial af antenatal thyrotropin-releasing hormone (ACTOBAT): 12 month follow-up. 4th Annual Congress of the Perinatal Society of Australia & New Zealand; 1998 March 30-April 4; Alice Springs, Australia. Alice Springs, 1998:77.
  • The ACTOBAT Study Group. Australian collaborative trial of betamethasone and thyrotropin releasing hormone (ACTOBAT) for the prevention of neonatal respiratory disease. Lancet 1995;345:877-82.
Ballard 1992b {published and unpublished data}
  • Ballard PL, Ballard RA, Creasy RK, Padbury J, Polk DH, Bracken M, et al. Plasma thyroid hormones and prolactin in premature infants and their mothers after treatment with thyrotropin-releasing hormone. Pediatric Research 1992;32(6):673-8.
  • Ballard RA, Ballard PL, Creasy R, Gross I, Main D, Padbury JF, et al. Prenatal treatment with thyrotropin releasing hormone plus corticosteroid: absence of maternal, fetal or neonatal side effects. Clinical Research 1990;38:192A.
  • Ballard RA, Ballard PL, Creasy R, Gross I, Main D, Padbury JF, et al. Prenatal treatment with thyrotropin releasing hormone plus corticosteroid: absence of maternal, fetal or neonatal side effects. Pediatric Research 1991;29:202A.
  • Ballard RA, Ballard PL, Creasy R, Gross I, Padbury JF, TRH Study Group. Thyrotropin releasing hormone plus corticosteroids decreases chronic lung disease in very low birth weight infants. Pediatric Research 1991;29(4):1828A.
  • Ballard RA, Ballard PL, Creasy R, Padbury J, Polk DH, Bracken M, et al. Respiratory disease in very-low birthweight infants after prenatal thyrotropin-releasing hormone and glucocorticoid. Lancet 1992;339:510-5.
Ballard 1998 {published data only}
  • Ballard PL, Ballard RA, Ning Y, Cnann A, Boardman C, Pinto-Martin J, et al. Plasma thyroid hormones in premature infants: effect of gestational age and antenatal thyrotropin-releasing hormone treatment. Pediatric Research 1998;44:642-9.
  • Ballard RA, Ballard PL, Boardman C, Cnaan A, Davis DJ, Hart MC, et al. Antenatal thyrotropin releasing hormone (TRH) for the prevention of chronic lung disease (CLD) in the preterm infant. Pediatric Research 1997;41:246A.
  • Ballard RA, Ballard PL, Cnaan A, Pinto-Martin J, Davis DJ, Padbury JF, et al. Antenatal thyrotropin-releasing hormone to prevention lung disease in preterm infants. New England Journal of Medicine 1998;338:493-8.
Campos 1993 {published data only}
  • Campos G, Herrman F, Dorner M. Combined hormonal therapy for the prevention of respiratory distress syndrome and its consequences. Seminars in Perinatology 1993;17(4):267-74.
Carlan 1991 {published data only}
  • Carlan SJ, Parsons M, O'Brien WF, Krammer J. Pharmacologic pulmonary maturation in preterm premature rupture of membranes. American Journal of Obstetrics and Gynecology 1991;164:371.
Ceriani 1992 {published data only}
  • Althabe F, Fustihara C, Althabe O, Cernades JMC. Controlled trial of prenatal betamethasone plus TRH vs betamethasone plus placebo for prevention of RDS in preterm infants. Pediatric Research 1991;29:200A.
  • Ceriani Cernadas J, Fustihara C, Althabe F, Althabe O. Controlled trial of prenatal betamethasone (B) plus TRH for prevention of respiratory distress syndrome (RDS) in preterm infants. Pediatric Research 1992;32:738.
Chile 1998 {published data only}
  • Collaborative Santiago Surfactant Group. Collaborative trial of prenatal thyrotropin-releasing hormone and corticosteroids for prevention of respiratory distress syndrome. American Journal of Obstetrics and Gynecology 1998;178:33-9.
  • Maturana A, Torres J, Salinas R, Moya F, for the Collaborative Group. Controlled trial of prenatal thyrotropin-releasing hormone (TRH) and betamethasone (B) for prevention of respiratory distress syndrome (RDS). Pediatric Research 1997;41:163A.
  • Reyes G, Gonzalez AR, Gomez G, Blasini I, Rivera CE. Comparative study of the effectiveness of thyroxine and steroids on reduction of neonatal morbidity: outcome at 20 months follow-up. Puerto Rico Health Sciences Journal 2004;23(1):9-12.
  • Santiago R, Romaguera J. Steroids vs steroids and thyroxine to accelerate fetal maturation of patients in arrested preterm labor. Puerto Rico Health Sciences Journal 1999;18:156.
Crowther 1995 {published data only}
  • Crowther C, Haslam R, Hiller J, McGee T, Ryall R, Robinson J. Thyrotropin-releasing hormone: Does two hundred micrograms provide effective stimulation to the preterm fetal pituitary gland compared with four hundred micrograms?. American Journal of Obstetrics and Gynecology 1995;173:719-23.
  • Crowther CA, Haslam RR, Hiller JE, McGee T, Robinson JS. Thyrotrophin releasing hormone (TRH) and lung maturation: does 200mcg TRH provide effective stimulation to the preterm fetal pituitary gland compared with 400mcg TRH?. International Journal of Gynecology and Obstetrics 1991;36 Suppl:32.
Europe 1999 {unpublished data only}
  • Alfirevic Z, Boer K, Brocklehurst P, Buimer M, Elbourne D, Kok J, et al. Two trials of antenatal thyrotrophin-releasing hormone for fetal maturation: stopping before the due date. British Journal of Obstetrics and Gynaecology 1999;106:898-906.
  • Alfirevic Z, Elbourne D, Brocklehurst P, Truesdale A, Neilson J. Randomised controlled trial of antenatal administration of thyrotropin releasing hormone (TRH) to women at risk of premature delivery. Prenatal and Neonatal Medicine 1996;1(1):10.
  • Briet JM, van Sonderen L, Buimer M, Boer K, Kok JH. Neurodevelopmental outcome of children treated with antenatal thyrotropin-releasing hormone. Pediatrics 2002;110(2 Pt 1):249-53.
  • Brocklehurst P. Antenatal thyrotropin-releasing hormone for fetal maturity: two concurrent randomised controlled trials (The Antenatal TRH Trial and the Thyroneth Trial). British Journal of Obstetrics and Gynaecology 1998;105:81.
Jikihara 1990 {published and unpublished data}
  • Jikihara H, Sawada Y, Imai S, Morishige K, Taniguchi T, Nohara A, et al. Maternal administration of thyrotropin-releasing hormone for prevention of neonatal respiratory distress syndrome. Proceedings of 6th Congress of the Federation of the Asia-Oceania Perinatal Societies; 1990 Oct 22-26; Perth, Western Australia. 1990:87.
Kim 2000 {published data only}
  • Kim EA, Park SJ, Yoon HS, Kim KS, Won HS, Lee IS, et al. Antenatal thyrotropin-releasing hormone to prevent respiratory distress syndrome in Korean preterm. Pediatric Academic Societies Annual Meeting; 2000 May 12-16; Boston, MA, USA. 2000.
  • Kim EA, Park SJ, Yoon HS, Kim KS, Won HS, Lee IS, et al. Antenatal thyrotropin-releasing hormone to prevent respiratory distress syndrome in Korean preterm. Pediatric Research 2000;47:407A.
Knight 1994 {published and unpublished data}
  • Knight DB, Liggins GC, Wealthall SR. A randomised controlled trial of the effect of thyrotropin-releasing hormone with betamethasone in mothers likely to deliver prematurely on neonatal outcome. Proceedings of the Australian Perinatal Society; 1992; Queensland, Australia. 1992:A9.
  • Knight DB, Liggins GC, Wealthall SR. A randomized, controlled trial of antepartum thyrotropin-releasing hormone and betamethasone in the prevention of respiratory disease in preterm infants. American Journal of Obstetrics and Gynecology 1994;171:11-6.
  • Knight DB, Wealthall SR, Liggins GC, Howie RN. A randomised double blind controlled trial of antepartum TRH with betamethasone in the prevention of neonatal respiratory disease. New Zealand Medical Journal 1989;102:195.
  • Liggins GC, Knight DB, Wealthall SR, Howie RN. A randomized double-blind trial of antepartum TRH and steroids in the prevention of neonatal respiratory disease. Clinical reproductive medicine - the Liggins years; 1988 July 29-30; Auckland, New Zealand. 1988.
Morales 1989 {published data only}
  • Morales WJ, O'Brien WF, Angel JL, Knuppel RA, Sawai S. Fetal lung maturation: the combined use of corticosteroids and thyrotropin-releasing hormone. Obstetrics and Gynecology 1989;73:111-6.
Voto 1998 {published data only}
  • Voto L, Lede R, Scaglia H, Zylberstein C, Zapasterio J, Orti J, et al. Effects of maternal administration of betamethasone, with and without TRH, on serum PRL, TSH and iodothyronine levels in Rh-isoimmunized fetuses: a randomized clinical trial. Prenatal and Neonatal Medicine 1998;3:447-51.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Devlieger 1997 {published data only}
  • Devlieger R, Vanderlinden S, de Zegher F, Van Assche FA, Spitz B. Effect of antenatal thyrotropin-releasing hormone on uterine contractility, blood pressure, and maternal heart rate. American Journal of Obstetrics and Gynecology 1997;177(2):431-3.
  • Spitz B, Devlieger R, Van Assche FA. Antenatal TRH-treatment: effects on uterine contractions, blood pressure and maternal heart rate. 10th World Congress of the International Society for the Study of Hypertension in Pregnancy; 1996 August 4-8; Seattle, Washington, USA. 1996:191.
Dola 1997 {published data only}
  • Dola C, Nageotte P, Rumney P, Towers C, Asrat T, Freeman R, et al. The effects of antenatal treatment with betamethasone and thyrotropin-releasing hormone (TRH) in patients with preterm premature rupture of the membrane (PPROM). American Journal of Obstetrics and Gynecology 1997;176:549.
  • Jackson D, Nageotte M, Towers C, Asrat T, Freeman R, Gardner K, et al. Thyroid-releasing hormone (TRH) versus betamethasone or placebo in preterm premature ruptured membranes: a prospective randomised study. American Journal of Obstetrics and Gynecology 1991;170:383.
Roti 1990 {published data only}
  • Roti E, Gardini E, Minelli R, Bianconi L, Alboni A, Braverman LE. Thyrotropin releasing hormone does not stimulate prolactin release in the preterm human fetus. Acta Endocrinologica 1990;122(4):462-6.
Torres 1994 {published data only}
Torres 1995 {published data only}
  • Torres J, Foradori A, Salinas R, Poblete JP, Maturana A, Roman A, et al. Dose related response of the fetal pituitary-thyroid axis to maternal administration of thyrotropin-releasing hormone (TRH). Pediatric Research 1995;2:241A.
Yoder 1997 {published data only}
  • Yoder BA. Trial to compare antenatal steroids alone, TRH alone, steroids + TRH and placebo in infants <32 weeks' gestation. Personal communication 1997.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Ballard 1992a
  • Ballard PL, Ballard RA, Creasy RK, Padbury J, Polk DH, Bracken M, et al. Plasma thyroid hormones and prolactin in premature infants and their mothers after treatment with thyrotropin-releasing hormone. Pediatric Research 1992;32(6):673-8.
Crowther 2011
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Jackson 1982
Li 2012
  • Li Z, Zeki R, Hilder L, Sullivan EA. Australia's Mothers and Babies 2010. Perinatal statistics series no. 27. Cat. no. PER 57. Canberra: AIHW National Perinatal Epidemiology and Statistics Unit, 2012.
Liggins 1972
  • Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25.
Liggins 1988
  • Liggins GC, Schellenberg JC, Manzai M, Kitterman JA, Lee CC. Synergisms of cortisol and thyrotropin releasing hormone in lung maturation in fetal sheep. Journal of Applied Physiology 1988;65:1880-4.
Moore 2012
  • Moore T, Hennessy EM, Myles J, Johnson SJ, Draper ES, Costeloe KL, et al. Neurological and developmental outcome in extremely preterm children born in England in 1995 and 2006: the EPICure studies. British Medical Journal 2012;345:e7961.
Nassar 2001
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References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to ongoing studies
  22. Additional references
  23. References to other published versions of this review
Crowther 1991
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Crowther 1995
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Crowther 1997
  • Crowther CA, Alfirevic Z, Haslam RR. Antenatal thyrotropin-releasing hormone (TRH) prior to preterm delivery. In: Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, Keirse MJNC (eds.) Pregnancy and Childbirth Module of The Cochrane Database of Systematic Reviews, [updated 03 June 1997]. Available in The Cochrane Library [database on disk and CDROM]. The Cochrane Collaboration; Issue 3. Oxford: Update Software; 1997. Updated quarterly.
Crowther 1999
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