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Postnatal thyroid hormones for respiratory distress syndrome in preterm infants

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Authors

Osborn DA, Hunt RW

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 14/11/2006
Date of last substantive update: 16/10/2006
Date of last minor update: / /
Date next stage expected 30/11/2008
Protocol first published: Issue 2, 2006
Review first published: Issue 1, 2007

Contact reviewer

Dr David A Osborn

Neonatologist
RPA Newborn Care
Royal Prince Alfred Hospital
Missenden Road
Camperdown
New South Wales AUSTRALIA
2050
Telephone 1: +61 2 95158363
Facsimile: +61 2 95504375

E-mail: david.osborn@email.cs.nsw.gov.au

Contribution of reviewers

Both authors contributed to all components of protocol and review. Both authors independently assessed trial eligibility and quality and extracted data.

Internal sources of support

RPA Newborn Care, Royal Prince Alfred Hospital, Sydney, AUSTRALIA
Department of Neonatal Medicine, Royal Children's Hospital, Melbourne, AUSTRALIA

External sources of support

Centre for Perinatal Health Services Research, University of Sydney, AUSTRALIA
NHMRC Grant ID 216757, AUSTRALIA

What's new

  • None noted.

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Synopsis

In preterm infants with breathing problems after birth, there is no evidence that thyroid hormone treatment given immediately after delivery reduces the severity of breathing difficulties or improves outcomes.

Infants born prematurely are at risk of breathing problems due to lack of surfactant production by the lungs in the first days after birth. In animal research, thyroid hormones given before birth stimulate surfactant production and reduce the incidence and severity of breathing problems. This review found two small trials that compared the use of thyroid hormones to no treatment in infants with breathing problems in the first hours after birth. No benefit was found from use of these hormones on severity of breathing problems or complications that occurred as a result of these breathing problems. The effect on longer term development was not reported.

Abstract

Background

Preterm infants with respiratory distress syndrome are at increased risk of adverse neonatal and developmental outcomes. In animal research, thyroid hormones stimulate surfactant production and reduce the incidence and severity of respiratory distress when given antenatally.

Objectives

To determine whether thyroid hormone therapy used postnatally in preterm infants with suspected respiratory distress syndrome results in clinically important improvements in respiratory morbidity and subsequent improvements in neonatal and long term outcomes.

Search strategy

Searches were performed of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), PREMEDLINE (March 2006), EMBASE (1980 - March 2006), previous reviews including cross references, abstracts and conference proceedings, supplemented by requests to expert informants.

Selection criteria

Trials that enrolled preterm infants with suspected respiratory distress syndrome and allocated infants thyroid hormone treatment compared to control commenced in the first 48 hours after birth.

Data collection & analysis

Independent assessment of trial quality and data extraction by each author. Synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration and its Neonatal Review Group.

Main results

Two studies enrolled preterm infants with respiratory distress. Amato (1988) allocated infants to L-thyroxine 50 μg/dose at 1 and at 24 hours or no treatment. Amato (1989) allocated infants to L-triiodothyronine 50 μg/day in two divided doses for two days or no treatment. Both studies had methodological concerns including quasi-random methods of patient allocation, no blinding of treatment or measurement and substantial post allocation losses. Neither study reported any significant benefits in neonatal morbidity or mortality from use of thyroid hormones. Meta-analysis of two studies (80 infants) found no significant difference in mortality to discharge (typical RR 1.00, 95% CI 0.47, 2.14). Amato 1988 reported no significant difference in use of mechanical ventilation (RR 0.64, 95% CI 0.38, 1.09). No significant effects were found in use of mechanical ventilation, duration of mechanical ventilation, air leak, CLD at 28 days in survivors, patent ductus arteriosus, intraventricular haemorrhage or necrotising enterocolitis. Neurodevelopment was not reported.

Reviewers' conclusions

There is no evidence from controlled clinical trials that postnatal thyroid hormone treatment reduces the severity of respiratory distress syndrome, neonatal morbidity or mortality in preterm infants with respiratory distress syndrome.

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Background

Preterm birth is a leading cause of perinatal morbidity and mortality (Laws 2004). Pulmonary immaturity, manifesting as respiratory distress syndrome (RDS), contributes substantially to this problem. Despite the proven efficacy of antenatal corticosteroids in preventing RDS, they are not effective at preventing all cases of RDS and are limited by the time required to exert an effect on lung maturation and surfactant production before preterm birth (Crowley 1996; Roberts 2006). Experimental studies have shown other hormones, including thyroid hormones, have an effect on lung growth and surfactant production, although not all effects are positive (Keijzer 2000). Human foetal lungs contain high levels of triiodothyronine (T3) receptors (Bernal 1984) and T3 receptors have been demonstrated in rat adult type II pneumocytes that secrete surfactant (Smith 1983). In animal models, thyroid hormones stimulate surfactant release synergistically with corticosteroids, but may have negative effects on surfactant synthesis. Schellenberg 1987 (The Liggins' group) reported that simultaneous infusion of cortisol, triiodothyronine and prolactin produced mature lungs in foetal sheep of preterm gestation. Similar results were obtained with thyrotropin releasing hormone (TRH) and cortisol. However, other combinations of cortisol, triiodothyronine and prolactin did not have the same effects (Schellenberg 1987). The use of thyroid hormones has the potential to stimulate surfactant release and reduce respiratory morbidity in preterm infants with RDS.

Some infants have low thyroid hormone levels at birth (as measured on cord blood samples), and have reduced postnatal surges of thyroid hormones in the first hours after birth. The levels of thyroid hormones in cord blood, including T4, free T4 (FT4) and T3, are lowest in those infants born at the lowest gestations, with cord blood T4 and FT4 two to three-fold higher in term infants than those born at 25 to 27 weeks (Oden 2002). In a cohort study, van Wassenaer 1997 reported that sick infants (with RDS requiring mechanical ventilation) failed to have the normal first day total T4 surge, had a FT4 surge that was quantitatively less than seen in healthy infants, had cord blood T3 levels similar to healthy infants, but had a T3 surge that was lower than in the healthy group. Low levels cord blood T3, free T3 and FT4 have also been reported in premature infants born to preeclamptic mothers with placental insufficiency (Belet 2003).

Antenatal or postnatal thyroid hormones or thyrotropin releasing hormone (TRH) have been used in an attempt to reduce respiratory morbidity. However, thyroid hormones do not cross the placenta in sufficient quantity to stimulate foetal lung development. As a result, TRH given to the mother to stimulate the foetal thyroid axis or thyroid hormones instilled into the amniotic fluid have been used. However, a systematic review (Crowther 2004) of five trials of antenatal TRH in addition to corticosteroids in women at risk of preterm delivery found TRH did not reduce the risk of neonatal respiratory disease, chronic oxygen dependence or any other foetal, neonatal or childhood outcome. In fact, antenatal TRH increased the risk of infants needing ventilation and was associated with poorer outcomes at childhood follow up. One potential explanation is that although antenatal TRH administration increases thyroid hormones and prolactin in preterm fetuses to levels similar to those normally occurring at term, the pituitary-thyroid axis is transiently suppressed after treatment in the foetus. Infants born during this early phase of suppression do not have the normal postnatal surge in thyroid hormones (Ballard 1992). Intra-amniotic injection of thyroid hormone has also been described in case series with apparent improvement in foetal lung maturity, but no adequate controlled trial has been reported to date (Romaguera 1993). Although antenatal strategies using thyroid hormones to promote lung maturity have not resulted in substantial proven benefits, it is possible that giving thyroid hormones to preterm infants with severe RDS may produce a surge in thyroid hormone similar to what occurs in healthy preterm infants, with a resultant increase in surfactant production, improvement in respiratory function and subsequent reduction in neonatal morbidity and mortality. Neonatal morbidity that may be expected to be improved by a reduction in severity of RDS includes duration of mechanical ventilation and oxygen therapy, reduction in chronic lung disease and peri/intraventricular haemorrhage. Thyroid hormones have substantial other effects and are important for energy metabolism, metabolism of nutrients and inorganic ions, thermogenesis, and for stimulation of growth and development of various tissues at critical periods including the central nervous system and skeleton (Ogilvy-Stuart 2002). As such, it is important to examine the short and long term effects of thyroid hormone supplementation on growth and neurodevelopment.

This review examines the evidence from randomised and quasi-randomised controlled trials of thyroid hormone therapy in preterm infants with respiratory distress for improvement of respiratory morbidity and subsequent neonatal morbidity and mortality. Separate reviews address the use of prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants (Osborn 2007a), and postnatal thyroid hormones for treatment of preterm infants with transient hypothyroxinaemia (Osborn 2007b).

Objectives

To determine the effect of postnatal thyroid hormone therapy in preterm infants with suspected respiratory distress syndrome on clinically important respiratory morbidity, neonatal morbidity and long term outcomes.

Subgroup analysis was planned to investigate the evidence for the use of different thyroid hormone preparations, doses and timing of treatment; evidence for a gestational specific effect of treatment and evidence for differences in effect according to study quality. As thyroid hormones may act synergistically with corticosteroids, analysis of trials that used a combination of early postnatal thyroid hormones and corticosteroids were planned separately.

Criteria for considering studies for this review

Types of studies

Trials using random or quasi-random patient allocation to treatment or control.

Types of participants

Preterm infants (< 37 weeks) in the early neonatal period (< 48 hours) with suspected respiratory distress syndrome (on the basis of prematurity and requiring early respiratory support).

Types of interventions

Thyroid hormone therapy compared to control (placebo or no therapy) commenced in the first 48 hours after birth. Thyroid hormone therapy could be either T4, T3 or both. Trials that compared different thyroid hormone regimens were also be included. Trials that used a combination of early postnatal thyroid hormones and corticosteroids were considered separately.

Types of outcome measures

Primary clinical outcome measures:

  1. Chronic lung disease defined as:
    • oxygen or respiratory support at 28 days post-natal age or
    • oxygen or respiratory support near term (36 - 40 weeks post-menstrual age)
  2. All cause mortality (either neonatal or to discharge)
  3. Abnormal neurodevelopmental outcome:
    • Abnormal mental development after 12 months corrected age (a validated development or intelligence quotient greater than/or equal to 2 standard deviations below the mean of a standardised test)
    • Abnormal neurological outcome (infants with either abnormal mental development or definite cerebral palsy)
    • Motor deficits
    • Sensorineural impairments (hearing deficit requiring aids or visual acuity < 6/60)

Secondary outcome measures included important neonatal morbidities and measures of potential adverse effects of thyroid hormone treatment:

  1. Severity of respiratory disease (use of IPPV or CPAP, maximum ventilation requirements, use of rescue therapies including nitric oxide, HFOV or ECMO, incidence of air leak, duration of mechanical ventilation)
  2. Intraventricular haemorrhage diagnosed by ultrasound or postmortem:
    1. all (Papile grades 1 to 4) and
    2. severe (Papile grade 3 or 4)
  3. Periventricular leucomalacia diagnosed by ultrasound or postmortem
  4. MRI detected white matter abnormality near term postmenstrual age
  5. Symptomatic patent ductus arteriosus (PDA) after day three of life treated by indomethacin or ibuprofen or ligation
  6. Necrotizing enterocolitis (at least stage 2 Bell's criteria)
  7. Retinopathy of prematurity including all stages and severe (stage 3 or greater)
  8. Growth including growth in weight (g/kg/day), head circumference (cm/week) and length (cm/week)
  9. Adverse effects of thyroid hormones including tachycardia, pyrexia or cardiovascular collapse
  10. Abnormal thyroid hormone levels in the neonatal period (< 28 days) (T4, free T4, T3 and free T3)

Search strategy for identification of studies

The standard search strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), PREMEDLINE (March 2006), EMBASE (1980 - March 2006), previous reviews including cross references, abstracts, conferences (SPR-PAS and PSANZ 1998 - 2005), expert informants (authors of published trials and neonatologists) and journal handsearching in the English language.

MEDLINE was searched using MeSH terms '(infant-newborn or infant-premature) and (thyroxine or triiodothyronine)' and text words using '(hypothyroxinemia or hypothyroxinaemia or thyroxine or triiodothyronine) and [MeSH terms] (infant-newborn or infant-premature)'. EMBASE and PREMEDLINE using terms ('hypothyroxinemia or hypothyroxinaemia or thyroxine or triiodothyronine') and 'newborn'. The Oxford Database of Perinatal Trials was searched using the term 'thyroid disease', and the Cochrane Central Register of Controlled Trials using 'thyroxine or triiodothyronine or hypothyroxinemia or hypothyroxinaemia'. No language restriction was applied. Abstracts of trials were eligible for inclusion.

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Methods of the review

Independent assessment of trial quality and data extraction was performed by both authors, with synthesis of data using relative risk (RR) and weighted mean difference (WMD) using standard methods of the Cochrane Collaboration and its Neonatal Review Group. Each identified trial was assessed for methodological quality with respect to

  1. masking of allocation
  2. masking of intervention
  3. completeness of follow up
  4. masking of outcome assessment

Attempts were made to contact authors of studies where details of methodology were unclear. Data was synthesised using relative risk (RR), risk difference (RD) and weighted mean difference (WMD) where appropriate. From 1/RD the number needed to treat (NNT) for benefits and the number needed to harm (NNH) for adverse effects were calculated. All results given include 95% confidence intervals unless otherwise stated. A fixed effects analysis was used. Heterogeneity was examined using the I-squared statistic. In a previous version of this review (Osborn 2001), an attempt was made to contact the authors of the included studies without success.

Separate comparisons were prespecified for the following:

  1. Postnatal thyroid hormones (any type of preparation) versus control (no treatment or placebo), all dosing strategies
  2. Postnatal thyroid hormones (any type of preparation) versus control (no treatment or placebo), according to dosing strategy used
  3. Postnatal thyroid hormones versus other thyroid hormone strategy (e.g. T3 and T4 versus T4 alone)
  4. Postnatal thyroid hormones (any type of preparation) combined with corticosteroids versus control (no treatment or placebo)
  5. Postnatal thyroid hormones (any type of preparation) combined with corticosteroids versus corticosteroids alone

Subgroup analysis was prespecified to determine if there is a gestational age effect of thyroid hormone treatment with separate analysis of trials enrolling infants:

  1. < 28 weeks gestation
  2. 28 - 31 weeks gestation
  3. > 31 weeks gestation

Subgroup analysis was prespecified for those trials using adequate methodology as defined by the use of a random method of allocation to treatment or control, if steps were taken to ensure allocation concealment, if there was adequate blinding or treatment and if there was at least 90% follow up of survivors.

Description of studies

Thirteen reports were excluded (see 'Table of excluded Studies'). Five excluded trials (Biswas 2003; Smith 2000; Valerio 2004; van Wassenaer 1997; Vanhole 1997) enrolled preterm infants on the basis of gestational age criteria, not on respiratory criteria. Four of these trials (Smith 2000; Valerio 2004; van Wassenaer 1997; Vanhole 1997) are included in the review of 'Prophylactic postnatal thyroid hormone treatment for prevention of morbidity and mortality in preterm infants' (Osborn 2007a). Biswas 2003 randomised preterm infants to hydrocortisone and thyroid hormone treatment, and it is excluded from all reviews. None of these studies reported infants with respiratory distress syndrome separately. One excluded trial (Chowdhry 1984) enrolled infants with transient hypothyroxinaemia, and is included in the review 'Thyroid hormones for treatment of transient hypothyroxinaemia in preterm infants' (Osborn 2007b). Two studies (Amato 1988; Amato 1989) enrolling infants with respiratory distress at one hour of age were included

Infants: Amato 1988 enrolled infants 29 - 34 weeks gestation with respiratory distress syndrome (signs of respiratory distress, FiO2 > 0.5, chest x-ray appearance). Use of antenatal steroids was not reported. Amato 1989 enrolled infants < 32 weeks gestation with respiratory distress syndrome (respiratory distress and chest x-ray changes, FiO2 > 0.4) and no antenatal steroids.

Treatment: Amato 1988 allocated infants to L-thyroxine 50 μg/dose IV at one and at 24 hours, or no treatment. Amato 1989 allocated infants to L-triiodothyronine 50 μg/day IV in two divided doses for two days or no treatment.

Outcomes: Amato 1988 reported mortality to discharge, peak oxygen concentrations, duration mechanical ventilation, bronchopulmonary dysplasia (Northway criteria: O2 at 28 days and chest x-ray changes) and TSH, T4 and T3 levels before and on day five. Amato 1989 reported mortality to discharge, peak oxygen concentrations, duration mechanical ventilation, periventricular haemorrhage, air leak, chronic lung disease (O2 at 28 days), patent ductus arteriosus, necrotising enterocolitis and retinopathy of prematurity (cicatricial disease only). Neither study reported neurodevelopmental outcomes.

Methodological quality of included studies

Both studies had inadequate allocation concealment. Amato 1988 and Amato 1989 reported alternate assignment to treatment or control, and did not report blinding of intervention or measurement of outcome. Amato 1988 reported 12 / 48 (24%) post-allocation exclusions (five treatment and seven controls) of infants without RDS. Amato 1989 reported 6 / 50 (12%) post-randomisation exclusions (three treatment and three controls).

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Results

Comparison 01: Thyroid hormones versus no thyroid hormones (all studies):

Neither study reported any significant benefits in neonatal morbidity or mortality from use of thyroid hormones. Meta-analysis of two studies (80 infants) found no significant difference in mortality to discharge (typical RR 1.00, 95% CI 0.47, 2.14). Amato 1988 reported no significant difference in use of mechanical ventilation (RR 0.64, 95% CI 0.38, 1.09). Amato 1989 reported no significant difference in air leak (RR 0.75, 95% CI 0.19, 2.97). Meta-analysis of two studies found no significant difference in duration of mechanical ventilation (WMD -1.64 days, 95% CI -4.68, 1.39) or CLD at 28 days in survivors (typical RR 0.58, 95% CI 0.26, 1.33). Amato 1989 reported no significant difference in patent ductus arteriosus (RR 1.14, 95% CI 0.50, 2.61), intraventricular haemorrhage (RR 1.33, 95% CI 0.34, 5.28) or necrotising enterocolitis (RR 0.33, 95% CI 0.01, 7.76). No significant heterogeneity was found.

Subgroup analyses according to gestational age strata:

  1. < 28 weeks gestation: no study enrolled infants < 28 weeks.
  2. 28 - 31 weeks gestation: Amato 1989 enrolled infants < 32 weeks gestation (results as above). No significant benefits reported.
  3. > 31 weeks gestation: Amato 1988 enrolled infants 29 - 34 weeks (results as above). No significant benefits reported.

Subgroup analysis of trials using adequate methodology:

Neither study met prespecified criteria for adequate methodology.

Comparison 02: Postnatal thyroid hormones versus control according to dosing strategy used:

  • Amato 1988 allocated infants to L-thyroxine 50 μg/dose at one hour and 24 hours or no treatment. No significant difference was reported for mortality to discharge (RR 1.00, 95% CI 0.15, 6.48), air leak (RR 0.75, 95% CI 0.19, 2.17), duration of mechanical ventilation (MD -2.10, 95% CI -5.25, 1.05), CLD at 28 days in survivors (RR 0.67, 95% CI 0.22, 2.04), patent ductus arteriosus (RR 1.14, 95% CI 0.50, 2.61), intraventricular haemorrhage (RR 1.33, 95% CI 0.34, 5.28) or necrotising enterocolitis (RR 0.33, 95% CI 0.01, 7.76). A significant increase in T4 was reported in infants receiving thyroxine (T4 [sd] before: 74 [37] nmol/l; day five: 194 [43] nmol/l, p < 0.05) but control infants were not reported. No significant difference in T3 or TSH level was reported. Free T4 and free T3 were not assessed.
  • Amato 1989 allocated infants to L-triiodothyronine 50 μg/day in two divided doses for two days or no treatment. No significant difference was reported for mortality to discharge (RR 1.00, 95% CI 0.44, 2.27), mechanical ventilation (RR 0.64, 95% CI 0.38, 1.09), duration of mechanical ventilation (MD 4.50, 95% CI -7.04, 16.04) or CLD at 28 days in survivors (RR 0.50, 95% CI 0.15, 1.70). A significant increase in T3 was reported in infants receiving triiodothyronine (T3 before 0.58 [0.23] nmol/l; day five: 1.55 [1.74] nmol/l, p < 0.01) but control infants were not reported. No significant difference in T4 or TSH level was reported. Free T4 and free T3 were not assessed.

Effects on thyroid hormone levels:

Amato 1988 reported a significant increase in T4 in infants receiving thyroxine (mean T4 [sd] before: 74 [37] nmol/l; day five: 194 [43] nmol/l, p < 0.05), but control infants were not reported. No significant difference in T3 or TSH levels were reported. Free T4 and free T3 were not assessed. Amato 1989 reported TSH, total T4 and T3 levels at five days in infants treated with T3 50 mg/day 1 and 2. The reported levels mean TSH [sd] was 14.3 [12.7] mU/l, T4 82.4 [42.7] nmol/l and T3 1.55 [1.74] nmol/l were reported as being within the reference ranges. The actual number of infants that had T4 or T3 levels above or below the reference ranges was not reported. The mean values for TSH and T4 were within the term infant reference ranges at birth and five days.

Comparison 03: Postnatal thyroid hormones versus other thyroid hormone strategy:

No study compared different thyroid hormone dosing strategies.

Comparison 04: Postnatal thyroid hormones combined with corticosteroids versus control:

No study enrolling infants with respiratory distress compared postnatal thyroid hormones combined with corticosteroids versus no treatment.

Comparison 05: Postnatal thyroid hormones combined with corticosteroids versus corticosteroids alone:

No study enrolling infants with respiratory distress compared postnatal thyroid hormones combined with corticosteroids versus corticosteroids alone.

Discussion

Two small studies enrolling a total of 98 infants (but reporting outcomes for 80 infants) studied the effects of substantial doses of thyroid hormones in the first hours after birth in very preterm infants with respiratory distress syndrome. One study used L-thyroxine, whereas the other study used triiodothyronine. Both studies had substantial methodological concerns including quasi-random methods of patient allocation, no blinding of treatment or measurement and substantial post-allocation losses. Neither study reported long term neurodevelopment. No significant effects were found for neonatal mortality or morbidity including need for mechanical ventilation, incidence of air leak, duration of mechanical ventilation or incidence of chronic lung disease (oxygen at 28 days). No significant difference was reported by one study for patent ductus arteriosus, intraventricular haemorrhage or end stage retinopathy of prematurity. Neither study reported the effect of thyroid hormone replacement on the levels of free (T3 or T4) or active (FT4) hormone levels, so the effects of the dosing strategies used on active and free thyroid hormone levels are unclear. Given the small size and methodological concerns of the eligible trials, it is possible that these studies failed to detect a moderate effect of postnatal thyroid hormones in preterm infants with respiratory distress. In view of the concerns regarding antenatal TRH treatment (Crowther 2004) and a lack of postnatal animal research supporting the use of thyroid hormones for treatment of respiratory distress syndrome, further trials of postnatal thyroid hormone treatment for infants with respiratory distress syndrome would be difficult to justify. Further research is needed using immature foetal or postnatal animal models with respiratory distress syndrome to determine the potential role of interventions affecting the thyroid axis in prevention or treatment of respiratory distress.

Reviewers' conclusions

Implications for practice

There is no evidence from controlled clinical trials that postnatal thyroid hormone treatment reduces severity of respiratory distress syndrome, neonatal morbidity or mortality in preterm infants with respiratory distress syndrome.

Implications for research

Further research is needed using immature foetal or postnatal animal models with respiratory distress syndrome to determine the potential role of interventions affecting the thyroid axis in prevention or treatment of respiratory distress. Additional human trials of postnatal thyroid hormones for treatment if infants with respiratory distress do not appear to be justified unless basic research provides new data suggesting a potential benefit.

Acknowledgements

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Amato 1988 Quasi-random study: alternate assignment.
Single center.
Blinding of randomisation: no.
Blinding of intervention: not reported.
Complete follow up: no, 12 (24%) post-allocation exclusions (5 treatment and 7 controls) as did not have RDS.
Blinding of outcome measurement: not reported.
Power calculation performed: not reported.
Inclusion criteria:
Forty eight infants 29-34 weeks gestation with respiratory distress syndrome - signs of respiratory distress, FiO2 >0.5, chest x-ray appearance.
Exclusion criteria: not respiratory distress syndrome.
Mean birth weight 1210 g (range 780-1710 g).
Use of antenatal corticosteroids not documented.
Treatment (n = 23): L-thyroxine 50 micrograms IV 2 doses at 1 hour and at 24 hours.
Control (n = 25): no treatment.
Mortality to discharge.
Peak oxygen concentrations.
Use of mechanical ventilation.
Duration mechanical ventilation.
Bronchopulmonary dysplasia - Northway criteria (oxygen at 28 days and chest x-ray changes).
Thyroid function before and on day 5 (TSH, T4 and T3).
C
Amato 1989 Quasi-random study: alternate assignment.
Single center.
Blinding of randomisation: no.
Blinding of intervention: not reported.
Complete follow up: no, 6 (12%) post-randomisation exclusions (3 treatment and 3 controls).
Blinding of outcome measurement: not reported.
Power calculation performed: not reported.
Inclusion criteria:
Fifty infants < 32 weeks gestation with respiratory distress syndrome diagnosed by presence of respiratory distress and chest x-ray changes.
FiO2 > 0.4
No antenatal steroids.
Exclusion criteria:
Not respiratory distress syndrome.
Treatment group: mean birth weight (sd) 1180 g (430), mean gestation 30.1 weeks (1.9) (n = 25).
Controls: mean birth weight 1210 g (380), mean gestation 29.2 weeks (2.1) (n = 25).
Treatment (n = 25): L-triiodothyronine 50 micrograms/day in 2 dIVded doses for 2 days IV, commenced day 1.
Control (n = 25): no treatment.
Mortality to discharge.
Peak oxygen concentrations.
Duration mechanical ventilation.
Development of major complications of RDS: periventricular hemorrhage, air leak, chronic lung disease (O2 at 28 days), patent ductus arteriosus, necrotising enterocolitis, retinopathy of prematurity (cicatricial disease only).
C

Characteristics of excluded studies

Study Reason for exclusion
Bettendorf 2000 Enrolled infants after cardiac surgery.
Biswas 2003 Randomised trial of triiodothyronine and hydrocortisone versus placebo in preterm infants < 30 weeks gestation.
Cassio A 2003 Enrolled infants with congenital hypothyroidism.
Chowdhry 1984 Enrolled infants with transient hypothyroxinaemia.
Chowdhury 2001 Enrolled infants after cardiac surgery.
Eggermont 1984 Non-randomized cohort comparison. Thyroxine given to 'sick' preterm infants and compared to a control group of 'non-sick' preterm infants.
Schonberger 1981 Inadequate randomisation. Used alternation and included 5 infants who were not alternated as controls.
Selva 2002 Enrolled infants with congenital hypothyroidism.
Smith 2000 Enrolled infants < 32 weeks gestation, birthweight 600-1500g, not on basis of respiratory distress.
Valerio 2004 Enrolled infants < 28 weeks gestation not on basis of respiratory distress.
van Wassenaer 1993 Not a randomised study. Used historical controls to compare the effect of three different doses of thyroxine on neonatal thyroid hormone levels. Dose was varied over 3 consecutive time periods (6, 8 and 10 micrograms/kg/day).
van Wassenaer 1997 Enrolled preterm infants 25-29 weeks gestation not on basis of respiratory distress.
Vanhole 1997 Enrolled infants 25-30 weeks gestation not on basis of respiratory distress.

Characteristics of ongoing studies

Study Trial name or title Participants Interventions Outcomes Starting date Contact information Notes
Golombek Hypothyroxemia trial Very preterm infants (< 28 weeks) Thyroid hormones - type and dose to be determined Include neurodevelopment To be announced SERGIO_GOLOMBECK@NYMC.EDU

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References to studies

Included studies

Amato 1988

{published data only}

Amato M, Pasquier S, Carasso A, Von Muralt G. Postnatal thyroxine administration for idiopathic respiratory distress syndrome in preterm infants. Hormone Research 1988;29:27-30.

Amato 1989

{published data only}

Amato M, Guggisberg C, Schneider H. Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. Hormone Research 1989;32:213-7.

Excluded studies

Bettendorf 2000

{published data only}

Bettendorf M, Schmidt KG, Grulich-Henn J, Ulmer HE, Heinrich UE. Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study. Lancet 2000;356:529-34.

Biswas 2003

{published data only}

Biswas S, Buffery J, Enoch H, Bland JM, Walters D, Markiewicz M. A longitudinal assessment of thyroid hormone concentrations in preterm infants younger than 30 weeks' gestation during the first 2 weeks of life and their relationship to outcome. Pediatrics 2002;109:222-7.

* Biswas S, Buffery J, Enoch H, Bland M, Markiewicz M, Walters D. Pulmonary effects of triiodothyronine (T3) and hydrocortisone (HC) supplementation in preterm infants less than 30 weeks gestation: results of the THORN trial--thyroid hormone replacement in neonates. Pediatric Research 2003;53:48-56.

Cassio A 2003

{published data only}

Cassio A, Cacciari E, Cicognani A, Damiani G, Missiroli G, Corbelli E, Balsamo A, Bal M, Gualandi S. Treatment for congenital hypothyroidism: thyroxine alone or thyroxine plus triiodothyronine? Pediatrics 2003;111:1055-60.

Chowdhry 1984

{published and unpublished data}

Chowdhry P, Scanlon JW, Auerbach R, Abbassi V. Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia. Pediatrics 1984;73:301-5.

Chowdhury 2001

{published data only}

Chowdhury D, Ojamaa K, Parnell VA, McMahon C, Sison CP, Klein I. A prospective randomized clinical study of thyroid hormone treatment after operations for complex congenital heart disease. Journal of Thoracic & Cardiovascular Surgery 2001;122:1023-5.

Eggermont 1984

{published data only}

Eggermont E, Vanderschueren Lodeweyckx M, De Nayer P, Smeets E, Vanacker G, Cornette C, Jaeken J, Devlieger H, Eeckels R, Beckers C. The thyroid-system function in preterm infants of postmenstrual ages of 31 weeks or less: evidence for a "transient lazy thyroid system". Helvetica Paediatrica Acta 1984;39:209-22.

Schonberger 1981

{published data only}

Schonberger W, Grimm W, Emmrich P, Gempp W. Reduction of mortality rate in premature infants by substitution of thyroid hormones. European Journal of Pediatrics 1981;135:245-53.

Selva 2002

{published data only}

Selva KA, Mandel SH, Rien L, Sesser D, Miyahira R, Skeels M, Nelson JC, Lafranchi SH. Initial treatment dose of L-thyroxine in congenital hypothyroidism. Journal of Pediatrics 2002;141:786-92.

Smith 2000

{published data only}

Smith LM, Leake RD, Berman N, Villanueva S, Brasel JA. Postnatal thyroxine supplementation in infants less than 32 weeks' gestation: effects on pulmonary morbidity. Journal of Perinatology 2000;20:427-31.

Valerio 2004

{published data only}

* Valerio PG, van Wassenaer AG, de Vijlder JJ, Kok JH. A randomized, masked study of triiodothyronine plus thyroxine administration in preterm infants less than 28 weeks of gestational age: hormonal and clinical effects. Pediatric Research 2004;55:248-53.

Valerio PG, van Wassenaer AG, Kok JH. A randomized, masked study of T3 plus T4 administration in preterm infants less than 28 weeks of gestational age: hormonal and clinical effects. In: Pediatric Research. Vol. 51. 2002:125A.

van Wassenaer 1993

{published data only}

van Wassenaer AG, Kok JH, Endert E, Vulsma T, de Vijlder JJ. Thyroxine administration to infants of less than 30 weeks' gestational age does not increase plasma triiodothyronine concentrations. Acta Endocrinologica 1993;129:139-46.

van Wassenaer 1997

{published and unpublished data}

Briet JM, van Wassenaer AG, Dekker FW, de Vijlder JJ, van Baar A, Kok JH. Neonatal thyroxine supplementation in very preterm children: developmental outcome evaluated at early school age. Pediatrics 2001;107:712-8.

Briet JM, van Wassenaer AG, van Baar A, Dekker FW, Kok JH. Evaluation of the effect of thyroxine supplementation on behavioural outcome in very preterm infants. Developmental Medicine and Child Neurology 1999;41:87-93.

Smit BJ, Kok JH, de Vries LS, van Wassenaer AG, Dekker FW, Ongerboer de Visser BW. Somatosensory evoked potentials in very preterm infants in relation to L-thyroxine supplementation. Pediatrics 1998;101:865-9.

Smit BJ, Kok JH, de Vries LS, van Wassenaer AG, Dekker FW, Ongerboer de Visser BW. Motor nerve conduction velocity in very preterm infants in relation to L-thyroxine supplementation. Journal of Pediatrics 1998;132:64-9.

van Wassenaer AG, Briët JM, van Baar A, Smit BJ, Tamminga P, de Vijlder JJM, Kok JH. Free thyroxine levels during the first weeks of life and neurodevelopmental outcome until the age of 5 years in very preterm infants. Pediatrics 2002;109:534-9.

Van Wassenaer AG, Kok JH, Briet JM, Pijning AM, de Vijlder JJ. Thyroid function in very preterm newborns: possible implications. Thyroid 1999;9(85-91).

van Wassenaer AG, Kok JH, Briet JM, van Baar A, de Vijlder JJ. Thyroid function in preterm newborns; is T4 treatment required in infants < 27 weeks' gestational age? Experimental and clinical endocrinology & diabetes 1997;105:12-8.

* van Wassenaer AG, Kok JH, de Vijlder JJ, Briet JM, Smit BJ, Tamminga P, van Baar A, Dekker FW, Vulsma T. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation. The New England Journal of Medicine 1997;336:21-6.

van Wassenaer AG, Kok JH, Dekker FW, Endert E, de Vijlder JJ. Thyroxine administration to infants of less than 30 weeks gestational age decreases plasma tri-iodothyronine concentrations. European Journal of Endocrinology 1998;139:508-15.

van Wassenaer, Kok JH, Dekker FW, de Vijlder JJ. Thyroid function in very preterm infants: influences of gestational age and disease. Pediatric Research 1997;42:604-9.

Vanhole 1997

{published and unpublished data}

Vanhole C, Aerssens P, Devlieger H, de Zegher F. L-Thyroxine treatment of preterm newborns. Pediatric Research 1996;40:555.

* Vanhole C, Aerssens P, Naulaers G, Casneuf A, Devlieger H, Van den Berghe G, de Zegher F. L-thyroxine treatment of preterm newborns: clinical and endocrine effects. Pediatric Research 1997;42:87-92.

References to ongoing studies

Golombek

{unpublished data only}

* indicates the primary reference for the study

Other references

Additional references

Abbassi 1977

Abbassi V, Merchant K, Abramson D. Postnatal triiodothyronine concentrations in healthy preterm infants and in infants with respiratory distress syndrome. Pediatric Research 1977;11:802-4.

Ballard 1992

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 prenatal treatment with thyrotropin-releasing hormone. Pediatric Research 1992;32:673-8.

Belet 2003

Belet N, Imdat H, Yanik F, Kucukoduk S. Thyroid function tests in preterm infants born to preeclamptic mothers with placental insufficiency. Journal of Pediatric Endocrinology 2003;16:1131-5.

Bernal 1984

Bernal J, Pekonen F. Ontogenesis of the nuclear 3, 5, 3'-triiodothyronine receptor in the human fetal brain. Endocrinology 1984;114:677-9.

Crowley 1996

Crowley P. Prophylactic corticosteroids for preterm birth. In: The Cochrane Database of Systematic Reviews, Issue 1, 1996.

Crowther 2004

Crowther CA, Alfirevic Z, Haslam RR. Thyrotropin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. In: The Cochrane Database of Systematic Reviews, Issue 2, 2004.

Keijzer 2000

Keijzer R, van Tuyl M, Tibboel D. Hormonal modulation of fetal pulmonary development: relevance for the fetus with diaphragmatic hernia. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2000;92:127-33.

Laws 2004

Laws PJ, Sullivan EA. Australia’s mothers and babies 2002. AIHW Cat. No. PER 28. Sydney: AIHW National Perinatal Statistics Unit (Perinatal Statistics Series No. 15) 2004.

Oden 2002

Oden J, Freemark M. Thyroxine supplementation in preterm infants: critical analysis. Current Opinion in Pediatrics 2002;14:447-52.

Ogilvy-Stuart 2002

Ogilvy-Stuart AL. Neonatal thyroid disorders. Archives of Disease in Childhood Fetal and Neonatal Edition 2002;87:F165-71.

Osborn 2001

Osborn DA. Thyroid hormones for preventing neurodevelopmental impairment in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2001.

Osborn 2007a

Osborn DA, Hunt RW. Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 1, 2007.

Osborn 2007b

Osborn DA, Hunt RW. Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia. In: Cochrane Database of Systematic Reviews, Issue 1, 2007.

Roberts 2006

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. In: Cochrane Database of Systematic Reviews, Issue 3, 2006.

Romaguera 1993

Romaguera J, Ramirez M, Adamsons K. Intra-amniotic thyroxine to accelerate fetal maturation. Seminars in Perinatology 1993;17:260-6.

Schellenberg 1987

Schellenberg JC, Liggins GC. New approaches to hormonal acceleration of fetal lung maturation. Journal of Perinatal Medicine 1987;15:447-52.

Smith 1983

Smith DM, Hitchcock KR. Thyroid hormone binding to adult rat alveolar type II cells. An autoradiographic study. Experimental Lung Research 1983;5:141-53.

van Wassenaer 1997

van Wassenaer AG, Kok JH, Dekker FW, de Vijlder JJ. Thyroid function in very preterm infants: influences of gestational age and disease. Pediatric Research 1997;42:604-9.

[top]

Data and analyses

01 Thyroid hormones versus no thyroid hormones

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Mortality to discharge 2 80 RR (fixed), 95% CI 1.00 [0.47, 2.14]
01.02 Mechanical ventilation 1 36 RR (fixed), 95% CI 0.64 [0.38, 1.09]
01.03 Air leak 1 44 RR (fixed), 95% CI 0.75 [0.19, 2.97]
01.04 Duration of mechanical ventilation (days) 2 80 WMD (fixed), 95% CI -1.64 [-4.68, 1.39]
01.05 CLD in survivors (oxygen at 28 days) 2 80 RR (fixed), 95% CI 0.58 [0.26, 1.33]
01.06 Patent ductus arteriosus 1 44 RR (fixed), 95% CI 1.14 [0.50, 2.61]
01.07 Intraventricular hemorrhage - any grade 1 44 RR (fixed), 95% CI 1.33 [0.34, 5.28]
01.08 Necrotizing enterocolitis 1 44 RR (fixed), 95% CI 0.33 [0.01, 7.76]

02 Thyroid hormones versus no thyroid hormones according to dosing strategy used

Comparison or outcome Studies Participants Statistical method Effect size
02.01 Mortality to discharge 2 80 RR (fixed), 95% CI 1.00 [0.47, 2.14]
02.01.01 T3 50 mcg/kg day 1 and 2 2 80 RR (fixed), 95% CI 1.00 [0.47, 2.14]
02.01.02 T4 50 mcg/kg at 1 and 24 hours 2 80 RR (fixed), 95% CI 1.00 [0.47, 2.14]
02.02 Mechanical ventilation 1 36 RR (fixed), 95% CI 0.64 [0.38, 1.09]
02.02.01 T3 50 mcg/kg day 1 and 2 1 36 RR (fixed), 95% CI 0.64 [0.38, 1.09]
02.02.02 T4 50 mcg/kg at 1 and 24 hours 1 36 RR (fixed), 95% CI 0.64 [0.38, 1.09]
02.03 Air leak 1 44 RR (fixed), 95% CI 0.75 [0.19, 2.97]
02.03.01 T3 50 mcg/kg day 1 and 2 1 44 RR (fixed), 95% CI 0.75 [0.19, 2.97]
02.03.02 T4 50 mcg/kg at 1 and 24 hours 1 44 RR (fixed), 95% CI 0.75 [0.19, 2.97]
02.04 Duration of mechanical ventilation (days) 2 80 WMD (fixed), 95% CI -1.64 [-4.68, 1.39]
02.04.01 T3 50 mcg/kg day 1 and 2 2 80 WMD (fixed), 95% CI -1.64 [-4.68, 1.39]
02.05.02 T4 50 mcg/kg at 1 and 24 hours 2 80 WMD (fixed), 95% CI -1.64 [-4.68, 1.39]
02.05 CLD in survivors (oxygen at 28 days) 2 80 RR (fixed), 95% CI 0.58 [0.26, 1.33]
02.05.01 T3 50 mcg/kg day 1 and 2 2 80 RR (fixed), 95% CI 0.58 [0.26, 1.33]
02.05.02 T4 50 mcg/kg at 1 and 24 hours 2 80 RR (fixed), 95% CI 0.58 [0.26, 1.33]
02.06 Patent ductus arteriosus 1 44 RR (fixed), 95% CI 1.14 [0.50, 2.61]
02.06.01 T3 50 mcg/kg day 1 and 2 1 44 RR (fixed), 95% CI 1.14 [0.50, 2.61]
02.07.02 T4 50 mcg/kg at 1 and 24 hours 1 44 RR (fixed), 95% CI 1.14 [0.50, 2.61]
02.07 Intraventricular hemorrhage - any grade 1 44 RR (fixed), 95% CI 1.33 [0.34, 5.28]
02.07.01 T3 50 mcg/kg day 1 and 2 1 44 RR (fixed), 95% CI 1.33 [0.34, 5.28]
02.07.02 T4 50 mcg/kg at 1 and 24 hours 1 44 RR (fixed), 95% CI 1.33 [0.34, 5.28]
02.08 Necrotizing enterocolitis 1 44 RR (fixed), 95% CI 0.33 [0.01, 7.76]
02.08.01 T3 50 mcg/kg day 1 and 2 1 44 RR (fixed), 95% CI 0.33 [0.01, 7.76]
02.08.02 T4 50 mcg/kg at 1 and 24 hours 1 44 RR (fixed), 95% CI 0.33 [0.01, 7.76]

Contact details for co-reviewers

Dr Rod Hunt

Consultant Paediatrician
Department of Neonatal Medicine
Royal Children's Hospitals, Melbourne
Level 2, Royal Children's Hospital
Flemington Road
Parkville, Melbourne
Victoria AUSTRALIA
3052
Telephone 1: +61 3 9345 5522 extension: 5008
Facsimile: +61 3 9345 5067

E-mail: rod.hunt@rch.org.au


This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2006 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.