Prophylactic postnatal thyroid hormones for prevention
of morbidity and mortality in preterm infants
Osborn
DA, Hunt RW
Dates
Date edited: 15/11/2006
Date of last substantive update: 13/10/2006
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.auContribution 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
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: / /
Text of review
Synopsis
A systematic review of the data from randomised controlled trials provides no evidence that routine thyroid hormone therapy is effective in preventing problems in preterm babies or improves their developmental outcomes.
Thyroid hormones are needed for the normal growth and maturity of the central nervous system, as well as the heart and lungs. Children born without sufficient thyroid hormones can develop serious mental retardation. It is believed that low levels of thyroid hormones in the first few weeks after birth (transient hyperthyroxinaemia) in preterm babies born before 34 weeks may contribute to this abnormal development. The review of trials found no evidence that using thyroid hormones routinely in preterm babies is effective in reducing the risk of problems caused by transiently low levels of thyroid hormones.
Abstract
Background
Observational studies have shown an association between transiently low thyroid hormone levels in preterm infants in the first weeks of life (transient hypothyroxinaemia) and abnormal neurodevelopmental outcome. Thyroid hormone replacement might prevent this.
Objectives
To determine whether prophylactic thyroid hormones given to preterm infants without congenital hypothyroidism result in clinically important changes in neonatal and long term outcomes.
Search strategy
The standard search strategy of the Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), EMBASE, PREMEDLINE, and searches of abstracts of conference proceedings, citations of published articles and expert informants.
Selection criteria
All trials using random or quasi-random patient allocation in which prophylactic thyroid hormone treatment was compared to control in premature infants.
Data collection & analysis
Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD), were performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group.
Main results
Four studies enrolling 318 infants were included. All studies enrolled preterm infants on the basis of gestational age criteria. All studies commenced treatment in the first 48 hours, but used different regimens, dose and durations of treatment. All four studies used thyroxine (T4). Valerio 2004 incorporated one arm with an early short course of T3, then T4 for 6 weeks. Only two studies with neurodevelopmental follow-up were of good methodology (van Wassenaer 1997; Vanhole 1997). All studies were small with the largest (van Wassenaer 1997) enrolling 200 infants.
No significant difference was found in neonatal morbidity, mortality or neurodevelopmental outcome in infants who received thyroid hormones compared to control. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99) or cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley MDI (WMD -1.14, 95% CI -5.46, 3.19) and PDI (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months. van Wassenaer 1997 reported no significant difference in the Bayley MDI (MD -3.50, 95% CI -11.21, 4.21) and PDI (MD 3.10, 95% CI -3.31, 9.51) at 24 months, IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71) and children in special schooling at 10 years (RR 0.88, 95% CI 0.43, 1.83). Meta-analysis of all four trials found no significant difference in mortality to discharge (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14). No significant differences were reported for neonatal morbidities, including the need for mechanical ventilation, duration of mechanical ventilation, air leak, CLD in survivors at 28 days or 36 weeks, intraventricular haemorrhage, severe intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis, necrotising enterocolitis or retinopathy of prematurity.
Reviewers' conclusions
This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required.
Background
In preterm infants, levels of serum T4 and free T4 in the first days after birth vary directly with gestation (Rooman 1996, Reuss 1997). However, unlike term infants, the concentrations of T4 and free T4 decrease to reach a nadir between day 10 and 14 after birth that is more severe at lower gestations and birth weights (Frank 1996, Rooman 1996). Thyroid hormone levels then tend to return to normal levels after three weeks, but continue to increase up to six to eight weeks after birth (van Wassenaer 1997). Reuss 1997 found the incidence of infants with severely depressed T4 values (below 4 mg/dL) ranged from 40% at 23 weeks gestation to 10.2% at 28 weeks gestation. Furthermore, the levels of T4 and free T4 found in premature infants are lower than those seen in the normal fetus at similar gestational ages (Ballabio 1989, Thorpe-Beeston 1991, Radunovic 1991).
In some infants, low thyroid hormone levels may be manifest at birth (as measured in cord blood samples) and some infants may have a reduced postnatal surge 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).
This period of low thyroid hormone levels in infants born prematurely has been termed "transient hypothyroxinaemia of prematurity" (low T4, normal thyrotropin [TSH]). Suggestions as to the cause of these low thyroid hormone values include an immaturity of the hypothalamic-pituitary-thyroid axis in the extremely premature infant or a form of "nonthyroidal illness" (the "sick euthyroid syndrome") reflecting the infant's response to severe illness (monograph review by Paneth 1998). Risk factors for transient hypothyroxinaemia reported in observational studies have included lower gestational age (Franklin 1986; Rooman 1996; Reuss 1997; Paul 1998; Kantor Herring 2003; Filippi 2004), maternal pre-eclampsia with placental insufficiency (Belet 2003), fetal growth restriction (Uhrmann 1981), perinatal asphyxia (Tahirovic 1994), respiratory distress syndrome (Uhrmann 1981; Franklin 1986), more severe respiratory disease (Reuss 1997), mechanical ventilation (Reuss 1997; Kantor Herring 2003), low diastolic blood pressure (Reuss 1997) and dopamine infusions (Filippi 2004; Kantor Herring 2003). Adverse neonatal outcomes associated with transient hypothyroxinaemia have included intraventricular haemorrhage (Paul 1998; Paul 2000), chronic lung disease (Reuss 1997) and death (Reuss 1997; Paul 1998; Hsu 1999).
Transient hypothyroidism (low T4, high TSH concentration) occurs in up to 5% of neonates admitted to neonatal intensive care (Rooman 1996), 0.4% of infants with birth weights < 1500 g (Frank 1996) and 1.8% of infants born < 29 weeks gestation (Reuss 1997). There is evidence to suggest that this may be due to exposure to iodine-containing antiseptics used in neonatal care (Linder 1997).
Thyroid hormones are necessary for the normal growth and maturation of the central nervous system (monograph reviews by Porterfield 1993 and Bernal 1995). Congenital hypothyroidism is strongly associated with abnormal neurodevelopment. Neurological cretinism in its severest form is characterised by profound mental retardation, deaf mutism, spastic diplegia and squint (Porterfield 1993). Even children who receive early thyroid hormone replacement therapy for congenital hypothyroidism have motor and cognitive deficits that persist to late childhood (Kooistra 1994). Infants born prematurely also have a high incidence of motor and cognitive deficits that are worse at lower gestations (Lorenz 1998). The question is whether the transient decrease in serum concentration of free T4 that occurs in some preterm infants during the first weeks after birth contributes to these neurodevelopmental problems. Three cohort studies (Lucas 1988; Lucas 1996, Meijer 1992; den Ouden 1996; Reuss 1996) have documented an association between low thyroid hormone levels (T3 or T4) in the first weeks after birth and abnormal neurodevelopmental outcome. All three cohorts documented a measure of abnormal mental development in children who had low neonatal thyroid hormone levels. One study (Reuss 1996) found a 4.4 fold increase in risk of disabling cerebral palsy at two years. Den Ouden 1996 in the same cohort found children who had low neonatal T4 levels to have an increased risk of school failure at nine years. The associations in the cohorts persisted despite correction for potential confounders including gestation, measures of fetal growth (either birth weight or presence of growth restriction) and, in some studies, many factors relating to severity of illness in preterm infants and independent risk factors for abnormal neurodevelopmental outcome.
Whether transient hypothyroxinaemia of prematurity is a causative factor for abnormal neurodevelopment is uncertain. Transient hypothyroxinaemia of prematurity is strongly correlated with low gestation and is more frequent in infants with respiratory distress syndrome and in ventilated infants. It may be that transient hypothyroxinaemia of prematurity is secondary to low gestation and/or illness severity in preterm infants. It is possible that other factors which are responsible for the abnormal neurodevelopmental outcome in preterm infants have not been taken into account adequately in the cohort studies.
This review examined the evidence from randomised and quasi-randomised controlled trials of thyroid hormone therapy in preterm infants for improvement of neonatal outcomes and neurodevelopment. Thyroid hormones have effects not only on neurological development, but also on the respiratory and cardiovascular systems and somatic growth. Therefore, studies that examined either neonatal morbidity, mortality and/or long term neurodevelopment were eligible for inclusion in this review.
Objectives
To assess whether thyroid hormone therapy used prophylactically in preterm infants thought to be at risk of transient hypothyroxinaemia, without congenital hypothyroidism or known transient hypothyroxinaemia, results in clinically important changes in neonatal and long term outcomes in terms of both benefits and harms.
Subgroup analysis of the trials was prespecified 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. Separate reviews address the use of postnatal thyroid hormones for respiratory distress in preterm infants (Osborn 2007a), and postnatal thyroid hormones for treatment of preterm infants with transient hypothyroxinaemia (Osborn 2007b).
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
Studies that enrolled preterm infants (born < 37 completed weeks gestation) in the neonatal period. Trials that enrolled infants on the basis of results of abnormal thyroid function tests (known congenital hypothyroidism or transient hypothyroxinaemia), or only with respiratory distress syndrome, were excluded.
Types of interventions
Prophylactic thyroid hormone therapy compared to control (placebo or no therapy). Thyroid hormone therapy could be either T4, T3 or both. Trials that compared different thyroid hormone regimens were eligible. Trials that included other co-interventions performed differentially in the treatment and control groups were excluded.
Types of outcome measures
Primary clinical outcome measures were mortality (either neonatal or prior to discharge) and neurodevelopmental status at follow up. Neurodevelopmental outcome was categorised where reported as:
1. Abnormal mental developmental after 12 months corrected age (a development or intelligence quotient > = 2 standard deviations below the mean of a standardised test)
2. Abnormal neurological outcome (infants with either abnormal mental development or definite cerebral palsy)
3. Motor deficits
4. Sensorineural impairments including:
- hearing deficit requiring aids
- 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, incidence of air leak, duration of mechanical ventilation)
2. Chronic lung disease defined as oxygen at 28 days postnatal age
3. Chronic lung disease defined as oxygen or respiratory support at near term (36 - 40 weeks) corrected age
4. Intraventricular haemorrhage diagnosed by ultrasound or postmortem - all (Papile grades 1 to 4) and severe (Papile grade 3 or 4)
5. Periventricular leucomalacia diagnosed by ultrasound or postmortem
6. MRI detected cerebral abnormality at near term corrected age
7. Symptomatic patent ductus arteriosus (PDA) after day three after birth treated by indomethacin or ibuprofen or ligation
8. Necrotizing enterocolitis (at least stage 2 Bell's criteria)
9. Retinopathy of prematurity including all stages and severe (stage 3 or greater)
10. Growth including growth in weight (g/kg/day), head circumference (cm/week) and length (cm/week)
11. Adverse effects of thyroid hormones including tachycardia, pyrexia or cardiovascular collapse
In addition, effects of the various strategies of thyroid hormone dosing on thyroid hormone levels including total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (free T3), free thyroxine (free T4), reverse triiodothyronine (rT3) and thyrotropin (TSH) was performed.
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 (1966 - March 2006) 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 (1980 to March 2006) 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.
Methods
of the review
Assessment of trial quality, data extraction and synthesis of data, using relative risk (RR) and weighted mean difference (WMD) was performed using standard methods of the Cochrane Collaboration and its Neonatal Review Group. Each identified trial was assessed for methodological quality with respect to:
a) masking of allocation
b) masking of intervention
c) completeness of follow up
d) masking of outcome assessment.
Authors of studies were contacted were details of methodology are unclear. Data was synthesized where appropriate using relative risk (RR), risk difference (RD) and weighted mean difference (WMD). From 1/RD the number needed to treat (NNT) for benefits and the number needed to harm (NNH) for adverse effects will be calculated. All results given will include the 95% confidence intervals unless otherwise stated. Heterogeneity was looked for using the chi-square statistic for heterogeneity, quantified using the I-squared statistic. The source of heterogeneity was examined in subgroup analysis of type of infant enrolled, treatment strategy and methodological quality as specified below. Where no heterogeneity existed, infants enrolled and interventions were similar, and there is no apparent heterogeneity, the fixed effect analysis was reported. In a previous version of this review (Osborn 2001), authors of studies were contacted where details of methodology or results were unclear and were provided by the authors of three studies (Smith 2000; van Wassenaer 1997; Vanhole 1997).
Separate comparisons were made of the following:
1. Prophylactic postnatal thyroid hormones (any type of preparation) versus control (no treatment or placebo), all dosing strategies,
2. Prophylactic postnatal thyroid hormones (any type of preparation) versus control (no treatment or placebo), according to dosing strategy used. This review documents the individual dosage regimens used in each of the studies. Future updates plan to assess trials according to dose: lower dose (≤ 8 μg/kg/day) versus higher dose (>8 μg/kg/day ) thyroxine; and timing: earlier (≤ 7 days of age) versus later (>7 days of age) treatment.
3 Prophylactic postnatal thyroid hormones versus other thyroid hormone strategy (e.g. T3 and T4 versus T4 alone).
Subgroup analysis was performed 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, or
3. > 31 weeks gestation.
Subgroup analysis was performed to determine if there is an effect of timing thyroid hormone treatment with separate analysis of trials treating infants:
1. < 48 hours after birth,
2. < 14 days after birth.
Subgroup analysis was performed 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 of treatment and if there was at least 90% follow up of survivors.
Description of studies
Eleven reports or studies were excluded (see 'Table of Excluded Studies'). Two excluded studies (Amato 1988; Amato 1989) enrolled infants with respiratory distress syndrome and are included in the review 'Postnatal thyroid hormones for respiratory distress syndrome in preterm infants' (Osborn 2007a). One excluded study (Chowdhry 1984) enrolled infants with transient hypothyroxinaemia and is included in the review 'Postnatal thyroid hormones in preterm infants with transient hypothyroxinaemia' (Osborn 2007b). One excluded study (Biswas 2003) randomised preterm infants to both thyroid hormone and hydrocortisone treatment and is not eligible for inclusion in any of the reviews. Four studies were eligible for inclusion in this review (Smith 2000; Valerio 2004; van Wassenaer 1997; Vanhole 1997).
Infants: Four studies enrolled infants using gestation and/or birthweight criteria. Smith 2000 enrolled infants < 32 weeks, birthweight 600 - 1500g and < 48 hours after birth. Valerio 2004 enrolled infants < 28 weeks gestation and < 24 hours. van Wassenaer 1997 enrolled infants 25 - 29 weeks gestation and < 24 hours. Vanhole 1997 enrolled infants 25 - 30 weeks gestation and < 24 hours.
Treatment: All four studies (Valerio 2004; van Wassenaer 1997; Vanhole 1997; Smith 2000) compared T4 treatment to no treatment or placebo. Smith 2000 treated infants starting before 48 hours age with T4 10 μg/kg/day intravenously until tolerating feeds, then 20 μg/kg/day for a total 21 days. Valerio 2004 compared infants treated with T3 0.5 μg/kg at 24 hours after birth and T4 8 μg/kg daily for 42 days with infants treated with T4 8 μg/kg daily for 42 days and a control who received a placebo. Vanhole 1997 treated infants with T4 20 μg/kg/day intravenously for two weeks from the first day. van Wassenaer 1997 treated infants with T4 8 μg/kg birthweight (intravenously until tolerating feeds, then orally) from 12 - 24 hours of age for six weeks.
Outcomes: A primary outcome was stated by three studies, van Wassenaer 1997 (Bayley Mental Development Index at 24 months), Smith 2000 (oxygen at 28 days) and Valerio 2004 (cortisol and thyroid hormone levels). Other studies stated broader objectives: Vanhole 1997 assessed its impact on a variety of endocrine and clinical outcomes.
Mortality was assessed by all the included studies with data for neonatal mortality available for van Wassenaer 1997, Vanhole 1997 and Smith 2000, and mortality to time of discharge for all studies.
Neurodevelopment was assessed by van Wassenaer 1997 and Vanhole 1997. The Bayley Mental Development Index and the Bayley Psychomotor Development Index (PDI) were used by van Wassenaer 1997 at 12 and 24 months corrected age and Vanhole 1997 at seven months corrected age. van Wassenaer 1997 assessed neurological outcome at six and 12 months (method of Touwen) and 24 months (method of Hempel). At mean age 5.7 years, van Wassenaer 1997 assessed cognitive (RAKIT IQ score), behaviour, motor and neurologic (method of Touwen) outcome.
Data for chronic lung disease defined as oxygen requirements at 28 days were obtained from the studies by van Wassenaer 1997, Valerio 2004 and Smith 2000. Vanhole 1997 defined chronic lung disease as oxygen requirements at 28 days with an abnormal chest x-ray. These data are pooled. Data were available from van Wassenaer 1997 and Vanhole 1997 for infants with chronic lung disease as defined by oxygen requirements at 36 weeks post-menstrual age.
Patent ductus was diagnosed clinically with ultrasound confirmation by van Wassenaer 1997. Intraventricular haemorrhage was detected by ultrasound by Valerio 2004, and ultrasound and post-mortem by van Wassenaer 1997. Data were obtained from the author for intraventricular haemorrhage and patent ductus arteriosus from the study by Vanhole 1997.
Thyroid hormone assays: Smith 2000 used RIA to measure free T4 and TSH on cord blood and weekly for four weeks. Valerio 2004 used RIA to measure T4, T3, and rT3, and time-resolved fluoroimmunoassay to measure free T3, free T4 and TSH on cord blood, 24 hours, days 3, 7, 14, 21, 42 and 56. Levels for T3 were also taken 30, 120 and 360 minutes after T3 administration for T3 levels. van Wassenaer 1997 used RIA to measure T4, T3 and rT3, and an immunochemiluminecent metric assay for TSH on days one and three and at weekly intervals to day 56. Vanhole 1997 used RIA to measure T4, T3, free T4 and rT3, and TSH by immunoradiometric assay weekly from week 0 (cord blood) to week six.
Methodological quality of included studies
Randomisation: All studies used a random method of allocation to treatment. Valerio 2004 used a computerised randomisation procedure in blocks of five stratified for gestation (< 27 weeks and 27 weeks). van Wassenaer 1997 used computerised block randomisation. Vanhole 1997 used randomised envelopes. Smith 2000 used sequentially numbered envelopes stratified by centre. There were no reported significant differences between treatment and control groups after randomisation in terms of birth weights, gestational ages, Apgar scores or the male/female ratio in any of the studies. van Wassenaer 1997 had fewer infants < 27 weeks gestation (19 versus 27) and more very small for gestational age infants (five versus two) in the treatment group compared to the control group. In the neurodevelopmental follow up of 25 - 26 weeks' gestation survivors, van Wassenaer 1997 found a significantly lower mean birth weight in the treatment group (n = 13) compared to the placebo group (n = 18) (856 +/- 153g versus 914 +/- 111g; p = 0.04). Smith 2000 had fewer infants randomised to control (20) than to treatment (29). No reason was given.
Blinding of treatment: Valerio 2004, van Wassenaer 1997, Vanhole 1997 and Smith 2000 used placebo treatment in the control arm.
Blinding of outcome assessment: Valerio 2004, van Wassenaer 1997, Vanhole 1997 and Smith 2000 performed blinded assessment of clinical and neurodevelopmental outcomes.
Exclusions after randomisation: van Wassenaer 1997 reported seven (4%) losses to neurodevelopmental follow up at 24 months corrected age (four treatment and three controls) due to withdrawals from trial or the diagnosis of a congenital anomaly, and nine (five treatment and four controls) at five years. Vanhole 1997 reported six (15%) exclusions of neonatal deaths from analysis of neonatal morbidities, but assessed neurodevelopment of all survivors at seven months corrected age. Smith 2000 reported two (4%) infants lost from the control group. Valerio 2004 reported outcomes for all enrolled infants for mortality and neonatal morbidities.
Studies with adequate methodology: All studies (Valerio 2004; van Wassenaer 1997, Vanhole 1997, Smith 2000) were of adequate methodology with adequate randomisation, allocation concealment and > 90% follow up of survivors. These studies also blinded treatment and measurement of outcomes using a placebo.
Results
PROPHYLACTIC THYROID HORMONES VERSUS NO THYROID HORMONES (COMPARISON 01):
All four studies (Valerio 2004; van Wassenaer 1997; Vanhole 1997) gave postnatal thyroid hormones to preterm infants on the basis of gestational age and/or birthweight criteria.
Neurodevelopment: No significant difference was found in any measure of neurodevelopmental outcome in infants who received neonatal thyroid hormone replacement compared to controls. There was no significant difference in the mortality rate or combined mortality and abnormal neurological outcome in infants who received thyroid hormone treatment compared to controls. van Wassenaer 1997 reported no significant difference in abnormal mental development at 6, 12, 24 months (RR 0.67, 95% CI 0.28, 1.56) or five years (RR 0.66, 95% CI 0.22, 1.99). van Wassenaer 1997 reported no significant difference in the risk of cerebral palsy assessed at five years (RR 0.72, 95% CI 0.28, 1.84). Meta-analysis of two studies (van Wassenaer 1997, Vanhole 1997) found no significant difference in the Bayley Mental Development Index (WMD -1.14, 95% CI -5.46, 3.19) and Psychomotor Development Index (WMD 0.22, 95% CI -4.80, 5.24) at 7 - 12 months (Outcomes 01.04 and 01.05). There was significant (p = 0.04) and substantial (I2 = 76.2%) heterogeneity between the studies for the Bayley PDI and borderline heterogeneity (p = 0.09) for the Bayley MDI. van Wassenaer 1997 found no significant difference in the Bayley Mental Development Index (MD -3.50, 95% CI -11.21, 4.21) and Psychomotor Development Index (MD 3.10, 95% CI -3.31, 9.51) at 24 months. van Wassenaer 1997 reported similar RAKIT IQ scores at 5 years (MD -2.10, 95% CI -7.91, 3.71). van Wassenaer 1997 reported behavioural outcomes at two and five years and schooling at 10 years. At 10 years, there was no significant difference in children in special schooling (RR 0.88, 95% CI 0.43, 1.83). At two years the risk of a clinically significant Child Behavioural Checklist (CBCL) score (RR 0.81, 95% CI 0.35, 1.86) was not significantly different. At five years, the risk of a clinically significant CBCL score (RR 1.17, 95% CI 0.57, 2.40) and Teacher Report Form (TRF) score (RR 1.08, 95% CI 0.55, 2.10) were not significantly different. van Wassenaer 1997 reported a subgroup analysis according to gestational age strata. As this analysis was not prespecified by the investigators and the numbers of infants in each gestational strata were dissimilar, the results of this analysis are not reported.
Mortality (Outcomes 01.13 - 01.15): Meta-analysis of two trials (van Wassenaer 1997; Vanhole 1997) found no significant difference in neonatal mortality (typical RR 0.68, 95% CI 0.37, 1.25) and meta-analysis of all four trials found no significant difference in mortality to discharge in infants receiving thyroid hormone treatment (typical RR 0.76, 95% CI 0.46 to 1.24). van Wassenaer 1997 reported no significant difference in death or cerebral palsy at five years (RR 0.70, 95% CI 0.43 to 1.14).
Neonatal morbidity: Meta-analysis of three trials found no significant difference in duration of mechanical ventilation (WMD -3.76 days, 95% CI -11.28, 3.77) (Outcome 01.16). Meta-analysis of all four studies found no significant difference in CLD in survivors at 28 days (typical RR 0.97, 95% CI 0.77, 1.23) and meta-analysis of two studies (van Wassenaer 1997; Vanhole 1997) found no significant difference in CLD at 36 weeks (typical RR 1.06, 95% CI 0.65, 1.74) (Outcomes 01.17 and 01.18). Meta-analysis of two studies (Vanhole 1997; van Wassenaer 1997) found no significant difference in any intraventricular haemorrhage (typical RR 1.19, 95% CI 0.86, 1.63) and meta-analysis of 4 studies (Smith 2000; Valerio 2004; van Wassenaer 1997; Vanhole 1997) found no significant difference in grade 3 or 4 intraventricular haemorrhage (typical RR 1.19, 95% CI 0.63, 2.24) (Outcomes 01.19 and 01.20). Meta-analysis of three studies (Smith 2000; Valerio 2004; van Wassenaer 1997) found no significant difference in periventricular leucomalacia (typical RR 0.97, 95% CI 0.23, 4.12) (Outcome 01.21). Meta-analysis of three studies (Smith 2000; van Wassenaer 1997; Vanhole 1997) found no significant difference in patent ductus arteriosus (typical RR 0.71, 95% CI 0.50, 1.02) (Outcome 01.22). Meta-analysis of three studies (Smith 2000; Valerio 2004; van Wassenaer 1997) found no significant difference in sepsis (RR 0.78, 95% CI 0.53, 1.16) (Outcome 01.23). Meta-analysis of two studies (Vanhole 1997, van Wassenaer 1997) found no significant difference in retinopathy of prematurity (typical RR 0.99, 95% CI 0.49, 2.01) Outcome 01.24).
Growth: Vanhole 1997 also reported no difference in weight growth rates of infants receiving T4 treatment (displayed as graph in paper).
PROPHYLACTIC THYROID HORMONES VERSUS NO THYROID HORMONES ACCORDING TO DOSING STRATEGY USED (COMPARISON 02):
Only two studies (Valerio 2004; van Wassenaer 1997) used the same dosing strategy (thyroxine 8 μg/kg/day from day 1 to 42 ). Dosing strategies included: Smith 2000 treated infants starting before 48 hours age with T4 10 μg/kg/day intravenously until tolerating feeds, then 20 μg/kg/day for a total 21 days. Valerio 2004 compared infants treated with T3 0.5 μg/kg at 24 hours after birth and T4 8 μg/kg daily for 42 days with infants treated with T4 8 μg/kg daily for 42 days and a control who received a placebo. Vanhole 1997 treated infants with T4 20 μg/kg/day intravenously for two weeks from the first day. van Wassenaer 1997 treated infants with T4 8 μg/kg birthweight (intravenously until tolerating feeds, then orally) from 12 - 24 hours of age for six weeks.
Meta-analysis of two studies (Valerio 2004; van Wassenaer 1997) that compared T4 8 μg/kg/day from day 1 to 42 found no significant difference for any outcome including mortality to discharge, chronic lung disease in survivors at 28 days, grade 3 or 4 intraventricular haemorrhage or periventricular leucomalacia (see 'analyses tables'). Smith 2000 reported a reduction in sepsis of borderline significance in infants receiving T4 (RR 0.51, 95% CI 0.26, 0.98) which was reported in the article as not significant using the chi-square test at the p = 0.05 level. No other study using any of the documented dosing strategies reported a significant difference for any other outcomes.
Effects on thyroid hormone levels: Smith 2000 reported TSH and free T4 levels in infants treated with 10 μg/kg/day within 48 hours of birth. Oral T4 20 μg/kg/day was commenced with enteral feedings and continued to 21 days. Significantly lower TSH levels and higher free T4 levels were found in infants receiving T4 at day 7, 14 and 21 but not 28 days. Actual numbers of infants with levels above and below the reference ranges were not reported. Reference ranges were not reported. Valerio 2004 reported T3, free T3, rT3, T4, free T4, TSH, and cortisol levels in infants treated with T3 0.5 μg/kg on day one and T4 8 μg/kg/day for 42 days, or T4 alone or placebo. The group receiving T3 had a significant rise in T3 up to six hours post administration. The were no significant differences in mean free T3 levels at any time. Changes to rT3 did not reach significance. Both groups receiving T4 had significant increases in free T4 levels day three to 21 compared to placebo. Changes in mean T4 levels were similar, but not significant. Mean TSH levels were suppressed in infants receiving thyroid hormones up to the end of thyroid hormone supplementation (day 42). Levels of all thyroid hormones and TSH were not significantly different between treated and control infants after cessation of thyroid hormone treatment (day 56). Actual numbers of infants with levels above and below the reference ranges were not reported. Reference ranges were not reported. van Wassenaer 1997 reported T4, T3, rT3, TSH and TBG levels in infants treated with T4 8 μg/kg/day from day one to 42. Levels of T4 increased from day three to 42 compared to a decrease in T4 levels in the control group from day three to day 21. The difference between the groups was significant from day three to day 42. Levels of T3 were significantly lower in T4 treated infants from day 14 to day 56, whereas levels of rT3 were significantly lower from day three to day 42. TSH was significantly lower in infants receiving thyroid hormones from day three to day 42. Level of all thyroid hormones except T3 were not significantly different after cessation of treatment on day 56. T3 levels were still significantly lower on day 56 in the treated infants. Actual numbers of infants with levels above and below the reference ranges were not reported. Reference ranges were not reported. Vanhole 1997 reported T4, T3, rT3, TSH and TBG in infants treated with T4 20 μg/kg/day for two weeks. Levels of T4 and rT3 were significantly higher in infants receiving T4 at week one and two, whereas levels of TSH were significantly lower at week one and two. Levels of TBG were lower at week two only. Levels of T3 were not significantly different. Actual numbers of infants with levels above and below the reference ranges were not reported. Reference ranges were not reported.
Subgroup analysis.
Prophylactic thyroid hormones versus no thyroid hormones: subgroup analysis according to timing of thyroid hormone treatment (Comparison 03):
All studies enrolled infants and commenced thyroid hormones before 48 hours after birth. Results as per analysis '1. Prophylactic thyroid hormones versus no thyroid hormones.'
All studies enrolled infants and commenced thyroid hormones before 48 hours after birth. Results as per analysis '1. Prophylactic thyroid hormones versus no thyroid hormones.'
Subgroup analysis. Prophylactic thyroid hormones versus no thyroid hormones: subgroup analysis according to gestational age (Comparison 04):
Studies mostly enrolled infants that overlapped prespecified gestational strata. Smith 2000 enrolled infants < 32 weeks (mean treatment 28.8 weeks [sem 0.5]; control 28.6 [sem 0.4]), Valerio 2004 enrolled infants < 28 weeks gestation, van Wassenaer 1997 enrolled infants 25 - 29 weeks gestation, and Vanhole 1997 enrolled infants 25 - 30 weeks gestation. Only one study (Valerio 2004) prespecified analyses according to gestational strata (< 27 weeks and 27 weeks) and no study randomised infants according to gestational strata. Valerio 2004 is reported for the gestation strata < 28 weeks. An analysis by one study (van Wassenaer 1997) by gestational strata was not prespecified. In addition, van Wassenaer 1997 reported fewer infants < 27 weeks gestation (19 versus 27) and more very small for gestational age infants (five versus two) in the treatment group compared to the control group.
Valerio 2004 reported no significant difference in mortality to discharge (RR 0.67, 95% CI 0.42, 6.62), duration of mechanical ventilation (MD -0.44, 95% CI -13.92, 13.04), CLD in survivors at 28 days (RR 0.82, 95% CI 0.54, 1.25), grade 3 or 4 IVH (RR 2.38, 95% CI 0.32, 17.78), periventricular leucomalacia (RR 1.50, 95% CI 0.07, 33.89) or sepsis (RR 0.83, 95% CI 0.32, 2.20).
No studies eligible.
No studies eligible.
Subgroup analysis. Prophylactic thyroid hormones versus no thyroid hormones: subgroup analysis of trials using adequate methodology (Comparison 05):
Four studies were of adequate methodology with adequate randomisation procedures and allocation concealment and > 90% ascertainment of outcomes (Valerio 2004; van Wassenaer 1997, Vanhole 1997, Smith 2000). The results of this review are not changed by incorporating only studies with good methodology. The neurodevelopmental outcomes were reported by the same studies, and meta-analyses found no significant difference in neonatal mortality (two studies; typical RR 0.68, 95% CI 0.37, 1.25), mortality to discharge (four studies, typical RR 0.76. 95% CI 0.46, 1.24), duration of mechanical ventilation (three studies; WMD -3.76, 95% CI -11.28, 3.77), CLD at 28 days in survivors (four studies; typical RR 0.97, 95% CI 0.77, 1.23), CLD at 36 weeks in survivors (two studies; typical RR 1.06, 95% CI 0.65, 1.74), any IVH (two studies; typical RR 1.19, 95% CI 0.86, 1.63), IVH grade 3 or 4 (four studies; typical RR 1.19, 95% CI 0.63, 2.24), periventricular leucomalacia (three studies; typical RR 0.97, 95% CI 0.23, 4.12), patent ductus arteriosus (three studies; typical RR 0.71, 95% CI 0.50, 1.02), sepsis (three studies; typical RR 0.78, 95% CI 0.53, 1.16) or retinopathy of prematurity (two studies; typical RR 0.99, 95% CI 0.49, 2.01).
PROPHYLACTIC POSTNATAL THYROID HORMONES VERSUS OTHER THYROID HORMONE STRATEGY (e.g. T3 AND T4 VERSUS T4 ALONE) (COMPARISON 06):
One study (Valerio 2004) compared infants treated with T3 0.5 μg/kg at 24 hours after birth and then T4 8 μg/kg daily for 42 days versus T4 8 μg/kg daily for 42 days alone. Valerio 2004 did not report neurodevelopment. Valerio 2004 reported no significant difference in mortality to discharge (RR 1.21, 95% CI 0.36, 4.14). Valerio 2004 reported no significant difference in duration of mechanical ventilation (MD 0.50, 95% CI -5.57, 6.57 days) or chronic lung disease in survivors at 28 days (RR 0.67, 95% CI 0.33, 1.35). Valerio 2004 reported no significant difference in grade 3 or 4 intraventricular haemorrhage (RR 3.64, 95% CI 0.48, 27.33), periventricular leucomalacia (RR 0.31, 95% CI 0.01, 6.74) or sepsis (RR 5.45, 95% CI 0.79, 37.81).
Discussion
Significance of findings: Four studies were included in this review examining the effects of prophylactic postnatal thyroid hormones in preterm infants. All studies gave postnatal thyroid hormones to preterm infants on the basis of gestational age and/or birthweight criteria. No significant benefits were reported in terms of neurodevelopmental outcomes, mortality or neonatal morbidities by any study and no significant benefits were found in meta-analysis for any outcome. The studies used a variety of different dosing strategies with only two studies (van Wassenaer 1997; Valerio 2004) incorporating the same dose and duration using T4 8 μg/kg/day from day one to 42. Higher dose but shorter duration thyroxine courses were given by Smith 2000 who used T4 10-20 μg/kg/day from day two to 21 and Vanhole 1997 who used 20 μg/kg/day from day one to 14. No significant clinical benefits were reported by any of these studies. van Wassenaer 1997 and Vanhole 1997 also reported neurodevelopmental outcomes that were not significantly different. van Wassenaer 1997 has now followed developmental and school outcomes at five and 10 years of age with no significant benefits from use of prophylactic thyroxine reported. Separate reviews also reported the use of postnatal thyroid hormones for respiratory distress syndrome in preterm infants (Osborn 2007a) and in preterm infants with transient hypothyroxinaemia (Osborn 2007b). Neither review found any evidence of benefit from use of thyroid hormones in terms of neonatal morbidities or mortality. However, no additional data were found examining the effects of thyroid hormones on longer term neurodevelopmental outcomes.
One study used triiodothyronine (Valerio 2004). Valerio 2004 enrolled infants < 28 weeks gestation to a course of combined T3 0.5 μg/kg day one and T4 8 μg/kg/day from day one to 42. Again, no significant clinical benefits were reported although neurodevelopment was not reported.
This review examines the clinical effect of prophylactic thyroid hormone therapy. An analysis of the effect of thyroid hormone supplementation on thyroid hormone levels was also undertaken. The analysis found that whereas most studies measured total thyroid hormone levels, only three studies (Smith 2000; Valerio 2004; van Wassenaer 1997) measured biologically active thyroid hormones, free T3 or free T4. Rates of infants with levels above or below reference ranges were not reported by any study. In studies using thyroxine, Smith 2000 reported that free T4 was increased compared to controls from day 7 to 21 after administration of thyroxine 10-20 μg/kg/day from day two for 21 days; Valerio 2004 reported a significant increase in free T4 day three to 14 but not free T3 after administration of thyroxine 8 μg/kg/day for 42 days. Studies reported variable changes in total T4 levels with thyroxine administration. Two studies (van Wassenaer 1997; Vanhole 1997) reported a significant increase during treatment with thyroxine. Valerio 2004 reported an increase that was not statistically significant. Levels of free T3 were reported as unchanged in one study (Valerio 2004) with thyroxine treatment. Levels of total T3 were reported as unchanged in two studies (Valerio 2004; Vanhole 1997) but decreased during treatment in another study (van Wassenaer 1997) with thyroxine treatment. All studies reported thyroid hormone levels returning to levels seen in controls after cessation of treatment. One study used triiodothyronine. Valerio 2004 used T3 on day 1 and reported significant increases in levels of total T3 up to 6 hours after infusion but no significant difference in free T3 levels. In summary, administration of thyroid hormones to preterm infants results in increases in total T3 or total T4 levels depending on which thyroid hormone is administered. Free T4 levels may be increased by the administration of thyroxine but free T3 levels have not been demonstrated to change in response to thyroxine or triiodothyronine. Rates of low and high thyroid hormone levels were not reported.
Limitations of the review: For primary outcomes, limited comparable data were available for meta-analytic pooling of results for neurodevelopment, but data were complete for all studies with respect to mortality to discharge. Major limitations of this review include the small number of infants enrolled in trials incorporated in the review resulting in limited power to detect moderate but clinically important differences in effect of thyroid hormone therapy in preterm infants. Studies used different treatments, doses and enrolment criteria which limits the ability to make conclusions from pooled results.
Limitations of studies: Two studies (van Wassenaer 1997; Vanhole 1997) with adequate neurodevelopmental follow up were of good methodology. Valerio 2004 was of good methodology but did not report neurodevelopmental outcomes. Smith 2000 had more infants randomised to the treatment group (29 versus 20). The largest study with 200 infants, van Wassenaer 1997, reported a subgroup analysis according to gestational strata. As there were potentially clinically significant differences in neonatal risk factors in the two groups after randomisation, with fewer infants < 27 weeks and more infants < 3rd percentile for weight in the treatment group, and the subgroup analysis was not prespecified by the investigators, this analysis has not been reported in this review.
There is no apparent heterogeneity in the findings of the different studies. The conclusions are not altered by excluding studies with inadequate methodology. The review finds no evidence of benefit from any individual thyroid hormone preparation, dose, timing or duration of treatment. There is insufficient evidence to determine whether there is a gestational age dependent effect of thyroid hormone supplementation as suggested by one study's authors (van Wassenaer 1997). Further research is needed to determine if prophylactic treatment with thyroid hormones to prevent the postnatal nadir in thyroid hormone levels results in improved neonatal and long term outcomes. Questions that require answering include which thyroid hormones should be supplemented and at what dose. It is unclear whether both substrate T4 and active T3 need to be supplemented to achieve 'normal' levels of biologically active hormones. It is also unclear whether fetal or neonatal levels of thyroid hormones should be targeted in the first weeks. Although low levels of thyroid hormones have been associated with adverse neonatal and long term developmental outcomes, it is unclear whether this effect is causal or an association. It is possible that low levels of thyroid hormones are an attempt to protect the sick infant by reducing the metabolic rate at a time of stress or illness. In a related review (Osborn 2007a), no benefit was found from the use of higher dose thyroid hormone supplementation to mimic the postnatal thyroid hormone surge that occurs after birth, although currently reported trials of thyroxine and triiodothyronine are underpowered to detect a clinically important difference. Prophylactic thyroid hormones should only be used in the context of adequately designed clinical trials. An adequately powered clinical trial that measures the effect on long term neurodevelopmental outcomes will be required before prophylactic thyroid hormones are used routinely in clinical practice in preterm infants without congenital hypothyroidism.
Reviewers' conclusions
Implications for practice
This review does not support the use of prophylactic thyroid hormones in preterm infants to reduce neonatal mortality, neonatal morbidity or improve neurodevelopmental outcomes.
Implications for research
Further research is needed to determine optimal thyroid hormone treatment and dosing strategy. An adequately powered clinical trial of thyroid hormone supplementation with the goal of preventing the postnatal nadir of thyroid hormone levels seen in very preterm infants is required. The trial should be powered to detect clinically important differences in long term neurodevelopment and behavioural outcomes.
Acknowledgements
Professor F de Zegher, Dr Aleid van Wassenaer and Dr Christine Vanhole for kindly responding to the request for additional information.
Potential conflict of interest
None.
Characteristics
of included studies
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Smith 2000 | Random study: yes, sequentially numbered envelopes in blocks of 8 allocated to individual centres.
Two centers.
Blinding of intervention: yes, placebo controlled.
Complete follow up: no, 2 losses in control (> 32 weeks, thyroid disease).
Blinding of outcome measurement: probably, but one investigator examined thyroid tests to determine need for thyroid treatment.
Power calculation performed: yes, 300 needed to detect reduced incidence of oxygen at 28 days from 30 to 15%. | Forty nine infants.
Inclusion criteria: Infants < 32 weeks, birthweight 600-1500g.
Exclusion criteria: maternal thyroid disease or illicit drug use, infant lethal malformation or congenital thyroid disease.
Second of twins not enrolled.
Treatment group: (+/-sd) 28.6 (0.4) weeks gestation, 1074g (46) birthweight (n = 29).
Control group: 28.8 (0.5) weeks, 1037g (66) birthweight (n = 18, 2 losses). | Treatment: IV thyroxine 10 micrograms/kg/day started before 48 hours age. Oral thyroxine 20 microgram/kg/day commenced as soon as oral feedings tolerated.
Control: placebo (saline).
Continued for 21 days. | Primary outcome: oxygen at 28 days.
Secondary: death before 12 months, intraventricular haemorrhage, periventricular leucomalacia, patent ductus arteriosus, sepsis and necrotising enterocolitis. | Study stopped early due to minimal effect seen on oxygen at 28 days. | A |
| Valerio 2004 | Random study: yes, computerised randomisation in blocks of five, stratified for gestation 27 weeks and <27 weeks.
Blinding of intervention: yes, placebo controlled.
Complete follow up: yes.
Blinding of outcome measurement: yes.
Power calculation performed: not reported. | Inclusion criteria: gestational age <28 weeks, consent within 24 hours of birth.
Exclusion criteria: severe congenital anomaly, maternal endocrine disease.
Treatment group 1: (+/-sem) 27.0 (0.18) mean weeks gestation, 889 (60)g mean birthweight (n = 11).
Treatment group 2: 27.1 (0.19) weeks, 982 (67)g (n = 10).
Placebo: 26.9 (0.15) weeks, 1067 (35)g (n = 10). | Treatment group 1 (n = 11): T3 0.5micrograms/kg intravenously 22-26 hours after birth, T4 8 micrograms/kg daily for 42 days, intravenously initially then enterally when on full enteral feeds.
Treatment group 2 (n = 10): T4 8 micrograms/kg daily for 42 days, intravenously initially then enterally when on full enteral feeds.
Control (n = 10): placebo.
| Primary outcomes: hormonal effects of thyroid hormones on cortisol and thyroid hormone levels.
Outcomes: T3, FT3, T4, FT4, TSH rT3 and cortisol on cord blood, on day 3, 7, 14, 21, 42 and 56. Daily mean heart rate, mean intra-arterial blood pressure and cummulative doses of inotropes. Also reported were mortality, septicemia, cystic periventricular leucomalacia, intraventricular haemorrhage grades 3 or 4, postnatal dexamethasone, oxygen dependency at 28 days, time on mechanical ventilation and parenteral nutrition. | | A |
| van Wassenaer 1997 | Random study: computerised block (size 10) randomisation. Not stratified.
Single center.
Blinding of randomization: yes.
Blinding of intervention: yes, placebo controlled.
Complete follow up: yes: 96% of survivors had neurodevelopmental followup. Treatment group had 4 losses and control group 3 (congenital abnormality or withdrawn). At 2.7 years, losses were treatment 5 and control 4. At 5 years 8/165 (5%) survivors lost to study. At 10 years, 112/156 (72%) had school outcomes reported.
Blinding of outcome measurement: yes.
Power calculation performed: not stated. | Two hundred preterm infants.
Inclusion criteria: preterm infants 25-29 weeks.
Exclusion criteria: severe congenital malformations, maternal endocrine disease or illicit drug use.
Treatment group: mean birth weight (+/-sd) 1078+/-218g, mean gestation 197+/-8 days (n = 100).
Controls: mean birth weight 1077+/-239g, mean gestation 196+/-9 days (n = 100). | Treatment: thyroxine 8 micrograms/kg daily (IV until tolerating feeds, then oral) for 6 weeks, starting 12-24 hours after birth.
Control: placebo for 6 weeks. | Neurodevelopment at 6 and 12 months (method of Touwen).
Neurodevelopment at 24 months (method of Hempel).
Bayley Mental Development Index at 6, 12 and 24 months.
Bayley Psychomotor Index at 6, 12 and 24 months corrected age. Child Behaviour Checklist (CBCL) for ages 2-3.
At mean age 5.7 years: Revised Amsterdam Children's Intelligence Test (RAKIT), CBCL and Teacher Report Form (TRF), Movement Assessment Battery for Children and neurologic outcome using method of Touwen (minor neurological dysfunction [MND] and cerebral palsy.
Mortality (to time of discharge), respiratory distress syndrome, patent ductus arteriosus, intraventricular haemorrhage,
cerebral ischemic lesions, chronic lung disease (at 36 weeks), retinopathy of prematurity.
At 10 years, schooling outcomes, Child Beharvioural Checklist, Teacher Report Form, Dutch TNO-AZL Children's Quality of Life Questionnaire, Nijmeegse Ouderlijke Stress Index, ABC Checklist performed. | Subgroup analysis stratified for gestation (24-25 weeks and 26-29 weeks) not prespecified. | A |
| Vanhole 1997 | Random study: used sealed envelopes.
Single center.
Blinding of randomisation: yes.
Blinding of intervention: yes, placebo controlled.
Complete follow up: yes - all survivors had neurodevelopmental follow up. 6 (15%) neonatal deaths excuded from analysis of neonatal morbidities (CLD and RDS).
Blinding of outcome measurement: yes.
Power calculation performed: not reported. | Forty preterm infants:
Inclusion criteria: inborn, gestation 25-30 weeks, cord blood available.
Exclusion criteria: congenital malformations and maternal thyroid disease.
Treatment group: mean birth weight (+/- sd) 1191+/-299g, mean gestation 28.4+/-1.7 weeks (n = 20).
Control group: mean birth weight 1206+/-411g, mean gestation 28.5+/-1.9 weeks (n = 20).
The mothers of 11/17 of the treatment group and 13/17 of controls received antenatal steroids and TRH. | Treatment: thyroxine 20 microgram/kg/day IV for two weeks from day 1.
Control: placebo. | Mean Bayley Mental Development Index at 7 months corrected age
Mean Bayley Psychomotor Index at 7 months corrected age
Neonatal mortality
Respiratory distress syndrome
Chronic lung disease (oxygen at 28 days and CXR changes)
Heart rate, daily inspired oxygen, weekly weight gain, and enteral fluid intake | Also evaluated thyroid hormone (T4, T3 and reverse T3), prolactin and growth hormone levels in infants and effects of dopamine infusions. | A |
Characteristics of excluded studies
| Study | Reason for exclusion |
| Amato 1988 | Enrolled preterm infants with respiratory distress syndrome. |
| Amato 1989 | Enrolled preterm infants with respiratory distress syndrome. |
| Bettendorf 2000 | Enrolled infants after cardiac surgery. |
| Biswas 2003 | Randomised trial of triiodothyronine and hydrocortisone versus placebo preterm infants <30 weeks gestation. |
| Cassio A 2003 | Enrolled infants with congenital hypothyroidism. |
| Chowdhry 1984 | Enrolled infants with 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. |
| 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). |
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 | |
References
to studies
References to included studies
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 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, Bri�t 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 AG, Westera J, Houtzager BA, Kok JH. Ten-year follow-up of children born at <30 weeks' gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial. Pediatrics 2005;116:e613-8.
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 excluded 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(5-6):213-7.
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.
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.
References to ongoing studies
Golombek {unpublished data only}* indicates the primary reference for the study
Other references
Additional references
Ballabio 1989Ballabio M, Nicolini U, Jowett T, Ruiz de Elvira MC, Ekins RP, Rodeck CH. Maturation of thyroid function in normal human foetuses. Clinical Endocrinology 1989;31:565-71.
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.
Beranl 1995
Beranl J, Nunez J. Thyroid hormones and brain development. European Journal of Endocrinology 1995;133:390-8.
Den Ouden 1996
Den Ouden AL, Kok JH, Verkerk PH, Brand R, Verloove-Vanhorick SP. The relation between neonatal thyroxine levels and neurodevelopmental outcome at age 5 and 9 years in a national cohort of very preterm and/or very low birth weight infants. Pediatric Research 1996;39:142-5.
Filippi 2004
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Meijer WJ, Verloove-Vanhorick SP, Brand R, van den Brande JL. Transient hypothyroxinaemia associated with developmental delay in very preterm infants. Archives of Disease in Childhood 1992;67:944-7.
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Oden J, Freemark M. Thyroxine supplementation in preterm infants: critical analysis. Current Opinion in Pediatrics 2002;14:447-52.
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Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal neurological development - current perspectives. Endocrine Reviews 1993;14:94-106.
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Other published versions of this review
Osborn 2001Osborn DA. Thyroid hormones for preventing neurodevelopmental impairment in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2001.
Comparisons
and data
01 Prophylactic thyroid hormones versus no thyroid hormones
01.01 Abnormal mental development in survivors
at 2 years (Bayley MDI > 2sd below mean)
01.02 Abnormal mental development in survivors
at 5 years (Bayley MDI > 2sd below mean)
01.03 Cerebral palsy in survivors
01.04 Bayley MDI in survivors at 7-12 months
01.05 Bayley PDI in survivors at 7-12 months
01.06 Bayley MDI in survivors at 24 months
01.07 Bayley PDI in survivors at 24 months
01.08 RAKIT IQ score in survivors at 5 years
01.09 Special schooling at 9-12 years
01.10 Clinically significant Child Behaviour Checklist
score in survivors at 2 years
01.11 Clinically significant Child Behaviour Checklist
score in survivors at 5 years
01.12 Clinically significant Teacher Report Form
score in survivors at 5 years
01.13 Neonatal mortality
01.14 Mortality to discharge
01.15 Death or cerebral palsy
01.16 Duration of mechanical ventilation (days)
01.17 CLD in survivors (oxygen at 28 days)
01.18 CLD in survivors (oxygen at 36 weeks)
01.19 Intraventricular haemorrhage - any grade
01.20 Intraventricular haemorrhage - grade 3 or
4
01.21 Periventricular leucomalacia
01.22 Patent ductus arteriosus
01.23 Sepsis
01.24 Retinopathy of prematurity (any grade) in
survivors
02 Prophylactic thyroid hormones versus no thyroid hormones according to thyroid hormone dosing strategy
02.01 Abnormal mental development in survivors
at 2 years (Bayley MDI >2sd below mean)
02.01.01 T4 8 mcg/kg/day day 1 to 42
02.02 Abnormal mental development in survivors
at 5 years (Bayley MDI >2sd below mean)
02.02.01 T4 8 mcg/kg/day day 1 to 42
02.03 Cerebral palsy in survivors
02.03.01 T4 8 mcg/kg/day day 1 to 42
02.04 Bayley MDI in survivors at 7-12 months
02.04.01 T4 8 mcg/kg/day day 1 to 42
02.04.02 T4 20 mcg/kg/day day 1 to 14
02.05 Bayley PDI in survivors at 7-12 months
02.05.01 T4 8 mcg/kg/day day 1 to 42
02.05.02 T4 20 mcg/kg/day day 1 to 14
02.06 Bayley MDI in survivors at 24 months
02.06.01 T4 8 mcg/kg/day day 1 to 42
02.07 Bayley PDI in survivors at 24 months
02.07.01 T4 8 mcg/kg/day day 1 to 42
02.08 RAKIT IQ score in survivors at 5 years
02.08.01 T4 8 mcg/kg/day day 1 to 42
02.09 Clinically significant Child Behaviour Checklist
score in survivors at 2 years
02.09.01 T4 8 mcg/kg/day day 1 to 42
02.10 Clinically significant Child Behaviour Checklist
score in survivors at 5 years
02.10.01 T4 8 mcg/kg/day day 1 to 42
02.11 Clinically significant Teacher Report Form
score in survivors at 5 years
02.11.01 T4 8 mcg/kg/day day 1 to 42
02.12 Neonatal mortality
02.12.01 T4 8 mcg/kg/day day 1 to 42
02.12.02 T4 10-20 mcg/kg/day day 2 to 21
02.12.03 T4 20mcg/kg/day day 1 to 14
02.13 Mortality to discharge
02.13.01 T4 8 mcg/kg/day day 1 to 42
02.13.02 T4 10-20 mcg/kg/day day 2 to 21
02.13.03 T4 20mcg/kg/day day 1 to 14
02.13.04 T3 0.5 mcg/kg/day day 1 and T4 8 mcg/kg/day day 1 to 42
02.14 Death or cerebral palsy
02.14.01 T4 8 mcg/kg/day day 1 to 42
02.15 Duration of mechanical ventilation (days)
02.15.01 T4 8 mcg/kg/day day 1 to 42
02.15.02 T4 10-20 mcg/kg/day day 2 to 21
02.15.03 T4 20 mcg/kg/day day 1 to 14
02.15.04 T3 0.5 mcg/kg/day day 1 and T4 8 mcg/kg/d day 1 to 42
02.16 CLD in survivors (oxygen at 28 days)
02.16.01 T4 8 mcg/kg/day day 1 to 42
02.16.02 T4 10-20 mcg/kg/day day 2 to 21
02.16.03 T4 20mcg/kg/day day 1 to 14
02.16.04 T3 0.5 mcg/kg/day day 1 and T4 8 mcg/kg/day day 1 to 42
02.17 CLD in survivors (oxygen at 36 weeks)
02.17.01 T4 8 mcg/kg/day day 1 to 42
02.17.02 T4 20mcg/kg/day day 1 to 14
02.18 Patent ductus arteriosus
02.18.01 T4 8 mcg/kg/day day 1 to 42
02.18.02 T4 10-20 mcg/kg/day day 2 to 21
02.18.03 T4 20mcg/kg/day day 1 to 14
02.19 Intraventricular hemorrhage - any grade
02.19.01 T4 8 mcg/kg/day day 1 to 42
02.19.02 T4 20mcg/kg/day day 1 to 14
02.20 Intraventricular hemorrhage - grade 3 or
4
02.20.01 T4 8 mcg/kg/day day 1 to 42
02.20.02 T4 10-20 mcg/kg/day day 2 to 21
02.20.03 T4 20mcg/kg/day day 1 to 14
02.20.04 T3 0.5 mcg/kg/day day 1 and T4 8 mcg/kg/day day 1 to 42
02.21 Periventricular leukomalacia
02.21.01 T4 8 mcg/kg/day day 1 to 42
02.21.02 T4 10-20 mcg/kg/day day 2 to 21
02.21.03 T3 0.5 mcg/kg/day day 1 and T4 8 mcg/kg/day day 1 to 42
02.22 Retinopathy of prematurity (any grade) in
survivors
02.22.01 T4 8 mcg/kg/day day 1 to 42
02.22.02 T4 20mcg/kg/day day 1 to 14
02.23 Sepsis
02.23.01 T4 8 mcg/kg/day day 1 to 42
02.23.02 T4 10-20 mcg/kg/day day 2 to 21
02.23.03 T3 0.5 mcg/kg/day day 1 and T4 8 mcg/kg/day day 1 to 42
03 Prophylactic thyroid hormones versus no thyroid hormones according to timing
03.01 Abnormal mental development in survivors
at 2 years (Bayley MDI > 2sd below mean)
03.01.01 Commenced <48 hours
03.01.02 Commenced after 48 hours
03.02 Abnormal mental development in survivors
at 5 years (Bayley MDI > 2sd below mean)
03.02.01 Commenced <48 hours
03.02.02 Commenced after 48 hours
03.03 Cerebral palsy in survivors
03.03.01 Commenced <48 hours
03.03.02 Commenced after 48 hours
03.04 Bayley MDI in survivors at 7-12 months
03.04.01 Commenced <48 hours
03.04.02 Commenced after 48 hours
03.05 Bayley PDI in survivors at 7-12 months
03.05.01 Commenced <48 hours
03.05.02 Commenced after 48 hours
03.06 Bayley MDI in survivors at 24 months
03.06.01 Commenced <48 hours
03.06.02 Commenced after 48 hours
03.07 Bayley PDI in survivors at 24 months
03.07.01 Commenced <48 hours
03.07.02 Commenced after 48 hours
03.08 RAKIT IQ score in survivors at 5 years
03.08.01 Commenced <48 hours
03.08.02 Commenced after 48 hours
03.09 Special schooling at 9-12 years
03.09.01 Commenced <48 hours
03.09.02 Commenced after 48 hours
03.10 Clinically significant Child Behaviour Checklist
score in survivors at 2 years
03.10.01 Commenced <48 hours
03.10.02 Commenced after 48 hours
03.11 Clinically significant Child Behaviour Checklist
score in survivors at 5 years
03.11.01 Commenced <48 hours
03.11.02 Commenced after 48 hours
03.12 Clinically significant Teacher Report Form
score in survivors at 5 years
03.12.01 Commenced <48 hours
03.12.02 Commenced after 48 hours
03.13 Neonatal mortality
03.13.01 Commenced <48 hours
03.13.02 Commenced after 48 hours
03.14 Mortality to discharge
03.14.01 Commenced <48 hours
03.14.02 Commenced after 48 hours
03.15 Death or cerebral palsy
03.15.01 Commenced <48 hours
03.15.02 Commenced after 48 hours
03.16 Duration of mechanical ventilation (days)
03.16.01 Commenced <48 hours
03.16.02 Commenced after 48 hours
03.17 CLD in survivors (oxygen at 28 days)
03.17.01 Commenced <48 hours
03.17.02 Commenced after 48 hours
03.18 CLD in survivors (oxygen at 36 weeks)
03.18.01 Commenced <48 hours
03.18.02 Commenced after 48 hours
03.19 Intraventricular haemorrhage - any grade
03.19.01 Commenced <48 hours
03.19.02 Commenced after 48 hours
03.20 Intraventricular haemorrhage - grade 3 or
4
03.20.01 Commenced <48 hours
03.20.02 Commenced after 48 hours
03.21 Periventricular leucomalacia
03.21.01 Commenced <48 hours
03.21.02 Commenced after 48 hours
03.22 Patent ductus arteriosus
03.22.01 Commenced <48 hours
03.22.02 Commenced after 48 hours
03.23 Sepsis
03.23.01 Commenced <48 hours
03.23.02 Commenced after 48 hours
03.24 Retinopathy of prematurity (any grade) in
survivors
03.24.01 Commenced <48 hours
03.24.02 Commenced after 48 hours
04 Prophylactic thyroid hormones versus no thyroid hormones according to
gestational strata
04.01 Mortality to discharge
04.01.01 Gestation < 28 weeks
04.01.02 Gestation 28 to <31 weeks
04.01.03 Gestation >31 weeks
04.02 Duration of mechanical ventilation (days)
04.02.01 Gestation < 28 weeks
04.02.02 Gestation 28 to <31 weeks
04.02.03 Gestation >31 weeks
04.03 CLD in survivors (oxygen at 28 days)
04.03.01 Gestation < 28 weeks
04.03.02 Gestation 28 to <31 weeks
04.03.03 Gestation >31 weeks
04.04 Intraventricular haemorrhage - grade 3 or
4
04.04.01 Gestation < 28 weeks
04.04.02 Gestation 28 to <31 weeks
04.04.03 Gestation >31 weeks
04.05 Periventricular leucomalacia
04.05.01 Gestation < 28 weeks
04.05.02 Gestation 28 to <31 weeks
04.05.03 Gestation >31 weeks
04.06 Sepsis
04.06.01 Gestation < 28 weeks
04.06.02 Gestation 28 to <31 weeks
04.06.03 Gestation >31 weeks
05 Prophylactic thyroid hormones versus no thyroid hormones (studies with
adequate methodology)
05.01 Abnormal mental development in survivors
at 2 years (Bayley MDI > 2sd below mean)
05.02 Abnormal mental development in survivors
at 5 years (Bayley MDI > 2sd below mean)
05.03 Cerebral palsy in survivors
05.04 Bayley MDI in survivors at 7-12 months
05.05 Bayley PDI in survivors at 7-12 months
05.06 Bayley MDI in survivors at 24 months
05.07 Bayley PDI in survivors at 24 months
05.08 RAKIT IQ score in survivors at 5 years
05.09 Clinically significant Child Behaviour Checklist
score in survivors at 2 years
05.10 Clinically significant Child Behaviour Checklist
score in survivors at 5 years
05.11 Clinically significant Teacher Report Form
score in survivors at 5 years
05.12 Neonatal mortality
05.13 Mortality to discharge
05.14 Death or cerebral palsy
05.15 Duration of mechanical ventilation (days)
05.16 CLD in survivors (oxygen at 28 days)
05.17 CLD in survivors (oxygen at 36 weeks)
05.18 Intraventricular haemorrhage - any grade
05.19 Intraventricular haemorrhage - grade 3 or
4
05.20 Periventricular leucomalacia
05.21 Patent ductus arteriosus
05.22 Sepsis
05.23 Retinopathy of prematurity (any grade) in
survivors
06 Prophylactic T3 and T4 versus T4 alone
06.01 Mortality to discharge
06.02 Duration of mechanical ventilation (days)
06.03 CLD in survivors (oxygen at 28 days)
06.04 Intraventricular haemorrhage - grade 3 or
4
06.05 Periventricular leucomalacia
06.06 Sepsis
| Comparison
or outcome | Studies | Participants | Statistical
method | Effect
size |
|---|
| 01 Prophylactic
thyroid hormones versus no thyroid hormones |
| 01
Abnormal mental development in survivors at 2 years (Bayley MDI > 2sd below
mean) | 1 | 157 | RR
(fixed), 95% CI | 0.67
[0.28, 1.56] |
| 02 Abnormal mental
development in survivors at 5 years (Bayley MDI > 2sd below mean) | 1 | 156 | RR
(fixed), 95% CI | 0.66
[0.22, 1.99] |
| 03 Cerebral palsy
in survivors | 1 | 156 | RR
(fixed), 95% CI | 0.72
[0.28, 1.84] |
| 04 Bayley MDI in survivors
at 7-12 months | 2 | 191 | WMD
(fixed), 95% CI | -1.14
[-5.46, 3.19] |
| 05 Bayley PDI in
survivors at 7-12 months | 2 | 191 | WMD
(fixed), 95% CI | 0.22
[-4.80, 5.24] |
| 06 Bayley MDI in
survivors at 24 months | 1 | 157 | WMD
(fixed), 95% CI | -3.50
[-11.21, 4.21] |
| 07 Bayley PDI in
survivors at 24 months | 1 | 157 | WMD
(fixed), 95% CI | 3.10
[-3.31, 9.51] |
| 08 RAKIT IQ score
in survivors at 5 years | 1 | 156 | WMD
(fixed), 95% CI | -2.10
[-7.91, 3.71] |
| 09 Special schooling
at 9-12 years | 1 | 112 | RR
(fixed), 95% CI | 0.88
[0.43, 1.83] |
| 10 Clinically significant
Child Behaviour Checklist score in survivors at 2 years | 1 | 144 | RR
(fixed), 95% CI | 0.81
[0.35, 1.86] |
| 11 Clinically significant
Child Behaviour Checklist score in survivors at 5 years | 1 | 144 | RR
(fixed), 95% CI | 1.17
[0.57, 2.40] |
| 12 Clinically significant
Teacher Report Form score in survivors at 5 years | 1 | 147 | RR
(fixed), 95% CI | 1.08
[0.55, 2.10] |
| 13 Neonatal mortality | 2 | 240 | RR
(fixed), 95% CI | 0.68
[0.37, 1.25] |
| 14 Mortality to discharge | 4 | 318 | RR
(fixed), 95% CI | 0.76
[0.46, 1.24] |
| 15 Death or cerebral
palsy | 1 | 200 | RR
(fixed), 95% CI | 0.70
[0.43, 1.14] |
| 16 Duration of mechanical
ventilation (days) | 3 | 107 | WMD
(fixed), 95% CI | -3.76
[-11.28, 3.77] |
| 17 CLD in survivors
(oxygen at 28 days) | 4 | 267 | RR
(fixed), 95% CI | 0.97
[0.77, 1.23] |
| 18 CLD in survivors
(oxygen at 36 weeks) | 2 | 204 | RR
(fixed), 95% CI | 1.06
[0.65, 1.74] |
| 19 Intraventricular
haemorrhage - any grade | 2 | 240 | RR
(fixed), 95% CI | 1.19
[0.86, 1.63] |
| 20 Intraventricular
haemorrhage - grade 3 or 4 | 4 | 318 | RR
(fixed), 95% CI | 1.19
[0.63, 2.24] |
| 21 Periventricular
leucomalacia | 3 | 278 | RR
(fixed), 95% CI | 0.97
[0.23, 4.12] |
| 22 Patent ductus arteriosus | 3 | 287 | RR
(fixed), 95% CI | 0.71
[0.50, 1.02] |
| 23 Sepsis | 3 | 278 | RR
(fixed), 95% CI | 0.78
[0.53, 1.16] |
| 24 Retinopathy of
prematurity (any grade) in survivors | 2 | 207 | RR
(fixed), 95% CI | 0.99
[0.49, 2.01] |
| 02 Prophylactic
thyroid hormones versus no thyroid hormones according to thyroid hormone dosing
strategy |
| 01 Abnormal mental development
in survivors at 2 years (Bayley MDI >2sd below mean) | | | RR
(fixed), 95% CI | Subtotals
only |
| 02 Abnormal mental development
in survivors at 5 years (Bayley MDI >2sd below mean) | | | RR
(fixed), 95% CI | Subtotals
only |
| 03 Cerebral palsy in survivors | | | RR
(fixed), 95% CI | Subtotals
only |
| 04 Bayley MDI in survivors
at 7-12 months | | | WMD
(fixed), 95% CI | Subtotals
only |
| 05 Bayley PDI in survivors
at 7-12 months | | | WMD
(fixed), 95% CI | Subtotals
only |
| 06 Bayley MDI in survivors
at 24 months | | | WMD
(fixed), 95% CI | Subtotals
only |
| 07 Bayley PDI in survivors
at 24 months | | | WMD
(fixed), 95% CI | Subtotals
only |
| 08 RAKIT IQ score in survivors
at 5 years | | | WMD
(fixed), 95% CI | Subtotals
only |
| 09 Clinically significant
Child Behaviour Checklist score in survivors at 2 years | | | RR
(fixed), 95% CI | Subtotals
only |
| 10 Clinically significant
Child Behaviour Checklist score in survivors at 5 years | | | RR
(fixed), 95% CI | Subtotals
only |
| 11 Clinically significant
Teacher Report Form score in survivors at 5 years | | | RR
(fixed), 95% CI | Subtotals
only |
| 12 Neonatal mortality | | | RR
(fixed), 95% CI | Subtotals
only |
| 13 Mortality to discharge | | | RR
(fixed), 95% CI | Subtotals
only |
| 14 Death or cerebral palsy | | | RR
(fixed), 95% CI | Subtotals
only |
| 15 Duration of mechanical
ventilation (days) | | | WMD
(fixed), 95% CI | Subtotals
only |
| 16 CLD in survivors (oxygen
at 28 days) | | | RR
(fixed), 95% CI | Subtotals
only |
| 17 CLD in survivors (oxygen
at 36 weeks) | | | RR
(fixed), 95% CI | Subtotals
only |
| 18 Patent ductus arteriosus | | | RR
(fixed), 95% CI | Subtotals
only |
| 19 Intraventricular hemorrhage
- any grade | | | RR
(fixed), 95% CI | Subtotals
only |
| 20 Intraventricular hemorrhage
- grade 3 or 4 | | | RR
(fixed), 95% CI | Subtotals
only |
| 21 Periventricular leukomalacia | | | RR
(fixed), 95% CI | Subtotals
only |
| 22 Retinopathy of prematurity
(any grade) in survivors | | | RR
(fixed), 95% CI | Subtotals
only |
| 23 Sepsis | | | RR
(fixed), 95% CI | Subtotals
only |
| 03 Prophylactic
thyroid hormones versus no thyroid hormones according to timing |
| 01 Abnormal mental development in survivors at 2 years
(Bayley MDI > 2sd below mean) | 1 | 157 | RR
(fixed), 95% CI | 0.67
[0.28, 1.56] |
| 02 Abnormal mental
development in survivors at 5 years (Bayley MDI > 2sd below mean) | 1 | 156 | RR
(fixed), 95% CI | 0.66
[0.22, 1.99] |
| 03 Cerebral palsy
in survivors | 1 | 156 | RR
(fixed), 95% CI | 0.72
[0.28, 1.84] |
| 04 Bayley MDI in survivors
at 7-12 months | 2 | 191 | WMD
(fixed), 95% CI | -1.14
[-5.46, 3.19] |
| 05 Bayley PDI in
survivors at 7-12 months | 2 | 191 | WMD
(fixed), 95% CI | 0.22
[-4.80, 5.24] |
| 06 Bayley MDI in
survivors at 24 months | 1 | 157 | WMD
(fixed), 95% CI | -3.50
[-11.21, 4.21] |
| 07 Bayley PDI in
survivors at 24 months | 1 | 157 | WMD
(fixed), 95% CI | 3.10
[-3.31, 9.51] |
| 08 RAKIT IQ score
in survivors at 5 years | 1 | 156 | WMD
(fixed), 95% CI | -2.10
[-7.91, 3.71] |
| 09 Special schooling
at 9-12 years | 1 | 112 | RR
(fixed), 95% CI | 0.88
[0.43, 1.83] |
| 10 Clinically significant
Child Behaviour Checklist score in survivors at 2 years | 1 | 144 | RR
(fixed), 95% CI | 0.81
[0.35, 1.86] |
| 11 Clinically significant
Child Behaviour Checklist score in survivors at 5 years | 1 | 144 | RR
(fixed), 95% CI | 1.17
[0.57, 2.40] |
| 12 Clinically significant
Teacher Report Form score in survivors at 5 years | 1 | 147 | RR
(fixed), 95% CI | 1.08
[0.55, 2.10] |
| 13 Neonatal mortality | 2 | 240 | RR
(fixed), 95% CI | 0.68
[0.37, 1.25] |
| 14 Mortality to discharge | 4 | 318 | RR
(fixed), 95% CI | 0.76
[0.46, 1.24] |
| 15 Death or cerebral
palsy | 1 | 200 | RR
(fixed), 95% CI | 0.70
[0.43, 1.14] |
| 16 Duration of mechanical
ventilation (days) | 3 | 107 | WMD
(fixed), 95% CI | -3.76
[-11.28, 3.77] |
| 17 CLD in survivors
(oxygen at 28 days) | 4 | 267 | RR
(fixed), 95% CI | 0.97
[0.77, 1.23] |
| 18 CLD in survivors
(oxygen at 36 weeks) | 2 | 204 | RR
(fixed), 95% CI | 1.06
[0.65, 1.74] |
| 19 Intraventricular
haemorrhage - any grade | 2 | 240 | RR
(fixed), 95% CI | 1.19
[0.86, 1.63] |
| 20 Intraventricular
haemorrhage - grade 3 or 4 | 4 | 318 | RR
(fixed), 95% CI | 1.19
[0.63, 2.24] |
| 21 Periventricular
leucomalacia | 3 | 278 | RR
(fixed), 95% CI | 0.97
[0.23, 4.12] |
| 22 Patent ductus arteriosus | 3 | 287 | RR
(fixed), 95% CI | 0.71
[0.50, 1.02] |
| 23 Sepsis | 3 | 278 | RR
(fixed), 95% CI | 0.78
[0.53, 1.16] |
| 24 Retinopathy of
prematurity (any grade) in survivors | 2 | 207 | RR
(fixed), 95% CI | 0.99
[0.49, 2.01] |
| 04 Prophylactic
thyroid hormones versus no thyroid hormones according to gestational strata |
| 01 Mortality to discharge | 1 | 31 | RR
(fixed), 95% CI | 1.67
[0.42, 6.62] |
| 02 Duration of mechanical
ventilation (days) | 1 | 31 | WMD
(fixed), 95% CI | -0.44
[-13.92, 13.04] |
| 03 CLD in survivors
(oxygen at 28 days) | 1 | 22 | RR
(fixed), 95% CI | 0.82
[0.54, 1.25] |
| 04 Intraventricular
haemorrhage - grade 3 or 4 | 1 | 31 | RR
(fixed), 95% CI | 2.38
[0.32, 17.78] |
| 05 Periventricular
leucomalacia | 1 | 31 | RR
(fixed), 95% CI | 1.50
[0.07, 33.89] |
| 06 Sepsis | 1 | 31 | RR
(fixed), 95% CI | 0.83
[0.32, 2.20] |
| 05 Prophylactic
thyroid hormones versus no thyroid hormones (studies with adequate methodology) |
| 01 Abnormal mental development in survivors at 2 years
(Bayley MDI > 2sd below mean) | 1 | 157 | RR
(fixed), 95% CI | 0.67
[0.28, 1.56] |
| 02 Abnormal mental
development in survivors at 5 years (Bayley MDI > 2sd below mean) | 1 | 156 | RR
(fixed), 95% CI | 0.66
[0.22, 1.99] |
| 03 Cerebral palsy
in survivors | 1 | 156 | RR
(fixed), 95% CI | 0.72
[0.28, 1.84] |
| 04 Bayley MDI in survivors
at 7-12 months | 2 | 191 | WMD
(fixed), 95% CI | -1.14
[-5.46, 3.19] |
| 05 Bayley PDI in
survivors at 7-12 months | 2 | 191 | WMD
(fixed), 95% CI | 0.22
[-4.80, 5.24] |
| 06 Bayley MDI in
survivors at 24 months | 1 | 157 | WMD
(fixed), 95% CI | -3.50
[-11.21, 4.21] |
| 07 Bayley PDI in
survivors at 24 months | 1 | 157 | WMD
(fixed), 95% CI | 3.10
[-3.31, 9.51] |
| 08 RAKIT IQ score
in survivors at 5 years | 1 | 156 | WMD
(fixed), 95% CI | -2.10
[-7.91, 3.71] |
| 09 Clinically significant
Child Behaviour Checklist score in survivors at 2 years | 1 | 144 | RR
(fixed), 95% CI | 0.81
[0.35, 1.86] |
| 10 Clinically significant
Child Behaviour Checklist score in survivors at 5 years | 1 | 144 | RR
(fixed), 95% CI | 1.17
[0.57, 2.40] |
| 11 Clinically significant
Teacher Report Form score in survivors at 5 years | 1 | 147 | RR
(fixed), 95% CI | 1.08
[0.55, 2.10] |
| 12 Neonatal mortality | 2 | 240 | RR
(fixed), 95% CI | 0.68
[0.37, 1.25] |
| 13 Mortality to discharge | 4 | 318 | RR
(fixed), 95% CI | 0.76
[0.46, 1.24] |
| 14 Death or cerebral
palsy | 1 | 200 | RR
(fixed), 95% CI | 0.70
[0.43, 1.14] |
| 15 Duration of mechanical
ventilation (days) | 3 | 107 | WMD
(fixed), 95% CI | -3.76
[-11.28, 3.77] |
| 16 CLD in survivors
(oxygen at 28 days) | 4 | 267 | RR
(fixed), 95% CI | 0.97
[0.77, 1.23] |
| 17 CLD in survivors
(oxygen at 36 weeks) | 2 | 204 | RR
(fixed), 95% CI | 1.06
[0.65, 1.74] |
| 18 Intraventricular
haemorrhage - any grade | 2 | 240 | RR
(fixed), 95% CI | 1.19
[0.86, 1.63] |
| 19 Intraventricular
haemorrhage - grade 3 or 4 | 4 | 318 | RR
(fixed), 95% CI | 1.19
[0.63, 2.24] |
| 20 Periventricular
leucomalacia | 3 | 278 | RR
(fixed), 95% CI | 0.97
[0.23, 4.12] |
| 21 Patent ductus arteriosus | 3 | 287 | RR
(fixed), 95% CI | 0.71
[0.50, 1.02] |
| 22 Sepsis | 3 | 278 | RR
(fixed), 95% CI | 0.78
[0.53, 1.16] |
| 23 Retinopathy of
prematurity (any grade) in survivors | 2 | 207 | RR
(fixed), 95% CI | 0.99
[0.49, 2.01] |
| 06 Prophylactic
T3 and T4 versus T4 alone |
| 01 Mortality
to discharge | 1 | 21 | RR
(fixed), 95% CI | 1.21
[0.36, 4.14] |
| 02 Duration of mechanical
ventilation (days) | 1 | 21 | WMD
(fixed), 95% CI | 0.50
[-5.57, 6.57] |
| 03 CLD in survivors
(oxygen at 28 days) | 1 | 14 | RR
(fixed), 95% CI | 0.67
[0.33, 1.35] |
| 04 Intraventricular
haemorrhage - grade 3 or 4 | 1 | 21 | RR
(fixed), 95% CI | 3.64
[0.48, 27.33] |
| 05 Periventricular
leucomalacia | 1 | 21 | RR
(fixed), 95% CI | 0.31
[0.01, 6.74] |
| 06 Sepsis | 1 | 21 | RR
(fixed), 95% CI | 5.45
[0.79, 37.81] |
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 for information).
Cochrane reviews are regularly updated as new evidence merges and in response
to comments and criticisms, and The Cochrane Library should be consulted
for the most recent version of the Review. |
