Iodine supplementation for the prevention of mortality and adverse neurodevelopmental outcomes in preterm infants

Ibrahim M, Sinn J, McGuire W

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

Cover sheet

Title

Reviewers

Ibrahim M, Sinn J, McGuire W

Dates

Date edited: 20/02/2006
Date of last substantive update: 14/02/2006
Date of last minor update: / /
Date next stage expected 30/11/2007
Protocol first published: Issue 2, 2005
Review first published: Issue 2, 2006

Contact reviewer

Dr Mohammed DH Ibrahim
Consultant Paediatrician
Department of Paediatrics
Victoria Hospital
Hayfield Road
Kirkcaldy
Fife UK
KY2 5AH
Telephone 1: 44 1592 643355
E-mail: Mohammed@doctors.org.uk

Contribution of reviewers

Mohammed Ibrahim, John Sinn, and William McGuire developed the protocol jointly. Mohammed Ibrahim and William McGuire undertook the electronic and hand searches, screened the title and abstract of all studies identified, and the full text of the report identified as of potential relevance. Mohammed Ibrahim and William McGuire independently assessed the methodological quality of the included trial, extracted the relevant information and data, and completed the final review.

Internal sources of support

ANU Medical School, AUSTRALIA

External sources of support

None

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

There is currently insufficient evidence to suggest that supplementing the diet of preterm infants with iodine is beneficial.

Iodine is essential for the production of thyroid hormones. Thyroid hormones are important for brain development in newborn infants. Preterm infants often have low levels of iodine and of thyroid hormones in the first few weeks after birth. This may in part be due to a lack of iodine in their diet. We found only one trial that assessed the effect of giving preterm babies extra iodine. This study did not find any evidence that providing extra iodine increased the level of thyroid hormones. The trial did not assess the effect of providing extra iodine on brain development. Further trials are needed.

Abstract

Background

Parenteral nutrition solutions, formula milks, and human breast milk contain insufficient iodine to meet recommended intakes for preterm infants. Iodine deficiency may exacerbate transient hypothyroxinaemia in preterm infants and this may be associated with adverse respiratory or neurological outcomes.

Objectives

To assess the evidence from randomised controlled trials that dietary supplementation with iodine reduces mortality and morbidity in preterm infants.

Search strategy

We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2005), MEDLINE (1966 - November 2005), EMBASE (1980 - November 2005), CINAHL (1982 - November 2005), conference proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that compared a policy of supplementing enteral or parenteral feeds with iodine (more than 30 micrograms per kilogram per day) versus placebo or no supplementation in preterm infants.

Data collection & analysis

The standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two reviewers, and synthesis of data using relative risk, risk difference and weighted mean difference. The primary outcomes for this review were neonatal mortality, death before hospital discharge, and longer term neurodevelopmental outcomes including severe neurodevelopmental disability.

Main results

We found only one randomised controlled trial (N = 121) that fulfilled the review eligibility criteria (Rogahn 2000). The participants were infants born before 33 weeks' gestation (but most were of birth weight greater than 1000 grams). The primary aim of this trial was to assess the effect of iodine supplementation on thyroid function. The investigators did not detect any statistically significant effects on the plasma levels of thyroxine (free and total), triiodothyronine, or thyrotrophin in preterm infants (measured up to 40 weeks' post-conceptional age). Only one infant died and the trial was therefore underpowered to detect an effect on mortality. The trial did not assess the effect of the intervention on neurodevelopmental morbidity. There was not a statistically significant difference in the incidence of chronic lung disease.

Reviewers' conclusions

There are insufficient data at present to determine whether providing preterm infants with supplemental iodine (to match fetal accretion rates) prevents morbidity and mortality in preterm infants. Future randomised controlled trials of iodine supplementation should focus on extremely preterm and extremely low birth weight infants, the group at greatest risk of transient hypothyroxinaemia. These trials should aim to assess the effect of iodine supplementation on clinically important outcomes including respiratory morbidity and longer term neurodevelopment.

Background

Transient hypothyroxinaemia, a temporary postnatal reduction in serum levels of thyroxine and triiodothyronine with normal levels of thyroid stimulating hormone, is well described in preterm infants (Rooman 1996). The incidence, and degree and duration, of hypothyroxinaemia is inversely related to birth weight and gestational age and positively correlated with illness severity (particularly the severity of respiratory distress syndrome). The incidence of transient hypothyroxinaemia, defined as plasma thyroxine levels below 40 micrograms per litre, ranges from 40% in infants born at 23 weeks' gestation to 10% in infants born at 28 weeks' gestation (Reuss 1996).

There is concern that transient hypothyroxinaemia may harm brain development. Observational studies have suggested a link between hypothyroxinaemia and poor neurodevelopmental outcomes including low intelligence and cerebral palsy (Meijer 1992; Reuss 1996; Lucas 1996; Den Ouden 1996). It is unclear whether transient hypothyroxinaemia is causally related to adverse neurodevelopmental outcomes or is a consequence of extreme prematurity or severe illness in preterm infants.

Studies in animal models have suggested that thyroid hormones may act synergistically with corticosteroids to accelerate surfactant production and reduce the severity of respiratory distress syndrome in preterm infants (Liggins 1988). However, meta-analyses of randomised controlled trials of antenatal administration of thyrotropin releasing hormone did not show any improvement in outcomes for preterm infants. In fact, antenatal exposure to thyrotrophin releasing hormone is associated with a higher risk of infants needing mechanical ventilation (Crowther 2004). Similarly, the Cochrane review of trials of thyroid hormones administered shortly after birth to very preterm infants did not find any evidence of effect on mortality or neurodevelopment, or on the severity of respiratory distress syndrome or the incidence of chronic lung disease (Osborn 2001). However, the small number of infants included in trials in that review limited the power of the meta-analyses to detect clinically important differences in outcomes.

The aetiology of transient hypothyroxinaemia is multifactorial. As well as the contribution of non-thyroidal illness and immaturity of the hypothalamic-pituitary-thyroid axis, it is speculated that iodine deficiency may contribute to transient hypothyroxinaemia (Ares 1997). The neonatal thyroid gland stores low levels of iodine and is very sensitive to iodine deficiency. Nutrient balance studies in healthy preterm infants indicate that daily iodine intakes of at least 30 micrograms per kilogram are needed to maintain a positive iodine balance (Ares 1997). An international consensus statement recommends daily iodine intakes of 30 to 60 micrograms per kilogram for healthy growing formula fed preterm infants (Tsang 1993).

The breast milk of mothers of preterm infants contains about 100 to 150 micrograms of iodine per litre (depending on the dietary iodine intake of the mother). The iodine content of formula milks ranges from 20 to 170 micrograms per litre (Ares 1994; Seibold-Weiger 1999; Semba 2001). Neither commercially available breast-milk fortifiers nor mineral and vitamin supplements contain iodine. Enterally fed preterm infants therefore may not achieve the recommended intake of iodine, especially during the first weeks of postnatal life when feed volumes are still being advanced (Ares 1997).

Preterm infants who are predominantly parenterally-fed are at even greater risk of negative iodine balance. Most commercially available parenteral nutrition solutions contain less iodine than breast or formula milk (even though gastrointestinal absorption of iodine is high). The American Society for Clinical Nutrition has recommended daily parenteral iodine intakes of about one microgram per kilogram. This conservative recommendation was influenced by an assumption that most parenterally fed preterm infants will also absorb iodine transcutaneously from topical iodinated antiseptic solutions. However, the use of iodinated antiseptics for preterm infants has decreased due to concern that excessive transcutaneous iodine intake (100 micrograms per day or more) causes early acquired neonatal hypothyroidism (Smerdely 1989). Evidence exists that parentally fed very preterm infants who have not been exposed to other sources of iodine achieve daily iodine intakes of about 1 to 3 micrograms per kilogram and are in negative iodine balance during the first week of postnatal life (Ibrahim 2003).

Given the potential for negative iodine balance to cause hypothyroxinaemia and consequently adverse neurological and respiratory outcomes, especially in parentally fed or sick preterm infants, and despite the lack of evidence that exogenous thyroid hormone supplementation is beneficial, we have reviewed the available evidence concerning iodine supplementation for preventing morbidity and mortality in preterm infants.

Objectives

To determine whether dietary supplementation with iodine affects mortality and morbidity in preterm infants. We planned to examine the evidence of effect of enteral and parenteral iodine supplementation in separate comparisons.

Sub group analyses:
1. Very low birth weight (less than 1.5 kilograms) or very preterm (born before 32 weeks' gestation) infants
2. Extremely low birth weight (less than 1 kilogram) or extremely preterm (born before 28 weeks' gestation) infants

Criteria for considering studies for this review

Types of studies

Controlled trials using random or quasi-random patient allocation.

Types of participants

Preterm infants (less than 37 weeks completed gestation).

Types of interventions

Supplementation with iodine compared with placebo or no supplementation. Iodine supplementation will be defined as aiming to provide more than 30 micrograms per kilogram of iodine per day. Enteral supplementation may be achieved either by:
1. Adding iodine to breast or formula milk, or
2. Feeding with formula milk that is already iodine enriched.

Similarly, parenteral supplementation may be achieved either by:
1. Adding iodine to the nutrient solution in the ward or pharmacy, or
2. Feeding with a pre-prepared iodine enriched solution.

The comparison groups should have received the same nutrient input (and other treatments) apart from the level of iodine input. Analysis should be as intention-to-treat.

Types of outcome measures

Primary:
1. Neonatal mortality and mortality prior to hospital discharge.
2. Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools such as Bayley Scales of Infant Development.
3. Severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. We planned to analyse each component individually as well as part of the composite outcome.
4 Cognitive and educational outcomes at aged more than five years old: Intelligence quotient and/or indices of educational achievement measured using a validated assessment tool (including school examination results).

Secondary:
1. Measures of the severity of respiratory distress syndrome: for example, duration of mechanical ventilation (days), incidence of air leaks, incidence of chronic lung disease (supplemental oxygen requirement at 36 weeks' post-conceptional age).
2. Biochemical measures of thyroid function and iodine status such as plasma levels of thyroxine (free and total), triiodothyronine, or thyrotrophin.

Search strategy for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2005), MEDLINE (1966 - November 2005), CINAHL (1982 - November 2005), and EMBASE (1980 - November 2005). The search strategy used the following text words and MeSH terms: Infant-Newborn; Infant-Low Birth Weight; Infant-Premature; infan$; neonat$; newborn; premature; low birth weight; LBW; Infant-Nutrition; enteral nutrition; milk; infant food; parenteral nutrition; TPN; iodine; iodide; Thyroid Hormones; Thyroxine; Triiodothyronine; hypothyroxin$. We limited the search outputs with the relevant filters for clinical trials. We did not apply any language restriction.

We examined references in previous reviews and in studies identified as potentially relevant. We hand searched the abstracts presented at the annual scientific meetings of the Society for Pediatric Research, the European Society for Pediatric Research, the North American Society of Pediatric Gastroenterology and Nutrition, and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (from 1980 - 2004). Unpublished studies and studies published only as abstracts were eligible for inclusion if assessment of study quality was possible and if other criteria for inclusion were fulfilled. We planned to contact authors of studies published as abstracts for further information.

Methods of the review

1. Mohammed Ibrahim (MI) screened the title and abstract of all studies identified by the above search strategy and obtained the full articles for all potentially relevant trials. MI and William McGuire (WM) re-assessed independently the full text of these reports using an eligibility form based on the pre-specified inclusion criteria. We excluded studies that did not meet all of the inclusion criteria. The reviewers resolve any disagreements by discussion until consensus was achieved.

2. MI and WM used the criteria and standard methods of the Cochrane Neonatal Review Group to assess independently the methodological quality of the included trial in terms of allocation concealment, blinding of parents or carers and assessors to intervention, and completeness of assessment in all randomised individuals.

3. MI and WM used a data collection form to aid extraction of relevant information and data from the included study. Each reviewer extracted the data separately, compared data, and resolved differences by discussion

4. We have presented outcomes for categorical data as relative risk, risk difference, and number needed to treat, with respective 95% confidence intervals. For continuous data, we planned to use the weighted mean difference with 95% confidence interval.

5. We planned estimate the treatment effects of individual trials and examine heterogeneity between trial results by inspecting the forest plots and quantifying the impact of heterogeneity in any meta-analysis using a measure of the degree of inconsistency in the studies' results (I- squared statistic). If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses. We planned to use a fixed effects model for meta-analyses.

Description of studies

We identified only one study that fulfilled the review inclusion criteria (Rogahn 2000). We did not identify any studies that appeared eligible, but did not meet all inclusion criteria following systematic appraisal.

The investigators randomly allocated 121 infants born before 33 weeks' gestation to receive either:
1. iodine-supplemented "preterm" formula milk (iodine concentration 272 micrograms per litre), or
2. the same formula without iodine supplementation (iodine concentration 68 micrograms per litre).

This strategy was designed to provide an iodine intake of 40 - 50 micrograms/kg/day in the intervention group versus 12 - 16 micrograms/kg/day in the control group. Infants were allocated to receive the trial formula milks until they reached 40 weeks' post conceptional age. Infants may have received parenteral nutrition prior to receiving formula milk. This is unlikely to have contained iodine (but this is not stated explicitly in the trial report). Similarly, it is not clear from the published report whether infants may have been exposed to iodine in skin disinfecting solutions.

The primary outcome was the plasma level of thyroid hormones. Short term clinical outcome data were also reported. Neurodevelopment and cognitive function were not assessed but longer term follow up of the trial cohorts may examine these outcomes. The formula milk was supplied on demand either as the sole feed or in addition to maternal breast milk. Infants who were enrolled in the study but who received sufficient maternal breast milk such that they never received any of the trial formula were still included in the primary intention-to-treat analyses.

Methodological quality of included studies

The methodological quality of the included study was good. The random sequence was derived from a random number table and allocation was concealed with sealed opaque envelopes. The intervention and control formula milks were identical in appearance and the iodine levels were not known to parents, carers, or outcome assessors. Complete biochemical outcome data up to 40 weeks' post-menstrual age were available for 114 (of 121) infants. Biochemical data were not available for six infants withdrawn from study post-randomisation (reasons not stated) and for one infant who died during the study period. The primary analyses were by intention-to-treat.

Results

Enteral iodine supplementation: One eligible trial (Rogahn 2000).

1. Mortality: Only one infant died during the study period. The infant was randomised to the control group but only received breast milk (personal communication Steven Ryan): Relative risk 0.33 (95% confidence interval 0.01 to 7.89); risk difference -0.02 (-0.06 to 0.03).

2. Neurodevelopmental and cognitive outcomes: not assessed.

3. Respiratory outcomes: The trial did not detect any statistically significant difference in the duration of mechanical ventilation or of treatment with supplemental oxygen. These data were reported as median (range) but without standard deviations and therefore relative risks and risk differences could not be calculated.

16 of 61 surviving infants in the intervention group developed chronic lung disease (supplemental oxygen requirement at 36 weeks' post-conceptional age) versus 24 of 59 surviving infants in the control group: Relative risk 0.64 (95% confidence interval 0.38 to 1.09); risk difference -0.14 (-0.31 to 0.02). Because death prior to hospital discharge and the development of chronic lung disease (supplemental oxygen requirement at 36 weeks' post-conceptional age) are competing outcomes, we aggregated these as a composite outcome "chronic lung disease or prior death". This outcome did not differ significantly between the groups: Relative risk 0.63 (95% confidence interval 0.38 to 1.06); risk difference -0.15 (-0.32 to 0.01).

4. Measures of thyroid function: The study did not detect any statistically significant differences in the plasma levels of thyroid hormones (thyroxine, triiodothyronine, free thyroxine, thyrotrophin) measured at 30, 35, and 40 weeks' post-conceptional age:

1. Total plasma thyroxine:
(i) mean difference at 30 weeks' post conception 3.0 (95% confidence interval -9.2 to 15.2) nmol/L.
(ii) mean difference at 35 weeks' post conception 0.0 (95% confidence interval -10.3 to 10.3) nmol/L.
(iii) mean difference at 40 weeks' post conception -2.0 (95% confidence interval -12.0 to 8.0) nmol/L.

2. Total plasma triiodothyronine:
(i) mean difference at 30 weeks' post conception 0.02 (95% confidence interval -0.16 to 0.20) nmol/L.
(ii) mean difference at 35 weeks' post conception 0.01 (95% confidence interval -0.14 to 0.16) nmol/L.
(iii) mean difference at 40 weeks' post conception 0.11 (95% confidence interval -0.07 to 0.29) nmol/L.

3. Free thyroxine:
(i) mean difference at 30 weeks' post conception -1.10 (95% confidence interval -4.05 to 1.85) pmol/L.
(ii) mean difference at 35 weeks' post conception -1.10 (95% confidence interval -3.48 to 1.28) pmol/L.
(iii) mean difference at 40 weeks' post conception -0.40 (95% confidence interval -1.67 to 0.87) pmol/L.

4. Thyrotrophin:
(i) mean difference at 30 weeks' post conception -0.30 (95% confidence interval -0.79 to 0.19) mU/L.
(ii) mean difference at 35 weeks' post conception -0.20 (95% confidence interval -0.69 to 0.29) mU/L.
(iii) mean difference at 40 weeks' post conception 0.08 (95% confidence interval -0.28 to 0.44) mU/L.

The data presented in the report did not allow birth weight and gestational age subgroup analyses to be undertaken. We will contact the trial authors to determine if these subgroup data are available for inclusion in a future update.

Parenteral iodine supplementation: No eligible trials found.

Discussion

The single trial that we have identified did not find any evidence that enteral iodine supplementation affected thyroid hormone levels or clinical outcomes in preterm infants. However, the infants who participated in this trial did not belong to the population most likely to be affected by iodine and thyroid hormone deficiency. Most of the infants were in the 1000 to 1500 grams birth weight range and were clinically stable. Only 17 of the 121 participants were of birth weight less than 1000 grams. Observational data suggest that transient hypothyroxinaemia is most strongly associated with adverse respiratory and neurological outcomes in extremely low birth weight or extremely preterm infants (Reuss 1996; Rooman 1996). Secondly, the intervention (iodine-supplemented formula milk) was started when the infants had established enteral feeding, usually two weeks after birth. In extremely preterm infants, iodine balance is negative and transient hypothyroxinaemia is established in the first one to two weeks after birth. Some of the participating infants received all or part of their intake as breast milk which has a higher iodine concentration than standard formula milk. Including these infants in the intention to treat analysis may have reduced the difference in the average amounts of iodine that each group actually received. Participating infants may also have received parenteral nutrition. However, this is not likely to have contained iodine. It is not clear whether infants may have been exposed to iodine containing antiseptics. If so, this may also have contributed to reducing the difference in actual iodine intake between the groups. We will attempt to clarify these issues with the trial investigators.

An alternative option to iodine supplementation for infants at risk of transient hypothyroxinaemia is treatment with thyroid hormones. The available data from randomised controlled trials of post-natal thyroid hormone supplementation have not provided any evidence that this intervention prevents morbidity or mortality in very preterm infants (Osborn 2001). However, in one trial post hoc subgroup analyses suggest that thyroxine replacement might prevent neurodevelopmental morbidity in extremely preterm infants (van Wassenaer 1997). The Cochrane review concluded that further trials in this population may be warranted. It is not clear whether direct thyroid hormone supplementation has any advantages over iodine supplementation. Theoretically, since iodine supplementation is metabolically "upstream" of thyroid hormone replacement, it is likely to result in more physiologically appropriate tissue levels of thyroxine and triiodothyronine than direct supplementation with thyroid hormones (Ares 1997). However, there is also the theoretical disadvantage that over-treatment with iodine can cause transient hypothyroidism in preterm neonates who are exquisitely sensitive to the anti-thyroid effects of iodine excess (Smerdely 1989).

Reviewers' conclusions

Implications for practice

The data are insufficient at present to determine whether iodine supplementation prevents mortality and morbidity in preterm infants.

Implications for research

There is a need for a large pragmatic randomised controlled trial to determine if iodine supplementation, started within a few days after birth, prevents morbidity and mortality in preterm infants. Trials should focus on extremely preterm and/or extremely low birth weight infants, the group at greatest risk of transient hypothyroxinaemia, and should aim to assess the effect of iodine supplementation on clinically important outcomes including respiratory morbidity and long term neurodevelopment. We are aware of one such trial that is currently in the development stage: see http://www.euthyroid.org/.

Acknowledgements

We thank Vijay Shingde for helpful discussions and input during the early stages of development of the protocol.

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Rogahn 2000	Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.	121 infants < 33 weeks' gestation at birth, clinically stable and receiving all their nutrition enterally by 2 weeks after birth (if more than or equal to 28 weeks' gestation at birth) or by 31 weeks after conception (if less than 28 weeks' gestation). 17 of the 121 participants were of birth weight less than 1000 grams.	Treatment (N=61): Iodine supplemented "preterm" formula milk: iodine concentration 272 micrograms/L. Control (N=60): Same milk without iodine supplementation: iodine concentration 68 micrograms/L. These milks were identical in appearance. Allocated formula continued until infants reached 40 weeks' postmenstrual age.	1. Nutrition and growth: volume of milk ingested (infants were demand fed), weekly change in weight, leg length, and head circumference during trial period. 2. Respiratory outcomes: days ventilated, days requiring supplemental oxygen therapy, incidence of chronic lung disease. 3. Incidence of severe intraventricular haemorrhage and of cystic periventricular leucomalacia. 4. Duration of hospital admission (days to discharge).	Study sites: Neonatal units in the Mersey Region, UK.	A

References to studies

References to included studies

Rogahn 2000 {published data only}

Rogahn J, Ryan S, Wells J, Fraser B, Squire C, Wild N, et al. Randomised trial of iodine intake and thyroid status in preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 2000;83:F86-90.

* indicates the primary reference for the study

Other references

Additional references

Ares 1994

Ares S, Quero J, Duran S, Presas MJ, Herruzo R, Morreale de Escobar G. Iodine content of infant formulas and iodine intake of premature babies: high risk of iodine deficiency. Archives of Disease in Childhood Fetal and Neonatal Edition 1994;71:F184-91.

Ares 1997

Ares S, Escobar-Morreale HF, Quero J, Duran S, Presas MJ, Herruzo R, Morreale de Escobar G. Neonatal hypothyroxinemia: effects of iodine intake and premature birth. Journal of Clinical Endocrinology and Metabolism 1997;82:1704-12.

Bremer 1987

Bremer HJ, Brooke OG, Orzalesi M. Nutrition and feeding of preterm infants. Committee on Nutrition of the Preterm Infant, European Society of Paediatric Gastroenterology and Nutrition (ESPGAN). Acta Paediatrica Scandinavica 1987;336:S1-14.

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.

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.

Greene 1988

Greene HL, Hambidge KD, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium and phosphorous in infants and children receiving total parenteral nutrition: report of the Subcommittee on Paediatric Parenteral Nutrient requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. American Journal of Clinical Nutrition 1988;48:1324-42.

Ibrahim 2003

Ibrahim M, Morreale de Escobar GM, Visser TJ, Duran S, van Toor H, Strachan J, et al. Iodine deficiency associated with parenteral nutrition in extreme preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 2003;88:F56-7.

Liggins 1988

Liggins GC, Schellenberg JC, Manzai M, Kitterman JA, Lee CC. Synergism of cortisol and thyrotropin releasing hormone in lung maturation in fetal sheep. Journal of Applied Physiology 1988;65:1880-4.

Lucas 1996

Lucas A, Morley R, Fewtrell MS. Low triiodothyronine concentration in preterm infants and subsequent intelligence quotient (IQ) at 8 year follow up. BMJ 1996;312:1132-3.

Meijer 1992

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.

Osborn 2001

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

Reuss 1996

Reuss ML, Paneth N, Pinto-Martin JA, Lorenz JM, Susser M. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. New England Journal of Medicine 1996;334:821-7.

Reuss 1997

Reuss ML, Leviton A, Paneth N, Susser M. Thyroxine values from newborn screening of 919 infants born before 29 weeks' gestation. American Journal of Public Health 1997;87:1693-7.

Rooman 1996

Rooman RP, Du Caju MV, De Beeck LO, Docx M, Van Reempts P, Van Acker KJ. Low thyroxinaemia occurs in the majority of preterm newborns. European Journal of Pediatrics 1996;155:211-5.

Seibold-Weiger 1999

Seibold-Weiger K, Wollmann H, Rendl J, Ranke M, Speer C. Iodine concentration in the breast milk of mothers of premature infants. Zeitschrift fur Geburtshilfe und Neonatologie 1999;203:81-5.

Semba 2001

Semba RD, Delange F. Iodine in human milk: perspectives for infant health. Nutrition Reviews 2001;59:269-78.

Smerdely 1989

Smerdely P, Lim A, Boyages SC, Waite K, Wu D, Roberts V, et al. Topical iodine containing antiseptics and neonatal hypothyroidism in very-low-birthweight infants. Lancet 1989;2:661-4.

Thorpe-Beeston 1991

Thorpe-Beeston JG, Nicolaides KH, Felton CV, Butler J, McGregor AM. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. New England Journal of Medicine 1991;324:532-6.

Tsang 1993

Tsang RC, Lucas A, Uauy R, Zlotkin S, editor(s). Nutritional needs of the preterm infant. Scientific basis and practical guidelines. New York: Caduceus Medical Publishers, 1993:288-9.

van Wassenaer 1997

van Wassenaer AG, Kok JH, de Vijlder JJ, Briet JM, Smit BJ, Tamminga P, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks’ gestation. New England Journal of Medicine 1997;42:87-92.

Comparisons and data

01 Enteral iodine supplementation versus control
01.01 Death before hospital discharge
01.02 Chronic lung disease in surviving infants (supplemental oxygen requirement at 36 weeks' post-conceptional age)
01.03 Chronic lung disease or prior death
01.04 Total plasma thyroxine (nmol/L) at 30 weeks' post-conception
01.05 Total plasma thyroxine (nmol/L) at 35 weeks' post-conception
01.06 Total plasma tryroxine (nmol/L) at 40 weeks' post-conception
01.07 Total plasma triiodothyronine (nmol/L) at 30 weeks' post-conception
01.08 Total plasma triiodothyronine (nmol/L) at 35 weeks' post-conception
01.09 Total plasma triiodothyronine (nmol/L) at 40 weeks' post-conception
01.10 Free thyroxine (pmol/L) at 30 weeks' post-conception
01.11 Free thyroxine (pmol/L) at 35 weeks' post-conception
01.12 Free thyroxine (pmol/L) at 40 weeks' post-conception
01.13 Thyrotrophin (mU/L) at 30 weeks' post-conception
01.14 Thyrotrophin (mU/L) at 35 weeks' post-conception
01.15 Thyrotrophin (mU/L) at 40 weeks' post-conception

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Enteral iodine supplementation versus control
01 Death before hospital discharge	1	121	RR (fixed), 95% CI	0.33 [0.01, 7.89]
02 Chronic lung disease in surviving infants (supplemental oxygen requirement at 36 weeks' post-conceptional a	1	120	RR (fixed), 95% CI	0.64 [0.38, 1.09]
03 Chronic lung disease or prior death	1	121	RR (fixed), 95% CI	0.63 [0.38, 1.06]
04 Total plasma thyroxine (nmol/L) at 30 weeks' post-conception	1	119	WMD (fixed), 95% CI	3.00 [-9.23, 15.23]
05 Total plasma thyroxine (nmol/L) at 35 weeks' post-conception	1	110	WMD (fixed), 95% CI	0.00 [-10.34, 10.34]
06 Total plasma tryroxine (nmol/L) at 40 weeks' post-conception	1	113	WMD (fixed), 95% CI	-2.00 [-11.96, 7.96]
07 Total plasma triiodothyronine (nmol/L) at 30 weeks' post-conception	1	115	WMD (fixed), 95% CI	0.02 [-0.16, 0.20]
08 Total plasma triiodothyronine (nmol/L) at 35 weeks' post-conception	1	109	WMD (fixed), 95% CI	0.01 [-0.14, 0.16]
09 Total plasma triiodothyronine (nmol/L) at 40 weeks' post-conception	1	110	WMD (fixed), 95% CI	0.11 [-0.07, 0.29]
10 Free thyroxine (pmol/L) at 30 weeks' post-conception	1	95	WMD (fixed), 95% CI	-1.10 [-4.05, 1.85]
11 Free thyroxine (pmol/L) at 35 weeks' post-conception	1	100	WMD (fixed), 95% CI	-1.10 [-3.48, 1.28]
12 Free thyroxine (pmol/L) at 40 weeks' post-conception	1	107	WMD (fixed), 95% CI	-0.40 [-1.67, 0.87]
13 Thyrotrophin (mU/L) at 30 weeks' post-conception	1	117	WMD (fixed), 95% CI	-0.30 [-0.79, 0.19]
14 Thyrotrophin (mU/L) at 35 weeks' post-conception	1	108	WMD (fixed), 95% CI	-0.20 [-0.69, 0.29]
15 Thyrotrophin (mU/L) at 40 weeks' post-conception	1	111	WMD (fixed), 95% CI	0.08 [-0.28, 0.44]

Notes

Published notes

Contact details for co-reviewers

Dr William McGuire
Associate Professor of Neonatology
Department of Paediatrics and Child Health
Australian National University Medical School
Canberra Hospital Campus
Canberra
ACT 2606 AUSTRALIA
Telephone 1: +61 2 62442222
Facsimile: +61 2 62443112
E-mail: william.mcguire@act.gov.au
Secondary address:
Tayside Institute of Child Health
Ninewells Hospital and Medical School
Dundee
Scotland UK
DD6 8DL
Telephone: 0044 1382 633942
Facsimile: 0044 1382 632597

Dr John KH Sinn
Staff Specialist
Neonatal Unit
Westmead Hospital
Hawkesbury Road
Westmead
New South Wales AUSTRALIA
2145
Telephone 1: 612 9845 8748
Facsimile: 02 9845 7490
E-mail: johnsinn@westgate.wh.usyd.edu.au

The review is published as a Cochrane review in The Cochrane Library, Issue 2, 2006 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the Review.