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

Review question: Does giving preterm infants iodine supplements reduce their risk of dying or improve their brain development?

Background: Infants born preterm (several weeks early) may not receive the recommended amounts of iodine in their diet, as both preterm human breast milk and nutrition given via a drip in hospitals do not contain enough iodine to meet their heightened needs. Deficiency of iodine may affect the production of thyroid hormones that are important for brain and lung development in newborn infants. Given concerns that iodine deficiency may be harmful, we reviewed all the available evidence from clinical trials that assessed the effects of giving preterm infants iodine supplements.

Study characteristics: The evidence is up to date as of February 2018. We found two relevant trials (including 1394 infants). Both trials used reliable methods to ensure that their findings were not biased.

Key results: Analysis of data from these trials showed that iodine supplements for preterm infants does not affect the chances of dying or improve longer-term brain development. This evidence was highly reliable.

Conclusions: The currently available evidence indicates that routine supplemental iodine does not have important benefits for preterm infants.

Authors' conclusions: 

The available trial data, predominantly from one large, high-quality multicentre study published in 2017, do not show any evidence of beneficial effects of iodine supplementation for preterm infants. Given the high certainty of these estimates of effect, further trials of this intervention in this population are unlikely to be considered research priorities.

Read the full abstract...

Parenteral nutrition solutions, artificial formulas, 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 neonatal and longer-term outcomes.


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 Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 1), Ovid MEDLINE, Ovid Embase, Ovid Maternity & Infant Care Database, and CINAHL to February 2018. We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: 

Randomised or quasi-randomised controlled trials that compared supplementing enteral or parenteral feeds with iodine (as iodide salt) versus placebo or no supplementation in preterm infants.

Data collection and analysis: 

Two review authors independently assessed trial eligibility and risk of bias, and extracted data. We analysed treatment effects as described in the individual trials and reported risk ratios (RR) and risk differences for dichotomous data, and mean differences (MD) for continuous data, with 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and planned to explore potential causes of heterogeneity in sensitivity analyses. We used the GRADE approach to assess the quality of evidence.

Main results: 

Two randomised controlled trials fulfilled the eligibility criteria. Both trials used methods to limit bias including allocation concealment and blinding of clinicians and investigators to the allocated intervention. The trials enrolled 1394 infants. One trial recruited 1273 participants. Most participants were born very preterm (less than 32 weeks' gestation) and about one-third were extremely preterm (less than 28 weeks' gestation). Analyses found no effect of iodine supplementation on mortality before hospital discharge (typical RR 1.01, 95% CI 0.72 to 1.42; typical RD 0.00, 95% CI -0.03 to 0.03; 2 studies, 1380 infants) or on neurodevelopmental assessments at two years post-term (Bayley Scales of Infant and Toddler Development, Third Edition main domain composite scores: cognitive: MD –0.30, 95% CI –2.44 to 1.84; motor: MD 0.20, 95% CI –2.15 to 2.55; language: MD –0.10, 95% CI –2.50 to 2.30; 1 study, 1259 infants). There were no differences in the proportion of infants who died or had a composite score less than 85 in any main Bayley domain (RR 1.05, 95% CI 0.94 to 1.17; RD 0.02 95% CI -0.03 to 0.08; 1 study, 1259 infants), or had visual impairment (RR 0.63, 95% CI 0.28 to 1.45; RD -0.01 95% CI -0.03 to 0.01; 1 study, 1092 infants) or auditory impairment (RR 1.05, 95% CI 0.51 to 2.16; RD 0.00 95% CI -0.02 to 0.02 1 study, 1093 infants). Using GRADE methods, we assessed the evidence for the effects on mortality and neurodevelopment outcomes as high-certainty.