Fiona L. R. Williams

Objectives Postnatal thyroid dysfunction is common in preterm infants but the relationship between mild dysfunction and neurodevelopment is unclear. Our aim is to describe the relationship between thyroid function and neurodevelopment. Design Cohort analysis. Patients 1275 infants born under 31 weeks’ gestation; there were no exclusion criteria. Setting The infants were part of a UK daily iodine supplementation trial. Main outcomes Thyroid-stimulating hormone, thyroid-binding globulin and total thyroxine levels were measured in dried blood spots on postnatal days 7, 14, 28 and the equivalent of 34 weeks’ gestation. Neurodevelopment was measured using the Bayley-III Scales of infant development at 2 years of age. Results No infant was identified as hypothyroid through routine screening. The 3% of infants consistently in the top decile of gestationally age-adjusted thyroid-stimulating hormone levels had a reduction in cognitive score of 7 Bayley units when compared with those not in the top decile (95% CI –13 to –1). A reduction in motor composite score of 6 units (95% CI −12 to <−0.1) and fine motor score of 1 unit (95% CI –2 to –0.1) was also identified. The 0.7% of infants consistently in the bottom decile of age-adjusted thyroxine levels had a reduction in motor composite score of 14 units (95% CI –25 to –2) and its two subset scores, fine and gross motor, of 2 units (95% CI respectively −4.5 to <−0.1 and –4.3 to –0.3). Conclusions Preterm infants with consistent ‘mild’ thyroid dysfunction score less on neurodevelopmental tests at 2 years of age. Many of these infants will not be detected by current clinical protocols or screening programmes.

BACKGROUND: The recommendation for enteral iodide intake for preterm infants is 30 to 40 μg/kg per day and 1 μg/kg per day for parenteral intake. Preterm infants are vulnerable to iodide insufficiency and thyroid dysfunction. The hypothesis tested whether, compared with placebo, iodide supplementation of preterm infants improves neurodevelopment. METHODS: A randomized controlled trial of iodide supplementation versus placebo in infants <31 weeks’ gestation. Trial solutions (sodium iodide or sodium chloride; dose 30 μg/kg per day) were given within 42 hours of birth to the equivalent of 34 weeks’ gestation. The only exclusion criterion was maternal iodide exposure during pregnancy or delivery. Whole blood levels of thyroxine, thyrotropin, and thyroid-binding globulin were measured on 4 specific postnatal days. The primary outcome was neurodevelopmental status at 2 years of age, measured by using the Bayley Scales of Infant Development-III. The primary analyses are by intention-to-treat, and data are presented also for survivors. RESULTS: One thousand two hundred seventy-three infants (637 intervention, 636 placebo) were recruited from 21 UK neonatal units. One hundred thirty-one infants died, and neurodevelopmental assessments were undertaken in 498 iodide and 499 placebo-supplemented infants. There were no significant differences between the intervention and placebo groups in the primary outcome: mean difference cognitive score, −0.34, 95% confidence interval (CI) −2.57 to 1.89; motor composite score, 0.21, 95% CI −2.23 to 2.65; and language composite score, −0.05, 95% CI −2.48 to 2.39. There was evidence of weak interaction between iodide supplementation and hypothyroxinemic status in the language composite score and 1 subtest score. CONCLUSIONS: Overall iodide supplementation provided no benefit to neurodevelopment measured at 2 years of age.

Background: Infants <32 weeks’ gestation should not be exposed to topical iodine and its avoidance is recommended during pregnancy and breast feeding. Exposure to contrast media and topical iodine is frequently used in many preterm neonates. Aim: To determine whether thyrotropin levels in preterm infants are affected by exposure to intrapartum/neonatal topical iodine and/or the use of iodinated contrast media. Design: Infants <32 weeks’ gestation were recruited. Maternal and neonatal exposures to iodinated contrast media and topical iodine were recorded; levels of thyrotropin and thyroxine were measured from blood-spot cards on postnatal days 7, 14, 28 and the equivalent of 36 weeks’ gestation. Results: One hundred and twenty-five infants were exposed to topical iodine/contrast media and 48 infants were unexposed. No infants were treated for hypothyroidism; three infants (exposed group) had transient hyperthyrotropinaemia. Mean thyrotropin levels were significantly higher on postnatal days 7, 14 and 28 in infants exposed to topical iodine prior to caesarean section compared to unexposed infants, a relationship which persisted after adjustment. Conclusions: In the context of this study, neonatal thyroid dysfunction was seen following exposure to iodine via caesarean section but not via exposure to contrast media.

Norepinephrine (NE) and epinephrine (EPI) levels are higher in cord arterial blood relative to venous blood, consistent with active mechanisms of placental-maternal clearance. There are no contemporary studies of cord arteriovenous blood levels of sulfated and non-sulfated catechols. To assess the arteriovenous differences in cord blood levels of dopamine (DA), the sulfated catecholamines and their sulfated and non-sulfated metabolites. To correlate levels of oxygen, H+/CO2, and glucose with cord catecholamine levels. Fifty-seven term infants, delivered by elective cesarean section, were recruited. Cord arterial and venous blood was sampled; levels of glucose, lactate, blood gases, six catechols and their sulfated conjugates were measured. With one exception (DOPA sulfate), mean cord arterial levels of sulfated and non-sulfated catechols were significantly higher than venous levels. Arterial lactate and glucose levels were independently associated with NE levels, but only lactate was associated with levels of EPI and DA. This study establishes that in vivo metabolic parameters of hypoxia, respiratory and metabolic acidosis are associated with catecholamine levels, a key relationship for perinatal adaptation and homeostasis, and findings that are consistent with in vitro studies of the regulators of catecholamine secretion.

Aim: Neurodevelopment is a key outcome for many childhood trials and observational studies. Clinically important decisions may rest on finding relatively small differences in neurodevelopment between groups receiving complex and costly interventions. Our purpose was to determine whether studies which measure neurodevelopment report the numbers, training, and auditing of assessors and, for multiple assessor studies, whether the results were adjusted and if so by which method?Method: Electronic searches were conducted using Medline, Embase, Cinahl, PsycINFO, and the Cochrane Library. A study was eligible if it reported neurodevelopmental outcome in children resident in the UK, less than or equal to 18 years and was published between 2000 and 2015. Trials and observational studies were included.Results: Three hundred and seven full papers were reviewed: 52% of papers did not report the number of assessors used; 21% used a single assessor; and 27% used multiple assessors. Thirty‐five per cent mentioned that assessors were trained in the use of the neurodevelopmental tool; 13% of assessors were audited; and only 1% of studies adjusted statistically for the number of assessors.Interpretation: At the very least, the quality of reporting the use of assessors in these research publications is poor, while at worst, the variability of assessors may mask the true relationship between an intervention/observation and neurodevelopmental outcome.

To assess factors contributing to cord venous glucose homeostasis in term infants delivered by elective cesarean section. Observational study of women-infant pairs at delivery. Biochemical and clinical data were collected about factors which might affect the levels of glucose, lactate, norepinephrine, epinephrine, cortisol, human growth hormone, glucagon, and insulin. In the context of this data-set, three models explained a substantial amount regarding the variation: 79% of the variation in cord glucose levels is explained by levels of maternal glucose, cord venous pH, and cord lactate; 77% of the variation of cord lactate is explained by levels of cord venous pH, valine, maternal lactate and glucose, and cord norepinephrine; and 71% of the variation in cord norepinephrine is explained by levels of cord venous pO2, maternal lactate, cord insulin, cord GABA (gamma-aminobutyric acid), cord lactate, cord epinephrine, cord norepinephrine sulfate, and cord valine. Term infants delivered by cesarean section are relatively hyperinsulinemic (insulin:glucose ratio of 2.4) and glucose levels are strongly associated with maternal glucose levels, cord pO2, and lactate levels. There were no associations with levels of cord glucose and levels of cortisol, epinephrine and lactate, which have been shown to be important contributors to postnatal glucose homeostasis in some infant groups.

This paper summarises the study protocol for the randomised controlled trial of iodine supplementation in preterm infants. Iodine is essential for the synthesis of thyroxine, and thyroxine is essential for normal brain development in utero and for the first 2-3 years of life. The recommended iodine intake in parenteral nutrition regimens is 1 μg/kg/day and commercially available parenteral solutions for infants reflect these recommendations. In the absence of other iodine sources, infants are vulnerable to negative iodine balance and insufficiency. As many preterm infants are fed parenterally for prolonged periods with solutions which have been shown to be iodine-deficient, the I2S2 Trial was designed to establish whether iodine supplementation of preterm infants benefits neurodevelopment.

Objective To determine whether maternal exposure to iodine or neonatal exposure to topical iodine-containing solutions increases the risk of transient thyroid dysfunction in neonates born Design Systematic review. Search strategy Electronic searches were conducted using Medline and the Cochrane Library. Eligibility criteria A study was eligible for review if it reported neonatal exposure to topical iodine or maternal iodine exposure. The key outcome measure was neonatal thyroid function. The search had no restrictions on date of publication, type of study or language. Results 794 papers were identified during the initial search; 15 studies were fully reviewed. The incidence of (transient) hypothyroidism/hyperthyrotropinaemia following exposure to topical iodine ranged from 12 to 33 per 100 infants; the incidence in non-exposed infants was 0. Conclusions There is evidence that neonatal exposure to iodine-containing disinfectants causes thyroid dysfunction in infants born <32 weeks. None of the studies evaluated neurodevelopment. Larger scale studies are needed to determine definitively the nature of the relationship and the impact of exposure on neurodevelopment. In the meantime, it would seem prudent to restrict exposure of iodine-containing skin disinfectants in preterm infants; chlorhexidine might be a credible alternative.