An explanatory randomised placebo controlled trial of levothyroxine supplementation for babies born <28 weeks' gestation: results of the TIPIT trial.

BACKGROUND: Babies born before 28 weeks' gestation have lower plasma thyroid hormone concentrations than more mature infants. This may contribute to their risk of poor developmental outcome. Previous studies have suggested that thyroxine supplementation for extremely preterm neonates may be beneficial. The aim of this study was to investigate the effect of administration of supplemental thyroxine to very premature babies on brain size and somatic growth at 36 weeks' corrected gestational age (CGA). METHODS: In this explanatory multicentre double blind randomised placebo controlled trial, 153 infants born below 28 weeks' gestation were randomised to levothyroxine (LT4) supplementation or placebo until 32 weeks' CGA. The primary outcome was brain size assessed by the width of the subarachnoid space measured by cranial ultrasound at 36 weeks' CGA. Lower leg length was measured by knemometry. RESULTS: Babies in the LT4-supplemented and placebo groups had similar baseline characteristics. There were no significant differences between infants given LT4 (n=78) or placebo (n=75) for width of the subarachnoid space, head circumference at 36 weeks' CGA, body weight at 36 weeks' CGA or mortality. Infants who received LT4 had significantly shorter leg lengths at 36 weeks' CGA although adjusted analysis for baseline length did not find a statistical difference. There was a significant correlation between low FT4 and wider subarachnoid space. No unexpected serious adverse events were noted and incidence of adverse events did not differ between the two groups. CONCLUSION: This is the only randomised controlled trial of thyroxine supplementation targeting extremely premature infants. Supplementing all babies below 28 weeks' gestation with LT4 had no apparent effect on brain size. These results do not support routine supplementation with LT4 for all babies born below 28 weeks' gestation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89493983EUDRACT number: 2005-003-09939.

Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia.

BACKGROUND: There are many pathological conditions leading to an elevated unconjugated bilirubin level (hyperbilirubinaemia) in neonates. Currently the standard therapies for unconjugated hyperbilirubinaemia include phototherapy and exchange transfusion. In addition to phototherapy, clofibrate has been studied as a treatment for hyperbilirubinaemia in several countries. OBJECTIVES: To determine the efficacy and safety of clofibrate in combination with phototherapy versus phototherapy alone in unconjugated neonatal hyperbilirubinaemia. SEARCH METHODS: Randomised controlled trials were identified by searching MEDLINE (1950 to April 2012) before being translated for use in The Cochrane Library, EMBASE 1980 to April 2012 and CINAHL databases. All searches were re-run on 2 April 2012. SELECTION CRITERIA: We included trials where neonates with hyperbilirubinaemia received either clofibrate in combination with phototherapy or phototherapy alone or placebo in combination with phototherapy. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed independently by two review authors (MG and HM). Treatment effects on the following outcomes were determined: mean change in bilirubin levels, mean duration of treatment with phototherapy, number of exchange transfusions needed, adverse effects of clofibrate, bilirubin encephalopathy and neonatal mortality. Study authors were contacted for additional information. Studies were analysed for methodological quality in a 'Risk of bias' table. MAIN RESULTS: Fifteen studies (two including preterm neonates and 13 including term neonates) were included in this review. All but one of the included studies were conducted in Iran. For preterm neonates, there was a significantly lower bilirubin level in the 100 mg/kg clofibrate group compared to the control group with a mean difference of -1.37 mg/dL (95% CI -2.19 mg/dL to -0.55 mg/dL) (-23 µmol/L; 95% CI -36 µmol/L to -9 µmol/L) after 48 hours. For the term neonates, there were significantly lower bilirubin levels in the clofibrate group compared to the control group after both 24 and 48 hours of treatment with a weighted mean difference of -2.14 mg/dL (95% CI -2.53 mg/dL to -1.75 mg/dL) (-37 µmol/L; 95% CI -43 µmol/L to -30 µmol/L] and -1.82 mg/dL (95% CI -2.25 mg/dL to -1.38 mg/dL) (-31 µmol/L; 95% CI -38 µmol/L to -24 µmol/L), respectively.There was a significantly lower duration of phototherapy in the clofibrate group compared to the control group for both preterm and term neonates with a weighted mean difference of -23.82 hours (95% CI -30.46 hours to -17.18 hours) and -25.40 hours (95% CI -28.94 hours to -21.86 hours), respectively.None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions. AUTHORS' CONCLUSIONS: There are insufficient data from different countries on the use of clofibrate in combination with phototherapy for hyperbilirubinaemia to make recommendations for practice. There is a need for larger trials to determine how effective clofibrate is in reducing the need for, and duration of, phototherapy in term and preterm infants with hyperbilirubinaemia.

Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland.

OBJECTIVES: To determine the incidence of severe hyperbilirubinaemia in the newborn, and to identify associated clinical and demographic variables, and short-term outcomes. DESIGN: Prospective, population-based study. SETTING: UK and Republic of Ireland, between 1 May 2003 and 31 May 2005. PARTICIPANTS: Infants in the first month of life with severe hyperbilirubinaemia (maximum unconjugated serum bilirubin >/=510 micromol/l). RESULTS: 108 infants met the case definition, 106 from the UK and 2 from the Republic of Ireland. The UK incidence of severe hyperbilirubinaemia was 7.1/100 000 live births (95% CI 5.8 to 8.6). Only 20 cases presented in hospital; 88 were admitted with severe jaundice. 64 (60.4%) cases were male, and 56 (51.8%) were of ethnic minority origin. 87 (80.5%) cases were exclusively breast fed. Co-morbidity included haemolysis, dehydration, infection and bruising. 14 infants showed evidence of bilirubin encephalopathy, of whom 3 died. The UK incidence of bilirubin encephalopathy was 0.9/100 000 live births (95% CI 0.46 to 1.5). CONCLUSIONS: This is the first large, prospective, population-based study of the incidence of severe hyperbilirubinaemia in the newborn. The clinical and demographic associations, and short-term outcomes identified, are the same as those reported recently in North America and Europe.

Proxy consent in neonatal care--goal-directed or procedure-specific?

The prescription of practice guidelines for consent in neonatal care that are appropriate for all interventions faces substantial problems. Current practice varies widely. Consent in neonatal care is compromised by postnatal constraints on information sharing and decision-making. Empirical research shows marked individual and cultural variation in the degree to which parents want to contribute to decision-making on behalf of their infants. Conflict between the parents' wishes and the infant's best interests could arise if consent for a recommended intervention were refused, and parental refusal of consent may have to be overridden. Consent to an appropriate package of care (such as special, intensive or palliative care) may be morally preferable to a universal requirement to seek consent for all individual interventions entailed by that package.