Through advances in neonatal medicine the worldwide prevalence of preterm and low-birth weight infants’ increases. (Katz & Bose, 1993) This development is also observed in the Netherlands. The foundation of Perinatal Registry in the Netherlands showed 77 per 1.000 preterm births. In 2008 the exact number of preterm births was 13.649. (Blencowe et al., 2012; Steering pregnancy and birth, 2009)
The World Health Organisation (WHO) defined preterm birth as all births before 37 completed weeks of gestation or fewer than 259 days since the first day of a woman’s last menstrual period. Sub-categories of preterm birth, based on gestational age are: extremely preterm (<28 weeks), very preterm (28 to <32 weeks) and moderate to late preterm (32 to <37 weeks). (World Health Organisation, 1977) Premature birth causes many health problems on the infant. Self-evident, extremely preterm have a higher risk on complications than moderate to late preterm. More widely known complications of premature birth are breathing problems, problems of the blood circulation, and problems of oxygen supply in vital organs. Nutritional problems may arise due to the immature gastrointestinal tract (Maarsingh, Aalderen & Kok, 2000). Also hypothermia can occur, because premature infants cannot keep their temperature up to standard (Nationaal Kompas Volksgezondheid, 2014). Moreover, circulating thyroid hormones are at very low levels. (Reus, Leviton, Paneth & Susser, 1997) Week 8 to 16 gestational age, the thyroid gland of the fetus synthesizes small amounts of thyroxine (T4) and triiodothyronine (T3). The serum levels of T4 and T3 are low in the gestational fetus, because there is also a minimal transmission of maternal T4 and T3 through the umbilical cord (Fisher, 1998; Fisher, 1999; LaFranchi, 1999). In the month before term, thyrotropin-releasing hormone (TRH) and thyrotropin and T4 reached its culmination. Hereby, the thyroid hormone levels found in preterm infants are lower than those in full-term infants (Ballabio, 1989; Thorpe-Beeston, 1991; Radunovic, 1991). Thyroid hormone is necessary for normal brain development (Morreale de Escobar, Obreg??n & Escobar del Rey, 2004). A positive association is also found between developmental delay and risk of cerebral palsy, and low plasma concentrations of thyroid hormones in the neonatal period (Ouden, Kok, Verkerk, Brand & Verloove-Vanhorick, 1996; Reuss, Paneth, Pinto-Martin, Lorenz & Susser, 1996). Low levels of thyroid hormones ' T3, T4, and normal or low TSH ' during a critical period of brain development in preterm infants are termed transient hypothyroxinemia (Gamma, 2008). Even though the found relationship between transient hypothyroxinemia of premature infants and abnormal neurodevelopment, transient hypothyroxinemia do not require medical treatment. This clinical decision of no treatment is evidence-based medicine. Evidence-based medicine is the integration of the best research evidence with clinical expertise and patient values to make clinical decisions (Sackett, Rosenburg, Gray, Haynes & Richardson, 1996). It is mainly based on results from clinical controlled studies, including double blind trials, randomized controlled trials (RCT's) and meta-analyzes of these RCT's. However, several studies show various treatment guidelines are not evidence-based medicine. A study of Booth A, Djulbegovic B, Guthrie B & Perleth M (2003) shows 11 till 70 per cent of of the medical interventions have any scientific foundation. The purpose of this study is to systematically review literature of the effect of thyroid hormone supplementation on preterm infants with transient hypothyroxinemia (low thyroid hormone level, normal TSH) on improvement of neurodevelopmental function. Herewith an evidence based treatment guideline, adapted to the latest surveys, can be prepared. An obvious research question would be: Is there evidence that transient hypothyroxinemia of prematurity requires medical treatment with thyroxine (T4) supplementation, which the aim to improve neurodevelopmental function? There is focused on randomized controlled trials (RCT), because these are considered as the gold standard for clinical trials (Needleman, Moles & Worthington, 2005). We also concentrate on relatively newer studies, because Osborn and Hunt (2009) already generated a systematic review about postnatal thyroid hormones for preterm infants with transient hypothyroxinemia. Because of the lack of new studies, also older A2 studies ' randomised comparative clinical studies of good quality and sufficient size and consistency ' are used. Methods Criteria for selecting studies This systematic review evaluates eight studies ' published between 1984 and 2014 - of T4 supplementation in preterm infants. These studies are summarized in Table 1. Only randomized double blind trials (RCT) were used. All participants were preterm infants in the neonatal period, varying from infants born at 26 to 30 weeks' gestation. The applied intervention was thyroid hormone supplementation compared to control (placebo). Thyroid hormone was given in different dosages with a different administration time. The clinical outcome was neurodevelopmental status, it was defined as: 1. Growth of head circumference (Chowdhry, 1984). 2. Mental, motor, or gross neurologic outcome (Chowdhry, 1984). 3. The score on the Bayley Mental Development Index (Wassenaer, 1997) 4. '' (Wassenaer, 1999). 5. IQ points, behavioral problems, motor outcome and neurologic outcome (Bri??t, 2001) 6. Teacher report, TACQOL-parent (questionnaire about physical functioning, motor, autonomy, cognitive functioning social functioning, positive emotions, negative emotions), TACQOL-kid (questionnaire about physical functioning, motor, autonomy, cognitive functioning social functioning, positive emotions, negative emotions). (Wassenaer, 2005) 7. Width of the subarachnoid space, head circumference, brain size (Sze, 2013) 8. Growth, developmental delay, cerebral palsy, visual impairment and hearing impairment (Atsushi, 2014). Table 1 8 trials with thyroid hormones in preterm infants Study Intervention Randomization Blind? Number patients Gestational Age Main results (TH versus untreated) Other features Chowdhry, 1984 T4, 10 ??g/kg. 2 times: 1 and 24 hour after birth Randomized blind 11 treated, 12 untreated. 26 to 28 weeks No significant difference is found in the mental, motor, or gross neurologic outcome after 1 year of follow-up Vanhole, 1997 T4, IV bolus 20 ??g/kg. 2 weeks Randomized blind 20 treated, 20 untreated. <31 weeks No significant difference is found in the Bayley score at the corrected age of 7 months. Steroids and TRH were given in 24 of 34 infants Wassenaer, 1997 T4 , 8 ??g/kg/day . 12 to 24 hour after birth. 6 weeks Randomized blind 100 treated, 100 untreated <30 weeks. Thyroxine supplementation does not improve the developmental outcome at 24 months in infants born before 30 weeks Wassenaer, 1999 T4 , 8 ??g/kg/day . 12 to 24 hour after birth. 6 weeks Randomized blind <30 weeks. No significant effect was found on neurodevelopmental outcome. A strong trend toward improvement of adverse outcome, defined as death or abnormal developmental outcome at 2 years of age was found. Mental outcome in the treated group was significantly better than in the untreated group for infants less than 27 weeks' gestation. Bri??t, 2001 T4, 8/g/kg/day. 6 weeks Randomized blind 81 treated, 75 untreated <30 weeks Benefits were found for the treated group (<29 weeks' gestation, especially 25/26 week's gestation). In the treated group (29 weeks' gestation) more developmental problems were found. Trotsenburg, 2005 T4 8/g/kg/day. Started within 24 hour after randomization. Until age 24 months. Randomized blind 99 treated, 97 untreated A 0.7-month smaller motor developmental age delay was found in the treated children. Also a 0.7-month smaller mental developmental age delay was found in the thyroxine group. This effect was not significant. Down-syndrome children Exclusion criteria: abnormal congenital hypothyroidism screening Wassenaer, 2005 T4, 8/g/kg/day. 6 weeks Randomized blind 58 treated, 55 untreated. <30 weeks. An association was found for T4 supplementation and better school outcome in preterm infants <27 weeks' gestation. Better motor outcome was found for preterm infants <28 weeks' gestation. For preterm infants <29 weeks' gestation the reverse was true. No significant differences were found for development until age 5.5, Neurologic outcome at 2 year, neurologic outcome at 5.5 year and school outcomes Follow-up moment at the age of 5.5 years. Respondents (N = 113) Nonrespondents (N = 43) Sze, 2013 T4, 8 mg/kg of birth weight. 12 to 24 hour after birth. 6 weeks. Randomized blind 78 treated, 75 untreated. <28 weeks. No significant differences for width of the subarachnoid space, head circumference at 36 weeks or brain size. Nomura, 2014 T4, 5-10 ??g/kg/day Retrospective study 18 treated, 18 untreated. Extremely low birth weight infants (ELBW) Levothyroxine (LT4) supplementation prevents the developmental delay of ELBW infants with transient hypothyroxinemia Retrospective study Atsushi, 2014 T4, 5??g/kg/day Randomized blind 25 treated, 45 untreated. Very-low-birth-weight (VLBW) No significant differences were found in developmental delay, cerebral palsy, visual impairment and hearing impairment at 18 months of corrected age Search methods 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 & CENTRAL, The cochrane library, Issue 4, 2001), MEDLINE, PREMEDLINE, Web of Science, previous reviews including cross-references, abstracts and journal hand searching in the Dutch and English language. The Cochrane Controlled Trials Register was searched using ('.. or'.. or'.). MeSH terms used in MEDLINE and PREMEDLINE (1984 to 2014) were (infant-newborn or infant-premature) and (thyroxine or triiodothyronine or hypothyroxinemia or hypothyroxinaemia) and (double-blind method). Web of Science (1997-2014) was searched using terms (transient hypothyroxinemia of prematurity) and (thyroxine supplementation).
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