Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. L-thyroxine treatment of preterm newborns: clinical and endocrine effects. Postnatal thyroxine supplementation in infants less than 32 weeks' gestation: effects on pulmonary morbidity. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation. Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia.
Improvements in the management of respiratory distress syndrome (RDS) include pre- and postnatal stimulation of pulmonary maturity, and triiodothyronine (T3) is believed to influence directly surfactant production. Its circulating levels are low in premature infants with RDS probably due to a low thyroxine T4-T3 hepatic conversion mechanism. While a state of hypotriiodothyroninemia exists at birth, we studied the influence of postnatal intravenous T3 administration on the course of RDS in preterm infants of less than 32 weeks' gestation. Fifty preterm infants with RDS were studied (mean gestational age 30.4 +/- 1.2 weeks and birth weight 1,180 +/- 220 g). They were at random assigned to treatment with 50 micrograms L-T3 (Thyrotardin) or to the control group. Mortality rate, peak oxygen concentrations, duration of artificial ventilation and development of major complications of RDS were the criteria to estimate the influence of T3 treatment on RDS. We failed to detect a statistically significant difference between the two groups in all of the mentioned criteria except for FiO2 concentrations required to maintain PaO2 between 50 and 60 mm Hg (p less than 0.05). These observations suggest a relative beneficial effect of T3 replacement on the course of RDS in preterm infants of less than 32 weeks of gestation. Preterm newborns have low serum thyroxine (T4) levels compared with late-gestational fetuses. Low thyroid hormone levels are associated with increased severity of neonatal illness and neurodevelopmental dysfunction. We assessed the endocrine and clinical effects of increasing serum T4 levels in preterm newborns with a gestational age <31 wk. Forty newborns were randomized in a double blind protocol: 20 infants received a daily dose of 20 microg/kg L-T4 for 2 wk, whereas 20 control infants received saline. Serum concentrations of T4, triiodothyronine (T3), reverse T3 (rT3), thyroglobulin (TG), and TSH were measured weekly as well as serum levels of GH, prolactin, and IGF-I. After 2 wk, a TSH-releasing hormone (TRH) test was performed. Neonatal illness and outcome was evaluated by noting heart rate, oxygen requirement, duration of ventilation, development of chronic lung disease, oral fluid intake, and weight gain; a Bayley score was done at the corrected age of 7 mo. L-T4 administration induced a marked increase in serum T4 without apparent change in T3 levels, whereas the postnatal decline in serum rT3 was more gradual. L-T4 treatment was associated with a decrease in serum TG and TSH levels. TRH injection induced a definite rise in serum TSH and T3 in controls, but not in L-T4 treated newborns. Neither L-T4 treatment, nor TRH administration appeared to alter circulating levels of prolactin, GH, or IGF-I. In contrast to the pronounced endocrine effects, no clinical effects of L-T4 administration were detected. Transient hypothyroxinemia in premature newborns has been linked with poor neonatal outcomes. We designed this study to evaluate the effects of early thyroxine (T4) administration in the premature infant.
                A total of 49 newborns less than 32 weeks' gestation, were randomized in a double-blind, placebo-controlled trial. Within the first 48 hours of life, T4 (10 or 20 micrograms/kg; intravenous or through nasogastric tube, respectively) was administered for a total of 21 days. Chronic lung disease, the primary outcome variable, was defined by oxygen dependency at 28 days of life.
                The incidence of chronic lung disease, death, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, and sepsis was not different in the placebo and treated groups.
                Early T4 supplementation in preterm newborns less than 32 weeks' gestation does not decrease the incidence of chronic lung disease or other complications of prematurity. Premature infants who have transient hypothyroxinemia in the first weeks of life may have developmental delay and neurologic dysfunction. Whether thyroxine treatment during this period results in improved developmental outcomes is not known.
                We carried out a randomized, placebo-controlled, double-blind trial of thyroxine supplementation in 200 infants born at less than 30 weeks' gestation. Thyroxine (8 microg per kilogram of birth weight) or placebo was administered daily, starting 12 to 24 hours after birth, for six weeks. Plasma free thyroxine concentrations were measured weekly for the first eight weeks after birth. Scores on the Bayley Mental and Psychomotor Development Indexes and neurologic function were assessed at 6, 12, and 24 months of age (corrected for prematurity).
                Mortality and morbidity up to the time of discharge from the hospital were similar in the study groups. At 24 months of age, 157 infants were evaluated. Overall, neither mental nor psychomotor scores differed significantly between the study groups at any time, nor was the frequency of abnormal neurologic outcome significantly different. In thyroxine-treated infants born at gestational ages of less than 27 weeks, the score on the Bayley Mental Development Index at 24 months of age was 18 points higher than the score for the infants with similar gestational ages at birth in the placebo group (P=0.01); for thyroxine-treated infants born at 27 weeks or later, the mental-development score was 10 points lower than that of their counterparts in the placebo group (P=0.03). There was no relation between the initial plasma free thyroxine concentration and the effect of treatment.
                In infants born before 30 weeks' gestation, thyroxine supplementation does not improve the developmental outcome at 24 months. The nature of hypothyroxinemia in sick very low-birth-weight (VLBW) infants was evaluated by assessment of the hypothalamic-pituitary axis and by the clinical response to thyroxine (T4) therapy. Twenty-three very low-birth-weight infants of gestational age 26 to 28 weeks, whose serum T4 concentrations were 4 micrograms/dL on two occasions, and thyrotropin less than 20 microU/mL, were included in a double-blind study. Following a thyrotropin-releasing hormone stimulation test, babies were given either T4 or placebo. Nine babies were thyrotropin-releasing hormone tested prior to therapy; four babies, two from each group, were tested 1 to 2 weeks after therapy. In 11 untreated babies, mean base line serum thyrotropin of 7.0 +/- 1.4 rose to 23.7 +/- 4.1 microU/mL in 30 minutes. This response was not significantly greater than the observed response in full-term babies, 23.7 +/- 4.1 v 16.6 +/- 0.97 microU/mL, respectively, P greater than .05. In two babies treated with T4 the thyrotropin response to thyrotropin-releasing hormone was completely suppressed. Serial serum T4 determinations showed normalization in both groups after a similar time interval. There was no beneficial effect of T4 therapy on growth of head circumference, length, or weight. Developmental data revealed no significant differences in the mental, motor, or gross neurologic outcome in the treated and nontreated infants after 1 year of follow-up. These observations imply that hypothyroxinemia in sick preterm infants is not a direct consequence of hypothyroidism. Despite the lack of demonstrable short-term beneficial effects of T4 therapy, follow-up studies are necessary to resolve the question of long-term benefits.
This review does not support the use of thyroid hormones in preterm infants to reduce neonatal mortality, improve neurodevelopmental outcome or to reduce the severity of respiratory distress syndrome. An analyses of data from one study (van Wassenaer 1997) which showed benefits in infants 24-25 weeks gestation was not prespecified and should be treated with caution. 
The small number of infants included in trials incorporated in this review limits the power of the meta-analysis to detect clinically important differences in neonatal outcomes.
Future trials are warranted and should be of sufficient size to detect clinically important differences in neurodevelopmental outcomes. They should consider enrolling those infants most likely to benefit from thyroid hormone treatment such as infants born at less than 27 weeks gestation.