PEDIATRICS Vol. 110 No. 3 September 2002, pp. 534-539
Free Thyroxine Levels During the First Weeks of Life and Neurodevelopmental Outcome Until the Age of 5 Years in Very Preterm Infants
* Departments of Neonatology
Experimental Pediatric Endocrinology, Academic Medical Center, Emma Children’s Hospital, Amsterdam, the Netherlands
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Background. We have conducted a randomized trial with thyroxine (T4) in 200 infants <30 weeks’ gestation. T4 treatment was associated with better 5-year outcome in infants <29 weeks’ gestation, but with worse outcome in infants of 29 weeks. These effects could be related to low, respectively high free thyroxine (FT4) levels
Methods. For each infant, the average FT4 of 5 scheduled measurements was calculated between day 3 and day 28. Infants of the placebo and the T4 group separately were divided in 2 groups. The placebo group consisted of a group of infants with average FT4 in the lowest quartile and a group in the upper 75%. The T4 group consisted of a group of infants with average FT4 in the upper quartile and a group in the lower 75%. Developmental outcome (mental/cognitive, motor, and neurologic) at 2 and 5.7 years was compared between high and low FT4 groups, and then compared separately for the T4 and placebo group.
Results. In the placebo group, low FT4 was associated with worse outcome on all domains at both time points. After correction for confounding variables, mental and neurologic outcome remained significantly different at 2 years, and motor outcome at 5 years.
In the T4 group, high FT4 was not associated with worse outcome, neither at 2 nor at 5 years.
Conclusions. In untreated infants, low FT4 values during the first 4 weeks after birth in infants born at <30 weeks’ gestation are associated with worse neurodevelopmental outcome at 2 and 5 years. In T4-treated infants, high FT4 is not associated with worse outcome. Other factors than high FT4 concentrations must play a role in the worse outcome of the T4-treated group of 29 weeks’ gestational age.
Key Words: thyroxine • very low birth weight infant • follow up studies • hypothyroidism
Abbreviations: T4, thyroxine • T3, triiodothyronine • FT4, free thyroxine
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Thyroid hormone is essential for brain maturation from early embryonic stages onward. 1,2 Materno-fetal transfer of thyroid hormones has been demonstrated in early fetal stages3 and continues, at least in the case of fetal inability, to produce sufficient thyroid hormone until term.4 Maternal thyroxine (T4) delivery to the fetus seems to be crucial in the protection of the fetus from too low T4 levels. In case of combined fetal and maternal hypothyroidism attributable to severe iodine deficiency, shortage of fetal T4 throughout pregnancy results in a very severe clinical picture of neurologic deficits.5 However, congenital hypothyroidism attributable to an inability of the fetal thyroid to synthesize thyroid hormones results in only subtle deficits or even normal outcome, if accompanied by normal maternal thyroid function and appropriately treated soon after birth.6
Very preterm infants suddenly lack the maternal thyroid hormone contribution at a developmental stage when maturation of the hypothalamo-pituitary-thyroid system and thyroid hormone metabolism has not been completed. This results in a period of transient hypothyroxinemia, during which bound and free plasma concentrations of T4 and triiodothyronine (T3) are low. This period lasts longer and is more severe in infants of lower gestational age.7–9
Three retrospective studies in large cohorts of preterm infants have studied the relation between a single total T4 measurement in the first week of life10–12 or the lowest total T3 measurement during a 10-week period13, 14 and developmental outcome at 18 months to 9 years; they all show an increased risk of impaired developmental outcome in infants with lowest thyroid hormone values. The question as to whether or not to treat the low thyroid state by supplementing thyroid hormone could not be answered by these studies.
Free thyroxine (FT4) levels, not the total (bound) levels, are important for clinical effects.15 Moreover, part of the low total T4 and T3 levels that are found in preterm infants are caused by low concentrations of thyroid-binding globulin, which are also lower in infants of lower gestation and in disease.16 Thus, it is important to demonstrate associations between low FT4 levels and later development. Only 1 report of a small study is available that does not show such an association.17
We have conducted a randomized trial of T4 supplementation in 200 infants of <30 weeks’ gestation. No overall effect of this treatment was found on neurodevelopmental outcome at 218 nor at 5.719 years of age. However at both time points, a gestational age-dependent effect was demonstrated, with a mostly positive direction of effects in infants born at <27 to 29 weeks and a negative direction of effects in infants of 29 weeks’ gestation.19, 20 We also have shown that longitudinal FT4 concentrations of infants of the placebo group are lower with decreasing gestational age, whereas longitudinal FT4 concentrations of infants belonging to the T4 group are higher with increasing gestational age.21
To further explore the relation between neonatal FT4 concentrations and developmental outcome, we analyzed the randomized groups separately. We studied first whether longitudinally measured FT4 values of infants of the placebo group are positively associated with 2 and 5 years’ developmental outcome, and, second, whether high, longitudinally measured FT4 levels of infants in the T4 group are negatively associated with 2 and 5 years outcome.
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PATIENTS AND METHODS |
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Patients
Patients in this study all participated in a randomized, controlled, double-blind trial of T4 supplementation.18 Two hundred infants of 25 to 30 weeks’ gestation were included into this study before the 24th hour of life between January 1991 and July 1993. Details of the randomization process and study design are described elsewhere.18 T4 (or placebo) was administered during the first 6 weeks of life in a dose of 8 µg/kg birth weight/day. Thirty-five infants died in the neonatal period, 7 were withdrawn from the study, and 1 child moved abroad, resulting in a follow-up group of 157 children. The endpoint of the study was developmental outcome at the age of 2 years. At the corrected age of 5.7 years, all remaining children were again invited for neurodevelopmental assessments at our outpatient clinic. For this extension of the study, separate approval of the Committee of Medical Ethics of the Academic Medical Center of Amsterdam was obtained.
FT4 Measurements and Classification of Low and High FT4 Subgroups
A blood sample of 1 mL (or less if the clinical condition did not allow for this quantity) was drawn within the first 24 hours after birth, before T4/placebo was started, and subsequently on day 3, weekly during trial medication and 2 weeks after discontinuation of the treatment. Cord blood was taken if available. Measurement of FT4 was conducted in each of these specimens by a 2-step radioimmunoassay (SPAC-ft4 fraktion; BYK-Sangtec Diagnostica, Dietzenbach, Germany). The detection limit of this assay was 1.0 pmol/L with an intra-assay variation of 2.8% and an interassay variation of 5.7%. There is no interference of T4-binding globulin in this assay.22
For each surviving infant, an average FT4 value of 5 scheduled FT4 measurements (on days 3, 7, 14, 21, and 28) was calculated. This period of time was chosen, because before day 3, FT4 can be rather high as a result of the (F)T4 surge after birth, whereas after day 28, FT4 values remain rather stable.9, 18
Low and high FT4 groups were distinguished within the placebo and T4 group separately. The placebo group was divided into 2 subgroups of children with (average) FT4 values in the lowest quartile and in the highest 75%. The T4 group was divided into 2 subgroups of children: a group with the lowest 75% (average) FT4 values and a group in the highest quartile.
Neurodevelopmental Assessments at the Corrected Age of 2 Years
The Bayley Mental and Psychomotor Developmental Indexes were assessed23 in relation to the Dutch norms (mean: 100; standard deviation: 16). Neurologic outcome was assessed according the method of Hempel24 and classified as normal, suspect, or abnormal. For more details see previous publications. 18
Neurodevelopmental Assessments at the Corrected Age of 5.7 Years
Cognitive Functioning
The short version of the Revised Amsterdam Children Intelligence Test for 4 to 11 years was used for assessment of cognitive functioning. The norm score (IQ score) of the test is 100 with a standard deviation of 15. 25
Motor Outcome
The Movement Assessment Battery for Children was used to assess motor skills as manual dexterity, throwing, and catching, and static and dynamic balance. Scores range from 0 to 5: a score of 0 is given when the child passes the task and a score of 5 when he or she fails the task. A total motor impairment score (ranging from 0–40) is computed by summing the scores on all motor tasks, with higher scores indicating more motor problems. Cutoff scores for mild and severe motor problems are represented by the 15th and 5th percentile of the reference population, respectively, corresponding with a total impairment score 
10.5 and 17. 26
Neurologic Outcome
Neurologic development was qualitatively assessed using the method according to Touwen.27 A 3-point classification was made: normal, minor neurologic dysfunction and cerebral palsy. Minor neurologic dysfunction was diagnosed when one or more abnormalities occurred in posture and muscle tone, muscle power, reflexes, coordination, and balance or if involuntary movements were seen. Cerebral palsy was diagnosed if the complete neurologic syndrome with abnormalities in posture, tone, and reflexes was present.
Collection of Perinatal Characteristics
Perinatal characteristics were collected prospectively, as described in earlier reports.18
Statistics
Univariate as well as multivariate analyses were conducted for comparison of high and low FT4 groups in the placebo and T4 group separately. The Student t test was used to compare continuous variables, and the 
2 test was used for analyzing categorical data. The effect of average FT4 grouping on outcome was also tested with multivariate linear or logistic regression analysis. Predefined factors that independently might affect developmental outcome and occurred before T4 treatment was installed were used as covariates: sex, educational level of the mother, gestation age, birth weight, antenatal steroids, intubation at birth, and use of surfactant. In a second phase, all multivariate analyses were repeated with addition of bronchopulmonary dysplasia, oxygen need at 36 weeks’ postmenstrual age, and cerebral ultrasound findings to the set of covariates. Multivariate analyses were done in 2 phases to discriminate between prerandomization factors and factors that developed thereafter. All statistical tests (SPSS version 9.0, Chicago, IL) were 2-sided, with P < .05 for statistical significance.
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RESULTS |
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Placebo Group
In the placebo group, 79 infants survived the neonatal period. Nineteen of them had FT4 values in the lowest quartile, which ranged from 10.1 to 12.5 pmol/L; 60 had FT4 values in the highest 75% ranging from 12.6 to 21.1 pmol/L. Infants in the lowest quartile had a lower gestational age, had chronic lung disease more often, and ventricular dilatation on the cerebral ultrasound more often. No other significant differences were found between these groups (Tables 1 and 2).
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T4 Group
In the T4 group, 86 infants survived the neonatal period. Sixty-four had FT4 values in the lower 75%, ranging from 13.3–23.2 pmol/L, and 22 had FT4 values in the highest quartile with FT4 values between 23.3 and 29.1 pmol/L. Infants in the highest quartile had a higher birth weight and APGAR score and tended to have less patent ductus arteriosus.
From these 165 surviving infants, 157 remained in study after term age (see "Methods"), who were all assessed at the corrected age of 2 years. Only 1 child was not seen at 5.7 years of age because of refusal to cooperate by the parents. In the placebo group, 75 children (18 in the lowest quartile) were available for neurodevelopmental assessments and in the T4 group, 81 were available (21 in the highest quartile).
Placebo Group
Table 3 shows mental/cognitive, motor, and neurologic outcome in children of the placebo group, divided on the basis of their average FT4 values. At both points in time, on all 3 domains, better scores are found in the children with 75% highest mean FT4-values in the neonatal period. At 2 years of age, mean Mental Development Index is 19 points better in the highest 75% FT4 group and in this group, abnormal neurologic outcome is 6 times less frequent. After correction for all covariates, at the age of 2 years mental and neurologic outcome remain significantly better in the highest 75%. At the age of 5.7 years, only motor outcome remains significantly better after correction for all neonatal factors (P = .003).
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T4 Group
In Table 4, outcome is shown for children belonging to the T4 group. Differences are found between the high and low FT4 group neither by univariate nor by multivariate analyses. High FT4 values are not associated with worse cognitive, motor, or neurologic outcome. Mental outcome at 2 years of age and motor outcome at 5.7 years are even somewhat better in the highest FT4 quartile.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Thyroid hormone is essential for normal brain development.1 Preterm infants are more at risk of both low plasma thyroid hormone levels and impaired developmental outcome28 when born at lower gestational age, whereas low neonatal T4 and T3 levels are associated with worse outcome.10–14 Because of these relationships there has been an ongoing discussion on the necessity of T4 and or T3 treatment in very preterm infants.29 This discussion is complicated by the fact that neonatal disease causes nonthyroidal illness,9 whereas it also is a risk factor for neurobehavioral deficits.30
For brain development, sufficient circulating FT4 and not total T4 is necessary for local intracellular T3 generation.2 Therefore, the relation between plasma FT4 levels in the neonatal period and developmental outcome is more important than plasma total T4. Until now, only 1 small study including 16 children was published on this subject.17
We were able to calculate average FT4 values over a 4-week period in a larger group of very preterm infants that participated in a randomized trial of T4 supplementation18 and that was followed up until 5.7 years of corrected age. Within the untreated group of 75 children, longitudinally measured FT4 seemed to be positively associated with outcome at both time points, mental and neurologic outcome being strongest associated at the age of 2 years. At the age of 5.7 years, the strongest association was found with motor and, to a lesser extent, with neurologic outcome.
This shift from the mental domain at 2 years to the motor domain at 5.7 years is interesting. It could be explained by the fact that the measurement of mental outcome at 2 years of age, or indeed even cognitive functioning itself is still much dependent on motor skills. Nevertheless, motor outcome at 5.7 years also includes some cognitive/memory skills, since the test must be conducted exactly according to the test instructions.26 In addition, at both ages, behavior plays a role; the child must show endurance, patience and concentration to finish a task. The mental to motor shift could also be the result of the increasing influence of rearing and social background with decreasing influence of biological factors as thyroid hormone deficiency on cognitive development, whereas such educational factors are less important for motor development.
Our trial was designed to improve mental outcome at 2 years18; indeed, mental outcome was significantly improved by 18 points in a subgroup of infants <27 weeks’ gestation, who had the lowest FT4 values.20 In this subgroup, this difference decreased at the age of 5.7 years, but the difference in motor outcome between 2 and 5.7 years increased, in accordance with the here described shift. In infants of <29 weeks’ gestation19, 32 motor and neurologic outcome at 5.7 years were significantly better in the T4 group, in concert with the here found associations. Also, after congenital hypothyroidism with low T4 values in the first weeks after (most often term) birth, motor tasks are often impaired at later ages.31 In the study by Den Ouden11 and Reuss12 minor neurologic dysfunction and disabling cerebral palsy were respective outcome parameters, associated with low first week’s T4 values.
In children of our study18, 19 born at 29 weeks, however, worse cognitive, motor and neurologic outcome was associated with T4 treatment. This finding resulted in the second research question of our study, ie, whether high longitudinal FT4 levels are associated with worse outcome. High FT4 seemed not to be associated with worse outcome.
Brain cells can protect themselves against higher FT4 and T3 values by decreasing deiodinase type II and increasing deiodinase type III activity.33 In case of thyroid hormone shortage, exactly the opposite happens. Apparently before the 29th week of gestation, FT4 values are in some infants too low and/or protective mechanisms may not be working well enough to provide sufficient T3 in the brain cells. At 29 weeks of gestation and probably thereafter, T4 supplementation seems not to be required to optimize brain maturation. Important thyroid hormone dependent processes (proliferation of neurons for the cerebral cortex, cochlea, and basal ganglia) may occur before the 29th week of gestation, and may be completed in the 29th week. Also in the timing of restoring materno-fetal iodine deficiency, there is a similar window of time in the second trimester, during which iodine supplementation can improve head circumference and developmental outcome, but after which iodine supplementation is unsuccessful.5 The negative findings in the T4 subgroup of 29 weeks’ gestation remain difficult to explain and may be attributable to bias or chance.
Until now, it is not clear what critical FT4 levels in plasma are below which the risk of impaired neurodevelopment attributable to thyroid hormone shortage increases. Probably, this cut off value differs per point of gestational and postnatal age. Moreover, it differs per assay used for FT4 measurement, of which various methods exist, with the dialysis method as the presumed golden standard.34 We took quartiles of FT4 as an arbitrary cutoff point. Because of the relatively small study population, we did not use the 10th percentile. Therefore, this study does not give the cutoff value for FT4 in plasma, below which treatment with T4 must be installed.
Only 3 randomized trials have been undertaken to find out whether T4 treatment improves developmental outcome,18, 35, 36 of which 235,36 were too small and ended follow-up too early to give a reliable answer. We were able to extend our follow-up until 5.7 years of corrected age,19 when we were able to assess 156 children. Although this is a considerable number, it is still too small to answer the question as to the necessity of T4 treatment in very preterm infants. On the basis of our results, it seems logic to advise a larger randomized, controlled trial of T4 supplementation in infants of <29 weeks’ gestation. We have administered T4 as an intravenous bolus in the first weeks of life. Although this way of administration led to the positive results described in the <29 week subgroup, other protocols could be more efficient; a more gradual increase of FT4 plasma concentrations by a longer period of infusion or daily more infusions of divided dosages could result in a better balance of cerebral deiodinase II activity, optimizing intracellular T3 availability.37
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Low, longitudinally FT4 plasma levels are associated with worse cognitive and neuromotor outcome at 2 and 5 years of age, whereas high FT4 values after T4 treatment are not associated with worse outcome. These findings should encourage design of new trials of T4 supplementation in very preterm infants.
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FOOTNOTES |
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Received for publication Oct 16, 2001; Accepted Mar 8, 2002.
Address correspondence to Aleid G. van Wassenaer, MD, PhD, Emma Childrens’ Hospital AMC, Department of Neonatology, H3N, Box 22700, 1100 DE Amsterdam, the Netherlands. E-mail: a.vanwassenaer{at}amc.uva.nl
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