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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1271-1279
Copyright © 2005 by The Endocrine Society

Serum Thyroid Hormones in Preterm Infants and Relationships to Indices of Severity of Intercurrent Illness

Judith Simpson, Fiona L. R. Williams, Caroline Delahunty, Hans van Toor, S.-Y. Wu, Simon A. Ogston, Theo J. Visser, Robert Hume with collaboration from the Scottish Preterm Thyroid Group1

Maternal and Child Health Sciences (J.S., C.D., R.H.) and Community Health Sciences (F.L.R.W., S.A.O.), University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom; Department of Internal Medicine (H.v.T., T.J.V.), Erasmus University Medical School, 3000 DR Rotterdam, The Netherlands; and Nuclear Medicine Service (S.-Y.W.), VA Medical Center, University of California–Irvine Medical Center, Long Beach, California 90822-5201

Address all correspondence and requests for reprints to: Professor Robert Hume, Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, United Kingdom. E-mail: r.hume{at}dundee.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The purpose of this study was to relate severity of illness at 1, 7, 14, and 28 postnatal days in preterm infants groups, 23–27 (n = 73), 28–30 (n = 160), and 31–34 (n = 208) wk gestation, to the corresponding sera levels of T4, free T4, T4-binding globulin, TSH, T3, rT3, and T4 sulfate. The British Association of Perinatal Medicine and Neonatal Nurses Association 1992 scoring categories (published elsewhere) were used as an index of illness severity: level 1 (maximal intensive care) was compared with level 2 (high-dependency intensive care) combined with level 3 (special care); infants were scored on 1, 7, 14, and 28 postnatal days. In level 1 infants, there were significant reductions in T3 at 7 d (28–30 wk), 14, and 28 d (23–27 and 28–30 wk); T4 at 7, 14, and 28 d (23–27 wk); at 14 and 28 d (28–30 wk); and at 7 d (31–34 wk); and free T4 at 14 d (23–27 wk). TSH was unchanged in all groups at all ages and with reductions in T4 and T3 being the key features of severe illness in extreme preterm infants.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN ADULTS, A decrease in serum T3 and an increase in rT3 levels are characteristic of the fasting state and the most common changes in nonthyroidal illness in response to a variety of acute and chronic illnesses (1). With increasing severity of illness, serum T4 levels as well as those of T3 decrease (2).

In preterm infants, respiratory distress syndrome is a critical illness over the first week of life and the most frequently studied to determine whether illness alters serum thyroid hormone levels (3, 4, 5, 6, 7, 8, 9, 10, 11). However, there may be problems with this rationale. Respiratory distress syndrome is gestationally age related, varies in severity, and hence must be clearly defined to allow comparability within and between studies, i.e. by selecting the most severely affected infants on explicit criteria (e.g. Refs.10 , 11). Respiratory distress syndrome is characteristically most severe in the few days after birth, but the majority of studies of thyroid hormone status in preterm infants have been limited to the first week of life (3, 4, 6, 8, 9, 10). Two early studies extending the study period beyond the first week of life suggested a persistent effect of respiratory distress syndrome on serum thyroid hormone levels (5, 7), but further studies have not confirmed this (9, 11). These results are not surprising given the acute and time-limited nature of respiratory distress syndrome. Preterm infants also suffer from a spectrum of other illnesses within, and without, this early phase of postnatal life.

Critical illness and thyroid hormone status in preterm infants have been studied for nearly 30 yr (3, 4, 5, 6, 7, 8, 9, 10, 11). Over this period, advances in perinatal care have extended the gestational age limit of survival for preterm infants (defined as < 37 completed weeks) to some infants born as early as 23 wk gestation. In addition, more mature preterm infants have also benefited by reductions in the severity of neonatal illness, especially respiratory distress syndrome by preventative measures such as antenatal corticosteroids and surfactant therapy. These temporal shifts in clinical management are reflected in changes in the demographic characteristics of the preterm infants studied. For example, in the last decade, the most severely ill infants are those less than 30 wk gestation (10, 11, 12), whereas before this time, studies were confined to preterm infants older than 30 wk gestation (3, 4, 5, 6, 7, 8, 9). Thyroid hormone levels in infants are crucially determined by the interrelationship between gestational and postnatal age (e.g. Refs.11 , 13 , 14), but it remains unclear whether changes in thyroid hormone status in response to illness are similar across the wide gestational age range of prematurity.

To determine the relationship between critical illness in preterm infants and thyroid hormone status, we analyzed data from a cohort of preterm infants born between 23 and 34 wk gestation. A range of thyroid hormones was measured on cord 7-, 14-, and 28-d sera; and levels were then correlated with severity of illness on the day blood was sampled.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Data were collected between January 1998 and September 2001.

A cohort of mothers and infants delivered at 23–34 wk gestation and were part of a multicenter study of transient hypothyroxinemia in 11 level III Scottish neonatal intensive care units. Gestational age of infants was calculated from menstrual history and, in most instances, was confirmed by ultrasound examination in the first trimester. Exclusion criteria from the study were known viral hepatitis or HIV positivity (or at high risk), major congenital abnormality, or if mothers were unable to provide informed consent. The study was approved, as appropriate, by the Multicenter Research Ethics Committee (Edinburgh) and the Tayside Committee on Medical Research Ethics; in all cases written informed consent was obtained.

All infants had intensive care support as required, including intermittent positive ventilation and, where appropriate, correction of fluid, electrolyte, blood glucose, and acid-base abnormalities. If necessary, blood pressure was supported by volume expansion using crystalloid solutions, plasma products, or inotropes. Blood transfusions, if required, were given using partially packed cells. Infants with significant persistence of the ductus arteriosus were treated with diuretics and indomethacin or surgical ligation if appropriate. Parenteral nutrition regimens, if required, were based on a solution of electrolytes, dextrose 10%, amino acids (Vaminolact, Fresenius Kabi, Cheshire, UK), a phosphate supplement (Addiphos, Fresenius Kabi), water-soluble vitamins (Solvito N, Fresenius Kabi), and trace elements (Peditrace, Fresenius Kabi) to levels recommended by the manufacturer. In tandem, a fat emulsion solution (Intralipid 20%, Fresenius Kabi) with added fat-soluble vitamins (Vitlipid, Fresenius Kabi) was used. Enteral feeds were started when the condition of the infant was stable. Thereafter enteral feed volumes were gradually increased as determined by the infants’ clinical condition, with reciprocal reductions in the volume of parenteral nutrition infused.

Cord blood (n = 812) was collected into a tube without anticoagulant as soon as possible after delivery of the live-born infants (23–42 wk gestation) from vessels running over the placental surface, and using a 19-gauge butterfly (Abbott Ireland, Sligo) needle (15). Blood was also collected at postnatal d 7, 14, and 28 from infants of between 23 and 34 wk. The blood samples were allowed to separate for at least 15 min and were then centrifuged at 4000 rpm for 5 min. If collected outside normal laboratory hours, the blood was stored at 4 C (maximum 12 h) before processing. The serum was removed, stored, and transported at a maximum of –20 C for assays in one laboratory (T.J.V.).

Provided sufficient serum was available, T4, free T4 (FT4), TSH, T3, rT3, T4 sulfate (T4S), and T4-binding globulin (TBG) levels were determined. Serum T4, T3, and rT3 were measured by in-house RIA; FT4 by Vitros ECI technology (Ortho-Clinical Diagnostics, Amersham, UK); TSH by Dynotest immunoradiometric assay; and TBG by Dynotest RIA (Brahms, Berlin, Germany). T4S was prepared by the method of Eelkman-Rooda et al. (16). The measurements of T4S in serum were done by a specific antibody, as described previously (17). Within-assay coefficients of variation were calculated as 2–8% for T4, 3–7% for FT4, 2–6% for T3, 3–4% for rT3, 6–17% T4S, 2–5% for TSH, and 2–4% for TBG. Between-assay coefficients of variation were 5–10% for T4, 5–10% for FT4, 8% for T3, 9–16% for rT3, 4–19% for T4S, 2–14% for TSH, and 2–3% for TBG. The mean interassay variation for T4S was 12.7% (17).

Preterm infants requiring neonatal care were categorized according to the criteria established by the British Association of Perinatal Medicine and Neonatal Nurses Association in 1992 (18). This is a system that is used routinely in all participating neonatal units. There are four levels of care: level 1 intensive care (maximal intensive care); level 2 intensive care (high-dependency intensive care); special care; and normal care (no infants could qualify in this category) (18). For this study and to allow numerical consistency in the levels of care, we assigned special care as level 3. Each infant was assigned a level of care on d 1, 7, 14, and 28, and during these study days, a blood sample was taken for thyroid hormone measurements; blood levels were not measured on d 1 because thyroid hormone levels change markedly with time over the first postnatal day, and although these are attenuated in preterm infants, relatively small differences in sampling times may introduce significant variability (19); to maintain consistency within the group, cord blood was taken and the d 1 level of care assigned.

Infant disorders were recorded as follows: respiratory distress syndrome (requiring oxygen with or without ventilatory support); chronic lung disease (requiring oxygen at 28 d; this was the maximum length any one infant was included in our study); cerebral pathology (defined by the presence of cerebral ultrasound changes); persistent ductus arteriosus (requiring treatment with fluid restriction and diuretics with or without indomethacin); necrotizing enterocolitis (requiring treatment with total parenteral nutrition and antibiotics). Birth weight ratios were calculated for each infant using reference values obtained from the Scottish Morbidity Record SMR2 as supplied by the Information and Statistics Division of the Common Services Agency (Edinburgh, UK).

The levels of T4, FT4, TSH, T3, rT3, T4S, and TBG in cord and 7-, 14-, and 28-d sera in level 1 infants were compared with those in level 2 and 3 combined within the gestational age groups 23–27, 28–30, and 31–34 wk. Levels 2 and 3 were combined so that there were sufficient numbers for statistical analysis; clinically this rationale is appropriate because level 1 infants are substantially sicker than those in level 2 and 3. The gestational age groupings were chosen to maintain continuity of analysis within this data set (e.g. Ref.19).

Mean sera levels of TSH, TBG, and iodothyronines at cord and postnatal d 7, 14, and 28 for each of the gestational groups (23–27, 28–30, and 31–34 wk) were plotted against the background of twice the SE of the mean of cord sera values for each gestational age calculated separately between 23 and 42 wk gestation (15). The mean gestational age at birth was determined for each of the groups (25.8 wk for the 23- to 27-wk group, 29.2 for the 28- to 30-wk group, and 32.5 for the 31- to 34-wk group). The postnatal data at d 7, 14, and 28 were plotted onto the baseline graph starting at the appropriate mean birth gestation for each group. For example, the most immature group started at 26 wk gestation and d 7 was plotted against 27 wk, d 14 against 28 wk, and d 28 against 30 wk. Thus, data for any particular postnatal age (i.e. 7, 14, or 28 d) were plotted and described in relation to the equivalent gestational age had the fetus remained in utero (referred to hereafter as equivalent gestational age). The assumption we make is that the cord levels of iodothyronines, TBG, and TSH reflect those of the normal fetus in utero of equivalent gestational age and who progresses to a term delivery.

Differences in mean levels of iodothyronines, TBG, and TSH between the gestational groups were found by using the t test for unequal variance; Bonferroni’s correction was applied to account for multiple testing.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The birth weight ratios of the infants in each of the gestational groups were normally distributed. There was a clear gestational age effect in the numbers of infants affected by the recognized disorders of prematurity (Table 1Go). The definition of level 1 care includes infants less than 27 wk gestation for the first 48 h of life (18); thus, none of our infants on d 1 could be placed in level 2 and 3 (Table 2Go).


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  		TABLE 1. Characteristics of the infants in each gestational age group

 

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  		TABLE 2. Comparison of mean iodothyronine, TBG, and TSH by gestational age group to the corrected gestational age had the fetus remained in utero, according to level of care

 
Comparisons of iodothyronines, TSH, and TBG by level of care

There are no differences in T4 cord levels in level 1 vs. level 2 and 3 infants in the 28- to 30- and 31- to 34-wk groups. At d 7, T4 values are significantly lower in level 1 vs. level 2 and 3 infants in all gestational age groups. At d 14, T4 values are lower in all level 1 infants in all gestational age groups and significantly so in the 23- to 27- and 28- to 30-wk groups. At d 28, T4 values are lower in level 1 vs. level 2 and 3 infants in all gestational age groups and significantly so in the 23- to 27-wk group (Table 2Go and Fig. 1Go).



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  		FIG. 1. Levels of iodothyronines, TBG, and TSH by level of care and gestational age group relative to cord values of equivalent gestational age: 23–27 wk, level 1; 23–27 wk, levels 2 and 3 (pink); 28–30 wk, level 1; 28–30 wk, levels 2 and 3 (red); and 31–34 wk, level 1; 31–34 wk, levels 2 and 3 (blue). The mean data were plotted against the background of twice the SE of the mean of cord sera values for each gestational age calculated separately (15 ). Error bars are not shown for the grouped data as they overlap and cause confusion on the graph.

 
Cord T3 values are similar in level 1 and level 2 and 3 infants in the 28- to 30-wk group but significantly lower in level 1 vs. level 2 and 3 infants in the 31- to 34-wk group. At d 7, 14, and 28, T3 values are lower in level 1 vs. level 2 and 3 infants in all gestational age groups and significantly so at postnatal d 7 in the 28- to 30-wk group and at postnatal d 14 and 28 in the 23- to 27- and 28- to 30-wk group (Table 2Go and Fig. 1Go).

Cord FT4 values are similar in level 1 and level 2 and 3 infants in the 28- to 30- and 31- to 34-wk groups. At d 7, 14, and 28, FT4 values are similar in level 1 and level 2 and 3 infants in all gestational age groups, with the exception of a significantly lower FT4 value in the 23- to 27-wk group at d 14 (Table 2Go and Fig. 1Go).

Cord TSH values are similar in level 1 vs. level 2 and 3 infants at 28–30 and 31–34 wk gestation. TSH values are similar in all level 1 and level 2 and 3 infants at d 7, 14, and 28 in all gestational groups (Table 2Go and Fig. 1Go). The peak of TSH evident in the 31- to 34-wk group is an artifact of small numbers (n = 3) exaggerated by an extreme value for one infant.

There were few differences in postnatal levels of T4S, rT3, and TBG by level of care (Table 2Go and Fig. 1Go).

Comparisons of postnatal values to cord levels of iodothyronines, TSH, and TBG

T4 levels are significantly lower than cord values at d 7 and 14 in 23–27 wk gestation infants assigned to level 1 on those days; at d 28 levels are still below cord values but not significantly so. T4 levels increase from cord and are significantly above cord values at 28 d in infants of 23–27 wk gestation assigned to level 2 and 3 on that day. In level 1 infants of 28–30 wk gestation, T4 levels at d 14 are significantly lower than cord values; at d 7 and 28, levels are below cord values but not significantly so. In level 2 and 3 infants of 28–30 wk gestation, T4 levels rise with postnatal age and by d 28, T4 levels are higher (but not significantly so) than cord. In level 1 infants of 31–34 wk, T4 levels decrease linearly to d 28. In level 2 and 3 infants of 31–34 wk gestation, T4 levels increase significantly from cord to peak at d 7 and are still significantly higher than cord at d 14; at 28 d T4 levels remain higher than cord values but not significantly so (Table 2Go and Fig. 1Go).

In level 1 infants of 23–27 wk gestation, T3 levels are higher (but insignificantly so) at d 7 and 14 but by d 28 are significantly higher than cord levels. In level 2 and 3 infants of 23–27 wk gestation, T3 levels increase significantly from cord levels at d 7, 14, and 28. In level 1 infants of 28–30 wk gestation, T3 levels at d 7, 14, and 28 are nonsignificantly higher than cord levels. In level 2 and 3 infants of 28–30 wk gestation, T3 levels increase significantly from cord levels at d 7, 14, and 28. In level 1 infants of 31–34 wk gestation, T3 levels are higher than cord levels at d 7, 14, and 28 but not significantly. In level 2 and 3 infants of 31–34 wk gestation, T3 levels increase significantly from cord levels at d 7, 14, and 28 (Table 2Go and Fig. 1Go).

In level 1 infants of 23–27 wk gestation, FT4 levels at d 7, 14, and 28 are similar to cord levels. In level 2 and 3 infants of 23–27 wk gestation, FT4 levels increase significantly from cord levels at d 14 and 28. In level 1 infants of 28–30 wk gestation, FT4 levels are higher than cord levels at d 7, 14, and 28 but not significantly so. In level 2 and 3 infants of 28–30 wk gestation, FT4 levels increase significantly from cord at d 7 only. In level 1 infants of 31–34 wk gestation, FT4 levels are not significantly different from cord levels at any time. In level 2 and 3 infants of 31–34 wk gestation, FT4 is significantly higher than cord levels at 7, 14, and 28 d (Table 2Go and Fig. 1Go).

In level 1 infants of 23–27 wk gestation, TBG levels decrease from cord values at d 7 but increase from cord nonsignificantly thereafter to d 14 and 28. In level 2 and 3 infants of 23–27 wk gestation, TBG levels increase from cord values at d 7 and 14 and are significantly higher by d 28. In level 1 infants of 28–30 wk gestation, TBG levels are similar to cord values at d 7, 14, and 28. In level 2 and 3 infants of 28–30 wk gestation, TBG levels are significantly higher than cord at d 28 only. In level 1 infants of 31–34 wk gestation, TBG levels decrease by d 7 and remain below cord thereafter. In level 2 and 3 infants of 31–34 wk gestation, TBG levels are similar to cord values (Table 2Go and Fig. 1Go).

In level 1 infants of 23–27 wk gestation, TSH levels decrease postnatally and are significantly lower at d 7 and 14. In level 2 and 3 infants of 23–27 wk gestation, TSH levels decrease significantly from cord at d 7, 14, and 28. In level 1 infants of 28–30 wk gestation, TSH levels decrease significantly from cord values by d 7, but thereafter there are no significant changes. The pattern is similar for level 2 and 3 infants of 28–30 wk gestation, with a significant decrease in TSH levels at d 7, similar levels at d 14, and a significant decrease in levels at d 28. In level 1 infants of 31–34 wk gestation, TSH levels are unreliable because of small and extreme values. In level 2 and 3 infants of 31–34 wk gestation, TSH levels decrease significantly to d 7, and thereafter levels remain constant but significantly lower than cord values (Table 2Go and Fig. 1Go).

In level 1 and level 2 and 3 infants of all gestational ages, rT3 levels reduce significantly to d 7 and thereafter remain constant and significantly below cord levels at d 7, 14, and 28 (Table 2Go and Fig. 1Go).

The pattern of T4S is similar in all gestational groups. T4S levels increase significantly from cord values and peak at d 7 with the exception of level 1 infants of 31–34 wk gestation. T4S levels then decrease at d 14 and 28, with the exception of level 1 infants of 23–27 wk gestation at 28 d (Table 2Go and Fig. 1Go).

Comparison of iodothyronines, TBG, and TSH at postnatal d 7, 14, and 28 to the equivalent gestational ages

In level 1 infants of 23–27 wk gestation, postnatal T4 values at d 7 and 14 are significantly below cord values of the equivalent gestational age, had the infant remained in utero. In level 1 infants of 28–30 wk gestation, T4 levels at d 14 are significantly lower than the equivalent gestational age cord value. In level 1 infants of 31–34 wk gestation, T4 levels are lower than the equivalent gestational age cord values but not significantly so. In level 2 and 3 infants of all gestational groups, all postnatal T4 values are within or above equivalent gestational age cord values except at d 7 in 31- to 34-wk infants, which is significantly higher (Table 2Go and Fig. 1Go).

T3 values in level 1 infants are within equivalent gestational age cord values in all gestational groups. In level 2 and 3 infants, T3 levels for all postnatal ages are significantly above equivalent gestational age cord values with the exception of d 14 in the 31- to 34-wk gestational age group (Table 2Go and Fig. 1Go).

FT4 values in level 1 infants in all groups are within equivalent gestational age cord values. FT4 values in level 2 and 3 infants are higher (significantly so in three of nine sampling points on postnatal d 7, 14, and 28) than equivalent gestational age cord values (Table 2Go and Fig. 1Go).

For all postnatal days in the different gestational groups, TBG levels are generally within equivalent gestational age cord values (Table 2Go and Fig. 1Go), with the exception of higher values of TBG than equivalent gestational age at d 28 in level 2 and 3 infants in the 23- to 27-wk group.

TSH values at d 7 in level 1 and level 2 and 3 infants at all gestational ages are significantly lower than equivalent gestational age cord values except level 1, 31- to 34-wk infants. At d 14 in level 1 and level 2 and 3 infants of all gestational age groups, TSH levels are lower, but not significantly so, than equivalent gestational age cord values (except level 1 infants at 31–34 wk). At d 28 level 1 infants in all gestational age groups are lower but not significantly so than equivalent gestational age cord values; in contrast, level 2 and 3 infants are significantly lower in all gestational age groups (Table 2Go and Fig. 1Go).

In level 1 and level 2 and 3 infants, rT3 levels are significantly lower than equivalent gestational age cord values in all gestational groups at all postnatal days with the exception of 31- to 34-wk infants on d 14 (Table 2Go and Fig. 1Go).

In 23- to 27- and 28- to 30-wk infants, T4S levels are significantly higher than equivalent gestational age cord values in level 1 and level 2 and 3 infants at d 7. In 31- to 34-wk infants on d 7, level 1 and level 2 and 3 T4S values are higher than equivalent gestational age cord values but only significantly so in the level 2 and 3 infants. At d 14, T4S values are similar in both level 1 and level 2 and 3 to equivalent gestational age cord values. At d 28, T4S values in level 2 and 3 infants of 28–30 wk are significantly lower than equivalent gestational age cord values (Table 2Go and Fig. 1Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The characterization of neonatal nonthyroidal illnesses has typically been made on the basis of serum iodothyronine changes in only one illness, namely respiratory distress syndrome. However, infants suffer illness in systems other than respiratory and often in multiple systems simultaneously. Furthermore, respiratory distress syndrome is an illness limited to the first week of life. The Score for Neonatal Acute Physiology is an established physiologic severity index for neonatal care involving 26 scored parameters (20) and correlates inversely with a single blood T4 level at 5 postnatal days in very low-birth-weight infants (21). However, the majority of the Score for Neonatal Acute Physiology parameters are dependent on a range of blood investigations. Many infants in this study did not require such a range of blood measurements for clinical management, and ethical constraints limited volumes of phlebotomy samples. To overcome these difficulties, we took a novel approach when exploring the relationship between illness and iodothyronine levels in neonates and used a routinely applied scoring system as a surrogate marker of illness severity (18). The scoring system was initially devised to quantify resources required by U.K. neonatal intensive care units, such as nursing staffing numbers, expertise, and equipment; with severity of illness being related to the amount of resource required. A disadvantage with this approach is that the categorization of level of care is rather broad and obscures the impact of specific disease conditions on iodothyronine levels. However, the advantage of this approach is that this is the first time that such as large sample of preterm infants has been systematically categorized by a uniform set of parameters describing illness severity. The key outcomes from this approach are that TSH is unchanged in all groups at all ages, with concomitant reductions in T4 and T3 in those infants requiring level 1 intensive care (maximal intensive care).

The fetal and postnatal development of cerebral structures in the rat is entirely dependent on the local generation of T3 from T4 by type II iodothyronine deiodinase (D2); the contribution of systemic T3 to these ontogenic requirements is negligible (see review in Ref.22). Spatial and temporal expression of D2 and type III iodothyronine deiodinase (D3) in developing brain regions appears to be the main mechanism of ensuring developmentally localized and appropriate T3 concentrations both in animals (e.g. Refs.23, 24, 25, 26) and humans (27, 28, 29). These studies suggest that, to ensure normal neurodevelopment, the brain of the preterm infant requires an appropriate serum T4 supply; the optimal ranges of serum thyroid hormone levels in preterm infants to achieve this (which is related both to gestation and postnatal age) have not been defined. A single T4 blood level in preterm infants measured at routine first-week screening has been associated with later neurodevelopmental deficits in motor and cognitive function (30, 31, 32). These studies made adjustments for only a few selected factors, some of which were related to the severity of illness (30, 31, 32). Unless T4 levels are adjusted for all the relevant illness factors, it is possible that the association with neurodevelopment may be obscured or artifactually absent. The strength of our approach, which uses a more general but all-encompassing indicator of intercurrent neonatal illness and populations of gestationally restricted age groups, is that it accounts for the entirety of illness. The value of this approach remains to be tested in subsequent studies of neurodevelopmental outcome.

The structural and functional maturation of early human brain follows an inherent developmental pattern (33). In the absence of adverse and injurious circumstances, the brain of the postnatal preterm infant appears to develop using the same fixed agenda of maturation as the comparable fetus in utero (33, 34). Thyroid hormone requirements for brain development are therefore probably also similar in the preterm infant and the equivalent fetus in utero. Using this rationale, we previously proposed that comparison of serum levels of thyroid hormones at fixed postnatal times should be made relative to equivalent cord levels had the infant remained in utero (15). For example, our data show that the majority of postnatal T4 levels in all preterm groups with less severe illness (level 2 and 3) are within or above cord values of equivalent gestational age. In contrast, all postnatal T4 levels in all preterm groups with the severest illnesses (level 1) are well below the equivalent gestational age values. Illness severity in preterm infants appears therefore to be an important determinant of low serum T4 levels. This is consistent with adult data because serum T4 levels are decreased in nonthyroidal illnesses in proportion to the severity and probably the duration of the illness, with T4 levels inversely related to mortality (2, 35, 36, 37, 38, 39, 40). Adult patients with mild to moderate illness or acute short-term trauma, such as cardiac bypass surgery (38) or short-term fast (39), show no decrease in serum T4 levels. We question whether the hypothyroxinemia associated with severe illness in preterm infants is causative per se of later neurodevelopmental deficits or simply an epiphenomenon of illness. This critical question has been previously stated (40). Also, in one study T4 supplementation in preterm infants, although correcting the hypothyroxinemia, made no difference to long-term neurodevelopmental outcome in the overall analysis (41). This neutral effect of T4 supplementation suggests that there are other factors associated with acute illness in preterm infants, which are having significant negative impacts on brain development and subsequent neurodevelopmental outcome.

TBG is a major determinant of serum T4 levels in adults and the major serum binding protein in the second trimester fetus (42). TBG levels have been measured in only a few previous studies of newborn infants, and the results are not consistent (9, 11, 43). There are no systematic differences in TBG levels in our infant groups with postnatal age and levels of care to account for the variations in serum T4 levels with severity of illness.

In term infants, FT4 levels are transiently reduced in severe illness (44). In preterm infants, the picture is less clear; FT4 is reduced in the first week of life in infants with respiratory distress syndrome (9, 11) but not in a more recent comparable preterm study (10). Our data show that in all preterm groups the majority of postnatal FT4 levels are within or above the cord values of equivalent gestational age irrespective of severity of illness. This disparity between comparable FT4 and T4 levels is remarkable, especially in those infants with the severest level of illness; protecting FT4 availability to the brain may be critically important in infants with low T4 levels.

Reduced T4 binding to TBG is a possible explanation for the relative maintenance of FT4 levels in our sickest infants when T4 levels are reduced. In some acutely sick adult patients, glycosylation of TBG is decreased with a decreased affinity for T4 (45). In newborn sera T4 binding to TBG may be reduced through proteolytic digestion by elastase derived from polymorphonuclear leukocytes (46), levels of which are 8-fold higher in newborn than adult sera (47), and further increased in inflammation and infection (48). Displacement of T4 from TBG by drugs, metabolites, and free fatty acids (FFAs) (49, 50) is a possible explanation for a reduction in T4 binding to TBG, particularly in the sickest preterm infant. Parenterally fed infants are infused with Intralipid (a triglyceride emulsion), typically at levels of 2.5 mg/kg·min, which generates average ratios of FFAs to albumin of 12 or more, whereas the ratio required to inhibit T4-TBG binding in vitro is around 3 (51, 52). Arterial and venous catheter patency is maintained by heparin infusions, but this also activates lipoprotein lipase, increasing generation of FFAs from triglycerides (53). Thus, infants with the most severe illness are more likely to have the conditions necessary for the displacement of T4 from TBG: intrinsically higher FFA levels, parenteral nutrition support, lower serum albumin levels, heparin infusions, and drugs that displace T4 such as furosemide.

Reduced T3 levels are a pathognomonic feature of nonthyroidal illnesses in adults (1). T3 levels are consistently lower in our most severely ill infants, as in preterm infants with severe respiratory distress syndrome (9, 11) and in those who die, compared with those who survive (12). In all our preterm groups, all postnatal T3 levels are within or above the equivalent gestational age values irrespective of severity of illness. Some preterm infants are therefore exposed postnatally to higher T3 levels than if they had remained in utero; this is particularly evident in the well preterm infants (level 2 and 3). If the function of the postnatal rise in T3 levels is to augment peripheral metabolic adaptations such as thermogenesis or gluconeogenesis (54), then this T3 elevation may be advantageous to the infant. The preterm brain is likely to be protected from these relatively elevated T3 levels because the systemic T3 contribution to the developing brain is negligible (21). Given the dependence of the developing brain on T4, it is surprising that low plasma T3 levels are associated with a reduced neurodevelopmental outcome (55). It may be that the low T3 is simply a reflection of severity of illness and/or reduced T4 levels; indeed this phenomenon is evident in our data.

In cases of congenital hyperthyroidism, exposure of the developing human brain to excess thyroid hormones, presumably T4 if not T3, appears to be detrimental (56). It is probably of more concern that there are preterm infants who have FT4 levels above cord values of equivalent gestational age than those with elevated T3 levels. However, a neurodevelopmental follow-up study of preterm infants randomized to T4 supplementation, and consequently raised FT4 levels, showed no deleterious effects (57). Perhaps in this situation compensatory adjustments in brain D2 and D3 activities are made, as occurs in response to hypo- and hyperthyroid states (see review in Ref.58).

Our preterm infants do not mirror exactly the decrease in serum T3 and concomitant rise of rT3 that is characteristic of adult nonthyroidal illness. rT3 levels remain unchanged with illness in all gestational age groups, a finding consistent with previous infant studies (6, 11, 12). However, rT3 is not invariably increased in adult ill health; for example, patients with acute and chronic renal failure have decreased T4 and T3 levels but normal rT3 levels, even with superimposed critical illness (59). The molecular bases for these variations in rT3 response are not entirely known, but in nonthyroidal illnesses, hepatic type I iodothyronine deiodinase activity is reduced in tissues from sick and starved animals, which may contribute to the increased rT3 levels (35, 60). In deceased intensive care patients, hepatic type I iodothyronine deiodinase is decreased, and liver and skeletal muscle D3 activities are increased (61). It is not known whether similar responses occur in the peripheral tissues of preterm infants, but if such alterations occur in the expression of D2 and D3 activities in the developing human brain, these could have adverse consequences.

TSH levels in adults with nonthyroidal illness are usually within the normal range, but some may be increased because TSH levels rise during the recovery phase (62, 63). TSH levels in our infant groups are similar with postnatal age and level of care, and this is consistent with a neutral effect of illness on TSH levels in most previous infant studies (9, 43, 44). In adults with nonthyroidal illnesses, serum concentrations of T4S are normal (64), and this is the same in our infants. In contrast, in adults with nonthyroidal illnesses serum concentrations of T3S are increased (65, 66).

The clear message from our data is that T4 and T3 are substantially reduced in infants with severe illness, irrespective of gestational age, yet TSH remains unchanged.


   Acknowledgments
 
We thank all mothers and infants who took part in this study; and the Scottish Preterm Thyroid Group, whose efforts enabled the study to proceed smoothly: Lawrence Armstrong, Jean Bain, Carol Barnett, Heather Barrington, Alex Baxter, Colin Begg, Aaron Bell, David Boag, Debbie Box, Rose Buchan, Alan Cameron, Mark Davidson, Malcolm Donaldson, Fiona Drimmie, Richard Evans, Tona Fernandez, Wendy Forester, Peter Fowlie, Yvonne Freer, Peter Galloway, Jan Gavey, Adrienne Gordon, Marianne Gordon, Allan Howatson, Ailene Hunter, Mohammed Ibrahim, Lesley Jackson, Cherry Jamieson, Mohammed Kibirige, Sheena Kinmond, Kate Lenton, Chris Lilley, John Mabon, Alistair McBain, Helen McDevitt, Peter McDonald, Una McFadyen, Laura McGlone, Janet McIIroy, Paula Midgley, Ruth Miller, Gary Mires, Talat Mushtaq, Bridget Oates, Mark Pierzchalo, Natalie Potts, Andrew Powls, Susan Provan, Mary Ray, Jackie Reid, Samantha Ross, Ursula Siliem, Robert Simpson, John Smith, Lorna Smith, Jonathon Staines, Chris Steer, Grant Stone, Judith Strachan, Georgetta Tanner, Tom Turner, Heather Watson, and Jennifer Watson.


   Footnotes
 
This work was supported by Commission of European Community (QLG3-2000-00930), Chief Scientist’s Office Scottish Executive (K/MRS/50/C741), Wellcome Trust, Tenovus (Scotland), and Paediatric Metabolic Fund.

First Published Online December 21, 2004

1 For a list of Group members, see Acknowledgments. Back

Abbreviations: D2, Type II iodothyronine deiodinase; D3, type III iodothyronine deiodinase; FFA, free fatty acid; FT4, free T4; TBG, T4-binding globulin; T4S, T4 sulfate.

Received October 22, 2004.

Accepted December 10, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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