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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0214
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4599-4606
Copyright © 2005 by The Endocrine Society

Transient Hypothyroxinemia in Preterm Infants: The Role of Cord Sera Thyroid Hormone Levels Adjusted for Prenatal and Intrapartum Factors

Fiona L. R. Williams, Gary J. Mires, Carol Barnett, Simon A. Ogston, Hans van Toor, Theo J. Visser, Robert Hume with collaboration from the Scottish Preterm Thyroid Group1

Community Health Sciences (F.L.R.W., C.B., S.A.O.) and Maternal and Child Health Sciences (G.J.M., R.H.), University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, United Kingdom; and Department of Internal Medicine (H.v.T., T.J.V.), Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Prof. 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
 Patients and Methods
 Results
 Discussion
 References
 
Context: Transient hypothyroxinemia is common in infants less than 30 wk gestation and is associated with neurodevelopmental deficits; it has no consensus definition. We previously suggested that appropriate ranges for postnatal serum T4 values are at least cord levels corrected to an equivalent gestational age if the fetuses had remained in utero.

Objective: The study objective is to investigate the contribution of prenatal and intrapartum factors (n = 27) to the variations in cord levels of iodothyronines, T4-binding globulin, and TSH, and to provide an appropriate definition of transient hypothyroxinemia.

Design: The study design is a cohort study (n = 620) in 11 Scottish neonatal intensive care units.

Patients: Infants were delivered at 23- to 42-wk gestation and recruited between January 1998 and September 2001.

Results: Using –2 SD of adjusted T4 cord levels applied to postnatal d-7 values of equivalent gestational age, 14% of the 23- to 27-wk group, 1% of the 28- to 30-wk group, and 3% of the 31- to 34-wk group are hypothyroxinemic; using –1 SD, the respective figures are 41, 23, and 12%.

Conclusions: In the absence of neurodevelopmental follow-up studies to quantify transient hypothyroxinemia, a pragmatic criterion is necessary for selection of extreme preterm infants into clinical trials of T4 supplementation. We suggest the use of serum T4 levels on postnatal d 7 that are below –1 SD of adjusted cord T4 levels of equivalent gestational age. This criterion avoids overrecruitment of the more mature infants in whom universal T4 supplementation is detrimental to neurodevelopmental outcome, but still allows selection of the least mature entrants on whom universal T4 supplementation is beneficial.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THYROID HORMONES ARE required for normal development of the human brain. Preterm infants are particularly vulnerable to an adverse neurodevelopmental outcome, but as yet, appropriate serum levels of thyroid hormones to achieve optimal brain maturation have not been quantified.

Preterm infant cord and postnatal thyroid hormone sera levels differ from those of the term infant and adult values (1, 2, 3, 4, 5); they differ across the range of prematurity (23–36 wk), changing with gestational age (6, 7, 8, 9, 10, 11). Longitudinal studies within gestationally restricted groups are limited in number and vary in the range and nature of the serum parameters analyzed (10, 12, 13, 14). Thyroid hormone reference ranges for preterm infants have been derived from blood sera data taken opportunistically during the first weeks of life in populations of gestationally restricted age groups (7, 15), but there are problems with the assumptions underpinning this approach. For example, the response of the hypothalamic-pituitary-thyroid axis is attenuated in preterm infants at birth for an unknown postnatal duration (16). In addition, nonthyroidal illnesses such as respiratory distress syndrome can also influence serum thyroid hormone levels (2, 11, 17, 18, 19, 20). These points raise the question of whether existing reference ranges are appropriate for assessing postnatal serum thyroid levels in preterm populations, especially for the brain, which is particularly sensitive to an inadequacy of thyroid hormone.

Transient hypothyroxinemia is the most common thyroid dysfunction in preterm infants and is characterized by a temporary postnatal reduction from cord values in serum levels of T4 and free T4 (FT4) but with normal TSH levels (1, 8). The etiology of transient hypothyroxinemia is not clear and may have contributions from the withdrawal of maternal-placental T4 transfer (21, 22, 23), hypothalamic-pituitary-thyroid immaturity (16, 24), developmental constraints on the synthesis (25, 26, 27) and peripheral metabolism of iodothyronines (28, 29, 30), iodine deficiency (13, 31), and nonthyroidal illness (11, 19, 28, 32).

Transient hypothyroxinemia is reported to be present in the majority of infants born at less than 30 wk gestation and is associated with later neurodevelopmental deficits (33, 34, 35, 36), but there is no consensus about the definition of transient hypothyroxinemia used in these studies and specifically what constitutes a "low" plasma T4 level. Transient hypothyroxinemia has been defined variously as blood T4 levels of 3.0 (35) or 2.6 (36) SDs below the mean of their preterm populations, or simply as cut-off values such as less than 40 nmol/liter for serum T4 (37) or 6 µg/dl for blood T4 (38). Other researchers have used only a plasma T3 level less than 0.3 nmol/liter as an outcome measure (33), or simply present data in SDs without using a definition of what constitutes transient hypothyroxinemia (34). None of these studies use thyroid hormone values adjusted for gestational age. T4 supplementation in infants less than 30 wk gestation has shown no overall benefit in neurodevelopmental outcome, but may improve outcome in infants less than 27 wk gestation (14). Therapeutic trials of T4 substitution in transient hypothyroxinemia have not used gestationally adjusted serum T4 levels as the criteria for entrance eligibility or to inform appropriate therapeutic T4 levels (39, 40). We have suggested previously that, for preterm infants, the appropriate ranges for postnatal T4 and FT4 levels are at least cord levels corrected to an equivalent gestational age had the fetuses remained in utero (27). Because of the potential importance of prenatal and intrapartum influences on cord levels of iodothyronines, TSH and T4-binding globulin (TBG), we now report the cord data for equivalent gestational age that are adjusted for the significant prenatal and intrapartum factors.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Data were collected between January 1998 and September 2001. The study encompassed two groups: a cohort of mothers and infants delivered at 23–34 wk gestation and who were part of a multicenter study of transient hypothyroxinemia in 11 level III Scottish neonatal intensive care units (26); second a consecutive sample of mothers and infants delivered at 35–42 wk gestation and recruited in a single center (Ninewells Hospital and Medical School, Dundee, Scotland, UK). Gestational age of infants was calculated from menstrual history and, in most instances, was confirmed by prenatal ultrasound examination during the first trimester. Gestation was recorded in completed weeks of pregnancy. 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 Multi-center Research Ethics Committee (Edinburgh) and the Tayside Committee on Medical Research Ethics; in all cases written informed consent was obtained.

Cord blood (n = 620) was collected into a tube without anticoagulant as soon as possible after delivery of live-born infants (23–42 wk gestation) from vessels running over the placental surface and using a 19-gauge Butterfly (Abbott Ireland, Sligo, Ireland) needle. The blood samples were allowed to separate for at least 15 min, then were centrifuged at 4000 rpm for 5 min. If collected outside of 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, FT4, TSH, T3, rT3, T4 sulfate (T4S), and 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. (41). The measurements of T4S in serum were done by a specific antibody, as described previously (42). 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% for 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.

Extensive prenatal data were collected about the women: smoking history; presence of disease such as antepartum hemorrhage (vaginal bleeding after 24 wk gestation), asthma, epilepsy, thyroid disease, and diabetes (treatments concurrent with pregnancy); hypertension (two or more diastolic blood pressure readings >90 mm Hg), Streptococcus agalactiae carriage where known (also referred to as group B streptococci); genito-urinary infection (in the week before delivery); and prenatal medications such as Ritodrine, anticonvulsant, antihypertensive, and corticosteroid usage. Extensive data were collected also during the intrapartum period: labor onset, mode of delivery, drugs prescribed for analgesia, duration of each stage of labor, umbilical artery pH and base deficit, multiple or singleton birth, gestation, gender, and birthweight ratio. Birthweight ratio is the infant’s birthweight divided by the mean birthweight of all Scottish infants born between 1987–1998 (male or female as appropriate) for the gestation at birth.

Means and SD values of the log iodothyronines, TBG, and TSH were calculated for each gestational age week. Univariate general linear modeling was used in three steps. First, to assess the impact of the prenatal and intrapartum factors, singly, upon the levels of iodothyronine, TSH and TBG, 27 variables from the prenatal and intrapartum period were used, as listed in the previous paragraph. Second, the factors that were significantly associated singly were then entered together into a model to determine their adjusted impact. Third, a final model used only the significant factors (as this minimizes the loss of data caused by missing information). The iodothyronines, TSH and TBG, were log transformed for this analysis.

In a previous paper (27), we presented graphically the unadjusted mean ± twice the SEM of cord levels of T4, FT4, T3, rT3, T4S, TBG, and TSH for each week of gestation between 23–42 wk, with grouped (23–27, 28–30, 31–34, 37+ wk) mean values for cord, and d 7, 14, and 28 postpartum superimposed. In this paper, the levels of iodothyronines, TSH and TBG, are adjusted using the regression equations generated by the univariate general linear modeling (Table 1Go). The d-7 postnatal levels of iodothyronines, TBG, and TSH were compared with the equivalent gestational age cord levels had the fetus remained in utero (referred to hereafter as equivalent gestational age). For example, the levels of postnatal d-7 iodothyronines, TBG, and TSH of a 26-wk gestation infant was compared with the cord sera levels (both adjusted and unadjusted) of 27-wk gestation infants.


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  		TABLE 1. Equations for adjustment of cord serum iodothyronines, TSH, and TBG for significant prenatal and intrapartum factors

 
Transient hypothyroxinemia is categorized as either ±1 or ±2 SD of the mean adjusted T4 level on postnatal d 7. The proportions of infants identified as transiently hypothyroxinemic are described in gestational age groups in accordance with our previously published work: 23–27, 28–30, and 31–34 wk.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Data were collected from 620 infants. The mean gestation at delivery is 33.2 wk (range, 23–42 wk), mean birthweight is 2099 g (range, 550-5060 g), mean birthweight ratio is 1.007 (range, 0.45–2.26), and mean umbilical artery pH is 7.27 (range, 6.88–8.03).

Cord sera T4 levels increase progressively from 23–42 wk gestation (Table 2GoGo). Of the explanatory factors analyzed, three contribute significantly to the variation in T4 levels (Table 3Go). Gestation and arterial pH are the most important factors effecting the variation in T4 level; contributing 3.9 nmol/liter increase per weekly increment week of gestation and 4.0 nmol/liter increase per 0.1 pH unit increment. Birthweight ratio contributes a much smaller effect (1.7 nmol/liter increase for each 0.1 U increment). Together, these factors contribute appreciably (36.5%) to the variation in T4 levels. There is very little difference between the unadjusted and adjusted (to a pH of 7.4 (43) and birthweight ratio of 1.000) baseline data for T4 (Table 2GoGo).


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  		TABLE 2. Mean ± SD (no.) for cord iodothyronines, TSH, and TBG by gestation

 

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  		TABLE 2A.

 

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  		TABLE 3. Significant factors that influence levels of cord sera iodothyronine, TSH, and TBG

 
Cord sera FT4 levels increase with gestational age until the early third trimester; thereafter, values plateau until after 40 wk gestation when FT4 levels are lower (Table 2GoGo). Contributing factors to the variation in FT4 levels are the use of epidural/spinal analgesia (a decrease of 1.33 pmol/liter if used), arterial pH (1.04 pmol/liter increase per 0.1 U increment), and birthweight ratio (0.27 pmol/liter increase per 0.1 U increment) (Table 3Go). These factors contribute a small (8.3%) amount to the variation in FT4 levels, and applying the regression equation (Table 1Go) shows that there is very little difference between the unadjusted and adjusted (to absence of epidural, pH of 7.4 and birthweight ratio of 1.000) baseline data for FT4 (Table 2GoGo).

Cord sera TSH levels are similar from 27–36 wk gestation with a trend toward lower values at the extremes of gestation (Table 2GoGo). Only some modes of delivery have a significant impact on the variation in TSH levels. Compared with those having elective cesarean sections, TSH levels are increased by instrumental delivery (2.43 mU/liter) and also by spontaneous vaginal delivery (1.28 mU/liter). These factors contribute little to the overall variation in TSH levels (1.2%) Applying the regression equation (Table 1Go), shows that there was very little difference between the adjusted and unadjusted TSH levels (Table 2GoGo). TSH levels were referenced to the presence of elective cesarean section; this was selected as we believe it represents the least physiologically stressed delivery option (Table 3Go).

Cord sera T3 levels increase from 23–42 wk gestation (Table 2GoGo). The two significant contributing factors to the variation are gestation (0.05 nmol/liter increment per week) (Table 3Go) and maternal carriage of group B streptococci (0.17 nmol/liter decrement). These factors contribute substantially (34.4%) to the variation in T3 levels, yet applying the regression equation (Table 1Go), shows that there is very little difference between the unadjusted and adjusted (to absence of group B streptococci) baseline data for T3 (Table 2GoGo).

Cord rT3 levels decrease from 23–42 wk gestation (Table 2GoGo). Contributing factors to the variation in rT3 levels are maternal smoking (0.41 pmol/liter increment in smokers), maternal hypertension (0.8 pmol/liter decrement), and gestation (0.14 pmol/liter decrement for each week of gestation) (Table 3Go). Applying the regression equation (Table 1Go) shows that these factors contribute a small (13.3%) amount to the variation in rT3 levels.

Cord sera TBG levels increase with gestation from 23 wk to term (Table 2GoGo). Many factors contribute to the variation in TBG levels. In those receiving general anesthesia or Entonox (nitrous oxide and oxygen), TBG levels are marginally reduced (2.79 and 1.38 mg/liter, respectively) compared with those who did not (Table 3Go). Compared with nonsmokers, current smokers have increased TBG levels (by 1.46 mg/liter). Gestation positively affects TBG levels by 0.87 mg/liter for each week of gestation. Intercurrent maternal thyroid disease increases TBG levels by 11.0 mg/liter. Applying the regression equation (Table 1Go), these factors contribute appreciably to the overall variation in TBG levels (32.8%), and are reflected in slight differences between adjusted and unadjusted TBG values (Table 2GoGo).

Cord sera T4S levels peak in the late second trimester and decline through the third trimester (Table 2GoGo). Contributing factors to the variation in T4S levels are maternal smoking (increment in smokers of 242 pmol/liter) and gestation (31 pmol/liter decrement per week of gestation) (Table 3Go). Applying the regression equation (Table 1Go) shows that these factors contribute a small (12.5%) amount to the variation in T4S levels.

Using –2 SD of adjusted T4 cord levels applied to postnatal d-7 values of equivalent gestational age, 14% of the 23–27 wk group, 1% of the 28–30 wk group, and 3% of the 31–34 wk group are hypothyroxinemic; using –1 SD, the respective figures are 41, 23, and 12%.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
These data represent the largest series of preterm and term infants for whom an extensive series of cord serum iodothyronines, TSH, and TBG measurements are available. For the clinically frequently measured parameters (T4, FT4, T3, rT3, T4S, TBG, and TSH), we describe their variation in the context of the literature and provide an adjusted range based on cord values. The relative importance of using adjusted levels varies with individual thyroid hormones. For instance some of the explanatory factors contribute little in the variation: TSH 1%, FT4 8%, T4S 13%, rT3 13%; where for others the factors contribute more to the variation in levels: TBG 33%, T3 34%, and T4 37%. The discordant impact of the contribution of explanatory factors to the variation in levels is especially obvious for T4 and FT4 where the same factors (gestation, arterial pH, and birthweight ratio) explain 37% of the variation of T4 but only 6% of the variation of FT4. The reasons for these differences in amount of variation contributed by the explanatory factors is not obvious and may be due to the inherent physiological regulation of individual iodothyronines, TSH, or TBG; or because we have not included explanatory factors that are currently unidentified. In addition, the development of the relationship between T4 and FT4 levels as shown in cord blood is complex and nonlinear (26). The data presented here have direct application in detection and monitoring preterm thyroid disorders.

Maintaining serum T4 or FT4 levels in preterm infants is the priority for sustaining postnatal brain development and for optimizing subsequent neurodevelopmental outcome (44). The structural and functional maturation of early human brain development is a programmed sequence (45, 46) such that the preterm infant brain develops in a similar manner to the equivalent fetus in utero. Magnetic resonance studies of children and adults born as preterm infants show that a normal brain structure is achievable, but in some there are structural changes secondary to the adverse consequences of a premature birth (47, 48). To achieve optimal brain development in preterm infants, it is not unreasonable to assume that thyroid hormone requirements are similar to the equivalent fetus in utero. The validation of the adequacy of postnatal thyroid hormone levels should ideally be neurodevelopmental outcome of preterm infants, and such studies have begun (14). In the meantime, other ways of informing the description of appropriate postnatal thyroid hormone levels need to be explored.

An alternative approach to neurodevelopmental follow-up studies is the determination of the correlation between iodothyronine levels in sera and brain regions with development. It is known that T3 levels and T3 receptor concentrations increase in the human brain until mid-gestation (49, 50, 51, 52). But only one study has described temporal and regional iodothyronine levels in a limited number of preterm infant brains (52). As yet, no study has correlated brain and serum iodothyronine levels in the human fetus or infant. In the interim we have suggested that, for preterm infants, the appropriate ranges for postnatal serum T4 and FT4 are cord levels corrected to an equivalent gestational age had the fetuses remained in utero (27). Sera levels from in utero cordocentesis samples of normal fetuses progressing to a term delivery would be optimal, but numbers to date are limited (25, 53, 54); hence the need for cord levels of thyroid hormones that are adjusted for the significant prenatal and intrapartum factors. For example, variations in cord serum T4 levels are affected by gestation, arterial pH, and birthweight ratio [fetal cordocentesis T4 levels are also reduced in small-for-gestational-age fetuses at 21–38 wk gestation (55)]. The impact of pH and birthweight ratio on the level of cord serum T4 is relatively small. However, if reference ranges are to be optimal, they should be adjusted for all currently recognized influences. Thus, we recommend the use of adjusted cord serum T4 levels at appropriate gestational ages, as the best suited for postnatal preterm infant monitoring.

Maintaining serum FT4 levels in extreme preterm infants may be a priority for sustaining postnatal brain development and neurodevelopmental outcome (56). Previous studies have reported that levels of FT4 are significantly lower in cordocentesis samples from intrauterine growth-restricted fetuses (54, 55); a decrease in FT4 levels has also been related to the degree of fetal acidemia (55). In contrast, an increased FT4 index has been described in the cord blood of infants at delivery whose mothers smoked (57). Associations of smoking with FT4 have not been reproduced either in this study or others (58, 59). In our study, three factors (arterial pH, epidural analgesia, and birthweight ratio) contribute statistically significantly to the variation in cord FT4 levels; however, the contribution in clinical terms is trivial. In addition, 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 (27) irrespective of severity of illness (32); leading us to conclude that lowered serum FT4 levels are not a pathognomonic feature of transient hypothyroxinemia in preterm infants, in contrast to previous studies (1, 11, 12). FT4 levels in more mature infants increase above gestationally equivalent cord values at d 7 and 14; FT4 postnatal levels of our extreme preterm infants, although higher than cord, may not yet be optimal.

We have reported previously that FT4 levels at 7 and 14 postnatal days in the most extreme preterm infant group, 23–27 wk gestation, are significantly higher than the corresponding cord values (27) as well as those of nonpregnant women (26). In contrast, the equivalent T4 values at 7 and 14 postnatal days are significantly lower than the corresponding cord values (27) as well as those of nonpregnant women (26). The depression of T4 levels and maintenance of FT4 levels at 2 wk postnatal age shown in our 23- to 27-wk group has also been previously described in a group of very low birth weight infants (<1500 g) (60). Because all these studies show deficit in T4 levels but not in FT4 levels, we recommend that (transient) hypothyroxinemia is more appropriately defined on the basis of T4 levels. The postnatal nadir of T4 levels on d 7 noted in this study, and which is in accordance with previously published data (10, 11, 12, 26), is probably the most appropriate day to quantify transient hypothyroxinemia.

The question of the quantitative criteria for defining transient hypothyroxinemia is complex; previous work has used various levels of SDs (34, 35, 36) for its definition. If we use –2 SD (which is a conservative limit compared with others) of unadjusted T4 cord levels applied to postnatal d-7 values of equivalent gestational age, then 7% of the 23- to 27-wk group, 1% of the 28- to 30-wk group, and 1% of the 31- to 34-wk group are hypothyroxinemic; using adjusted T4 cord levels, the respective percentages are 14, 1, and 3%. However, the use of –2 SD may be overly stringent with contemporary T4 levels. For instance, Reuss et al. (36) used –2.6 SD, which resulted in 33% of their 22- to 27-wk gestation infants being classified as severely hypothyroxinemic; whereas using this criterion with our data resulted in no infants in the 23- to 27-wk group being classified as severely hypothyroxinemic. This suggests that there has been a temporal change in the levels of T4 in extreme preterm infants over the past 20 yr. Such changes, for example, may be due to reduction in the severity of nonthyroidal illness with the advent of prenatal corticosteroid use and postnatal surfactant administration.

The aim of establishing quantitative criteria is to enable appropriate selection for clinical trials. In the absence of neurodevelopmental outcome, which is the only objective method for setting criteria, it may be more appropriate in the meantime to use a different level of SD as the pragmatic criterion for defining transient hypothyroxinemia. For example, if we use –1 SD as the criterion with our unadjusted T4 cord levels applied to the postnatal d-7 levels of equivalent gestational age then 45% in the 23–27 wk gestation group are hypothyroxinemic, as are 19% of the 28- to 30-wk and 8% of the 31- to 34-wk group; using adjusted T4 levels, the respective percentages are: 41, 23, and 12%. The selection criterion for inclusion in clinical trials of T4 supplementation in transient hypothyroxinemia is critical, as van Wassenaer et al. (14) have shown that universal T4 supplementation is detrimental to neurodevelopmental outcome in infants 27–29 wk gestation but overall beneficial to 25- to 26-wk gestation infants.

FT3 levels have been reported to be lower in intrauterine growth-retarded fetuses (54). Unlike Narin et al. (61), we found no relationship of cord sera T3 levels with maternal hypertension, but we have shown that variation in cord sera T3 level is affected by gestation and by the maternal carriage of group B streptococci. We can only speculate that this novel latter observation is related to the presence of inflammatory mediators, which contribute to the nonthyroidal illness response (62). All postnatal T3 levels in our preterm groups are within or above the equivalent gestational age values irrespective of severity of illness (27, 32) or adjustment for maternal carriage of group B streptococci. It is likely that the preterm brain is protected from these relatively elevated T3 levels (compared with the in utero fetus of equivalent gestational age), as the T3 source in developing brain is largely dependent on local deiodination of T4 (44). This leads us to conclude that additional T3 supplementation in preterm infants is unnecessary in clinical trials to test the efficacy of T4 substitution therapy in hypothyroxinemic infants in terms of neurological development (it may be of benefit though to postnatal maturation of peripheral tissues).

Previous research has shown that cord TSH levels are higher in infants who are considered to have experienced more fetal stress during birth. There are associations between TSH levels and vaginal delivery (63, 64), longer duration of the second stage of labor (65, 66), nuchal encirclement of the cord (65), small for gestational age (55), meconium-stained amniotic fluid (65, 66), instrumental delivery (67), low APGAR scores (68), and male sex (67). Reduced TSH levels have also been described in the cord blood of infants whose mothers smoked (57), although these findings have not been reproduced either in this study or others (58, 59). Our data show that only aspects of the mode of delivery had a significant impact on the variation in levels of TSH and then only a very small effect. TSH levels are lower than the equivalent gestational age values irrespective of gestational age group, postnatal age, severity of illness (27, 32), or adjustment for mode of delivery; hence TSH levels do not further clarify the characterization of transient hypothyroxinemia.

Cord serum TBG levels are higher in our infants whose mothers smoke compared with the infants of nonsmoking mothers. We also show that cord TBG levels are marginally reduced in infants born to women who have Entonox and/or general anesthesia. For all postnatal days in the different gestational groups, TBG levels are generally within equivalent gestational age cord values even in the presence of severe illness (32); hence TBG levels are not specifically characteristic or indicative of transient hypothyroxinemia. Cord serum T4S and rT3 levels are increased in mothers who smoke, but without an obvious explanation. Postnatal T4S levels are generally higher and rT3 levels lower than the equivalent gestational age values (27, 32). Neither rT3 nor T4S is specifically characteristic or indicative of transient hypothyroxinemia.

Our data show that an appreciable number of extreme preterm infants have low postnatal T4 levels but, in general, normal or above-normal levels of FT4 and T3 compared with the equivalent fetus in utero. We have questioned whether low T4 levels, particularly that associated with severe illness in preterm infants, is causative per se of later neurodevelopmental deficits or simply an epiphenomenon of illness (32). This critical question has been previously stated (69) and the resolution of this issue is important. Further appropriate clinical trials of T4 substitution in extreme preterm infants have been suggested (70). The application of our data would allow selection (as well as monitoring) of only those preterm infants as entrants to clinical trials who are hypothyroxinemic; based solely on serum T4 levels of equivalent gestational age that are adjusted for prenatal and intrapartum factors. Although serum T3 and TSH levels do not contribute to the diagnosis of transient hypothyroxinemia, measurement of their levels would be nevertheless required for trial monitoring to avoid inadvertent suppression of the developing hypothalamic-pituitary-thyroid axis by excess T4 substitution.


   Acknowledgments
 
The Scottish Preterm Thyroid Group: Lawrence Armstrong, Jean Bain, Heather Barrington, Alex Baxter, Colin Begg, Aaron Bell, David Boag, Debbie Box, Rose Buchan, Alan Cameron, Mark Davidson, Caroline Delahunty, 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, Talat Mushtaq, Bridget Oates, Mark Pierzchalo, Natalie Potts, Andrew Powls, Susan Provan, Mary Ray, Jackie Reid, Samantha Ross, Ursula Siliem, Judith Simpson, Robert Simpson, John Smith, Lorna Smith, Jonathon Staines, Chris Steer, Grant Stone, Judith Strachan, Georgetta Tanner, Tom Turner, Heather Watson, and Jennifer Watson.

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.


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

First Published Online May 10, 2005

1 See Acknowledgments for members of Scottish Preterm Thyroid Group. Back

Abbreviations: FT4, Free T4; TBG, T4-binding globulin; T4S, T4 sulfate.

Received February 1, 2005.

Accepted May 3, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Rooman RP, DuCaju MVL, DeBeeck LO, Docx M, VanReempts P, VanAcker KJ 1996 Low thyroxinaemia occurs in the majority of very preterm newborns. Eur J Pediatr 155:211–215[CrossRef][Medline]
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F. L. R. Williams, S. A. Ogston, H. van Toor, T. J. Visser, R. Hume, and with collaboration from the Scottish Preterm Thyro
Serum Thyroid Hormones in Preterm Infants: Associations with Postnatal Illnesses and Drug Usage
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Perinatal Factors and Transient Hypothyroxinemia of Prematurity
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