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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 4097-4103
Copyright © 2004 by The Endocrine Society

Human Fetal and Cord Serum Thyroid Hormones: Developmental Trends and Interrelationships

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

Maternal and Child Health Sciences (R.H., J.S., C.D.) and Community Health Sciences (F.L.R.W.), 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.), Veterans Affairs 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
 
Thyroid hormone is essential for fetal and neonatal development in particular of the brain, but little is known about regulation of fetal thyroid hormone levels throughout human gestation. The purpose of this study was to clarify developmental trends and interrelationships among T4, free T4 (FT4), thyroxine-binding globulin (TBG), TSH, T3, rT3, and T4 sulfate (T4S) levels in cord and fetal blood sera (n = 639, 15–42 wk gestation) and correlate infant levels (23–42 wk gestation) to maternal values (n = 428, 16–45 yr) and those of nonpregnant women (n = 233, 16–46 yr). In cord and fetal serum, T4, T3, and TBG levels increase with gestation until term; TSH, FT4, T4S, and rT3 levels increase and peak in the late second/early third trimester and then decline to term; T4/TBG ratios increase until late second trimester and plateau to term. Term cord sera TSH, TBG, and all iodothyronine levels, except T3, are higher than nonpregnant women. In the third trimester, cord serum FT4, TSH, rT3, and T4S levels are also higher than corresponding maternal levels, but T4, T3, and TBG levels are lower than maternal values. The late second/early third trimester is a critical transition period in fetal thyroid hormone metabolism, which may be interrupted by preterm birth and contribute to postnatal thyroid dysfunction.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THYROID HORMONES ARE required for normal development of the human fetal brain and also for the maturation of other organs and functions, some of which are important to allow the successful transition to extrauterine life. A complete account of the temporal changes of the serum levels of iodothyronines, TSH, and transport proteins with gestation is essential to the understanding of these thyroid hormone-responsive processes. There are a number of limitations restricting the attainment of a comprehensive developmental series of serum levels. For example, cardiocentesis in the first trimester is possible, but the amounts of serum obtained are limited. In one of the largest studies to date (1), in which fetal sampling took place before termination of pregnancy, the fluids obtained were limited to amniotic and coelomic fluids.

The options are greater in the early second trimester during which fetal blood samples have been obtained by cardiocentesis before termination of pregnancy (1, 2), cordocentesis (2, 3), cardiocentesis after termination of pregnancy (4, 5), and cord blood sampling at delivery (e.g. Ref. 6). Third-trimester blood sampling is restricted to cordocentesis (2, 3) and cord sampling at delivery (e.g. Ref.6). Many studies have yielded important physiological information based on serum samples from relatively narrow gestational age ranges and limited numbers (e.g. Ref.1, 4) and in addition have been restricted to specific assays (e.g. Ref.7). Combining data from such multiple individual studies from limited periods of gestation to construct a developmental profile over the second and third trimester is possible (8) and has the advantage of increasing the sample numbers and study power but has the inherent limitations of combining different sampling techniques, assay methods, and sensitivities. The most complete single developmental study over the second and third trimesters is that by Thorpe-Beeston et al. (2) in which blood samples were obtained by cardiocentesis (<14 wk gestation) or cordocentesis (17–37 wk gestation) in 62 normal fetuses. This study had the intrinsic advantage of in utero sampling, excluding potential influences of labor and or delivery, but lacked sufficient power to fully inform developmental trends. Maternal-to-fetal T4 transfer during pregnancy is essential before an effective fetal hypothalamic-pituitary-thyroid axis is established, and may continue in varying degrees throughout pregnancy (9, 10, 11). Maternal sera levels have been related to corresponding fetal or infant values in specific studies over selected and limited gestational ranges (e.g. Ref.7, 12, 13).

In this paper we report the results from a large data set of cord and fetal blood sera levels of T4, free T4 (FT4), thyroxine-binding globulin (TBG), TSH, T3, rT3, T4 sulfate (T4S) over the gestational range 15–42 wk. In addition, these results are related to maternal values at delivery (23–42 wk gestation) and nonpregnant women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Data were collected between January 1998 and September 2001. The study encompassed four distinct groups: 1) a cohort of mothers and infants delivered at 23–34 wk gestation and who were part of a multicenter study of transient hypothyroxinemia in eleven level III Scottish neonatal intensive care units; 2) a consecutive sample of mothers and infants delivered at 35–42 wk gestation and recruited in a single center at Ninewells Hospital and Medical School, Dundee; 3) a cohort of fetuses 15–20 wk gestation after therapeutic termination of pregnancy in a single center at Ninewells Hospital and Medical School, Dundee; and 4) a cohort of nonpregnant women, recruited from Dundee. 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 inability of mothers 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.

Cord blood (n = 617) was collected into a tube without anticoagulant as soon as possible after delivery of the live-born infants (23–42 wk gestation) from fetal 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 and 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 by one investigator (T.J.V.). Blood was taken at or within 1 h either side of delivery from mothers (n = 428, 16–45 yr) corresponding to these infants and processed in a similar manner to cord blood. Blood was taken and sera prepared from a cohort of apparently healthy nonpregnant women (n = 233, 16–46 yr) employed within the university or health services and who were based at Ninewells Hospital and Medical School.

Fetal blood was collected by cardiac puncture (n = 22) within 1 h after termination of pregnancy using misoprostol vaginal pessaries. Fetal developmental age (range 15–20 wk) was estimated solely (by R.H.) based on size, including crown-heel, crown-rump, and heel-toe measurements (14); menstrual history; and ultrasound dating of pregnancy. Normality of fetuses was confirmed by autopsy. Pregnancies were terminated in accord with the Abortion Act 1967 (United Kingdom) and fetal samples and data handled according to the recommendations of the U.K. government (15). Fetal blood was processed in a similar manner to cord and maternal blood.

Provided sufficient serum was available, T4, FT4, TSH, T3, rT3, 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. (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% 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.

Data were analyzed in groups of 23–27, 28–30, 31–34, 35–36, and 37–42 wk gestation. Scatter plots were constructed for each iodothyronine and gestation at delivery. Because we were unsure of the regression model that would best describe the data (i.e. linear, quadratic, or cubic), we used Lowess smoothing to construct the line of best fit to the data. For each value of the independent variable, Lowess smoothing computes a predicted value using the cases that have similar values for the independent variable. It is a robust methodology that is not greatly affected by extreme values (18). Means and twice the SEM were plotted; means and SDs were calculated for all iodothyronines, TSH, and TBG. Ratios were transformed to log ratios to allow the calculation of means and SDs. Differences in mean levels of iodothyronines, TBG, and TSH among the gestational groups were found by using the t test for unequal variance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Fetal and cord sera T4 levels increase progressively from 15 to 42 wk gestation (Fig. 1Go); by term the T4 levels are substantially lower than the maternal values and substantially higher than nonpregnant women (Table 1Go). Maternal T4 levels (23–42 wk) are generally similar irrespective of gestation at delivery and substantially higher than in nonpregnant women (Table 1Go).



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  		FIG. 1. Levels of iodothyronines, TSH, and TBG by gestational age.

 

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  		TABLE 1. Levels of serum iodothyronines, TSH, and TBG in cord, maternal, and nonpregnant women

 
Fetal and cord sera TBG levels increase progressively from 15 to 42 weeks gestation (Fig. 1Go); by term the TBG levels are significantly higher than those of nonpregnant women (Table 1Go). Maternal TBG levels (23–42 wk) show variation according to gestation (Table 1Go).

Fetal and cord sera FT4 levels increase with gestational age until late second trimester and peak at 31–34 wk (Fig. 1Go); by term the mean value has fallen significantly lower (Table 1Go). By term, the infant values are significantly higher than nonpregnant women, and both are higher than term maternal levels (Table 1Go).

The T4/TBG ratios of fetal and cord sera increase with gestational age until late second trimester, and thereafter the ratios are constant to term (Fig. 1Go). In the third trimester until term, cord serum T4/TBG log ratios are higher than maternal values and similar to those in nonpregnant women, and maternal levels are lower than those in nonpregnant women (Table 1Go).

Fetal and cord sera T3 levels increase with gestation (Fig. 1Go); by term the T3 levels are about half those of nonpregnant levels (Table 1Go) and significantly lower at all gestations than maternal levels (Table 1Go).

Fetal and cord sera rT3 levels increase through the second trimester to reach a peak between 25 and 30 wk gestation (Fig. 1Go), which precedes the third trimester decline (Table 1Go). By term, the infant levels remain substantially above the levels for nonpregnant women and maternal levels (Table 1Go).

Fetal and cord sera T4S levels increase through the second trimester to reach a peak in the late second/early third trimester (Fig. 1Go). During the remainder of the third trimester, T4S levels decline, although at term they are still present at very high levels in the cord blood, compared with maternal levels (Table 1Go).

Fetal and cord sera TSH levels increase from 13 wk gestation, peaking around 31–34 wk (Table 1Go and Fig. 1Go). In the earliest fetuses, the TSH level is proportionally higher, which is reflected in an increased TSH/FT4 ratio (Fig. 1Go), although this ratio decreases through the remainder of the second trimester. Thereafter in the third trimester, the log TSH/FT4 ratio is fairly constant but at term remains substantially elevated, compared with ratios in mothers and nonpregnant women (Table 1Go).

There is an overall lack of correlation among maternal serum iodothyronines, TSH, and TBG levels at the time of delivery and infant cord levels; with the exception of the relatively strong positive correlations between maternal T4 and cord rT3 (r = +0.382, 23–42 wk gestation), and between maternal rT3 and cord T3 (r = +0.416, 23–42 wk gestation). The developmental patterns of serum levels of rT3 and T4S are similar, with a positive association (r = +0.442, t = 57.6, P < 0.001, matched paired t test).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This series represents the largest data set investigating iodothyronine, TBG, and TSH levels in cord blood from live-born infants, with corresponding maternal sera samples, and in fetal blood collected by cardiocentesis after termination of pregnancy. No maternal samples were collected in this latter group because we did not have ethical approval for this. The distribution of samples is very biased toward the last trimester of pregnancy, with comparatively few in the second trimester of pregnancy and a gap of no samples for 21–22 wk gestation. Our sample size for mothers and infants in the 35- to 36-wk gestational group is small, which has led to wide confidence limits around the mean values. This potential bias is compounded by an imbalance in the lower number of maternal to cord sera samples in some gestational groups.

In our study cord serum T3 levels increased with gestation but even at term were lower than adult values in agreement with previous studies (2, 5, 19), although Santini et al. (20) showed no change in cord T3 levels from 24 wk gestation to term. Serum T3 levels may not accurately reflect tissue levels. For example, in the human fetal cortex, T3 levels are much higher than would be expected from the serum T3 levels, a finding that may be explained by the active transport of thyroid hormone through the plasma membrane, the difference in intracellular vs. extracellular thyroid hormoneprotein binding, and mainly local deiodination of iodothyronines (1, 21)

Our data showed that cord serum T4 levels increase progressively from 15 to 42 wk gestation. This is consistent with a previous study that showed that T4 levels increased between 11 and 24 wk gestation in blood samples obtained from 21 normal fetuses after therapeutic termination of pregnancy by hysterotomy (4). Our data were also in agreement with cordocentesis samples from 23 subjects (18–31 weeks) in which T4 levels increased linearly with gestation (3). Furthermore, the studies of Thorpe-Beeston et al. (2) showed that T4 levels increase progressively through pregnancy in 62 normal fetuses in which blood samples were obtained by cardiocentesis (<14 wk gestation) or cordocentesis (17–37 wk gestation) and adult levels were reached at 36 wk. A somewhat different pattern was observed in a study of approximately 150 cord blood samples in which T4 levels increase linearly from 26 wk until 34 wk and thereafter remain constant to 43 wk (6).

In adults TBG is the major serum T4-binding protein (accounting for around 70% of plasma T4 binding) with smaller contributions from albumin (15–20%) and transthyretin (around 15–20%) (22). Quantitatively albumin is the major contributor to total fetal serum protein levels, and serum albumin levels increase with gestation over the range 13–41 wk (23). Serum transthyretin levels, on the other hand, are highest at 13 wk and decline with gestational age (23). TBG is not detectable in first-trimester fetal fluids (1) but thereafter is measurable in fetal serum, and concentrations increase linearly for the remainder of pregnancy (2, 4).

Although levels of TBG are low in the early midtrimester fetus, TBG is already the main T4 binding serum protein (4). However, the ratio of T4/TBG is low, which suggests low T4 production or high T4 clearance rates. Thereafter, until late second trimester, T4 levels increase more rapidly than TBG levels, which results in an increase in T4/TBG ratio, which is in agreement with the data shown by Greenberg et al. (4). In the third-trimester fetus, T4 and TBG levels both increase. The T4/TBG ratio is now constant with a value similar to that of nonpregnant women. This indicates that T4 levels are largely determined by TBG concentrations, as in adults.

The pattern of fetal and cord T4/TBG ratios shows a remarkable similarity to that of FT4 levels because both increase with gestational age until late second/early third trimester. Thereafter T4/TBG ratios are constant, and FT4 shows only a slight decrease until term. A similar pattern of FT4 levels has previously been shown in around 150 cord samples with a linear increase from 26 until 34 wk but thereafter remaining constant to 43 wk (6). In contrast, FT4 levels were shown to increase progressively through pregnancy in 62 normal fetuses in which blood samples were obtained by cardiocentesis (<14 wk gestation) or cordocentesis (17–37 wk gestation) with adult levels reached at 36 wk (2).

In the developing fetus, the relationship between serum levels of T4 and FT4 and T4 binding proteins is complex. The T4 concentrations are more than 100-fold lower in amniotic fluid and coelomic fluid in first-trimester fetuses and in amniotic fluid and serum in early second-trimester fetuses than in maternal serum, and yet FT4 levels are one third of the maternal serum values (1). This is as a consequence of a low iodothyronine protein binding capacity in the serum of the early fetus with a high dialyzable T4 fraction (4). This may be advantageous to the fetus in terms of tissue T4 bioavailability, but this lack of fetal serum T4 buffering capacity potentially leaves the fetus vulnerable to maternal hypothyroxinemia (1). Our data on early second-trimester fetuses confirm that without this binding capacity, the proportion of FT4 to T4 is high, and although it decreases to term, it is still higher than comparable maternal values. In our third-trimester sample, cord FT4 concentrations are higher than corresponding maternal levels and those of nonpregnant women, whereas they were lower than maternal levels in the early second trimester (1). The reasons for this decrease in fetal FT4 during the late third trimester and for the maternal decrease over the range 23–42 wk are not apparent. This raises the possibility that the fetal requirements are completely different from maternal needs. Clarification of the reason for the decline in cord FT4 levels in the late third trimester might shed light on this controversy.

TSH has been described in fetal serum as early as 11 wk gestation (1, 4, 24, 25). Our data showed that fetal TSH rises from 15 wk gestation to late second trimester, and thereafter the mean TSH is similar until a near term decrease in level. This pattern is consistent with previous studies, which showed that TSH increased between 12 and 24 wk gestation (4, 26) but not thereafter in 150 cord samples (6). These results are at variance with the intrauterine fetal blood sampling studies in which TSH levels increased progressively with gestation (18–31 wk) in 23 subjects (3) and 62 normal fetuses in which blood samples were obtained by cordocentesis (17–37 wk gestation) or cardiocentesis (<14 wk gestation) (2). But the sample sizes in these studies are probably too small to confirm this trend. Maternal serum TSH levels are lower than fetal in which blood was obtained by fetal sampling after hysterotomy (4), cardiocentesis at 11–17 wk gestation (1, 2), and cordocentesis at 17–37 wk gestation (2).

The developmental pattern in TSH/FT4 ratios with gestation is similar to that described by Fisher et al. (8) using combined data from multiple individual studies. The TSH/FT4 ratio decreases in term infants from around 2 wk postnatal age, without significant changes in free T4 but with a decrease in TSH levels through childhood and adolescence. This implies a progressive modulation of the set point for T4-negative feedback regulation of TSH secretion (8). The relative pituitary-hypothalamic resistance to FT4 in utero with the consequence that TSH production, and presumably also that of TRH, is overstimulated may be part of the mechanism that potentially allows higher fetal iodothyronine turnover and at the same time prepares the hypothalamic-pituitary-thyroid axis for the exaggerated postnatal response of this axis to the stimulus of birth.

The steady decline in cord rT3 levels through the last trimester of pregnancy has been previously demonstrated (5, 20), but in addition, our data show that rT3 levels increased appreciably through the second trimester to reach a peak between 25- and 30-wk gestation before the last trimester decline in rT3 levels. Serum rT3 levels decrease rapidly and substantially after delivery of the infant with the removal of placental, fetal membrane, and uterine D3 activities and consequent decrease in inner ring deiodination of T4 to rT3 (27, 28). D3 activity in fetal tissues (e.g. liver, brain) (29, 30) may also contribute to fetal serum rT3 levels. In embryonic and early fetal life, rT3 levels in amniotic and coelomic fluids are high, compared with T4 and T3 levels (1, 10), and in the absence of significant fetal thyroid hormone production, maternal supply is the predominant T4 source with a potentially increasing fetal contribution with gestation. Little is known about the placental regulation of maternal-to-fetal T4 transfer, but changes in placental D3 activities with development cannot alone explain this pattern of cord rT3 levels with gestation, because although D3-specific activity decreases, total placental D3 activity increases with gestation (27). rT3 is a preferred substrate for iodothyronine deiodinase D1, and the third-trimester decline in cord rT3 levels may reflect a contribution from increased D1 expression in fetal liver, although significant activity is already present earlier in the second trimester (29). It is possible that rT3 limits D1 and D2 availability for T4-to-T3 deiodination and is part of the mechanism to maintain low serum T3 levels during fetal life; the rapid postnatal decline in rT3 levels secondary to the loss of placental D3 activity could allow increased generation of T3 after birth. Santini et al. (20) also suggest that placental D3 contributes to this mechanism by restricting rises in serum T3 levels in utero through conversion of T3 to T2 (T3 is the best substrate for D3), at the same time allowing maturation of D1 activities.

Sulfation has profound effects on iodothyronine metabolism and homeostasis (31). Once sulfated, T4S is exclusively metabolized to the inactive rT3S and cannot be converted to receptor-active T3 (32). Sulfation also accelerates the inner ring deiodination of T3 to T2 (32). There is a large family of sulfotransferase (SULT) enzymes in humans, comprising at least 11 members (33). It is clear that the sulfation of iodothyronines is carried out by more than one SULT isoform (at least in vitro), including SULTs 1A1, 1A3, 1B1, 1C2, and 1E1 (34, 35). Microsomal 3,3'-T2S sulfatase activity is also present in developing human liver and to a lesser extent in fetal lung and brain (36) and thus has the potential to generate free iodothyronines from their respective sulfate conjugates, i.e. T2S and T3S (37). T3S is present at very high levels in cord blood and declines through the last trimester (20, 38), but T4S levels also increase through the second trimester to reach a peak in late second/early third trimester before the last trimester decline in T4S levels. Sulfation is therefore likely to play a key role in regulating the amount of receptor-active thyroid hormone in target fetal tissues.

Our data showed a strong positive association between rT3 and T4S levels. We are not sure what the explanation for this is. It is not clear whether, or how, the coordination of the metabolic processes of sulfation of T4 to T4S and inner-ring deiodination of T4 to rT3 are linked in the fetus. T4S is predominantly generated in fetal tissues and not placenta (39), whereas the converse may be true of rT3. There is no specific sulfotransferase isoform responsible for sulfation of T4 to T4S, and the contribution of different isoforms and tissues to T4S serum levels, or even whether the contribution changes with development (34, 35), is not known. It has been previously shown that rT3 and T3S are also positively correlated in third-trimester fetal and postnatal life (20). A possible explanation for the strong association among T4S, T3S, and rT3 is that all these metabolites are predominantly cleared by D1; thus, changes in D1 expression have similar effects on rT3, T4S, and T3S levels.

Regulation of T4 levels in the fetus appears to involve preferential metabolism of T4 to biologically inactive products by two different mechanisms: deiodination by iodothyronine deiodinase D3 to rT3 and sulfation by SULTs to T4S. This is likely to have significant effects on T4 turnover and certainly the production and clearance rates of T4 as well as T3 and rT3, which in neonatal lambs are higher than adults. In addition, production and clearance rates of T4 are similar in fetal and neonatal lambs, but T3 production is lower and clearance higher in fetal than in neonatal lambs. In contras, rT3 production is increased and clearance lower in fetal than in neonatal lambs (26, 40, 41). Comparable human data are more limited, but production rates of T4 per gram of thyroid gland or per kilogram body weight are approximately 5-fold higher in the term infant, compared with adult (11, 42, 43).

The overall lack of correlation of maternal serum iodothyronine, TSH, and TBG levels at the time of delivery to those found in cord blood was perhaps not surprising, given the increasing autonomy of the fetal thyroid axis over the period of gestation when most of the samples were collected. Cord blood was carefully collected from placental fetal vessels to avoid maternal contamination. Significant maternal-fetal hemorrhage is rare, and the more common minor transfusions are likely to have little impact on cord iodothyronine levels. For example, in a recent study, 14% of the cord blood samples had detectable maternal blood in the range of only 0.04–1% (44). The relationship between maternal and fetal serum levels in the first and early second trimester, when the fetus is in a more dependent state, needs to be explored with sufficient sample power to augment the seminal studies already done (1, 2, 10).

We suggested previously that there might be a critical gestation above which the postnatal hypothalamic-pituitary-thyroid axis response to birth follows the general pattern described for full-term infants, albeit in an attenuated manner. In contrast, below this gestation the effect, in terms of a sustained provision of T4 and FT4 by 24 h postnatal age, is minimal or absent and that this critical gestation is around the end of the second trimester of pregnancy (45). This concept of a crucial gestation determining thyroid hormone responsiveness has been suggested previously by the neurodevelopmental outcome of extreme preterm infants to thyroxine supplementation, which was given to correct transient hypothyroxinemia. For example, in the studies by van Wassenaer et al. (46), T4 substitution in a group of preterm infants less than 30 wk gestation showed no benefit. But subgroup analysis showed that in infants less than 27 wk, developmental scores increased by 18 points, but in infants 28–30 wk, the scores decreased by 10 points (46). Other studies have linked low plasma T4 levels in preterm infants with later neurodevelopmental deficits in motor and cognitive function (47, 48, 49) and low plasma T3 levels with reductions in IQ at 8 yr of age (50). Our current data further emphasize that the late second trimester (around 25–27 wk) is an important period of transition of fetal thyroid hormone metabolism reflected in fundamental alterations in the developmental trends of FT4, rT3, and T4S levels. The late second trimester appears to be a critical transition period in fetal thyroid hormone metabolism, which may be interrupted by extreme preterm birth and so contribute to the thyroid dysfunctions commonly present in these infants.


   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, Rosanne 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, Scott Nelson, Bridget Oates, Simon Ogston, 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.

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

1 For a list of members of the Scottish Preterm Thyroid Group, see Acknowledgments. Back

Received March 25, 2004.

Accepted May 3, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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