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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2824-2831
Copyright © 2004 by The Endocrine Society

The Hypothalamic-Pituitary-Thyroid Axis in Preterm Infants; Changes in the First 24 Hours of Postnatal Life

Nuala Murphy, Robert Hume, Hans van Toor, Tom G. Matthews, Simon A. Ogston, Sing-Yung Wu, Theo J. Visser and Fiona L. R. Williams

Department of Paediatrics (N.M., T.G.M.), The Rotunda Hospital, Dublin 1, Ireland; Tayside Institute of Child Health (R.H.) and Department of Epidemiology and Public Health (S.A.O., F.L.R.W.), University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland; 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: Dr. F. L. R. Williams, Department of Epidemiology and Public Health, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, United Kingdom. E-mail: f.l.r.williams{at}dundee.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The purpose of this study was to measure serum T4, free T4, TSH, T3, rT3, T4 sulfate, and thyroxine binding globulin at four time points within the first 24 h of life (cord and 1, 7, and 24 h) in infants between 24 and 34 wk gestation. The infants were subdivided into gestational age groups: 24–27 wk (n = 22); 28–30 wk (n = 26); and 31–34 wk (n = 24). The TSH surge in the first hour of postnatal life was markedly attenuated in infants of 24–27 wk gestation [8 compared with 20 (28–30 wk) and 23 mU/liter (31–34 wk)]. T4 levels in the most immature group declined over the first 24 h, whereas levels increased in the more mature groups [mean cord and 24-h levels: 65 and 59 (NS) vs. 70 and 84 (P < 0.002) vs. 98 and 125 (NS) nmol/liter]. Free T4 and T3 showed only small, transient increases in the most immature group and progressively larger and sustained increases in the other gestational groups. rT3 and T4 sulfate levels in cord serum were higher in the most immature infants, and in all groups levels decreased initially and then variably increased. The features of a severely attenuated or failed hypothalamic-pituitary-thyroid response to delivery critically define this 24- to 27-wk group as distinct from more mature preterm infants.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TRANSIENT HYPOTHYROXINEMIA IN preterm infants is characterized by a temporary postnatal reduction in serum levels of T4, free T4 (FT4) and T3, with normal levels of TSH (1, 2). Transient hypothyroxinemia is present in the majority of infants less than 30 wk gestation and is associated with neurodevelopmental deficits, characteristically reductions in intelligence quotient scores (3, 4, 5, 6) but also increased risks of cerebral palsy (6). T4 supplementation in infants less than 30 wk has shown no overall benefit in neurodevelopmental outcome but may improve outcome in infants less than 27 wk gestation (7). The etiology of transient hypothyroxinemia is not clear and may have contributions from the withdrawal of maternal-placental T4 transfer (8, 9), developmental constraints on the synthesis (10), peripheral metabolism of iodothyronines (11, 12), nonthyroidal illness (13, 14, 15), iodine deficiency (16, 17), and hypothalamic-pituitary-thyroid immaturity (18).

TRH stimulation tests have been used to assess the maturity of the pituitary-thyroid axis (19, 20, 21, 22). All of these involved postnatal administration of TRH and subsequent measurement of TSH and in some cases T4 and T3. In all examples, TRH stimulation resulted in marked increases in TSH, T3, and/or T4. These studies included both preterm and term infants from 24 wk gestation onward and were conducted between 16 h and 28 d postpartum. In addition, maternal administration of TRH before preterm delivery demonstrated that the pituitary is responsive to TRH because early as 24–28 wk gestation. This was interpreted as consistent with a tertiary (i.e. central of hypothalamic origin) rather than a primary cause of hypothyroxinemia, which is evident in many premature infants (21).

The response of the hypothalamic-pituitary-thyroid axis can be studied immediately post birth because cooling and other birth stresses are natural stimulants of hypothalamic TRH production. After delivery in term infants, there is a marked postnatal surge of serum TSH levels at around 30 min of age. This in turn stimulates T3 and T4 secretion and increases serum T3 and T4 levels that peak at between 24 and 36 h (23). Few studies have investigated preterm infants in sufficient detail, gestational ages, and numbers to allow the complete temporal description of the relationships within the hypothalamic-pituitary-thyroid axis (14, 15, 21, 24, 25).

In this paper we report the results of a study that measured serum T4, FT4, TSH, T3, rT3, T4 sulfate (T4S), and thyroxine binding globulin (TBG) at four time points within the first 24 h of life in a large group of preterm infants.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study was performed at the Rotunda Hospital, Dublin, a tertiary referral center with approximately 6500 deliveries per year. Inclusion criteria were gestational age between 24 and 34 wk, absence of major congenital abnormality, and an absence of maternal endocrine disease. The gestational age was calculated from menstrual history and, in most instances, was confirmed by ultrasound examination in the first trimester. The study protocol was approved by the Rotunda Hospital Ethics Committee, and written informed parental consent was obtained.

Maternal and cord whole blood samples were obtained at delivery. Thereafter, infant blood samples were obtained between 30 and 90 min (referred to hereafter as 1 h); between 6 and 8 h (referred to hereafter as 7 h); and at 24 h. The first infant sample was taken at the time of insertion of a nonheparinized arterial catheter; subsequent samples were drawn from this indwelling catheter, in which patency was maintained by infusion of heparin at 0.5–1 U/h. The blood samples were allowed to separate for 15 min and centrifuged at 5000 rpm for 10 min; sera were stored at –70 C until analyzed. Provided sufficient blood was collected, the levels of T4, FT4, TSH, T3, rT3, T4S, and TBG 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. (26). The measurements of T4S in serum were done by a specific antibody, as described previously (27). 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.

The means and twice the SEM were produced for each of the measurements of the iodothyronines, TSH, and TBG. To minimize confusion on the graph, only one side of the error bar was used. The error bar shown (positive or negative) was selected according to the characteristics of each graph. A t test for unequal variance was used to quantify the differences between mean values of iodothyronines, TBG, and TSH at the various times of sampling and for the three gestational age groups. Bonferroni correction was calculated for the number of t tests used with each iodothyronine, TBG, and TSH; the resultant P value for assuming statistical significance was P = 0.002. Spearman rank order correlation coefficients were calculated for maternal and infant iodothyronines, TSH, and TBG. Using the Bonferroni correction factor gave P = 0.001 for assuming statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The 72 recruited infants were subdivided into gestational age groups for data analysis: 24–27 wk; 28–30 wk; and 31–34 wk (Table 1Go). A high proportion (39%) of the infants were a result of multiple births. Apgar scores at 1 min were lowest in most immature infants (Table 1Go). The incidence of cardiorespiratory disease (respiratory distress syndrome, chronic lung disease, persistent ductus arteriosus) and cerebral pathology was related to gestational age; it was highest in the most immature gestational group and lowest in the 31- to 34-wk gestational group (Table 1Go).


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  		TABLE 1. Characteristics of the sample

 
Associations between maternal and infant cord blood iodothyronines, TSH, and TBG are shown in Fig. 1GoGo. Maternal levels of TSH were correlated significantly with infant TSH for all gestations combined; no correlations within the gestational groupings reached statistical significance (Table 2Go).



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  		FIG. 1. Associations of maternal and infant cord blood levels of iodothyronines, TSH, and TBG (none of the associations reached statistical significance).

 


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  		FIG. 1A. Continued

 

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  		TABLE 2. Maternal and fetal serum thyroid parameters

 
Mean cord serum TSH levels were similar in the three gestational groups (Table 2Go and Fig. 2Go). During the first hour, mean serum TSH increased significantly to 23 mU/liter in the 31- to 34-wk gestation group; thereafter, levels decreased significantly to 10 mU/liter at 7 h and 7 mU/liter at 24 h (Table 2Go). This pattern was similar, but not significant, in the 28–30 gestational age group. In the 24- to 27-wk group, the pattern over the first 24 h was further attenuated and not significant (Table 2Go and Fig. 2Go).



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  		FIG. 2. Means and x2 SEM of iodothyronines, TSH, and TBG during the first 24 h of life. To minimize congestion, only half of the error bar is shown. Conversion factors: T3 and rT3 to nanograms per deciliter, multiply by 65.1; T4 to micrograms per deciliter, multiply by 0.0777; T4S to nanograms per deciliter, multiply by 0.085.

 
Mean T4 levels in cord serum increased with gestation. The cord levels of T4 at 24–27 wk and 28–30 wk were significantly lower than levels at 31–34 wk (Table 2Go and Fig. 2Go). These differences persisted at 7 and 24 h. No differences were evident at 1 h (Table 2Go). Over the first postnatal hour, mean T4 levels remained constant in all of the gestational age groups. Thereafter, none of the changes in mean T4 levels were statistically different, although both the 28- to 30-wk group and the 31- to 34-wk group increased from 1 h, whereas the 24- to 27-wk group decreased.

Mean TBG levels in cord serum increased with gestation. The cord levels of TBG at 24–27 wk and 28–30 wk were significantly lower than levels at 31–34 wk (Table 2Go and Fig. 2Go). Over the first 24 h, there were no significant differences in mean values of TBG within any of the gestational groups.

Mean FT4 in cord serum was similar in all gestational groups (Table 2Go and Fig. 2Go). Mean serum FT4 showed only a small, nonsignificant transient increase in the most immature gestational group but progressively larger and sustained increases in older groups. FT4 in 24-h blood was significantly higher (P < 0.002) than cord for the 28–30 group (Table 2Go). At 24 h the 24- to 27-wk group had significantly lower FT4 levels than the 31- to 34-wk group (P < 0.002) and the 28- to 30-wk group (NS).

Mean T3 levels in cord serum increased significantly with gestational age (Table 2Go). Like FT4, T3 showed only a small, nonsignificant, transient increase in the most immature group; at 24 h, T3 in this group had fallen to just above cord values. T3 levels in the older gestational groups were increased from cord values and largely sustained at 24 h. In the 28- to 30-wk group, T3 was significantly higher at 1, 7, and 24 h than cord levels (Table 2Go). In the 31- to 34-wk group, T3 was significantly higher at 7 and 24 h than cord levels (Table 2Go). At 24 h, T3 levels in the 24- to 27-wk group were significantly lower than the 28- to 30- and 31- to 34-wk groups (Table 2Go).

In cord serum, mean rT3 was higher, although not significantly, in the most immature group than in the other groups (Table 2Go). Mean serum rT3 decreased in all gestational groups during the first hour; the decrease was significant for the 24- to 27- and 28- to 30-wk groups (Table 2Go). At 7 h, rT3 was significantly lower than cord levels in the 24- to 27- and 28- to 30-wk groups. At 24 h, mean serum rT3 increased (nonsignificantly) in the 28- to 30- and 31- to 34-wk groups; no rise was apparent in the most immature group (Table 2Go and Fig. 2Go). At 24 h, rT3 was significantly lower in the 24- to 27-wk group than in the 28- to 30- and 31- to 34-wk groups (Table 2Go).

Mean T4S levels in cord serum were significantly higher in the 24- to 27-wk group than the 28- to 30-wk group but not different from the 31- to 34-wk group (Table 2Go and Fig. 2Go). In all gestational age groups, mean serum T4S showed a slight but nonsignificant decrease during the first hour and subsequent increases to maximum levels at least up until 24 h. In all gestational groups, 24-h levels of T4S were significantly higher than cord levels (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Postnatally, TSH levels increase abruptly in term infants from cord values of 8 mU/liter (28) to approximately 70 mU/liter at 30 min postnatal age (25). In preterm (32–33 wk gestation) infants, the postnatal TSH peak is lower at 50 mU/liter as a consequence of immaturity of the hypothalamic-pituitary axis (25). Our data are consistent with this conclusion because the postnatal TSH peak at 1 h in our groups of even more premature infants is gestational age related with a nearly 3-fold difference in TSH levels between the most mature and immature groups. The extreme preterm infants of our sample are distinct and, even allowing for minor differences in sampling time, their mean peak TSH level of around 8 mU/liter is substantially lower than other preterm infants (25).

In our most mature infants (31- to 34-wk gestation), in response to this TSH peak and as a result of presumed increased thyroidal secretion, T4 levels increased at 7 and 24 h from their 1 h levels. Infants of 28- to 30-wk gestation showed similar, but attenuated, TSH and T4 patterns. In the least mature infants (24- to 27-wk gestation), serum TSH levels not only showed a much lower postnatal surge, but also their levels subsequently decreased to levels lower than cord values by 7 h and fell further by 24 h. The consequence of a limited and unsustained postnatal rise in TSH in this group of extreme preterm infants results in a failure to increase thyroidal T4 output, and thus T4 levels are not sustained after 7 h. In fact, at 24 h, T4 values are slightly lower than cord levels in this extreme preterm group. These features critically define the 24- to 27-wk group as distinct. Hormonal responses in the 28- to 30-wk and 31- to 34-wk groups are reminiscent of term infants (20, 25, 29, 30) because both T4 and T3 increase postnatally and above cord values.

In contrast to our data for extreme preterm infants (24–27 wk), Ballard et al. (21) described T3 values at 24 h, which were substantially higher than cord levels in a group of 24- to 28-wk gestation infants. However, Pavelka et al. (15) described a group of preterm infants with a mean gestational age of 27 wk who appear to show some features consistent with our 24- to 27-wk gestation group. Their levels of TSH were lower at 24 h than cord values; T4 and T3, although not decreased from cord values, showed no increments at 24 h. Similarly, Van Wassenaer et al. (14) reported T3 and T4 levels that were higher at 12–24 h than cord in a group of infants less than 28 wk gestation. The divergences between these studies and our findings may be explained by small but important differences in the gestational ranges analyzed and the sampling times. In our study, infants of 28 wk gestation and above were excluded from the least mature group but were included in those of Ballard et al. (21) and Pavelka et al. (15). This suggests that there might be a critical gestation above which the postnatal thyroidal axis response to birth follows the general pattern described for full-term infants, albeit in an attenuated manner. In contrast, below this gestation the response, in terms of a sustained provision of T4 and FT4 by 24 h, is absent, which might indicate the failed response of the hypothalamic-pituitary-thyroid axis. It is likely that this change in response will occur as a consequence of individual maturational variations in the developing fetus and infant. On the basis of our data and in comparison with that of others, we believe that this change in postnatal thyroidal axis responsiveness to birth, whether this is considered as a severely attenuated or a failed response, will be centered around 27 wk gestation.

The postnatal TSH, T4, and T3 responses to birth in 24- to 27-wk gestation infants are distinctive and may constitute hypothalamic-pituitary-thyroid failure. However, some other postnatal changes in iodothyronine metabolism are similar in pattern to the more mature groups of infants. These include the early increases in T3 and FT4 levels at 1 h; the postnatal reductions at 1 h in rT3 levels; and the 24-h pattern of T4S levels. It is likely that such modifications represent alterations in peripheral metabolism, rather than consequences of activation, or in the case of these extreme preterm infants, failure of activation of the hypothalamic-pituitary-thyroid axis.

Cord rT3 levels were highest in the extreme preterm infant group but with lower and similar levels in the more mature groups. The relationship of cord rT3 levels to gestation has been previously described (25, 31). Similarly, a decline in rT3 levels at 24 h in preterm infants has also been described (14, 15, 30, 32). Our data, with rT3 measurements at 1 and 7 h, add further new information to the understanding of these changes. rT3 levels vary within the gestational groupings. Our data show that there is a marked decrease in rT3 during the first hour of life in all preterm groups, which was most evident in the extreme preterm group.

The immediate postnatal reduction in rT3 levels is most likely secondary to the removal of placental type III iodothyronine deiodinase (D3) activities and was most marked in the most immature group in which cord values were highest. It is not unexpected that subsequent rT3 values are distinct between groups and with time because levels are determined in part by the availability of precursor T4 and further production of rT3 at peripheral sites such as brain and other tissues (15) as well as further hepatic metabolism and clearance. The pattern of rT3 over the first 24 h of life in 10 preterm infants (mean gestation 32–33 wk) has been described (30) and is similar to our more mature groups. Our extreme premature group (24–27 wk) remains distinctive, with a failure to increase rT3 levels at 24 h; this is perhaps due to the concomitant deficit in available T4 over the same period.

The increment in T3 levels at 1 h occurs before the sustained rise (in more mature infants) in postnatal T4 levels at 7 h. This pattern has been described previously in term and preterm infants, mean gestation 32–33 wk (30). The immediate postnatal increase in serum T3 may be explained by increased thyroidal T3 secretion, peripheral T4 to T3 conversion, or reduced T3 clearance. In the newborn lamb, this early increment in T3 levels can be dissociated from the TSH surge by delayed cutting of the umbilical cord or administration of {alpha}-methyl tyrosine (18, 33), suggesting that it does not result from increased thyroidal secretion. Our human data appear to support this concept because increments in T3 at 1 h relative to cord levels are similar in all groups and not related to peak TSH levels, which differed markedly between groups. Thyroidal secretion is the predominant source of circulating T3 in the early postdelivery phase as suggested by studies in thyroidectomized fetal lambs (34), with an initial negligible contribution of peripheral T3 production. Therefore, the immediate postnatal increase in serum T3 may be largely due to the sudden decrease in T3 degradation by the separation from D3 expressed in placenta and uterus (35, 36), and perhaps the decrease in D3 expression in other tissues (e.g. liver, brain) (11, 37) may also play an important role. Only later on, the peripheral contribution to T3 levels becomes more important, linked with an increased hepatic conversion of T4 to T3 by the type I iodothyronine deiodinase (27); although hepatic type I iodothyronine deiodinase activities in the midgestation human fetus, and in extreme preterm infants, are sufficient to allow the generation of T3 (11).

Heparin is known to activate lipoprotein lipase and increase plasma generation of free fatty acids, both in vivo and in vitro, which in turn displaces plasma protein-bound T4 and gives rise to spurious increases in FT4 (38). This phenomenon is related to not only the plasma level of free fatty acids but also plasma albumin levels (39), which are reduced in preterm infants. These circumstances could explain part of the mechanism why extreme preterm infants show apparently sufficient FT4 levels, whereas T4 fails to increase. Triglyceride emulsions are a component part of parenteral nutrition solutions and are commonly used in preterm infants and may result in increased levels of plasma free fatty acids. Whereas it is possible at 7 and 24 h that some infants had systemic heparin infusions to maintain patency of vascular lines, in our study no infant was infused with triglyceride emulsion solutions.

In all groups of infants, FT4 levels increased over the first hour of life, but T4 and TBG levels changed little and cannot explain adequately the increments in FT4. Furthermore, at the time of the first hour sample, vascular access is normally only being established for the first time and infants have not received heparin or triglyceride emulsions or even drugs with potential protein displacement activity. It is possible that structural changes in TBG over the first hour, which decrease the affinity of T4 binding, could have occurred (40).

Multiple factors may contribute to the etiology of transient hypothyroxinemia in preterm infants including hypothalamic-pituitary-thyroid immaturity. The features of an attenuated or failed hypothalamic-pituitary-thyroid response to delivery critically define extreme preterm infants as distinct from more mature preterm infants and term infants. Further carefully controlled investigations of this axis in extreme preterm infants are clearly required to allow the development of preventative therapies for these infants, which maximize the role of thyroid hormones in successful adaptation to extrauterine life.


   Acknowledgments
 
We thank the following for their invaluable input at various stages of the project: Mrs. Judith Strachan, Mrs. Jennifer Watson, and all participating staff and patients at the Rotunda Hospital.


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

Abbreviations: D3, Type III iodothyronine deiodinase; FT4, free T4; TBG, thyroxine binding globulin; T4S, T4 sulfate.

Received February 24, 2003.

Accepted January 23, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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