Original Article
Maturation of the Secretion of Thyroid Hormone and Thyroid-Stimulating Hormone in the Fetus
N Engl J Med 1991; 324:532-536February 21, 1991
- Abstract
- Abstract
Background.
Data on human fetal thyroid function have largely been derived from histologie studies or studies of cord-blood samples obtained at hysterotomy or delivery. These data may not represent true normal values. Cordocentesis (ultrasound-guided blood sampling from the umbilical cord) is a technique that allows investigation of physiologic processes in fetuses not under stress.
Methods.
We measured serum thyroid-stimulating hormone, total and free thyroxine (T4), total and free triiodothyronine (T3), and thyroxine-binding globulin in blood samples from 62 fetuses. The samples were obtained by cordocentesis (n = 58) or cardiocentesis (n = 4) at 12 to 37 weeks of gestation. Maternal serum samples were obtained immediately before fetal blood sampling.
Results.
Fetal serum thyroid-stimulating hormone, thyroxine-binding globulin, and total and free T4 and T3 concentrations increased significantly with the length of gestation (P<0.001). The only significant association among these variables, independent of the length of gestation, was between thyroid-stimulating hormone and free T4 (P<0.0001). Maternal serum concentrations of these variables did not change during gestation, and there was no significant relation between fetal and maternal values. Most fetal serum concentrations of thyroid-stimulating hormone were higher, whereas most serum total and free T3 concentrations were lower than the respective values for normal adults. The fetal serum total T4, free T4, and thyroxine-binding globulin values reached the level of the mean adult values at approximately 36 weeks of gestation.
Conclusions.
The increases in fetal serum concentrations of thyroid-stimulating hormone, thyroxine-binding globulin, and total and free T4 and T3 during gestation reflect increasing maturation of the pituitary, thyroid, and liver. The finding of increasing fetal serum concentrations of thyroid-stimulating hormone in the presence of increasing thyroid hormone concentrations suggests that the sensitivity of the fetal pituitary gland to negative feedback is limited or is counterbalanced by increasing stimulation by thyrotropin-releasing hormone from the hypothalamus. (N Engl J Med 1991; 324:532–6.)
Media in This Article
Figure 1
Individual Fetal and Maternal Serum Thyroid-Stimulating Hormone Concentrations Plotted as a Function of Length of Gestation.Figure 2
Individual Fetal and Maternal Serum Free and Total T4 Concentrations Plotted as a Function of Length of Gestation.Article Activity
- Article
THYROID hormones have a vital role in fetal development in many species. The best studied are fetal rats and sheep, in which thyroid hormones have important physiologic functions, including stimulation of neural growth and pulmonary development.1 What is known about pituitary and thyroid development in humans is based on histologic studies of abortuses or analysis of blood samples obtained in early pregnancy at hysterotomy for elective abortion or in later pregnancy at delivery.2 3 4 5 However, the results derived from samples obtained at the time of hysterotomy or cesarean section may have been influenced by maternal fasting or transient hypotension, which could alter placental perfusion and therefore affect the supply of oxygen and nutrients to the fetus.6 Furthermore, samples obtained after premature delivery may not be representative of normal prelabor values, since thyroid-stimulating hormone levels undergo marked and rapid changes in the immediate postnatal period. Indeed, the condition causing premature delivery itself could influence fetal serum thyroid-stimulating hormone and thyroid hormone levels, since it is unlikely that fetuses delivered before 37 weeks of gestation can truly be described as normal. Despite their limitations, such studies indicate that the thyroid gland begins to produce thyroxine at 10 to 12 weeks of gestation.7 , 8 However, there is conflicting evidence about the time during gestation at which functional maturation of the fetal pituitary—thyroid axis is achieved. Some authors suggest that the secretion of thyroid-stimulating hormone is responsive to changes in serum free thyroxine (T4) concentrations as early as 11 weeks of gestation2; others suggest that such maturation occurs largely during the last half of pregnancy.3 , 4 , 9
Recently, Ballabio et al. used cordocentesis — that is, ultrasound-guided blood sampling from the umbilical cord — to study thyroid function at 18 to 31 weeks of gestation.10 However, only 23 fetuses were studied, 15 of whom were severely anemic as a result of red-cell isoimmunization. Nevertheless, the study demonstrated that fetal serum thyroid-stimulating hormone, total T4, and free T4 concentrations increased during gestation. Fetal serum thyroid-stimulating hormone levels were always higher and total T4 levels always lower than adult values, whereas free T4 values reached adult levels by 28 weeks of gestation. Ballabio et al. explained these findings by suggesting that the threshold for negative feedback from thyroid hormones to the pituitary is set at a higher level in fetal than in postnatal life.
The aim of this study was to establish reference ranges for fetal serum thyroid hormone and thyroid-stimulating hormone concentrations and examine the interrelation of these hormones at 12 to 37 weeks of gestation in normal fetuses.
Methods
Blood was obtained by cordocentesis ( 17 to 37 weeks of gestation) or cardiocentesis (<14 weeks of gestation) from 62 fetuses.11 Blood was collected from the antecubital fossa in 52 of the mothers immediately before fetal blood sampling. Cordocentesis was used to obtain blood from 58 fetuses for the following purposes: prenatal diagnosis of blood disorders such as hemophilia A (n = 9); fetal karyotyping in women of advanced age or with a low serum alpha-fetoprotein level when amniocyte culture had been unsuccessful or when results were needed rapidly (n = 14); karyotyping for fetal malformations, such as mild hydronephrosis, unilateral polycystic kidney, or congenital diaphragmatic hernia (n = 24); investigation of maternal primary toxoplasmosis (n = 2); and fetal blood typing of those at risk for red-cell isoimmunization, in which the fetal blood was found to be negative on Coombs' testing (n = 9). In all cases, the fetal abdominal circumference and blood gas values at the time of cordocentesis were within our reference ranges for the length of gestation and the fetal karyotype was normal. Furthermore, the fetuses did not have the blood disorder or infection for which they were tested. Blood was obtained from four fetuses by cardiocentesis immediately before the intracardiac injection of potassium chloride for feticide in multifetal pregnancies. Kleihauer—Betke testing confirmed that all samples contained only fetal blood. The project was approved by the hospital ethics committee, and informed consent was obtained from all the mothers.
For measurements of serum thyroid-stimulating hormone, thyroxine-binding globulin, and thyroid hormones, fetal (0.3 to 0.8 ml) and maternal (5 ml) blood samples were collected in plain tubes and centrifuged for 10 minutes at 2000 rpm; the serum was then collected and stored at –20°C. Thyroid-stimulating hormone was measured in all fetal serum samples, and total T4, free T4, total triiodothyronine (T3), free T3, and thyroxine-binding globulin were measured in most samples. Thyroid-stimulating hormone was measured by immunoradiometric assay (Celltech Diagnostics, Slough, United Kingdom). Total T4 and T3 were measured by solid-phase radioimmunoassays; free T4 and T3 were measured by solid-phase analogue radioimmunoassays (Diagnostic Products, Los Angeles). Thyroxine-binding globulin was also measured by radioimmunoassay (Behring, Marburg, Germany). The manufacturers of the kits used for the measurement of free T4 and T3 have demonstrated a lack of interference by thyroxine-binding globulin (up to 0.86 mmol per liter), albumin (up to 1.2 mmol per liter), or nonesterified fatty acids (up to 10 mmol per liter). The interassay and intraassay coefficients of variation for the thyroid-stimulating hormone, thyroxine-binding globulin, total T4, free T4, total T3, and free T3 assays were 4.5 and 3.9 percent, 4.5 and 3.4 percent, 4.9 and 4.1 percent, 6.5 and 4.4 percent, 6.6 and 5.4 percent, and 4.8 and 4.5 percent, respectively. The ranges in nonpregnant adults (mean ±2 SD) used for thyroid-stimulating hormone, thyroxine-binding globulin, total T4, free T4, total T3, and free T3 were those of the test manufacturers and were obtained from 347, 368, 335, 251, 335, and 405 normal subjects, respectively.
Regression analysis was used to examine any relation between measured variables and gestational age. Data or residuals from linear regression were tested for normality. For the measurements that were not distributed normally, the distribution was made to conform to a gaussian curve by logarithmic transformation. For those that changed significantly with the length of gestation, the regression lines were used to calculate the adjusted means and residual standard deviations. To determine the reference ranges during gestation in the original units, the limits of the calculated reference range in logarithms were subjected to antilogarithmic transformation.
Results
Fetal serum concentrations of thyroid-stimulating hormone (Fig. 1Figure 1
Individual Fetal and Maternal Serum Thyroid-Stimulating Hormone Concentrations Plotted as a Function of Length of Gestation.), total and free T4 (Fig. 2Figure 2Individual Fetal and Maternal Serum Free and Total T4 Concentrations Plotted as a Function of Length of Gestation.), total and free T3 (Fig. 3Figure 3
Individual Fetal and Maternal Serum Free and Total T3 Concentrations Plotted as a Function of Length of Gestation.), and thyroxine-binding globulin (Fig. 4Figure 4
Individual Fetal and Maternal Serum Thyroxine-Binding Globulin Concentrations Plotted as a Function of Length of Gestation. The sloping lines are the mean and 5th and 95th percentile values for fetal serum thyroxine-binding globulin (r = 0.805, n = 52, P<0.0001). The maternal serum concentrations of thyroxine-binding globulin did not change significantly with the length of gestation (r = 0.13, n = 52). The vertical line on the right is the normal range in nonpregnant adults (mean, 0.35 μmol per liter; range, 0.19 to 0.51).) increased progressively during gestation, and the associations between each of them and the length of gestation were significant. Although there were also significant associations among these variables (data not shown), multiple regression analysis demonstrated that the only significant association independent of the length of gestation was that between serum thyroid-stimulating hormone and free T4 (free T4 = – 1.0873 + 0.768 [thyroid-stimulating hormone] + 0.042 week of gestation; R = 0.896, P<0.0001).There were no changes in maternal hormone or thyroxine-binding globulin concentrations as a function of the length of gestation (Fig. 1 through 4). Likewise, there were no significant associations between the values in maternal serum and those in fetal serum.
The vertical lines at the right side of each figure are the mean (±2 SD) serum concentrations in normal nonpregnant adults. Most fetal serum thyroid-stimulating hormone values were higher and most fetal serum total and free T3 values were lower than the adult values. The fetal serum total T4, free T4, and thyroxine-binding globulin values reached the level of the mean adult values at approximately 36 weeks of gestation.
Discussion
Maternal serum levels of thyroid hormones are higher than those in nonpregnant adults. The increases in serum total T4 and T3 concentrations are primarily a consequence of an estrogen-induced elevation of serum thyroxine-binding globulin levels. Thyroid stimulation due to the weak thyroid-stimulating hormone-like activity of human chorionic gonadotropin contributes to the increase in total T4 and T3 concentrations and accounts for the slight increase in free T4 and T3 concentrations.12 13 14 Although in this study the maternal levels of thyroid-stimulating hormone did not change significantly with the length of gestation, in a larger series Fung et al. reported that the levels increased with increasing lengths of gestation.15 The absence of a significant correlation between fetal and maternal thyroid hormone and thyroid-stimulating hormone levels is compatible with the results of previous studies of cord-blood and maternal serum thyroid hormone levels at delivery.1
The increase in the fetal serum thyroid hormone concentrations during gestation presumably reflects the increasing stimulation and maturation of the fetal thyroid gland and increasing serum thyroxine-binding globulin concentrations. However, although fetal serum total and free T4 concentrations reached adult levels by 36 weeks of gestation, fetal serum total and free T3 concentrations were always less than half the respective maternal concentrations. Since the chief source of T3 is peripheral conversion of T4, these findings suggest that during intrauterine life the processes required for this conversion either are immature or lack the necessary stimulus for their activation. In vitro studies in sheep have demonstrated that during labor and in the neonatal period there is a dramatic increase in the capacity for hepatic conversion of T4 to T3.16 Similarly, Fisher et al. found a 10-fold increase in the ratio of serum T3 to T4 from 30 weeks of gestation to 1 month after birth in humans.1 An alternative explanation for the low fetal T3 concentrations could be rapid deiodination by the placenta.
Fetal serum concentrations of thyroid-stimulating hormone increased significantly during gestation and were always higher than maternal levels. After birth the chief determinant of negative feedback is T3, produced largely by intrapituitary local monodeiodination of T4.17 In this study, there was a positive association between serum free T4 and thyroid-stimulating hormone that was independent of the length of gestation, and thyroid-stimulating hormone levels continued to rise even in the third trimester, when adult concentrations of total and free T4 were reached. These findings suggest that the fetal pituitary is relatively insensitive to negative feedback from T4 or that the inhibitory action of T4 on the secretion of thyroid-stimulating hormone is counterbalanced by increasing secretion of thyrotropin-releasing hormone from the hypothalamus. Alternatively, circulating T3 has a more important role in feedback in the fetus than in the adult; since serum total and free T3 concentrations are much lower before than after birth, the threshold for negative feedback is never reached in utero.
Fetal serum concentrations of thyroxine-binding globulin increased with increasing lengths of gestation and reached adult levels during the third trimester. This increase presumably reflects the functional maturation of the fetal liver and its increasing capacity to manufacture proteins; fetal albumin concentrations also increase with gestation.18
Our results support the findings of Greenberg et al. that serum concentrations of thyroid-stimulating hormone and total and free T4 increase between 11 and 24 weeks of gestation. However, adult levels were not reached by 16 to 20 weeks of gestation, as they reported.2 Similarly, although our results are in general agreement with those of Fisher et al., we did not confirm their finding that fetal serum concentrations of thyroid-stimulating hormone rise between 12 and 24 weeks of gestation but not thereafter.1 Our results agree most closely with those of Ballabio et al., 10 who also obtained blood by cordocentesis and who similarly demonstrated pituitary resistance to increasing serum thyroid hormone concentrations.
During the second trimester of pregnancy, it is likely that the increase in fetal serum concentrations of thyroid-stimulating hormone, thyroid hormones, and thyroxine-binding globulin reflects the independent maturation of the pituitary, thyroid, and liver, respectively. With longer gestation there is an increase in serum thyroid-hormone levels, reflecting functional maturation of the thyroid gland and increasing serum thyroxine-binding globulin concentrations. Despite this increase, the serum total and free T3 concentrations were always lower before birth than after birth, and production of thyroid-stimulating hormone was not inhibited.
Source Information
From the Department of Obstetrics and Gynaecology, Harris Birthright Research Centre for Fetal Medicine (J.G.T.-B., K.H.N.); the Departments of Clinical Biochemistry (J.B.) and Medicine (A.M.M.), King's College School of Medicine and Dentistry; and the Wynn Institute for Metabolic Research (C.V.F.); all in London. Address reprint requests to Dr. Nicolaides at the Harris Birthright Research Centre for Fetal Medicine, King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX, United Kingdom.
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