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ONTOGENESIS OF FETAL THYROID FUNCTION

Formation of the fetal thyroid gland occurs during weeks 7 to 9 of gestation. The fetal thyroid gland originates as an epithelial proliferation in the floor of the pharynx at the site of the foramen caecum linguae.62 The gland reaches its final position by 9 weeks, having descended into the neck attached to the thyroglossal duct. At this point, the thyroid is a bilobed structure connected by the isthmus. Structural maturity of the gland is approached at 17 weeks. Control of the fetal thyroid system develops through maturation of the hypothalamic-pituitary-thyroid axis.63,64,65

Hypothalamic thyrotropin-releasing hormone (TRH) production and pituitary portal function mature between weeks 18 and 40 of gestation. Prior to mature TRH production by the fetal hypothalamus, extra-hypothalamic tissues, such as the placenta, fetal pancreas and other gastrointestinal tissues, are capable of producing the high levels of TRH found in fetal blood.66 Fetal serum TSH concentrations appear to increase in parallel with increasing concentrations of TRH. Serum TSH is also detectable in fetal serum as early as 10 weeks, although levels remain relatively low until about 18 weeks' gestation. Between weeks 18 and 28, TSH levels increase up to 15 mU/ml and then fall to approximately 10 mU/ml near term.67 At birth, the exposure of the neonate to the cold, extrauterine environment stimulates an acute surge of TSH release that results in increased secretion of thyroid hormones.

Fetal thyroid follicles and T₄ synthesis are first demonstrable at approximately 10 weeks after conception, although at this point, the biosynthetic process is immature. Ultrasound-guided blood sampling from the umbilical cord, or cordocentesis, has been used to evaluate fetal thyroid function. In a study of normal fetuses between 12 and 37 weeks' gestation,68,69 fetal serum TSH, TBG, and total free T₄ and T₃ were found to increase significantly with the length of gestation. However, the predicted rise and fall of serum TSH between 18 and 28 weeks was not seen.

As the thyroid gland matures, the secretory response to stimulation with TSH matures as well. Fetal pituitary control of thyroid function may commence as early as 12 weeks' gestation, but does not mature until mid-gestation. After mid-gestation, elevations in fetal TSH result in coincident increases in fetal serum T₄ concentrations, with T₄ levels increasing from 2 to 3 mg/dl at 10 weeks to 10 mg/dl at 30 weeks (Fig 2). Progressive, incremental increases in serum free T₄ parallel the increases in total serum T₄ concentrations. As the hypothalamic-pituitary-thyroidal axis develops, elevated levels of TSH may be found in the presence of elevated serum free T₄, reflecting early immaturity of the negative feedback system. Second trimester increases in fetal serum TSH, TBG, T₄ and T₃ concentrations are thought to reflect maturation of the pituitary, liver, and thyroid, respectively.

Figure 2. Thyroxine (T4) Concentrations During Gestation (Adapted from Burrow GN, Fisher D, Larsen PR: Maternal and fetal thyroid function. N Engl Med 331:1072, 1994. Copyright©1994 Massachusetts Medical Society. All rights reserved.)

The ontogeny of the three deiodinases (Fig 3) that catalyze the progressive deiodination of T₄ varies in the fetus. Type II and type III deiodinases are present at mid-gestation, whereas type I deiodinase does not appear until later in gestation.70 As noted earlier, type II and type III deiodinase activity have been documented in placental tissue. This may help regulate fetal exposure to maternal thyroid hormones, with local conversion of T₄ to T₃, T₄ to rT₃, and T₃ to T2. It also provides a source of iodine for the fetus. In the fetus, rT₃ is the predominant metabolite of T₄, produced by inner ring deiodination of T₄ by type III deiodinase. The rT₃ concentration in fetal serum is three times the maternal serum concentration.71 Activity levels of the three deiodinases are modulated by the hormonal milieu. In the hypothyroid fetus, activity of the type I and type III deiodinases is decreased, while activity of the type II deiodinase, in placenta , brain, and other tissues, is enhanced. These changes favor shunting of T₄ to brain tissues, where deiodination to T₃ is increased, the local concentration of T₃ is increased, and T₃ degradation is decreased. Because of these adaptive responses, even limited transfer of maternal thyroid hormone to the fetus may be sufficient to protect brain maturation.72

Figure 3. Peripheral Metabolism of Thyroid Hormone

Anencephalic fetuses have the ability to synthesize iodotyrosines. This was initially taken as evidence that TSH is not necessary for iodotyrosine production. However, careful studies suggest that, despite an absent hypothalamus in these fetuses, pituitary tissue is usually present. In fact, it was demonstrated that anencephalic fetuses had a hyperresponse of TSH to TRH.73

MATERNAL CONTRIBUTION

The maternal thyroid provides all thyroid hormone necessary for fetal development until the fetal thyroid is able to produce sufficient amounts of endogenous hormone. Recent investigations into the effects of maternal thyroid status on pregnancy outcome suggest that there are perinatal consequences of maternal gestational hypothyroxinemia, including effects on fetal neuropsychological development. Past studies have demonstrated that maternal thyroid hormone transfer to the fetus is limited. Measurements of cord-serum total T₄ concentrations in the athyreotic fetus reveal T₄ levels that are approximately 30% of those found in a normal fetus. This supports transfer of maternal thyroid hormone to the fetus throughout pregnancy.74

Placental Transfer Of Thryoid Hormone

The ability of an agent to affect fetal thyroid function is dependent on its ability to cross the placental barrier. Likewise, any effect of maternal thyroid hormone on the fetus must depend on placental transfer.

How effectively T₃ and T₄ cross the placenta is controversial. Based on the results of early studies, using radioisotopes in pregnant women at term or before pregnancy termination between 11 and 26 weeks, it was thought that limited transfer of thyroid hormones occurred across the placenta. However, only serum-precipitable radioactivity was measured. Studies have also been performed in which women at term were infused with large doses of T₄. These studies have limitations, however, as placental transfer of thyroid hormone may change with duration of pregnancy and aging of the placenta.

The amniotic cavity containing the developing embryo is surrounded by the extraembryonic coelomic fluid, which is in turn surrounded by the placenta.75 T₄ concentration in the coelomic fluid at 6 to 12 weeks is low, but varies directly with the maternal serum T₄ concentration. A recent study of fetuses up to mid-gestation documented concentrations of total T₄ in fetal compartments (coelomic fluid, amniotic fluid and fetal blood) up to 100-fold lower than maternal concentrations, although fetal compartment FT₄ concentrations consistently reached values up to one-third of those in maternal blood76.

During the second and third trimesters, there are marked maternal-to-fetal gradients of free T₄ and T₃. T₃ appears to cross more easily than T₄; however, fetal serum T₃ concentrations are normally low. The available evidence suggests that thyroid hormone transfer across the placenta reaches the fetus, but not in adequate amounts. A recent study of antenatal diagnosis and treatment of fetal goitrous hypothyroidism successfully employed intra-amniotic injections of thyroxine at a dose of 10 mg/kg/day every 7 days. Investigators documented improvement in the fetal goiter with intra-amniotic T₄ therapy.77

A study of 25 neonates born with a complete organification defect, whose mothers also had a complete organification defect, examined the amount of maternal transfer of physiological amounts of administered T₄.78 The serum T₄ concentration at birth in the affected neonates was 20%-50% (35 to 70 nmol/L vs 80 to 170 nmol/L) that of normal neonates. The serum T₄ concentration in these infants reflected placental transfer of maternal thyroid hormone. This transfer may be inadequate to induce euthyroidism in the fetus. Whether it is sufficient to ensure T₃ concentrations in the fetal brain adequate to promote psychoneurological development remains to be determined.

Animal studies suggest that it may be possible to modify the structure of the thyroid hormone molecule to increase placental transfer. Placental transfer depends on molecular weight, protein binding, and lipid solubility.79 We found that dimethyl-isopropyl thyronine (DIMIT), a nonhalogenated thyroid hormone analog, is 20 times as effective as T₄ in preventing fetal rat goiter without inducing maternal thyrotoxicosis.80 DIMIT is smaller, more lipid soluble, and less tightly protein-bound than T₄.

Amniotic Fluid

The accessibility of the amniotic fluid compartment via amniocentesis in pregnant women has led to an interest in TSH and thyroid hormone concentrations in amniotic fluid. While TSH has been difficult to detect in amniotic fluid, yielding unreliable results81, thyroid hormone concentrations, and their iodothyronine metabolites, have been measured (Fig 3). Amniotic fluid iodothyronine concentrations reflect both maternal and fetal metabolism.82 Maternal iodothyronines in amniotic fluid can enter the fetal circulation. In late gestation, this appears to be accomplished by fetal swallowing of amniotic fluid.

The pattern of iodothyronines in amniotic fluid reflects a predominance of type III deiodinase activity in fetal and placental tissue, although significant type II deiodinase activity may be demonstrated as well. As described earlier, type III deiodinase catalyzes the inner ring monodeiodination of T₄ to rT₃ and T₃ to T2. Type II deiodinase catalyzes outer ring deiodination, converting T₄ to T₃ and rT₃ to T2.

Reverse T₃, T₄, and their sulfated conjugates account for more than 95% of thyroid hormones in amniotic fluid. The majority of the T₃ (3,5,3'-triiodothyronine) in amniotic fluid is generated from outer ring monodeiodination of T₄ by type II deiodinase. Reverse T₃ concentrations are markedly increased in the amniotic fluid, reaching peak levels at 17 to 20 weeks, again reflecting an increase in 5'-iodothyronine monodeiodinase activity in the fetal compartment. rT₃ has minimal biologic activity. Throughout the course of gestation, amniotic T₃ concentrations decrease progressively, whereas T₄ increases

At term, T₄ concentrations in amniotic fluid are approximately 0.6 mg/dl lower than maternal or fetal serum. 83

The question has been raised as to whether the amount of thyroid hormone transferred is physiologically significant, particularly early in pregnancy.84,85 As mentioned earlier, a recent study measured TSH and thyroid hormone levels in maternal blood (maternal compartment), as well as in coelomic fluid, amniotic fluid and fetal blood (fetal compartments), in order to evaluate fetal tissue exposure to maternal thyroid hormones up to mid-gestation.86 Comparison of maternal total T₄ concentrations with those in the fetal compartments revealed that the concentrations of total T₄ in the fetal compartments were up to 100-fold lower than maternal concentrations. Interestingly, however, FT₄ concentrations were more similar between the fetal and maternal compartments, with fetal fluid FT₄ concentrations reaching values up to one-third of maternal concentrations. This suggests that fetal tissues are exposed to biologically relevant concentrations of FT₄ during the first trimester. Fetal FT₄ concentrations are determined by maternal T₄ and FT₄ concentrations, as well as by available concentrations of thyroid hormone-binding proteins. Thus, maternal hypothyroxinemia would directly impact the thyroid status of the developing fetus, resulting in relative hypothyroxinemia, and potentially resulting in adverse developmental effects.

Despite recent insights into the importance of thyroid hormone for normal fetal development, the specific role of thyroid hormone in development remains unclear.87 Fetal tissues appear to be exposed to biologically relevant concentrations of FT₄ in early gestation, the result of transfer of maternal thyroid hormone to the fetus. T₃ receptors have been documented in the brain at early stages of fetal development. Adequate maternal serum T₄ concentrations are thus important for the provision of adequate substrate to the fetus. Conversion of T₄ to T₃ in the fetal brain is accomplished by the activity of the 5'D-II isoform of iodothyronine deiodinase.88 In rat studies, 17.5% of T₄ in fetal tissues of near-term rats came from the mother, supporting the continued importance of maternal serum T₄ transfer throughout gestation89. Whether the rat model is directly applicable to pregnant women is not clear.

DETECTION OF FETAL THYROID DYSFUNCTION

In a fetus at risk for thyroid dysfunction, surveillance with ultrasound may be performed, directed at detecting the presence of fetal goiter. This is of clinical relevance, as fetal goiter may result in local airway compromise during delivery. Measurement of maternal serum levels of thyroid-stimulating immunoglobulins (TSI), TSH-receptor blocking antibodies (TBA), or TSH-binding inhibitory immunoglobulins (TBII) may also be useful in predicting development of fetal thyroid disorders. For example, one study suggests that the fetus is at risk for hypothyroidism if TBII results show inhibition of TSH binding greater than or equal to 50-fold.90 Likewise, if the TBII value is greater than 30%, or the TSI is in excess of 300%, the fetus is at increased risk for hyperthyroidism.91

Iodothyronine concentrations in amniotic fluid surrounding fetuses with congenital hypothyroidism predominantly reflect maternal thyroid function. Percutaneous umbilical cord sampling (cordocentesis) is currently the most reliable means to determine fetal thyroid status, and may be used to evaluate fetuses at risk for thyroid dysfunction.92,93 For example, amniotic fluid rT₃ concentrations were measured in a fetus whose mother had inadvertently received a therapeutic dose of 131I at 10 to 11 weeks' gestation. This dose would be expected to abolish fetal thyroid function. The amniotic fluid rT₃ concentration was normal at first measurement, and the fetus was treated with an intra-amniotic injection of T₄. Investigators documented a rise in amniotic fluid rT₃ concentrations after the T₄ injection, suggesting preservation of function of placental deiodinases. The neonate was euthyroid at birth.94 Another recent study employed intra-amniotic injections of thyroxine in the treatment of fetal goitrous hypothyroidism.95 Fetal plasma T₃ sulfate concentrations have been found to be normal in fetal hypothyroidism, and T₃ sulfate may help attenuate the effect of hypothyroidism during intrauterine life, perhaps functioning as a local source of T₃ in tissues containing T₃ sulfatase.96,97

NEONATAL THYROID FUNCTION

As noted above, at birth, the fetus emerges in the cold extra-uterine world, stimulating an acute release of TSH from the pituitary that peaks at 30 minutes post partum. TSH levels decrease rapidly during the first 24 hours of life, with a more gradual decrease over the next 2 days98 (Fig 4). The TSH surge elicits increased secretion of thyroid hormones, and, as a result, total and free T₄ concentrations are increased at birth. Reverse T₃ (rT₃) concentrations are also elevated at birth. In contrast, serum T₃ concentrations are low at birth, and increase dramatically thereafter. Part of the neonatal increase in T₃ appears to be TSH independent, and may be attributed to the rapidly increasing capacity of neonatal tissues to monodeiodinate T₄ to T₃. This capacity is reflected in the progressively changing serum T₃/T₄, rT₃/T₄ ratios between 30 weeks' gestation and the first postnatal month.99

Figure 4. Changes in TSH and Thyroxine (T4) at term. (Adapted from Fisher D, Klein A: Medical progress. Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 304:702, 1981)

Preterm infants exhibit a decreased TSH response at parturition, reflecting persistent immaturity of the hypothalamic-pituitary-thyroid axis. Although serum T₄ increases during the first few weeks of life, the the T₄ concentration remains below that found in full-term infants. Neonates exhibit elevated radioactive iodine thyroid uptake as early as 10 hours post partum. This increased uptake reaches a peak by the second day and drops to adult normal limits by the fifth day post partum. Iodide kinetic studies suggest that the plasma inorganic iodine and iodine pool are increased, as is the absolute amount of iodide taken up by the thyroid gland.100 The factors responsible for this stimulation of iodide transport are unknown.