|FETAL THYROID FUNCTION
Chapter 1 (Section 2) - Gerard N Burrow, MD and Lauren H Golden, MD
October 28, 2002
The maternal thyroid provides all thyroid hormone necessary for fetal development until the fetal thyroid is able to produce sufficient amounts of endogenous hormone. The fetal thyroid gland and negative feedback loop with the pituitary develop and mature throughout gestation. (Table 2). Fetal TSH and T4 are first detectable at 10 weeks gestation.
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.
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
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
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
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.
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.
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
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
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.