Thyroid disease in pregnancy
1. How does normal pregnancy affect maternal thyroid function?
The profound hormonal influences that change the physiology of pregnancy and the increased metabolic demands of the fetus cause significant changes in maternal thyroid function (Table 40-1).
2. Why must thyroid function tests be interpreted cautiously in pregnancy?
The influence of estrogen and human chorionic gonadotropin (hCG) on circulating thyroid hormone levels requires that thyroid function tests in pregnancy be interpreted cautiously. Estrogen increases thyroid-binding globulin (TBG) by two- to threefold beginning a few weeks after conception. The result is an approximately 50% increase in serum total thyroxine (TT4) and total triiodothyronine (TT3) levels because circulating thyroid hormones are highly protein bound. Throughout pregnancy, the range for both hormones should be approximately 1.5 times the nonpregnant range. Measurement of the triiodothyronine (T3) resin uptake (T3RU), which is inversely related to serum thyroid binding capacity, is correspondingly low, so that the calculated free thyroxine (T4) index (FT4I; product of multiplying the total T4 by the T3RU) is usually normal. Although the measured free T4 (FT4) and free T3 (FT3) levels are usually normal in pregnancy, they must be interpreted with caution because the reference ranges provided by manufacturers have been established using pools of nonpregnant sera. These free assays may also be influenced by changes in TBG and albumin unless they are measured by an equilibrium dialysis method or online solid phase extraction–liquid chromatography/tandem mass spectrometry (LC/MS/MS), but these methods are expensive and usually not available. Only 0.03% of serum TT4 content is unbound to serum proteins and is the FT4 available for tissue uptake. Further, the very high TBG levels, the low albumin levels, and the high nonesterified fatty acids characteristic of pregnancy may all affect the FT4 immunoassays. A slightly low FT4 in the late second or third trimester may be normal or may represent true hypothyroidism and should be interpreted in the context of the thyroid-stimulating hormone (TSH) and TT4 levels. If TSH is less than 3.0 mU/L and TT4 is 1.5-fold elevated, it is unlikely that the patient has true hypothyroidism. If possible, pregnancy-specific norms for FT3 and FT4 should be established by the laboratory.
TSH values are also affected by the thyrotropic effect of hCG; in one large series, the 95% confidence limits were as low as 0.03 mU/L in the first and second trimesters and 0.13 mU/L in the third trimester, with an upper limit of normal of less than 3.0 mU/L in the first trimester and less than 3.5 mU/L in the second and third trimesters. Ethnicity-related differences are also significant. Black and Asian women have TSH values that are, on average, 0.4 mU/L lower than in white women. Guidelines from both the American Thyroid Association (ATA) and the Endocrine Society recommend that an upper TSH limit of 2.5 mU/L be used in the first trimester and 3.0 mU/L in the second and third trimesters, especially if thyroid peroxidase (TPO) antibodies are positive and individual laboratories do not offer gestation-specific normal ranges. The TSH must also be interpreted in the context of the actual thyroid hormone levels. If the TT4 and TT3 are less than 1.5-fold elevated compared with the nonpregnancy range and the FT4 and FT3 hormones are not increased, the suppressed TSH may reflect the effect of hCG, but it could also be caused by subclinical hyperthyroidism from Graves’ diseases or a hot nodule. None of these conditions warrants treatment.
3. What particular effects may be seen during the first trimester?
During the first trimester, high hCG levels may stimulate thyroid T4 secretion sufficiently to suppress the serum TSH into the range of 0.03 to 0.5 mU/L in up to 15% of pregnant women. In a study of women with hCG concentrations higher than 200,000 IU/L (which is not uncommon in twin pregnancies), the TSH was less than or equal to 0.2 mU/L in 67% of women. The TSH may be slightly suppressed in the second trimester, but by the third trimester, it is usually within the normal range. The beta subunit of hCG has 85% sequence homology in the first 114 amino acids with TSH and can bind to and stimulate the TSH receptor. Levels of hCG higher than 50,000 IU/L, which may be seen when hCG peaks at the end of the first trimester, can therefore increase the FT4 level enough to suppress the serum TSH. However, the TSH is usually detectable, the TT4 is less than 1.5-fold elevated above the nonpregnancy range, and FT4 is usually within the normal range. A TSH in the high-normal range (> 2.5-3.0) during the first trimester is therefore suggestive of subclinical hypothyroidism.
4. Why must the mother significantly increase thyroid hormone production during pregnancy?
Maternal plasma volume expands 30% to 40%, requiring a concomitant expansion of the thyroid hormone pool.
Placental type 3 deiodinase (D3) activity results in increased maternal T4 metabolism to reverse T3.
Transfer of T4 across the placenta to the fetus occurs.
5. What factors may compromise maternal ability to increase thyroid hormone production?
Women with limited thyroid reserve as a result of thyroiditis, partial ablation, or surgical resection may be unable to increase thyroid hormone production during pregnancy and often develop hypothyroidism. Women with inadequate iodine intake may also develop hypothyroidism and a goiter because iodine requirements increase by approximately 40% to 50% in pregnancy.
6. What is the “goiter of pregnancy”?
The goiter of pregnancy has been well described in iodine-deficient areas of the world, but it does not occur in geographic regions that are iodine replete. In fact, one of the first pregnancy tests to be developed in iodine-deficient areas was a loosely braided choker necklace that broke when a woman developed such a goiter. The thyroid gland increased in size with each subsequent pregnancy.
7. Why do iodine requirements increase in pregnancy?
Iodine requirements increase markedly during pregnancy as a result of increased urinary iodine losses secondary to the 50% to 100% increase in glomerular filtration rate (GFR) during pregnancy, the diversion of iodine to the fetus for thyroid hormone synthesis, and increased maternal thyroid hormone requirements.
8. What is the recommended iodine intake during pregnancy, and how can it be met?
The World Health Organization’s recommendations for iodine intake are 250 μg/day during pregnancy and lactation and 150 μg/day in the nonpregnant state. Iodine insufficiency is an increasing problem in the United States as a result of the availability of deiodinated salt and is estimated at 5% to 10%. Because most prenatal vitamins do not contain iodine, women of childbearing age should be instructed to use only iodinated salt or to make sure to ingest a prenatal vitamin containing iodine.
9. What happens if iodine intake is insufficient?
If iodine intake is insufficient, thyroid hormone production drops, resulting in increased secretion of TSH, which then stimulates thyroid gland growth. Thyroid volume commonly increases by 30% or more during pregnancy in iodine-deficient regions and often does not completely regress after delivery. Many European and developing countries with endemic iodine deficiency do not supplement with iodine; therefore, women are at risk of iodine-deficiency goiters during pregnancy. When iodine intake is severely deficient, overt hypothyroidism results both in the mother and the fetus. Endemic cretinism occurs if severe hypothyroidism secondary to iodine deficiency goes unrecognized and untreated at birth.
10. What happens to thyroid gland volume in iodine-replete areas during pregnancy?
In iodine-replete areas, such as the United States, thyroid gland volume may increase by 10% to 15%, primarily as a result of pregnancy-induced vascular swelling of the gland. Although this enlargement can be recognized by ultrasound, it cannot usually be appreciated by palpation. Therefore, any goiter found during pregnancy in an iodine-replete area should be evaluated in the same manner as a goiter occurring outside of pregnancy.
11. Does thyroid hormone cross the placenta?
Thyroid hormone crosses the placenta poorly but significantly, partly because of the high placental activity of the type 3 monodeiodinase (D3) that converts T4 to reverse T3 (rT3) and T3 to T2. However, it is now clear that some T4 does cross the placenta, because fetuses with complete thyroid agenesis have approximately 30% to 40% of the normal amount of thyroid hormone at birth. The amount of maternal thyroid hormone transported across the placenta appears to be protective to the brain, and neurologic development of the newborn usually progresses normally as long as thyroid supplementation is begun immediately after birth. Evidence also suggests that transthyretin, a circulating thyroid hormone binding protein synthesized and secreted by the placenta, may provide a mechanism for delivery of thyroid hormone to the fetus. To date, six thyroid hormone transporters have been identified in placental tissue. However, T3 crosses the placenta poorly, and T3 preparations should not be used in pregnancy.
12. Does iodine cross the placenta?
Iodine easily crosses the placenta for use by the fetal thyroid, which, after 12 to 14 weeks of gestation, takes up iodine even more avidly than does the maternal thyroid.
13. What about thyrotropin-releasing hormone (TRH) and TSH?
TRH, but not TSH, also crosses the placenta and has been used in experimental protocols to attempt to accelerate fetal lung maturity.
14. Summarize the ability of thyroid-related antibodies to cross the placenta.
Immunoglobulin G (IgG) TSH receptor-stimulating antibodies (thyroid-stimulating immunoglobulins [TSI] and TSH receptor antibodies [TRAB]) cross the placenta as early as 18 to 20 weeks of gestation and can occasionally cause fetal or neonatal hyperthyroidism in infants of women with Graves’ disease when antibody levels are at least 2.5-fold elevated. It is recommended that both TSI and TRAB be measured because if either antibody is 2.5 to 3 times normal, surveillance for fetal Graves’ disease is indicated. Although anti-TPO antibodies and antithyroglobulin (TG) antibodies can also cross, they usually have no clinical significance in affecting fetal thyroid function. In rare cases, they may be associated with thyrotropin receptor-blocking antibodies that can cause transient neonatal hypothyroidism.
15. List common medications that cross the placenta.
16. Describe fetal thyroid function and brain development.
At approximately 12 to 14 weeks of gestation, the fetal thyroid gland develops, and the hypothalamic-pituitary-thyroid axis begins to function. Before 16 weeks, however, the fetus relies solely on transplacental delivery of T4. Significant amounts of thyroid hormone cross the placenta in the first trimester and early second trimester before the fetal thyroid begins functioning, and they appear necessary for normal brain development. Thyroid hormones and type 2 deiodinase (D2) have been observed in the fetal cerebral cortex by 5 to 7 weeks. These findings emphasize the importance of maternally derived T4 conversion to T3 in the brain in influencing neuronal and astrocyte proliferation and migration early in pregnancy. Rat studies indicate that fetal brain T3 depends on an adequate supply of T4 and cannot be replenished by T3 alone. In early pregnancy, when adequate fetal thyroid hormone is crucial for normal neurologic development, fetal brain T4 levels reflect maternal levels. Further, T4 is taken up by receptors on fetal brain astrocytes and is deiodinated to produce T3, thus underscoring the importance of maternal T4 in pregnancy.
17. Is fetal thyroid hormone production independent of the mother?
After the first and early second trimesters, the fetal hypothalamic-pituitary-thyroid axis is fairly independent of the mother, with the exception of its dependence on adequate maternal iodine stores. Antithyroid drugs or high levels of TSI or TRAB may, however, affect fetal thyroid function or cause goiter development at this stage. Thyroid hormone and TBG levels increase in the fetus and plateau at about 35 to 37 weeks of gestation. High fetal levels of rT3 and low T3 levels are maintained throughout the pregnancy as a result of the high placental D3 activity. The fetal pituitary-thyroid axis is relatively immature, however, considering the increased fetal TSH levels relative to the low level of T4 production at birth. At the time of labor and in the early neonatal period, there are dramatic increases in T4 levels and the capacity of the liver to convert T4 to T3.
18. What is gestational transient thyrotoxicosis or thyrotoxicosis related to hyperemesis gravidarum?
Gestational transient thyrotoxicosis (GTT) refers to maternal hyperthyroidism caused by elevated levels of hCG, which binds to the TSH receptor and can stimulate thyroid hormone release. Levels greater than 75,000 IU/mL, which may be seen in women with hyperemesis gravidarum, twin gestation, and especially molar pregnancies, can often cause hyperthyroidism. Posttranslational modification of the sialylation of hCG can change its affinity for the TSH receptor and half-life in the circulation, thus resulting in elevated thyroid hormone levels in the first half of pregnancy. A woman who presents with hyperthyroidism, vomiting, and a positive pregnancy test should have a fetal ultrasound examination to exclude a molar pregnancy.
Women with hyperemesis gravidarum (persistent nausea and vomiting accompanied by electrolyte derangements and at least a 5% weight loss) commonly have abnormal thyroid function tests. In one of the largest series yet to be published, half of the 57 women with hyperemesis gravidarum had elevated FT4 levels.
19. What are the most common causes of hyperthyroidism in pregnancy? During what period of gestation is hyperthyroidism most likely to occur?
Hyperthyroidism complicates pregnancy in about 0.2% of women. Graves’ disease, the most common cause of hyperthyroidism in pregnancy, accounts for nearly 85% of the cases. Autoimmune thyroid disease is most likely to manifest in the first trimester or the postpartum period because the immune suppression of pregnancy has been shown to decrease thyroid antibody levels significantly during the second and third trimesters. Other causes include toxic multinodular goiters, solitary toxic adenomas, iodine-induced hyperthyroidism, and subacute thyroiditis. As noted earlier, hCG-induced hyperthyroidism is common in women with hyperemesis gravidarum or hydatidiform moles and also usually manifests in the first trimester.
20. Summarize the diagnostic approach to the pregnant woman with hyperthyroidism.
Normal pregnancy can produce clinical features that mimic hyperthyroidism, such as heat intolerance, mild tachycardia, increase in cardiac output, a systolic flow murmur, peripheral vasodilatation, and a widened pulse pressure. Weight loss may be obscured by the weight gain of pregnancy. As in the nonpregnant state, hyperthyroidism in pregnancy is usually characterized by low serum TSH levels and increased serum levels of FT4. However, in interpreting thyroid tests in pregnant women, it is important to realize that serum TSH levels are also frequently low in normal pregnant women, especially during the first trimester of pregnancy (see Question 2).
21. How can the various causes of hyperthyroidism be differentiated with certainty?
Radioisotope scans are contraindicated during pregnancy; therefore, the differential diagnosis of hyperthyroidism in pregnant women must be based on the history, physical examination, and laboratory testing. An obstetric ultrasound study may be indicated to exclude a hydatidiform mole or to look for twin pregnancies.
22. What findings help distinguish Graves’ disease from GTT?
Although a diffusely enlarged thyroid gland with a bruit in a woman with ophthalmopathy and pre-pregnancy symptoms strongly suggests Graves’ disease, the diagnosis is often less clear because these findings may be absent. If a woman is actively vomiting, the distinction between early Graves’ disease and gestational hyperthyroidism accompanied by hyperemesis gravidarum may be particularly difficult. It is unusual, however, for women to develop hCG-induced hyperthyroidism at hCG levels less than 50,000 IU/mL. Clues pointing to Graves’ disease rather than hCG-induced hyperthyroidism include the presence of a goiter, ophthalmopathy, onycholysis, or preexisting hyperthyroid symptoms antedating the pregnancy. In addition, TSI or TRAB levels are often positive and T3 levels are generally higher in Graves’ disease because hyperemesis gravidarum results in a compromised nutritional state and decreased conversion of T4 to T3 in peripheral tissues.
23. Why is it important to distinguish GTT from Graves’ disease?
It may be difficult to differentiate GTT from other causes of hyperthyroidism because autoimmune hyperthyroidism also commonly manifests during the first trimester of pregnancy, and the biochemical profile of the two conditions is similar. However, it is extremely important to determine whether the thyrotoxicosis results from Graves’ disease or GTT because the latter usually resolves without antithyroid treatment by approximately 18 weeks when hCG levels decline. It is rarely necessary to treat with beta-blocker therapy or antithyroid drugs given that the hyperthyroid state is usually self-limited. Hyperthyroidism is probably not the cause of the nausea. Instead, it appears that hCG mediates both the hyperthyroidism and the nausea by different mechanisms.
24. Why is the woman’s original country of residence significant?
Women who have goiters from areas of endemic iodine deficiency and who move to the United States may develop iodine-induced hyperthyroidism when they suddenly become iodine replete. Hot nodules can also occur and do not improve in later pregnancy with the immune suppression of pregnancy.
25. What are the risks of Graves’ disease to the mother?
Inadequately treated hyperthyroidism in the mother can result in preeclampsia, weight loss, tachycardia, proximal muscle weakness, anxiety, and atrial fibrillation. Left ventricular dysfunction can occur and is usually reversible, but it may persist for several weeks after biochemical hyperthyroidism has been corrected. This cardiac condition may place the pregnant woman at risk for the development of congestive heart failure, especially in the presence of superimposed preeclampsia, infection, anemia, or at the time of delivery. Thyroid storm can rarely occur in these women.
26. What are the risks to the fetus of maternal Graves’ disease?
Inadequately treated maternal hyperthyroidism can result in fetal tachycardia, severe growth restriction, premature births, and a ninefold increased incidence of low birth weight in the infants. Congenital malformations are probably not increased in babies born to mothers with either treated or untreated hyperthyroidism. Inadequately treated maternal hyperthyroidism can cause suppression of the hypothalamic-pituitary-thyroid axis, thus resulting in temporary central hypothyroidism in the neonate and the inability of the neonate to mount an appropriate TSH response.
27. Describe the possible effects on the fetus of high levels of TSH receptor-stimulating antibodies and how they manifest in the fetus,
