Increased iodine clearance. Starting early in pregnancy, increased renal blood flow and glomerular filtration lead to increased clearance of iodine from maternal plasma. Iodine is also transported across the placenta for iodothyronine synthesis by the fetal thyroid gland after the first trimester. These processes increase the maternal dietary requirement for iodine but have little impact on the maternal plasma iodine level or maternal or fetal thyroid function in iodine-sufficient regions such as the United States. To ensure adequate intake, supplementation with 150 mcg per day of iodine is recommended for pregnant and lactating women; of note, many prenatal vitamins lack iodine. In contrast, in regions with borderline or deficient iodine intake, increased iodine clearance and transplacental transfer may lead to decreased thyroxine (T₄) and increased thyroid-stimulating hormone (TSH) levels, as well as increased thyroid gland volume in both the mother and fetus.

Human chorionic gonadotropin (hCG) has weak intrinsic TSH-like activity. The high circulating level of hCG in the first trimester leads to a small, transient increase in free T₄ accompanied by partial suppression of TSH that resolves by approximately the 14th week of gestation.

Increased thyroxine-binding globulin (TBG) levels occur early in pregnancy. TBG doubles by mid-gestation then plateaus at a high level. This TBG rise occurs largely as a result of diminished hepatic clearance of TBG from the plasma due to increased estrogen-stimulated sialation of the TBG protein. Estrogen also stimulates TBG synthesis in the liver.

Increased total triiodothyronine (T₃) and T₄ levels occur from early in gestation as a result of rapidly increasing TBG levels (see I.C.). Free T₄ levels rise much less than total T₄ in early pregnancy (see I.B.), then decline progressively in the second and third trimesters. This physiologic decline is minimal (<10%) in iodine-sufficient regions but may be more pronounced in regions with borderline or deficient iodine intake. Direct free T₄ assays may be affected by TBG and should not be used to monitor maternal thyroid function during pregnancy.

TSH levels decline in the first trimester in the setting of elevated levels of hCG (see I.B.) and may transiently fall below the normal range for nonpregnant women in approximately 20% of healthy pregnancies. After the first trimester, TSH levels return to the normal, nonpregnant range.

The negative feedback control mechanisms of the hypothalamic-pituitary-thyroid (HPT) axis remain intact.

Placental metabolism and transplacental passage. Iodine and TSH-releasing hormone (TRH) freely cross the placenta. The placenta is also permeable to
thyroid stimulating and blocking IgG antibodies, as well as antithyroid drugs, but is impermeable to TSH. T₄ crosses the placenta in limited amounts due to inactivation by the type 3 deiodinase (D3) enzyme, which converts T₄ to inactive reverse T₃, rather than to T₃. T₃ is similarly inactivated. In the setting of fetal hypothyroxinemia, maternal—fetal transfer of T₄ is increased, particularly in the second and third trimesters, protecting the developing fetus from the effects of fetal hypothyroidism.

Graves’ disease accounts for ≥85% of clinical hyperthyroidism in pregnancy. Hyperemesis gravidarum is associated with transient subclinical or mild hyperthyroidism that may be due to the thyroid stimulatory effects of hCG and typically resolves without treatment.

Signs and symptoms of hyperthyroidism may be nonspecific and include tachycardia, increased appetite, tremor, anxiety, and fatigue. The presence of goiter, ophthalmopathy, and/or myxedema suggests Graves’ disease.

Poorly controlled maternal hyperthyroidism is associated with serious pregnancy complications, including spontaneous abortion, preterm delivery, intrauterine growth restriction (IUGR), fetal demise, preeclampsia, placental abruption, thyroid storm, and congestive heart failure (CHF).

Treatment of maternal hyperthyroidism substantially reduces the risk of associated maternal and fetal complications.

Fetal and neonatal hyperthyroidism occurs in approximately 1% to 5% of cases of maternal Graves’ disease and results from transplacental passage of TSH receptor—stimulating antibodies. High levels of these antibodies in maternal serum are predictive of fetal and neonatal hyperthyroidism. All pregnant women with Graves’ disease should be monitored for fetal hyperthyroidism through serial assessment of fetal heart rate and prenatal ultrasound to detect the presence of fetal goiter and monitor fetal growth. Maternal treatment with antithyroid drugs is effective in treating fetal hyperthyroidism, but if excessive, it can also suppress the fetal thyroid gland and cause hypothyroidism.

Fetal and neonatal hypothyroidism and maternal Graves’ disease. Fetal exposure to PTU or MMI can cause transient hypothyroidism that resolves rapidly and usually does not require treatment (see VI.A.2.a.). In the setting of a history of prior maternal Graves’ disease, transplacental passage of TSH receptor—blocking antibodies may cause fetal hypothyroidism. A rare neonatal outcome of maternal Graves’ disease is transient pituitary suppression and central hypothyroidism, which may be due to prolonged intrauterine hyperthyroidism. Usually, the serum concentration of TSH receptor—stimulating antibodies is only modestly elevated. Infants of mothers with Graves’ disease can present with thyrotoxicosis or hypothyroidism in the newborn period and require close monitoring after birth (see VII.).

The most common cause of maternal hypothyroidism in iodine-sufficient regions is chronic autoimmune thyroiditis. Other causes include previous treatment of Graves’ disease or thyroid cancer with surgical thyroidectomy or radioablation, drug- and external radiation—induced hypothyroidism, congenital hypothyroidism in the mother, and pituitary dysfunction. Chronic autoimmune thyroiditis is more common in patients with type 1 diabetes mellitus. Rarely, mothers with a prior history of Graves’ disease become hypothyroid due to the development of TSH receptor—blocking antibodies.

Signs and symptoms of hypothyroidism in pregnancy include weight gain, cold intolerance, dry skin, weakness, fatigue, and constipation and may go unnoticed in the setting of pregnancy, particularly in subclinical hypothyroidism.

Unrecognized or untreated hypothyroidism is associated with spontaneous abortion and maternal complications of pregnancy, including anemia, preeclampsia, postpartum hemorrhage, placental abruption, and need for cesarean delivery. Associated adverse fetal and neonatal outcomes include preterm birth, IUGR, congenital anomalies, fetal distress in labor, and fetal and perinatal death. However, these complications are avoided with adequate treatment of hypothyroidism, ideally from early in pregnancy. Affected fetuses may experience neurodevelopmental impairments, particularly if both the fetus and the mother are hypothyroid during gestation (e.g., iodine deficiency, TSH receptor—blocking antibodies).

Women with preexisting hypothyroidism who are treated appropriately typically deliver healthy infants. Thyroid function tests should be measured as soon as pregnancy is confirmed, 4 weeks later, at least once in the second
and third trimesters, and additionally 4 to 6 weeks after any L-thyroxine dose change. The TSH level should be maintained in the low-normal range (<2.5 mU/L), which often requires a T₄ dose 30% to 50% higher than in the nonpregnant state.

Routine thyroid function testing in pregnancy is currently recommended only for symptomatic women and women with a family history of thyroid disease. Because this strategy detects only two-thirds of women with hypothyroidism, many authors advocate universal screening in early pregnancy; however, this topic remains controversial.

TSH receptor—blocking antibodies cross the placenta and may cause fetal and transient neonatal hypothyroidism (see VI.A.2.e.).

Fetal ultrasound by an experienced ultrasonographer is an excellent tool for intrauterine diagnosis and monitoring of fetal goiter.

Maternal Graves’ disease is the most common cause of fetal and neonatal goiter, which results most often from fetal hypothyroidism due to PTU or MMI. Fetal and neonatal goiter can also result from fetal hyperthyroidism due to TSH receptor-stimulating antibodies. Antibody-mediated fetal effects can occur in women with active Graves’ disease or women previously treated with surgical thyroidectomy or radioablation. Maternal history and serum antibody testing is usually diagnostic. Rarely, cord blood sampling is necessary to distinguish between PTU- or MMI-induced fetal hypothyroidism and TSH receptor-stimulating antibody-induced fetal hyperthyroidism. After delivery, neonates exposed in utero to PTU or MMI eliminate the drug rapidly. Thyroid function tests usually normalize by 1 week of age, and treatment is not required.

Other causes of fetal and neonatal goiter include fetal disorders of thyroid hormonogenesis (usually inherited), excessive maternal iodine ingestion, and iodine deficiency. Goiter resolves with suppression of the serum TSH concentration by L-thyroxine treatment on iodine replacement.

Fetal goiter due to hypothyroidism is usually treated with maternal L-thyroxine administration. Rarely, treatment with intra-amniotic injections of L-thyroxine in the third trimester is used to reduce the size of fetal goiter and minimize complications of tracheoesophageal compression, including poly-hydramnios, lung hypoplasia, and airway compromise at birth.

The fetal HPT axis develops relatively independent of the mother due to the high placental concentration of D3, which inactivates most of the T₄ presented from the maternal circulation (see I.G.).

Thyroid embryogenesis is complete by 10 to 12 weeks’ gestation, by which time the fetal thyroid gland starts to concentrate iodine and synthesize and secrete T₃ and T₄. T₄ and TBG levels increase gradually throughout gestation. Circulating T₃ levels remain low, although brain and pituitary T₃ levels are considerably higher as a result of a local intracellular type 2 deiodinase (D2) enzyme, which converts T₄ to the active isomer T₃. In the setting of fetal hypothyroidism, D2
activity in the brain maintains local T₃ concentration, allowing normal development to proceed.

TSH from the fetal pituitary gland increases from mid-gestation. The negative feedback mechanism of the HPT axis starts to mature by 26 weeks of gestation. Circulating levels of TRH are high in the fetus relative to the mother, although the physiologic significance is unclear.

The ability of the thyroid gland to adapt to exogenous iodine does not mature until 36 to 40 weeks’ gestation. Thus, premature infants are more sensitive than are full-term infants to the thyroid suppressing effects of exogenous iodine.

Neonatal physiology. Within 30 minutes after delivery, there is a dramatic surge in serum TSH, with peak levels as high as 80 mU/L at 6 hours of life, followed by a rapid decline over 24 hours, then a slower decline over the first week of life. The TSH surge causes marked stimulation of the neonatal thyroid gland. Serum T₃ and T₄ levels increase sharply and peak within 24 hours of life, followed by a slow decline.

In the preterm infant, the pattern of postnatal thyroid hormone change is similar to the pattern seen in the full-term infant, but the TSH surge is less marked, and the T₄ and T₃ responses are blunted. In very preterm infants (<31 weeks’ gestation), no surge is seen and, instead, the circulating T₄ level may fall for the first 7 to 10 days. Umbilical cord blood thyroid hormone levels are directly related to gestational age and birth weight (Table 3.1).

CH is one of the most common preventable causes of mental retardation. The incidence of CH varies globally. In the United States, the incidence is approximately 1:2,500 and appears to be rising. CH is more common among Hispanic (1:1, 600) and Asian Indian (1:1, 757) infants but less common among non-Hispanic black infants (1:11, 000). The female-to-male ratio is 2:1. CH is also more common in infants with trisomy 21, congenital heart disease, and other congenital malformations, including renal, skeletal, gastrointestinal anomalies, and cleft palate. CH may be permanent or transient. Hypothyroxinemia with delayed TSH rise can be caused by permanent or transient conditions.