THYROID ADAPTATION DURING NORMAL PREGNANCY DR ABOTORABI PERINATOLOGIST

THYROID ADAPTATION DURING NORMAL PREGNANCY DR ABOTORABI PERINATOLOGIST

• The thyroid gland is a bilobed gland composed of spherical follicles • Each follicle has a colloid center surrounded by a single layer of follicle cells • Intimately involved with the follicle cells are parafollicular C cells, lymphatic drainage channels, and capillary networks.

• Iodide ions are actively transported from the blood onto the apical surface of the follicle cells and are oxidized to iodine through the action of thyroid peroxidase

• The thyroid gland regulates the amount of iodide it actively traps and can withstand fluctuations in dietary supply. • In the lumen, colloid iodide is incorporated into the tyrosine residues of thyroglobulin (also made in the follicle cells) to produce inactive mono-iodotyrosine and di-iodotyrosine.

• This process is known as organification of iodide. • Combinations of these products lead to the formation of the active thyroid compounds thyroxine (T 4) and triiodothyronine (T 3), which are released into the capillary network at the apical surface of follicle cells having re -entered from the colloid at their basal surface(endocytosis)

• Pregnancy is a state of relative iodine deficiency because of increased renal loss (increased glomerular filtration rate in the early first trimester) and transfer of iodine to the developing fetus.

• To compensate, the thyroid gland increases its uptake of iodine from the blood. • If the supply is insufficient, cellular hyperplasia and goiter result.

• Although a physiologic goiter may be seen on ultrasound examination by a change in gland size of 10 to 20%, this change is not clinically detectable. • A clinically apparent goiter suggests iodine deficienry or pathology

• The fetal thyroid gland begins to form at 5 weeks' gestation and has some function at 10 weeks, but it is only autonomous at 12 weeks, when T 3, T 4 and TSH levels can be measured in fetal serum

• Levels continue to increase until 35 to 37 weeks' gestation, when they reach adult levels.

• The fetal thyroid concentrates iodine at a significantly higher rate than the maternal thyroid. • Diagnostic scanning or uptake with radioactive tracers, such as iodine- 131 or technetium-99, or radioactive iodine therapy should be avoided because of the risks of exposure to the developing fetus.

h. CG and thyroid function • h. CG is one of a family of glycoprotein hormones, including TSH, with a common alpha-subunit and a unique beta-subunit. • there is considerable homology between the betasubunits of h. CG and TSH

• As a result, h. CG has weak thyroid-stimulating activity • In a human thyroid cell-culture assay, as an example, 1 micro. U of h. CG was equivalent to 0. 0013 micro. U of TSH

• Serum h. CG concentrations increase soon after fertilization and peak at 10 to 12 weeks. • During this peak, total serum T 4 and T 3 concentrations increase. • Serum free T 4 and T 3 concentrations increase slightly, usually within the normal range, and serum TSH concentrations are appropriately reduced

• The reason for this increase may be to provide the fetus with T 4 before it becomes autonomous. • These changes must be considered when a diagnosis of hyperthyroidism is contemplated in early pregnancy, especially in the context of hyperemesis gravidarum, where h. CG secretion may be exaggerated, or in trophoblastic disease, where it is grossly elevated

• The increase in h. CG that occurs in early pregnancy "spills over" and stimulates the TSH receptor, suppressing TSH and increasing T 4.

Thyroid physiology • The major changes in thyroid function during pregnancy are an increase in serum thyroxine-binding globulin (TBG) concentrations and • stimulation of the thyrotropin (TSH) receptor by human chorionic gonadotropin (h. CG).

Thyroxine binding globulin • During pregnancy, serum TBG concentrations rise almost two-fold because estrogen increases TBG production and TBG sialylation, which results in decreased clearance of TBG • To maintain adequate free thyroid hormone concentrations during this period, thyroxine (T 4) and triiodothyronine (T 3) production by the thyroid gland must increase

• Total T 4 and T 3 concentrations rise during the first half of pregnancy, plateauing at approximately 20 weeks of gestation, at which time a new steady state is reached and the overall production rate of thyroid hormones returns to prepregnancy rates. • TBG excess leads to an increase in both serum total T 4 and T 3 concentrations

• TWO thirds of women with hyperemesis have abnormal thyroid function test results in the absence of thyroid disease, with 30% having undetectable TSH, 60% having suppressed TSH, and 59% having an elevated free T 4 level

• Little T 4 crosses the placenta after the first trimester, and the placenta is relatively impermeable to TSH and T 3 • Thyroid-releasing hormone, antithyroid medications (propylthiouracil, carbimazole, and methimazole), and iodine cross the placenta and may alter the fetal physiology

• Pregnanry causes an increase in thyroid-binding globu. Iin (and transthyretin) through the effecs of estrogen, which increases synthesis and decreases clearance • The elevation is present at 2 weeks' gestation and peaks at 20 weeks' gestation

• This elevation necessitates a small increase in the production of T 4 1 -3% and T 3 until this plateau is reached total T 3 and T 4 are elevated • Because only the free hormone is biologically active, only free hormone measurements are used in pregnancy

• TSH decreases in early pregnancy, but may increase in the third trimester although some authors have not shown this finding

• Concentrations of free T 4 decrease in the second half of pregnancy (below the range seen outside pregnanry) • Peripheral conversion of free T 4 to free T 3 is enhanced, and this increased efficiency may be in preparation for the exertions of labor and delivery

• However, in 10 to 20 percent of normal women, serum TSH concentrations are transiently low or undetectable • In a report of 63 women with extremely high h. CG concentrations (>200, 000 IU/L), TSH was <0. 2 micro. U/m. L in 67 percent of samples and free T 4 was above 1. 8 ng/d. L in 32 percent of samples. All women whose h. CG was greater than 400, 000 IU/L had a suppressed TSH concentration

• This transient, usually subclinical, hyperthyroidism should be considered a normal physiologic finding. • It is not known if this action of h. CG benefits the mother or fetus. • Later in pregnancy, as h. CG secretion declines, serum free T 4 and T 3 concentrations decline and serum TSH concentrations rise slightly to or within the normal range

Trimester-specific reference ranges • Because of the changes in thyroid physiology during pregnancy, the Guidelines of the American Thyroid Association (ATA) for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum recommend using trimester-specific reference ranges for TSH and method and trimester-specific reference ranges for serum free T 4

• Commercial laboratories should provide these reference ranges, but many commercial laboratories currently do not do this.

• In several population studies, the lower limit of the reference range for TSH in healthy pregnant women during the first trimester ranged from 0. 03 to 0. 1 m. U/L

• In one of the largest population-based studies (over 13, 000 pregnant women), the reference range (2. 5 to 97. 5 th percentile) for TSH in the first trimester was 0. 08 to 2. 99 m. U/L

• if the laboratory does not provide trimester-specific reference ranges for TSH (m. U/L), the following reference ranges can be used: • ●First trimester 0. 1 to 2. 5 • ●Second trimester 0. 2 to 3. 0 • ●Third trimester 0. 3 to 3. 0

• Some studies report a decrease in free T 4 during pregnancy, others report no change or even an increase

• Direct free T 4 measurements may be unreliable during pregnancy. • Measurement of free T 4 in the dialysate or ultrafiltrate of serum samples using liquid chromatography/tandem mass spectrometry appears to be the most reliable, and when this method is used, free T 4 concentrations were shown to decrease gradually with advancing gestational age, particularly between the first and second trimester

• This assay is relatively expensive and not universally available. • Other free T 4 assays (and probably free T 3 assays) frequently fail to meet performance standards in pregnant patients, owing to increases in TBG and decreases in albumin concentrations that cause the immunoassay to be unreliable

• To compensate, some kits have provided different free T 4 normal ranges for pregnant patients, usually lower than those of nonpregnant patients

• As an alternative, serum total T 4 measurements, which are more reliable during pregnancy, can be measured to assess thyroid function • When free T 4 measurements appear discordant with TSH measurements, serum total T 4 should be measured. • Total T 4 and T 3 levels during pregnancy are 1. 5 -fold higher than in nonpregnant women due to TBG excess. .

• The World Health Organization (WHO) recommends 250 mcg of iodine daily during pregnancy and lactation. • The Institute of Medicine recommends daily iodine intake of 220 mcg during pregnancy and 290 mcg during lactation. • For women in the United States to achieve this level of daily intake, the ATA recommends that women from the United States receive a supplement of 150 mcg of iodine daily during pregnancy and lactation, which is the dose included in the majority of prenatal vitamins marketed in the United States

• The tolerable upper intake amount for iodine, as established by European and United States expert committees, ranges from 600 to 1100 mcg daily for adults and pregnant women >19 years of age.