Reference values — Total Thyroxine (T4)

Total T4 increases during pregnancy as thyroxine-binding globulin (TBG) rises in response to estrogen. Free T4 remains within or slightly below the nonpregnant range when TBG and binding changes are properly accounted for.

Units Nonpregnant Adult First Trimester Second Trimester Third Trimester
µg/dL 5.4 – 11.7 6.5 – 10.1 7.5 – 10.3 6.3 – 9.7
nmol/L 69 – 151 84 – 130 97 – 133 81 – 125
Total T4 (serum). Ranges adapted from Abbassi-Ghanavati et al. and thyroid function references. Exact cutoffs vary by assay and laboratory.
Physiologic changes in pregnancy
  • Estrogen-induced ↑TBG: Rising maternal estrogen (especially from the late first trimester) increases hepatic synthesis and sialylation of TBG, prolonging its half-life and raising circulating TBG concentrations 2–3 fold.
  • Rise in total T4: Because >99% of T4 is protein-bound, the increase in TBG leads to a ~1.5-fold rise in total T4 concentrations by mid-gestation compared with nonpregnant values.
  • Free T4 stays near normal: After a brief early shift while equilibrium is re-established, free T4 usually remains within (or slightly below) nonpregnant reference limits when measured accurately.
  • hCG effect in early pregnancy: hCG weakly stimulates the TSH receptor, transiently increasing thyroid hormone secretion and suppressing TSH (particularly in the late first trimester). Total T4 may be modestly higher at that time.
  • Use pregnancy-adjusted reference ranges: Where trimester-specific reference ranges for total T4 are not available, some guidelines suggest that the nonpregnant upper reference limit can be increased by ~50% to approximate the pregnancy-adjusted upper limit.
Causes of elevated total T4

Elevated total T4 may reflect true hyperthyroidism or increased binding proteins with normal free hormone. Interpret in conjunction with TSH, free T4, and clinical findings.

  • Physiologic / binding protein–mediated
    • Normal pregnancy (estrogen-mediated ↑TBG)
    • Exogenous estrogen (oral contraceptives, hormone therapy, estrogen-producing tumors)
    • Hereditary or idiopathic TBG excess
    • Acute hepatitis or cholestatic liver disease increasing TBG
  • True thyrotoxicosis
    • Graves’ disease
    • hCG-mediated hyperthyroidism (hyperemesis gravidarum, molar pregnancy, choriocarcinoma)
    • Toxic multinodular goiter or autonomous (toxic) nodule
    • Thyroiditis (subacute, painless, or postpartum with thyrotoxic phase)
    • Excess exogenous thyroid hormone
  • Analytical or binding abnormalities
    • Familial dysalbuminemic hyperthyroxinemia
    • Interference from heterophile antibodies or assay artifacts
Causes of low total T4

Low total T4 may result from true hypothyroidism, reduced TBG, or non-thyroidal illness. Free T4 and TSH are needed to clarify etiology.

  • Primary hypothyroidism
    • Chronic autoimmune (Hashimoto) thyroiditis
    • Post-ablative or post-surgical hypothyroidism
    • Iodine deficiency or excess iodine exposure
    • Inadequate thyroid hormone replacement therapy
  • Central (secondary/tertiary) hypothyroidism
    • Pituitary or hypothalamic disease (tumor, surgery, radiation, Sheehan syndrome)
  • Reduced TBG or protein binding
    • Nephrotic syndrome
    • Severe liver disease or cirrhosis
    • Hereditary or idiopathic TBG deficiency
    • Androgen or glucocorticoid therapy, anabolic steroids
    • Severe systemic illness or malnutrition
  • Non-thyroidal illness (euthyroid sick syndrome)
    • Severe acute or chronic illness (sepsis, cardiac failure, trauma)
    • Medications altering thyroid hormone metabolism (amiodarone, dopamine, high-dose glucocorticoids)

References

  1. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114(6):1326–1331. PMID: 19935037.
  2. Brent GA. Maternal thyroid function: interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol. 1997;40(1):3–15. PMID: 9103946.
  3. Fischbach FT, Dunning MB III, eds. A Manual of Laboratory and Diagnostic Tests, 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2004.