Congenital hypothyroidism occurs in approximately 1 in 6,000 infants (literature range, 1-3/10,000), which makes it about 3 times as common as phenylketonuria (PKU). Approximately 85% of cases are due to thyroid agenesis and 10% are defects of enzymes in thyroid hormone synthesis, so that about 95% of all cases are primary hypothyroidism and 3%-5% are secondary to pituitary or hypothalamic malfunction. Screening tests that have received the most attention include T4, TSH, and reverse T3.

There is minimal T4 and T3 placental transfer from mother to fetus in utero. At birth, cord blood T4 values range from the upper half of normal to mildly elevated, compared with nonpregnant adult reference values (e.g., cord blood average levels of 11-12 µg/100 ml [142-154 nmol/L] compared with nonpregnant adult average values of about 9 µg/100 ml [116 nmol/L]). The T3-RIA level is about one third to one half of adult levels, the reverse T3level is about 5 times the adult levels, and the TSH has a mean value about twice that of adults but ranges from near zero to nearly 3 times adult upper limits. There is a strong correlation between birth weight and neonatal T4 and TSH values. At birth, premature infants have T4 values averaging one third lower than those of normal birth weight infants (although individual measurements are variable), with the subsequent changes in T4levels between premature and full-term infants remaining roughly parallel for several days. The TSH value at birth is also about one third lower in premature than in full-term infants but becomes fairly close to full-term infant levels at 24 hours of age.

After birth, the TSH value surge about 5-7 times birth values to a peak at 30 minutes, then falls swiftly to levels about double birth values at 24 hours. The fall continues much more slowly to values about equal to those at birth by 48 hours and values about one half of birth levels at 4-5 days. After birth, the T4 level increases about 30%-40%, with a plateau at 24-48 hours, and returns to birth levels by about 5 days. The TBG value does not change appreciably.

There is some disagreement in the literature regarding the best specimen to use for neonatal screening (heel puncture blood spot on filter paper vs. cord blood) and the best test to use (T4 vs. TSH assay). Most screening programs use filter paper methods because cord blood is more difficult to obtain and transport. Most programs use T4 assay as the primary screening test because T4 assay in general is less expensive than TSH assay, because TSH is more likely to become falsely negative when the specimen is subjected to adverse conditions during storage and transport, and because TSH assay values will not be elevated in the 10% of cases that are due to pituitary or hypothalamic dysfunction. Disadvantages of T4 assay include occasional mildly hypothyroid infants with T4 levels in the lower portion of the reference range but with clearly elevated TSH values. In one series this pattern occurred in 2 of 15 hypothyroid infants (13%). Some institutions therefore retest all infants whose T4 values fall in the lower 10% of the reference range. Another problem concerns approximately 20% of neonatal T4 results in the hypothyroid range that prove to be false positive (not hypothyroid), most of which are due to prematurity or decreased TBG.

In conclusion, the box lists conditions that can produce various T4 (TI or FT4) and TSH patterns.

Interpretation of T4 and TSH Patterns*

T4 Low, TSH Low
Lab error (T4 or TSH)
Some patients with severe non thyroid illness (esp. acute trauma, dopamine, or glucocorticoid drugs)†
Pituitary insufficiency
Cushing’s syndrome (and some patients on high-dose glucocorticoid therapy)
T3 toxicosis plus dilantin therapy or severe TBG deficiency
T4 Low, TSH Normal
Lab error (T4 or TSH)
Severe nonthyroid illness*
Severe TBG or albumin deficiency
Dilantin, valproic acid (Depakene) or high-dose salicylate therapy)
Moderate iodine deficiency
Furosemide combined with decreased albumin or TBG
Few patients with secondary hypothyroidism (mild TSH decrease in patient with previous TSH in upper-normal range)
Pregnancy in third trimester (many, not all, FT4 kits)
Some female distance runners in training
Some patients with mild hypothyroidism plus prolonged fasting or severe non thyroid illness
Heparin effect (some FT4 kits)
T4 Low, TSH Elevated
Lab error (T4 or TSH)
Primary hypothyroidism
Some patients with severe non thyroid illness in recovery phase†
Large doses of inorganic iodide (e.g., SSKI)
Some patients on lithium or amiodarone therapy
Some patients on Synthroid therapy with slightly insufficient dose or patient noncompliance
Some patients on dilantin or high-dose salicylate therapy or with severe TBG deficiency plus some non-hypothyroid cause for elevated TSH
“T4 low-TSH normal” conditions plus presence of antibodies interfering with TSH assay§
Severe iodine deficiency
Some patients (30%) with Addison’s
Disease interleukin-2 therapy (15%-26% of cases)
Alpha-interferon therapy (1.2% of cases)
T4 Normal, TSH Low
Lab error (T4 or TSH)
T3 toxicosis
Mild hyperthyroidism plus decreased TBG, Dilantin therapy, and/or severe non thyroid illness
Early hyperthyroidism (TSH mildly decreased, T4 upper normal [Free T3 may be elevated])
Pituitary insufficiency plus increased TBG
Some patients with Synthroid therapy in slightly excess dose
Few patients with severe non thyroid illness†
Some patients 4-6 weeks (2 weeks-2 yrs) after RAI, surgery, or antithyroid drug therapy for hyperthyroidism
Some patients with multinodular goiter containing areas of autonomy
“T4 low-TSH low” plus heparin therapy
T4 Normal, TSH Normal
Normal thyroid function
Lab error (T4 or TSH)
Few patients with early hypothyroidism (only the TRH test abnormal)
“T4 low-TSH normal” plus heparin therapy†
T4 Normal, TSH Elevated
Lab error (T4 or TSH)
Mild hypothyroidism
Hypothyroidism plus increased TBG
Hypothyroidism with slightly inadequate dose of replacement therapy
Addison’s disease (majority of cases)
TSH specimen drawn in the evening (peak of diurnal variation)
Few patients with iodine deficiency (T4 is usually decreased)
Few patients with severe non thyroid illness in recovery phase†
Some patients with mild Hashimoto’s disease
Insufficient time after start of therapy for hypothyroidism; usually need 3-6 weeks (range, 1-8 weeks, sometimes longer when pre-therapy TSH is over 100)
“T4 normal-TSH normal” status plus antibodies interfering with TSH assay§
Some patient on lithium therapy (T4 usually but not always decreased)
Few patients with acute psychiatric illness
Hypothyroidism with familial dysalbuminemic hyperthyroxinemia
“T4 low-TSH elevated” plus heparin therapy†
T4 Elevated, TSH Low
Lab error (T4 or TSH)
Primary hyperthyroidism
Excess therapy of hypothyroidism
Some patients with active thyroiditis (subacute, painless, early active Hashimoto’s disease)
Jod-Basedow hyperthyroidism
TSH drawn 2-4 hours after Synthroid dose (few patients)
Postpartum transient toxicosis
Factitious hyperthyroidism
Struma ovarii
Hyperemesis gravidarum
Alpha-interferon therapy (1.2% of cases)
Interleukin-2 therapy (3%-6% of cases)
T4 Elevated, TSH Normal
Lab error (T4 or TSH)
TBG increased
Some patients with Synthroid therapy in adequate dose
Occasional patient with severe nonthyroid illness†
Some acute psychiatric patients (esp. paranoid schizophrenics)
T4 sample drawn 2-4 hours after T4 dose
Peripheral resistance to T4 syndrome (some patients)
Some patients with pituitary TSH-secreting tumor (when pretumor TSH was low normal)
Some patients on amiodarone therapy
Occasional patients on propranolol therapy
Certain x-ray contrast media‡
Acute porphyria
Heroin abuse or acute hepatitis B (causing increased TBG)
Heparin effect (some FT4 kits)
Familial dysalbuminemic hyperthyroxinemia (analog FT4 methods)
Amphetamine or PCP abuse (some patients)
Desipramine drugs (some patients)
T4 Elevated, TSH Elevated
Lab error (T4 or TSH)
Pituitary TSH-secreting tumor
Some patients with certain x-ray contrast media‡
Peripheral resistance to T4 syndrome (some patients)
Some patients on amiodarone therapy or amphetamines
“TSH elevated-T4 normal” status plus some independent reason for T4 to become elevated
Few patients with acute psychiatric illness
*High-sensitivity TSH method is assumed; FT4 or TI can be substituted for T4, but in general are not altered as frequently as T4 in nonthyroid conditions.
†Depends on individual TSH and/or FT4 kit.
‡Telepaque (iopanoic acid) and Oragrafin (ipodate).
§Some (not all) sandwich-method double-antibody kits, using mouse-derived monoclonal antibody.