Neonatal Thyroid Screening

Changes in Thyroid Hormone Levels Around Birth

Fetal Thyroid Hormone Milieu

• During the final weeks of pregnancy, the fetal thyroid hormone profile is characterized by predominantly inactive metabolites, which prevents tissue thermogenesis and promotes the anabolic state necessary for rapid fetal growth.
• Fetal serum thyroxine (T4) and free T4 concentrations increase steadily from midgestation, reaching approximately 9.5 $\mu$g/dL and 1.4 ng/dL, respectively, at term.
• Fetal serum triiodothyronine (T3) levels remain low prior to 20 weeks of gestation, gradually increasing after 30 weeks to approximately 60 ng/dL at term.
• This low T3 state is maintained by low type I iodothyronine monodeiodinase activity (reducing T4 to T3 conversion) and high type III monodeiodinase activity in the placenta and fetal tissues, which degrades T3 to diiodothyronine (T2).
• Conversely, fetal reverse T3 (rT3), an inactive metabolite produced by inner ring monodeiodination of T4, is high in the fetus, reaching 300 ng/dL at 30 weeks and decreasing to 200 ng/dL at term.
• Fetal serum thyroid-stimulating hormone (TSH) levels gradually increase from low levels at midgestation to peak values of 6 to 10 mIU/L at term.

The Postnatal TSH Surge

• Immediately following birth, the separation of the neonate from the maternal blood supply and the exposure to the relatively colder extrauterine environment triggers an acute, cold-stimulated release of hypothalamic thyrotropin-releasing hormone (TRH) and pituitary TSH.
• Peak serum TSH concentrations reach 70 to 100 mIU/L approximately 30 minutes after delivery in full-term infants.
• Following this acute surge, TSH levels decline rapidly over the ensuing 24 hours, and then more gradually over the next 5 days, returning to baseline infant levels of 5 to 10 mIU/L by the end of the first week of life.
• After the first 1 to 3 months of life, normal serum TSH levels stabilize at less than 5 mIU/L.

Postnatal Changes in Thyroxine (T4) and Triiodothyronine (T3)

• The profound postnatal surge in TSH vigorously stimulates the thyroid gland, leading to an abrupt increase in the secretion and circulating levels of T4 and T3.
• Serum T4 levels increase to approximately 16 $\mu$g/dL and T3 levels rise to approximately 300 ng/dL within about 4 hours after birth, with both hormones peaking on the second to third day of life.
• The dramatic postnatal increase in serum T3 is driven both by direct TSH-stimulated thyroidal secretion and by a massive increase in the peripheral conversion of T4 to T3.
• This peripheral conversion is mediated by a cortisol- and T4-stimulated activation of hepatic type I deiodinase, as well as the activation of type II deiodinase in brown adipose tissue.
• The localized conversion of T4 to T3 by type II deiodinase in brown adipose tissue is essential for potentiating catecholamine-stimulated nonshivering thermogenesis, allowing the neonate to maintain body temperature.
• Simultaneously, placental separation halts placental type III deiodinase-mediated degradation of T3, further contributing to the elevated postnatal T3 pool.
• Following their peak on the second or third day, T4 levels gradually decrease over the first 2 to 4 weeks of life to reach levels characteristic of later infancy.
• Reverse T3 levels remain elevated at around 200 ng/dL for the first 2 weeks of life before decreasing to approximately 50 ng/dL by 4 weeks of age.

Thyroid Hormone Dynamics in Preterm and Low Birthweight Infants

• The postnatal changes in thyroid function in premature and low birthweight (LBW) infants are qualitatively similar to term infants but are quantitatively blunted.
• Cord blood T4 concentrations are proportionally decreased relative to gestational age and birthweight.
• The acute postnatal TSH surge is significantly reduced in these infants.
• Unlike term infants who experience an increase in T4, very premature or very LBW infants frequently experience a transient decrease in serum total T4 concentrations during the first week of life.
• Serum T4 levels in preterm infants gradually increase to approximate the ranges observed in term infants by about 6 weeks of postnatal life.
• These altered dynamics reflect immaturity of the hypothalamic-pituitary-thyroid axis, loss of the third-trimester maternal thyroid hormone contribution, nonthyroidal illness, and exposure to medications like dopamine or glucocorticoids.

Salient Features of the Neonatal Thyroid Screening Programme

Rationale and Importance

• Congenital hypothyroidism (CH) is the most common preventable cause of intellectual disability, with an approximate incidence of 1 in 2,000 to 1 in 4,000 newborns.
• The vast majority of affected neonates are entirely asymptomatic at birth because of the transplacental passage of maternal T4, which provides fetal levels that are roughly one-third of normal.
• Clinical manifestations of hypothyroidism (such as myxedema, large fontanels, macroglossia, and delayed psychomotor milestones) appear gradually during the early months of life, by which time irreversible brain damage may have already occurred.
• Universal newborn screening is thus critical to detect the disorder in its presymptomatic phase, allowing for immediate initiation of levothyroxine therapy within the first 2 weeks of life to ensure normal neurocognitive development.

Timing and Method of Sample Collection

• Screening relies on a blood sample obtained by a heel-prick, which is blotted onto a filter paper card (the Guthrie card) and sent to a central screening laboratory.
• To avoid an unacceptable rate of false-positive results caused by the physiologic postnatal TSH surge, the blood sample must be collected after the first 24 hours of life, typically between 2 to 5 days of postnatal age.
• In situations where postnatal dried blood spot sampling is not feasible (e.g., very early discharge), umbilical cord blood may be utilized, although this approach requires specific reference parameters.

Primary Screening Strategies

• Primary TSH Screening: This is the most commonly used strategy globally. It possesses the highest sensitivity for detecting primary hypothyroidism, including milder and compensated forms where TSH is elevated but T4 remains normal. However, a primary TSH approach will miss infants with central (secondary/tertiary) hypothyroidism, as their TSH levels are typically low or inappropriately normal.
• Primary T4 Screening with Reflex TSH: This strategy measures total T4 first and tests TSH only if the T4 level is in the lowest percentile. This approach can successfully identify primary CH, central hypothyroidism, and infants with delayed TSH elevations. It also detects thyroxine-binding globulin (TBG) deficiency (a benign variant). Its major disadvantage is that it may miss compensated primary hypothyroidism where T4 levels are still within the normal range.

Interpretation and Cut-off Values

• Screening results must be interpreted strictly based on age-specific reference ranges tailored to the first weeks of life.
• Traditional screening programs utilized TSH cut-offs of 20 to 50 mU/L; however, many programs have recently lowered their thresholds to 6 to 20 mU/L (provided the sample is taken after 24 hours) to detect milder or transient cases.
• Typically, TSH levels above 40 mU/L in the first week, above 20 mU/L between 7 and 21 days, and above 10 mU/L beyond 21 days strongly indicate the need for immediate treatment.

Special Populations Requiring a Second Screening

• Preterm and Low Birthweight Infants: These infants have an increased incidence of CH and frequently exhibit a delayed TSH elevation that is missed on the initial screen, necessitating a routine second screening test 2 to 4 weeks after birth.
• Monozygotic Twins: Due to fetal blood mixing through shared placental circulations, a hypothyroid twin might initially present with normal thyroid tests due to compensation by the euthyroid twin. A second screening sample is strongly recommended at 14 days for same-sex twins.
• Infants with Trisomy 21 or Cardiac Defects: These infants have a higher baseline risk for CH and may warrant closer surveillance and secondary screening.
• Iodine Exposure: Premature and full-term neonates exposed to excessive iodine (e.g., iodinated contrast media or topical iodine antiseptics) can develop acute transient hypothyroidism (the Wolff-Chaikoff effect) days after the initial screen, justifying a repeat evaluation.

Confirmatory Testing and Post-Screening Evaluation

• Any positive newborn screening result mandates immediate recall for confirmatory venous blood sampling to accurately measure serum TSH and free T4.
• If the initial screening TSH is highly elevated (e.g., >40 mU/L), treatment with oral levothyroxine (10–15 $\mu$g/kg/day) must be initiated immediately without waiting for the results of the confirmatory venous tests.
• Diagnostic imaging, particularly radionuclide scintigraphy (using Technetium 99m or Iodine-123), should ideally be performed to definitively identify the etiology (e.g., thyroid agenesis, ectopy, or a normally located gland suggestive of dyshormonogenesis).
• Imaging can be performed within a few days of initiating therapy, provided the TSH remains elevated above 20 to 30 mU/L, ensuring that treatment is not delayed.
• If scintigraphy shows no uptake, serum thyroglobulin (Tg) measurement is utilized to distinguish between true athyreosis (low/undetectable Tg) and apparent athyreosis caused by maternal TSH-receptor blocking antibodies or TSH receptor mutations (detectable Tg).