Version May 2024
INTRODUCTION — Congenital hypothyroidism occurs in approximately 1 in 2000 to 1 in 4000 newborns worldwide, with considerable regional and racial/ethnic variation. It is one of the most common treatable causes of intellectual disability. However, most newborn babies with this disorder have few or no clinical manifestations of thyroid hormone deficiency. In addition, the majority of cases are sporadic, so it is not possible to predict which infants are likely to be affected. For these reasons, newborn screening programs were developed to detect and treat this condition as early as possible, by measuring either thyroxine (T4) and/or thyrotropin (thyroid-stimulating hormone [TSH]) in heel stick blood specimens. These screening efforts were initiated in the mid-1970s and have been largely successful, although severely affected infants may still have a slightly reduced intelligence quotient (IQ) and other neurologic deficits despite prompt diagnosis and initiation of therapy. (See "Clinical features and detection of congenital hypothyroidism".)
Interpretation of screening tests in a preterm neonate requires an understanding of thyroid physiology in the fetus throughout gestation. This topic will review normal thyroid physiology in the fetus and following birth in preterm and term infants.
NORMAL THYROID PHYSIOLOGY IN THE FETUS — The bilobed thyroid shape is evident by seven weeks of gestation, and thyroid follicles containing colloid are seen histologically by 10 weeks. With respect to thyroid function, thyroglobulin synthesis can be detected at four weeks, iodine trapping at 8 to 10 weeks, and thyroxine (T4) and, to a lesser extent, triiodothyronine (T3) synthesis and secretion at 12 weeks. Hypothalamic neurons contain thyrotropin-releasing hormone (TRH) at six to eight weeks, the pituitary-portal vascular system begins to develop at 8 to 10 weeks, and thyrotropin (thyroid-stimulating hormone [TSH]) secretion can be detected at 12 weeks. Maturation of the hypothalamic-pituitary-thyroid axis occurs during the second half of gestation, but completely normal feedback relationships are not mature until term gestation or early postnatal life. (See "Thyroid hormone synthesis and physiology".)
The pattern of changes during gestation is as follows (figure 1) [1,2]:
●During the first trimester, T4 in the circulation is of maternal origin, as the fetal thyroid does not produce significant amounts of T4 until the second half of pregnancy [3]. Thereafter, the rise in serum T4 concentrations is a result of both an increase in hepatic production of thyroxine-binding globulin (TBG) and, to a lesser degree, an increase in fetal thyroidal T4 production stimulated by TSH secretion. Fetal serum T4 concentrations rise from a mean of approximately 2 mcg/dL (26 nmol/L) at 12 weeks to 10 mcg/dL (128 nmol/L) at term [1,2]. Fetal serum free T4 concentrations also increase progressively, from a mean value of approximately 0.1 ng/dL (1.3 pmol/L) at 12 weeks to 2 ng/dL (25.7 pmol/L) at term.
●Fetal serum total and free T3 concentrations increase much less because of placental inner ring deiodination of T4 to reverse T3 (rT3). Fetal serum T3 concentrations rise from approximately 6 ng/dL (0.09 nmol/L) at 12 weeks to 45 ng/dL (0.68 nmol/L) at term.
●Serum TSH concentrations rise gradually from approximately 4 mU/L at 12 weeks to 8 mU/L at term.
The fetus is dependent on maternal iodine intake, and iodine is transferred across the placenta for fetal thyroid hormone production. To meet the iodine needs of the fetus, the recommended iodine intake for a woman is higher during pregnancy (250 to 300 mcg daily) than in nonpregnant women (150 mcg daily) [4,5]. Maternal hypothyroidism (including maternal iodine deficiency) is a risk factor for preterm birth and may have adverse effects on neurodevelopment in the offspring. (See "Overview of thyroid disease and pregnancy", section on 'Iodine requirements' and "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment".)
POSTNATAL THYROID FUNCTION
Term infants — Serum thyrotropin (thyroid-stimulating hormone [TSH]) concentrations rise abruptly to 60 to 80 mU/L within 30 to 60 minutes after delivery in healthy term babies [6]; this rise is associated with exposure of the infant to a colder environment and clamping of the umbilical cord. The serum TSH concentration then decreases rapidly to approximately 20 mU/L 24 hours after delivery and then more slowly to 6 to 10 mU/L at one week (figure 1).
The initial surge in TSH stimulates thyroidal thyroxine (T4) secretion, so that serum total and free T4 concentrations rise to a peak at 24 to 36 hours of life of approximately 10 to 22 mcg/dL (129 to 283 nmol/L) and 2 to 5 ng/dL (25 to 64 pmol/L), respectively [7]. Serum triiodothyronine (T3) concentrations also rise, to a peak of approximately 250 ng/dL (3.8 nmol/L), at the same time (figure 1). The increase in serum T3 is a result of increases in both thyroidal secretion and conversion of T4 to T3 in peripheral tissues.
Serum T4, free T4, and T3 concentrations gradually fall in the first four weeks of life, leveling off at slightly higher values than are found in adults [7]. At this time, the reference range for serum total T4 concentrations is 7 to 16 mcg/dL (90 to 206 nmol/L) and the reference range for serum free T4 concentrations is 0.8 to 2 ng/dL (10 to 26 pmol/L). After the first four weeks, the reference range for TSH is 0.5 to 6 mU/L, also higher than adult levels. TSH values reach the adult reference range at approximately two years of age.
Preterm infants
●Relation to gestational age – As one would expect from the above description of fetal changes during normal gestation, cord serum total and free thyroxine (T4) concentrations are proportional to either birth weight or gestational age [8,9]. The same is true for heel stick blood values, as collected for routine newborn screening for hypothyroidism two to five days after delivery (table 1). The cord serum T4 concentration averages 5.4 mcg/dL (70 nmol/L) in infants less than 1000 gm [8] and 6.3 mcg/dL (81 nmol/L) in infants born at less than 30 weeks gestation [10,11]. Cord serum free T4 concentrations are not proportionately as low, averaging 1.2 ng/dL (15 pmol/L) in infants born at less than 30 weeks gestation [10].
●Relation to postnatal age – After birth, preterm infants undergo changes in serum thyrotropin (thyroid-stimulating hormone [TSH]), T4, and triiodothyronine (T3) concentrations that are similar to those of term infants, described above (see 'Postnatal thyroid function' above). However, these changes are quantitatively smaller, especially in the most premature infants, most likely because of immaturity of the hypothalamic-pituitary-thyroid axis [11,12]. The reference range for thyroid hormones thus varies by gestational age and also by postnatal age (table 2).
As in term infants, serum T4 concentrations fall in the first week of life in low-birth-weight preterm infants [8]. This fall is greater in very-low-birth-weight, more premature infants, in whom T4 clearance is more rapid. In infants from areas in which iodine deficiency is endemic, lack of adequate iodine intake contributes to the fall in serum T4 concentrations [13].
After the first week, serum T4 and T3 concentrations gradually rise in the most premature infants (those born at 23 to 27 weeks gestational age). By three to six weeks of life, the values in these infants (<28 weeks of gestation) overlap the range of normal in term infants, although the mean values are slightly lower (table 2). In less premature infants judged to be healthy (30 to 35 weeks of gestation), serum T4 rises and peaks at seven days, and then falls. In these infants, the thyroid hormone measurements overlap with the reference range for a term newborn after the first week of life [14].
NEWBORN SCREENING — Three major strategies are used for newborn screening:
●Initial thyroxine (T4) assay, with reflex thyrotropin (thyroid-stimulating hormone [TSH]) assay
●Initial TSH assay
●Simultaneous T4 and TSH assay
Most programs in the United States started with the initial T4/reflex TSH testing approach but many have switched to initial TSH testing, citing that this method is more cost-effective with lower false-positive rates. Infants with a delayed rise in blood TSH concentration (who typically have a low T4-normal TSH on initial testing) and those with central hypothyroidism are detected more reliably by the initial T4/follow-up TSH assay method, whereas infants with subclinical hypothyroidism (high blood TSH, normal blood T4) are detected more reliably by TSH testing. (See "Clinical features and detection of congenital hypothyroidism", section on 'Technique'.)
Implications of variation in thyroid function in preterm infants
False-positive and false-negative screening results — Compared with full-term infants, preterm infants are more prone to both false-positive and false-negative results of initial newborn screening tests for hypothyroidism. This is due to physiologic differences in thyroid function, including the lower T4 levels after birth and the later rise in TSH levels with maturation of the hypothalamic-pituitary-thyroid axis, as well as fluctuations as they recover from nonthyroidal illness. A pattern of a more dramatic delayed TSH elevation occurs in some preterm infants; when these cases are included, the incidence of congenital hypothyroidism is higher in preterm than term infants. Studies report that most preterm babies with delayed TSH elevation have transient hypothyroidism. If these transient cases are excluded, the prevalence of permanent congenital primary hypothyroidism in preterm infants is likely similar to that in term infants [15].
Because of the potential for false-negative and false-positive screening results in this population, we suggest that very preterm infants (eg, birth weight <1500 g or gestational age <32 weeks) undergo a routine repeat screening test (eg, at two to four weeks of age) (algorithm 1). This strategy applies regardless of the thyroid function test approach used by the screening program, and is recommended by many programs [16-18].
●False-positive results – Preterm infants often have a characteristic fluctuation in thyroid hormones during the first few weeks of life, consisting of transient mild hypothyroxinemia, followed by a compensatory mild and transient elevation in serum TSH levels. These abnormalities can be considered physiologic because they usually resolve spontaneously, but can cause false-positive results of initial newborn screening tests.
The transient hypothyroxinemia (low T4) may cause false-positive results in screening programs that use T4 as the primary screening test [19]. Preterm infants (<37 weeks gestation) account for approximately 12 percent of births, yet they account for a much higher percent of infants with blood T4 concentrations below a selected cutoff, (eg, <10th percentile, equivalent to approximately 8 mcg/dL [103 nmol/L]).
The resultant TSH rise also may cause false-positive results, especially in infants with extremely low birth weight [20]. The TSH elevation usually is mild (typically 6 to 15 mU/L), and usually returns to normal within the first few weeks of life. Thus, this pattern can be considered a normal response to the physiologic hypothyroxinemia seen in some healthy preterm infants.
Some preterm infants have greater and more persistent deviations from normal values, typically seen as low screening blood T4 values and delayed elevation in screening TSH values (eg, TSH rising to >20 mU/L [serum] or >10 mU/L [whole blood] at 15 to 30 days of age) [20-22]. In such cases, it may be difficult to distinguish between physiologic fluctuations in thyroid hormones due to prematurity and true primary hypothyroidism, which may be transient or permanent. While some infants with a TSH elevation as high as 50 mU/L may ultimately have normal thyroid function without treatment [23], they may still be at risk for adverse effects on brain development [24]. Until there are randomized controlled trials to address this question, we recommend treating these patients. A clinical strategy for making the diagnosis of primary hypothyroidism and initiating treatment is outlined below. (See 'Primary hypothyroidism' below and 'Transient versus permanent hypothyroidism' below.)
●False-negative results – In addition, some preterm infants with congenital primary hypothyroidism are more likely to have a delayed rise in serum TSH, creating the potential for a false-negative result in screening programs that employ a primary TSH test. This form of hypothyroidism developing over time would be missed if screening were performed only once within the first few days of life. For example, infants with birth weight <1500 g who are ultimately shown to have primary hypothyroidism have a rate of delayed TSH elevation between 1:54 to 1:294 [20,23,25,26].
Effects of nonthyroidal illness — Thyroid function testing also may be affected by medical complications associated with preterm birth, such as respiratory distress syndrome (RDS) or intrauterine growth restriction [27,28]. Preterm infants with RDS and other medical problems tend to not have the expected postnatal increases in serum TSH, T4, and triiodothyronine (T3) concentrations; their serum T4 and T3 concentrations may decrease at 24 hours of age and be low until the infant recovers from their acute illness or gains weight [29,30]. Thereafter, the concentrations rise slowly in the survivors [29]. A study of late preterm and term infants with RDS showed that serum free T4 remains low for the first five days of life; the decrease in free T4 levels correlates with severity of illness scores [31].
These medical conditions tend to depress serum total T4 concentrations more often than serum free T4 concentrations [32]. Thus, at least some of the fall in serum total T4 concentrations is a result of decreases in serum protein binding of T4. In contrast, serum total and free T3 concentrations are low, because peripheral conversion of T4 to T3 is decreased. In addition, some very sick infants have low serum TSH concentrations, which further lowers serum T4 and T3 concentrations (see "Thyroid function in nonthyroidal illness"). Furthermore, if sick preterm infants are treated with glucocorticoids [33] or dopamine [34], these drugs also may decrease TSH secretion.
Reversible/transient causes of hypothyroidism — Exposures that can cause transient hypothyroidism in neonates and young infants include:
●Iodine exposure, including from iodinated contrast agents
●Maternal iodine deficiency, which varies globally
●Maternal autoimmune thyroid disease due to placental transfer of antithyroid drugs or blocking antibodies
The US Food and Drug Administration released a warning about the risk of iodine-induced hypothyroidism in infants receiving iodinated contrast media for medical imaging [35]. Preterm and acutely ill term infants, typically those with congenital heart disease or renal insufficiency, appear to be at highest risk for hypothyroidism. We recommend that preterm infants receiving iodinated contrast media undergo measurement of serum TSH approximately two to three weeks after exposure. (See 'Diagnosis and treatment decisions' below.)
These issues are discussed separately. (See "Clinical features and detection of congenital hypothyroidism", section on 'Transient congenital hypothyroidism'.)
Screening protocol and interpretation — Newborn screening for hypothyroidism is recommended for all preterm infants, as it is for full-term infants. Blood for screening is collected onto filter paper cards after heel prick, and the cards are then sent to a centralized laboratory for testing. The initial sample is usually collected between 24 and 48 hours after birth. Most newborn screening programs obtain a routine second specimen at two to four weeks of age in preterm infants, both to resolve abnormal results on the first test (low T4 in a primary T4-reflex TSH test program) and to detect cases with delayed TSH elevation (in primary TSH test programs). The threshold birth weight or gestational age for which the additional screening test is performed varies among screening programs. For babies <32 weeks gestation, many programs will obtain an additional third specimen around four to six weeks of age (or before discharge, whichever comes first) [36]. (See 'Implications of variation in thyroid function in preterm infants' above.)
The timing and type of follow-up testing depends on the initial results, as outlined below (algorithm 1).
Initial and follow-up screening tests — The initial screen is performed on a sample collected between 24 and 48 hours after birth. The recommended response to screening results is as follows (algorithm 1):
●Normal results – Preterm infants with normal results on the initial newborn screen should have a second newborn screen performed, recommended at two to four weeks of age. If the second screen is performed before 36 weeks corrected gestational age, a repeat (third) screening test is recommended four weeks later (six to eight weeks of life) or at 36 weeks corrected gestational age, whichever is earlier [37].
●Abnormal results – Preterm infants with elevated TSH on any of the screening tests (with low T4 or normal T4) should undergo measurement of serum free T4 and TSH. (See 'Confirmatory serum testing' below.)
If the abnormal result is a low T4 and non-elevated (normal or low) TSH, most programs recommend a second screening test (on a heel stick sample) performed at two to four weeks of age. This is a common finding in preterm babies when screened by the primary T4-reflex TSH method, and most infants will have normal results on the second screen (see 'Hypothyroxinemia of prematurity: Treatment versus observation?' below). Those with persistent low T4 require further evaluation with serum testing to evaluate for the possibility of central hypothyroidism, as described below.
Confirmatory serum testing — Preterm infants with abnormal results on the initial screen or subsequent screening tests should undergo measurement of serum free T4 and TSH. If the serum screening is performed at two to four weeks of age and is entirely normal, then no further screening is needed.
Interpretation of abnormal results is discussed in the next section.
DIAGNOSIS AND TREATMENT DECISIONS — The possibility of congenital hypothyroidism is suspected based on abnormal results of the first or subsequent newborn screens. The diagnosis is confirmed by serum testing.
Threshold for abnormal TSH — In most cases, serum thyrotropin (thyroid-stimulating hormone [TSH]) is the key diagnostic test. The threshold for defining an elevated TSH level varies only slightly by gestational age; once a preterm infant reaches a postnatal "term" age, ranges for term infants can be used. In general, a serum TSH >10 mU/L is elevated for preterm babies who have not reached a "term" postnatal age (<37 weeks), while a TSH >6 mU/L is the cutoff for babies who have reached "term" postnatal age (≥37 weeks).
Free thyroxine (T4) and T4 levels vary with gestational and postnatal age. The thyroid function data in the table (table 2) can be used as a guideline in interpreting serum thyroid function test results, based on gestational age and postnatal age of the baby (where normal is defined as ±2 standard deviations).
The results of confirmatory serum testing are interpreted as follows:
Primary hypothyroidism — The finding of low free T4 and elevated TSH on serum testing is diagnostic of primary hypothyroidism (algorithm 1). These infants should be treated using a starting levothyroxine dose of 10 to 15 mcg/kg/day. (See "Treatment and prognosis of congenital hypothyroidism".)
In some cases, the hypothyroidism will prove to be transient and levothyroxine can be withdrawn later. (See 'Transient versus permanent hypothyroidism' below.)
Central hypothyroidism — The finding of low free T4 and non-elevated (normal or low) TSH raises the possibility of central hypothyroidism (algorithm 1). If the initial free T4 test was performed by the standard "analog" assay, it should be repeated by measuring free T4 by equilibrium dialysis, a more accurate type of assay that can aid in distinguishing nonthyroidal illness syndrome from central hypothyroidism [38,39]. Some preterm infants may manifest low serum free T4 levels on both the standard analog and equilibrium dialysis method. In these cases, it may be impossible to separate these results, more likely attributable to prematurity and nonthyroidal illness syndrome, from the relatively rare case of central hypothyroidism. Evidence for other pituitary hormone deficiencies or congenital midline brain defects (see below) strengthens the possibility of true central hypothyroidism.
We recommend levothyroxine treatment in those cases where the free T4 measured by equilibrium dialysis is low after four weeks of age.
Central hypothyroidism can be due to isolated TSH deficiency, but is more likely in infants with evidence for other pituitary hormone deficiencies, presence on imaging of pituitary abnormalities (eg, ectopic posterior pituitary gland) or midline defects (eg, absent septum pellucidum), or a history of central nervous system insult that may have caused hypothalamic-pituitary injury. Therefore, all cases with laboratory testing compatible with central hypothyroidism should be evaluated for other pituitary hormone deficiencies, especially central adrenal insufficiency, if not already done. (See "Clinical features and detection of congenital hypothyroidism", section on 'Central hypothyroidism'.)
Thyrotropin-releasing hormone (TRH) stimulation testing may also be used to support the diagnosis of central hypothyroidism. Infants with central hypothyroidism tend to have a delayed but excessive TSH increase after TRH stimulation, followed by delayed TSH decrease [40]. TRH is available in some countries in Europe but not in the United States.
Subclinical hypothyroidism — The interpretation of normal free T4 with slightly elevated TSH depends on the age of the infant:
●Before two weeks of age, these results usually reflect transient TSH elevations following recovery from a "physiologically" low T4 level due to prematurity. These infants should not be treated, but serum testing should be repeated at two to four weeks of age. In most cases, the TSH will normalize. (See 'Implications of variation in thyroid function in preterm infants' above.)
●After four to six weeks of age, persistently elevated TSH with normal free T4 likely represents subclinical hypothyroidism. In some infants with mildly abnormal thyroid function tests, eg, infants with serum TSH 6 to 20 mU/L and normal free T4 results, information from imaging studies (typically, thyroid ultrasound examination) will help in the decision to start levothyroxine (eg, finding thyroid hypoplasia or an ectopic gland) or to further monitor (eg, a eutopic, normal-appearing gland). If the decision is made to treat these infants with subclinical hypothyroidism, we recommend starting levothyroxine at a lower dose (8 to 10 mcg/kg/day) than used to treat overt congenital primary hypothyroidism. Thyroid function should be reevaluated after two to three years of age; clinical judgment is required in managing these cases. (See "Treatment and prognosis of congenital hypothyroidism", section on 'Assessment of permanent versus transient hypothyroidism'.)
Thyroxine-binding globulin deficiency — Thyroxine-binding globulin (TBG) deficiency, detected by screening programs that use a primary T4 methodology, is characterized by low serum total T4 but normal free T4 and TSH. The diagnosis is confirmed by measuring TBG concentrations, which are low for age. These infants have normal thyroid function and do not require treatment.
TRANSIENT VERSUS PERMANENT HYPOTHYROIDISM — Infants with hypothyroidism diagnosed on serum testing as outlined above should be treated with levothyroxine. However, in some of these infants, the hypothyroidism will be transient and resolve spontaneously within months to years. As an example, in one study, 24 preterm infants were diagnosed with hypothyroidism by serum testing at 15 to 30 days of age (thyrotropin [thyroid-stimulating hormone (TSH)] >10 m/L) and were treated with levothyroxine [41]. When thyroid function was retested at two years of age after discontinuation of levothyroxine therapy, 75 percent had normal thyroid function, while the remainder had permanent hypothyroidism.
Because no clinical or laboratory characteristics reliably predict outcome, we recommend treating these children until two years of age; at that time, thyroid hormone can be discontinued and thyroid function checked one month later. (See "Treatment and prognosis of congenital hypothyroidism", section on 'Assessment of permanent versus transient hypothyroidism'.)
HYPOTHYROXINEMIA OF PREMATURITY: TREATMENT VERSUS OBSERVATION?
●Thyroid hormone replacement (not recommended) – There is insufficient evidence to support routine thyroid hormone replacement (levothyroxine) for preterm infants, unless they have confirmed primary or central hypothyroidism, as defined above (see 'Diagnosis and treatment decisions' above). Available evidence has not demonstrated benefit in this population, although larger trials with long-term follow-up are needed to definitively answer this question. Instead, interventions should focus on avoiding the established risk factors for transient hypothyroxinemia, which are iodine deficiency, exposure to excess iodine, nonthyroidal illness, and use of medications that affect the hypothalamic-pituitary-thyroid axis [42].
The relevant evidence is outlined below:
•Association with comorbidities – Some investigators have proposed that the hypothyroxinemia of prematurity is a state of clinical hypothyroidism and that all premature infants might benefit from thyroid hormone replacement (or iodide treatment if deficient) until the hypothalamic-pituitary-thyroid axis matures. This hypothesis arises from observations of low thyroid hormone levels in preterm infants, in combination with nonspecific symptoms and signs that might be attributed to hypothyroidism, such as hypothermia, jaundice, immature pulmonary function (with low surfactant concentrations), apnea, bradycardia, slow oral feeding, sluggish gut motility and constipation, edema, lethargy, hypotonia, and slow growth and development [43]. However, available evidence has not demonstrated benefits of routine thyroid hormone replacement or iodide treatment for these infants, as discussed below.
•Association with neurodevelopmental outcomes – Several observational studies demonstrate a relationship between the low T4 concentrations in premature infants and intellectual disability or problems in neurodevelopment [44-49]. While some report an increased odds ratio for lower intelligence quotient (IQ) and disabling cerebral palsy [45], below-normal attention span [47], and vision disturbances [48], others did not find an association with developmental quotient at one year [44] or neurodevelopmental outcome at 19 years [49]. Because it is difficult to adjust for other complications of prematurity that may have contributed to the outcome, a causal relationship has not been established.
The efficacy of routine thyroid hormone replacement in preterm infants has been investigated in several studies, with endpoints including growth, recovery from respiratory distress syndrome, neurologic development, and mortality; most have not demonstrated a benefit [50-56]. A randomized clinical trial comparing placebo versus levothyroxine treatment in 200 infants <30 weeks gestational age did not show benefit [57], although subsequent analysis in the subgroup <27 weeks gestation appeared to show benefit in one score of neurodevelopment [58]. However, in follow-up studies at 5.7 years of age [59] and again at 10 years of age, this benefit was no longer present [60].
This issue continues to be unresolved. In a study of preterm infants weighing <1500 g, a comparison of outcomes in infants with and without hypothyroxinemia did not find any significant differences in neurodevelopmental, visual, or hearing impairment at five years of age [61]. A double-blind, randomized, placebo-controlled trial in preterm babies <28 weeks gestation showed statistically better motor, language, and cognitive domains in the group treated with levothyroxine [62]. However, the investigators concluded that the improvements shown were not strong enough to warrant a change in practice.
Larger randomized trials with long-term follow-up are needed to definitively determine whether routine thyroid hormone replacement is beneficial in preterm infants [63]. This is especially important because of the large size of this population (approximately 25,000 infants born at <28 weeks' gestation each year in the United States alone) and because this population is already at risk for cognitive disabilities.
●Supplemental iodine (not recommended) – Given that preterm infants are at risk for iodine deficiency, a randomized controlled trial of sodium iodide 30 mcg/kg/day versus placebo, given until the equivalent of 34 weeks gestation, was undertaken in 1273 preterm infants in the United Kingdom [64]. Follow-up Bayley Scales of Infant Development III did not show any significant differences in language, motor, or overall cognitive scores at two years of age. As with all infants, preterm infants should receive the recommended dietary allowance of iodine (30 mcg/kg/day).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric thyroid disorders".)
SUMMARY AND RECOMMENDATIONS
●Postnatal changes in thyroid hormones – In full-term babies, levels of thyrotropin (thyroid-stimulating hormone [TSH]), thyroxine (T4), and triiodothyronine (T3) rise sharply after birth, fall rapidly during the first five days of life, and then fall more gradually between one and four weeks of life (figure 1). Preterm infants undergo similar but smaller changes in thyroid hormone levels. The reference ranges for thyroid hormones thus vary by birth weight (table 1) and also by gestational age and postnatal age (table 2). (See 'Postnatal thyroid function' above.)
●Newborn screening
•All preterm infants – As for all newborns, preterm infants should undergo routine screening for hypothyroidism (algorithm 1). The first screening specimen is most commonly obtained between 24 and 48 hours after birth. (See 'Screening protocol and interpretation' above.)
•Very preterm infants – We recommend an additional screening test in very preterm infants (eg, birth weight <1500 g or gestational age <32 weeks) (Grade 1B) (algorithm 1). The second test is recommended at two to four weeks of age. In many programs, three screening tests are performed in infants who remain hospitalized beyond one month of age (at 24 to 48 hours, 10 to 14 days, and four to six weeks of age). (See 'Initial and follow-up screening tests' above.)
This additional screening test reduces the risk of misleading screening results, which are common in premature infants because of delayed rise in serum TSH (causing false-negative results) or physiologic immaturity (causing false-positive results). (See 'False-positive and false-negative screening results' above.)
●Confirmatory testing and treatment decisions – Abnormal results of screening tests should be confirmed by serum studies consisting of TSH and free T4 (or T4 and some measure of thyroid hormone-binding proteins) (algorithm 1). The results should be interpreted based on the reference range for gestational age and postnatal age (table 2). The cutoff for defining an elevated TSH level varies slightly by gestational age; in general, a serum TSH >10 mU/L is elevated for preterm babies who have not reached "term" postnatal age, while a TSH >6 mU/L is the cutoff for babies who have reached "term" postnatal age. (See 'Diagnosis and treatment decisions' above.)
•Low free T4, elevated TSH – Preterm infants with this result on screening and confirmatory serum tests have primary hypothyroidism and should be treated with levothyroxine. (See 'Primary hypothyroidism' above and "Treatment and prognosis of congenital hypothyroidism".)
•Normal free T4, mildly elevated TSH – This finding may be transient and does not require immediate treatment. If it persists after four weeks of age, the infant may have "subclinical hypothyroidism"; we recommend levothyroxine treatment in these cases. (See 'Subclinical hypothyroidism' above.)
•Low free T4, normal TSH – If this result is found on initial confirmatory serum testing, diagnostic possibilities are central hypothyroidism (uncommon) or nonthyroidal illness syndrome. Repeat serum studies should be performed, with repeat free T4 measurement by equilibrium dialysis. Evidence for other pituitary hormone deficiencies or congenital midline brain defects strengthens the possibility of true central hypothyroidism. We recommend levothyroxine treatment in cases with a subnormal free T4 confirmed by equilibrium dialysis method. (See 'Central hypothyroidism' above.)
•Low total T4 with normal free T4 – This result (with normal TSH) is likely caused by low serum thyroid hormone-binding globulin (TBG) and does not require treatment. (See 'Thyroxine-binding globulin deficiency' above.)
●Infants with nonthyroidal illness – In infants with clinical features of nonthyroidal illness (eg, respiratory distress syndrome) and characteristic abnormalities in thyroid hormones (normal or low serum total and free T4 concentrations, low serum T3 concentrations, and low-normal or low serum TSH concentrations), beneficial effects of levothyroxine treatment have not been established. (See 'Effects of nonthyroidal illness' above.)
●Hypothyroxinemia of prematurity – Abnormal thyroid function tests on the initial newborn screen in premature infants often normalize by the second or third newborn screens. There is insufficient evidence to support routine thyroid hormone replacement (levothyroxine) in preterm infants unless they have confirmed primary or central hypothyroidism. (See 'Hypothyroxinemia of prematurity: Treatment versus observation?' above.)
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