Congenital Hypothyroidism

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Program Design and Operation

Interpretation Of All Test Results

Evaluation And Therapy

Protocol For Newborn Screening Specimen Collection

Defects of Thyroxine-Binding Globulin

Guidelines For Health Care Professionals

symptoms or clinical signs are present, they may include prolonged neonatal jaundice, constipation, lethargy, poor muscle tone, feeding problems, a large tongue, mottled and dry skin, distended abdomen and umbilical herniaCongenital hypothyroidism screening has been a part of the Texas Department of State Health Services (DSHS) Newborn Screening Program since February of 1980. The Texas program is the largest in the world in terms of total number of specimens processed. About 120-150 newborns are identified annually in Texas with congenital hypothyroidism. Around six to twelve percent of these babies have a normal initial screen and are identified on the basis of an abnormal second screen.

Early identification and appropriate treatment of infants with congenital hypothyroidism has been highly successful in reducing the severity of impairment from this disorder. Screening programs were begun because of the realization that clinical detection of congenital hypothyroidism before irreversible damage had occurred was very difficult. The development of sensitive techniques which could reliably measure thyroid hormone (T4) and thyroid stimulating hormone (TSH) on dried blood from filter paper discs paved the way for newborn screening tests. The incidence of congenital hypothyroidism in Texas is approximately 1 in 2500 newborns. Our goal is to have every newborn in Texas screened for hypothyroidism and promptly follow up the out of range or marginal results with appropriate studies to establish a diagnosis for those who will require treatment. 

Program Design and Operation

  1. Blood specimens are collected from a heel puncture on filter paper.
    1. State law requires that blood should be collected at least 24-48 hours after the first feeding (because other metabolic tests will also be done) and at least 36 hours after birth. Special circumstances such as severe illness and extreme prematurity may require the physician's judgement on timing of the collection. Nonetheless, state law states that all infants, regardless of age, be tested prior to discharge from the hospital.
    2. A second screen is required at age one-two weeks on all infants.
  2. The State Laboratory in Austin measures the thyroxine (T4) content in a disc punched from the filter paper. Specimens with the lowest 10% of T4 values are repeated on a second disc and the TSH value will also be checked. The T4 and TSH is repeated again with the lowest 0.5% of the total specimens being reported as abnormal. Centralization of testing to a single laboratory allows computer standardization and low cost analysis possible only in high volume, automated programs.
  3. If a very high TSH is detected on the screen, both the primary physician as well as a regional pediatric endocrinology consultant is notified. The regional consultant will be available to help you at your request.
  4. If the T4 is low on the screen but the TSH is normal, or if the T4 is normal but the TSH is slightly elevated, instructions for further testing are given by letter. If these results are reported from the first screen, we will ask for the second screen to be obtained as soon as possible. In most cases, when the initial screen shows a low T4 or a mild TSH elevation, the second screen is normal. If these results are reported from the second screen, we will request a blood sample to run a thyroid profile. Our screening program is designed to keep the numbers of abnormal screens and repeat tests to a minimum. However, some marginal tests which require confirmation are inevitable. Please let the follow-up program know if you are unable to contact the family of the infant. DSHS can enlist the help of the local public health department to contact the family to avoid any delays in the collection of follow-up specimens.

    Abnormal tests on filter paper specimens are not considered diagnostic and should be confirmed with venipuncture blood samples. Serum testing is recommended when the TSH is very elevated on the screen or if both T4 and TSH are abnormal. For non-urgent cases, 1cc of serum may be sent to one of the Texas Department of State Health Services laboratories for T4, free T4, and TSH testing. There are postal regulations pertaining to mailing liquid biological specimens, call the laboratory at (512) 776-7661 for further information. There is no charge for this service. The physician will be contacted by telephone/fax of the results. All reports are mailed to the submitter of the specimen. The laboratory reference number should be used when submitting a serum specimen.

Interpretation Of All Test Results

The following is a list of conditions which have been associated with low T4 values in newborn infants:  

  1. Primary hypothyroidism
  2. Secondary hypothyroidism
  3. Low TBG levels, congenital and acquired
  4. Maternal drugs; e.g. iodides, lithium, PTU
  5. Prematurity
  6. Severe neonatal illness or stress
  7. Twinning (when associated with #5 or #6)
  8. Idiopathic transient hypothyroidism
  9. Maternal thyroiditis with transplacental passage of antithyroid antibodies

All but the first three causes are usually transient and safeguards need to be built into any program to avoid unnecessary treatment before adequate evaluation. Although primary and secondary hypothyroidism require treatment to prevent intellectual disabilities, care should be taken to exclude the other more common conditions that may also give positive test results.

Several diagnostic possibilities exist which can usually be distinguished by history, examination, and appropriate testing.  

  1. A low T4 combined with a high TSH level is presumed to indicate some form of primary hypothyroidism. The most common causes (approximately 75%) are agenesis or dysgenesis of the thyroid gland. In these situations there is either no detectable thyroid tissue or an inadequate fragment of the gland which is usually in an ectopic position somewhere in the neck of oropharynx. If the thyroid is easily identified or enlarged on examination, a iosynthetic defect in thyroid hormone synthesis (dyshormonogenesis) or maternal drug effects should be suspected. We recommend that serum evaluation be done and a thyroid scan be performed. Treatment can be started immediately. If test results indicate normal thyroid functions, treatment can be discontinued.
  2. A low T4 with normal TSH values is most likely due to a low thyroid binding globulin or one of the transient causes of neonatal thyroid hypofunction listed earlier. Such situations rarely require treatment. However, secondary hypothyroidism, due to either hypothalamic or pituitary dysfunction, occurs in approximately 1 of every 60,000 newborns and must be considered. Repeat testing with a serum sample is usually sufficient to identify those infants who will need more definitive studies of pituitary function. We recommend that treatment not be started until the serum results are available, unless the infant has symptoms suggestive of hypothyroidism.
  3. Infants with normal T4 levels but high TSH values will not be detected by our screening program, unless the T4 falls within the lowest 10% of the samples. Infants with dysplastic thyroid glands may have such values and may also become hypothyroid late in infancy. Our experience shows that 6-8% of our diagnosed cases annually are identified with an elevated TSH on the second screen after a normal initial screen.
  4. Low T4 values in low birth weight infants present a special problem. Low values are seen with increased frequency, but only rarely is primary hypothyroidism the cause. TSH values are usually not elevated or only slightly above the upper limits set by the screening program. As the stresses associated with the illnesses common to these infants resolve and as nutrition improves to allow normal growth, the thyroid tests usually return to normal. Treatment with thyroid hormone is not felt to be necessary and is not recommended.

Very rarely, low T4 values in low birth weight infants will be associated with very high levels of TSH or goiters. In most cases, it would be appropriate to treat such infants similarly to term infants with these findings. Parenteral preparations of thyroxine are available. A dosage of 8-10 ug/kg/day is recommended.

Evaluation And Therapy  

  1. Evaluation should include a careful history, physician examination, x-rays for bone age estimation (lateral knee is most helpful), and serum confirmation.
  2. If hypothyroidism is suspected, a thyroid scan should be done. This should not delay treatment since this study can be done within the first week of treatment.
  3. Prompt treatment should be instituted if there is any clinical evidence of hypothyroidism, scan evidence of thyroid dysgenesis, or low T4 values associated with elevated TSH levels.
  4. Recommended treatment is oral L-thyroxine therapy at an initial dose of 25-50 ug/day for term infants and 8-10 ug/kg/day for preterm infants. Lower doses may be desirable for infants with co-existing symptomatic cardiac disease.
  5. Low T4 values and slightly elevated TSH values can usually be managed by repeat testing and clinical observation.
  6. Re-examination should be done within 2-4 weeks after starting therapy and at least every 3 months during the first year. 
  7. General guidelines for dosage during the first year are as follows:
    0-6 months 25-50 ug/day or 8-10 ug/kg/day
    6-12 months 50-75 ug/day or 6-8 ug/kg/day

    The dose must be individualized for each patient according to his/her clinical and laboratory response, since both excessive as well as inadequate treatment may be detrimental to optimal neurological development. Maintenance of T4 and/or T3 values in the high normal range and normal longitudinal growth have been found to be more useful than TSH in regulating therapy.

  8. Thorough evaluation of neurological development should be made on each follow-up visit.
  9. The Newborn Screening Clinical Care Coordination Program will contact the endocrinologist or primary care provider of children diagnosed with hypothyroidism periodically until the child is four years of age to verify that the child is still being followed.

List of pediatric endocrinologists who are available for consultation. All of them have participated in preparing these guidelines and are eager to ensure the success of this program.

Protocol For Newborn Screening Specimen Collection.

PROTOCOL FOR NEWBORN SCREENING SPECIMEN COLLECTION
* TERM INFANT (37 weeks or greater)
First specimen obtained at: 36 hours of age (or just before child leaves hospital).
Second specimen obtained at: 7-14 days of age.
* PREMATURE AND/OR SICK NEWBORNS
First specimen obtained at: 36 hours of age or prior to transfusion.
Second specimen obtained at: 1 month of age, weight of 2000 grams (if doing well), or at discharge or when requested by DSHS staff; whichever comes first.
Third specimen obtained at: 3 months if still in hospital (not necessary if previous tests are normal).

Premature Infants

  1. Premature infants often show a low T4, or a low T4 with a borderline TSH elevation until they are well stabilized and gaining weight. Screens can be repeated or serum T4/TSH done.
  2. Written notification from the Newborn Screening Program will be sent when an abnormal test is reported. If a repeat test or results of serum tests are not received, the hospital unit will be contacted by phone or fax. A certified letter will be sent to the parent if results of confirmatory testing have not been received by the NBS Program and the baby has been discharged.
  3. When a TSH is significantly elevated a telephone call will be made to the primary physician and a pediatric endocrinology consultation recommended. These cases will be followed by telephone.
  4. Laboratory evaluation should include T4, free T4, and TSH.
  5. IF AN INFANT IS STARTED ON REPLACEMENT THERAPY, NOTIFY DSHS AS SOON AS POSSIBLE.

Remember-Premature Infants Have the Same Incidence Of Hypothyroidism As Full Term Infants

Defects of Thyroxine-Binding Globulin (TBG)

Abnormalities in levels of TBG are not associated with clinical disease and do not require treatment. They are usually uncovered by a chance finding of abnormally low or high levels of T4 and may be sources of confusion in the diagnosis of hypo- and hyper- thyroidism.

TBG deficiency occurs as an X-linked dominant disorder. Congenital TBG deficiency is most often discovered through screening programs for neonatal hypothyroidism that utilize levels of T4, as the primary screen. Affected patients have low levels of T4, normal levels of free T4 and TSH. Hypothyroidism is ruled out by the finding of absent or low levels of TBG. The disorder is more readily recognized in males because it is caused by a gene on the short arm of the X chromosome. TBG deficiency occurs in 1 in 2,800 newborn males, of whom 36% have TBG levels below 1 mg/L. Complete TBG deficiency (<5 ug/L) occurs much less frequently. Three of eight families with complete TBG deficiency have been found to have codon mutation (leucine to proline); other patients with reduced affinity of TBG for T4 have had other point mutations that affect the tertiary structure of the protein.

Last updated October 18, 2012