How do we approach borderline TSH results on newborn screening and subsequent tests for hypothyroidism? #thyroid #hypothyroidism

What is the thyroid gland?

Our body has a network of glands called endocrine glands, which secrete small amounts of chemicals called hormones-these hormones have very important (essential) roles in regulating various aspects of our body function. The Thyroid hormone is very important for various body functions and is secreted by the thyroid gland located in our neck. As for all hormones, there is a feedback regulation with the control center. The pituitary gland produces TSH (thyroid stimulating hormone) to stimulate and regulate the thyroid gland function (secretion). When the fetus is in the mother’s womb, the mother’s thyroid hormone can cross over to the fetus through the placenta, and this protects the developing fetus even if the fetal thyroid gland is not effective.

Why should we detect congenital hypothyroidism at the earliest possible?

In the young (newborn) baby, having an adequate level of the thyroid hormone is very important for brain development-so a baby who is low on thyroid hormone is at high risk of developing learning difficulty or a low IQ. For this reason, it’s very important to diagnose hypothyroidism at the earliest possible because even two to three weeks delay can lead to significant IQ drop in the baby in case of severe disease/deficiency. Till a few years ago (20-30 years ago), we used to see babies with symptomatic hypothyroidism as in the image below (cretin like appearance-also called cretinism for that reason) but now we don’t see it commonly due to increased awareness related to screening for this condition.

What is the role of newborn screening in early detection of hypothyroidism?

As early diagnosis is key, screening for this condition in all newborn babies is the best way to diagnose and treat early. In the developed world, newborn screening has been fully implemented and the ‘blood spot’ or ‘Guthrie card’ test is carried out in the first few days in all babies-the thyroid screening is part of this newborn screening process (you can learn more about this here https://youtu.be/RoO-r18Md_M). However, in the developing world, it is still not a routine practice especially in the non-urban centers-so, it is imperative that we take efforts to incorporate this in all babies (possibly by forming a local partnership to eliminate logistic challenges and reduce cost). The Government should also support this and introduce a countrywide program.

The newborn screening (as currently performed in the developed world) is a very important tool and hypothyroidism and phenylketonuria are the two primary diseases that were screened for, and subsequently multiple conditions have been added-we nearly have 40 to 50 conditions now. Early diagnosis and treatment ameliorate severe cognitive problems in congenital hypothyroidism-this is beyond doubt. The earlier we diagnose, the better it is. Because the labs do it on multiple samples at the same time (batch screening of the filter paper ‘spot’ samples, with individual tests repeated only if there is an abnormal result in a batch), it is relatively cheap as well.

Most newborn screening tests cover the TSH (thyroid stimulating hormone) in the test-there are some regions in US who use the T4 measurement, and some use a combination of the TSH and T4 (which is ideal, but increases cost). The most common reason for congenital hypothyroidism is from defects at the gland level and this is usually picked up by an increased TSH (thyroid stimulating hormone) which is part of the newborn screening test as mentioned above. But it is important to remember that a small proportion of babies who have central hypothyroidism (pituitary defects) will have a low TSH result and will be hypothyroid (as there is failure of TSH release from the pituitary gland)-so even if there is a normal newborn screening, do send free T4 and TSH as part of your investigations in any baby with clinical concerns like prolonged jaundice, significant constipation etc.

The newborn screen should be done ideally before the patient goes home-the baby born by vaginal delivery often goes home by 24 to 36 hours. To avoid missing out, we send the sample early even though there is a slight increase in the false positive related to the normal TSH surge seen in the immediate postnatal period. But with the cutoff in the lab changing to age dependent cutoff (using slightly higher cutoff or say 15 or 20 in the first 72 hours, and 10 as the cutoff subsequently-this would vary between labs though), we are not seeing that issue (related to false positives) in our practice.

All the centers that send newborn screening samples should have a clear pathway to report abnormal results immediately to the physicians, and in case the TSH is abnormal, the family should be contacted for the repeat test ideally before 10 days of age (ie, if sample is sent by day 2-3, the result should be available and acted on within the next 6-7 days).

In the next section I will include some of the important recommendations of the AAP guidelines (2023-Congenital Hypothyroidism: Screening and Management | Pediatrics | American Academy of Pediatrics (aap.org)).

What should we do if the newborn screening result for TSH is abnormal?

If the first NBS is normal, perform a second NBS at 2 to 4 weeks of age in newborns who are acutely ill (admitted to a NICU), are preterm (<32 weeks gestation), have very low birth weight (<1500 g), received a transfusion before obtaining the NBS, have a monozygotic twin (or a same-sex twin, if zygosity is not known) or multiple birth or have trisomy 21.

Once we receive the results of the newborn screening, the action needed would depend on the result noted. It is very important to get a thorough history (including maternal thyroid status, risk of thyroid antibodies (as in maternal Graves disease), and clinical examination including jaundice, weight assessment, heart rate and feeding pattern.

1. If the result is within the lab range for the age, no action is needed unless a repeat sample is indicated (as above) or if there are clinical concerns in which case we still need the Free T4 and TSH (so we don’t miss out central hypothyroidism).

2. The level is more than 40 (TSH), the treatment with Levo-thyroxine should be started at the same time soon after obtaining the venous sample for free T4 and TSH, and possibly, the repeat spot test (if the lab requests the same). In these cases, it’s very urgent and delay should be avoided at any cost.

3. If serum TSH is elevated and serum FT4 is low on the repeat sample, initiate Levo-thyroxine (L-T4) treatment.

4. If serum TSH is >20 mIU/L and serum FT4 is normal, initiate (or continue) L-T4 treatment.

5. If serum TSH is elevated but ≤20 mIU/L and serum FT4 is normal, L-T4 treatment may be initiated, or serum TSH and FT4 may be monitored closely every 1 to 2 weeks without treatment. If FT4 becomes low, or if TSH elevation >10 mIU/L persists beyond 4 weeks of age, L-T4 treatment is recommended.

6. In infants with serum TSH elevation >5 mIU/L but ≤10 mIU/L that persists beyond 4 weeks of age, there is insufficient evidence to recommend treatment versus observation. In such cases, consultation with a pediatric endocrinologist (if it has not already occurred) is recommended to formulate a management plan specific to the patient.

7. If serum TSH is normal or low and serum FT4 is low, evaluate for possible central hypothyroidism with further testing as clinically indicated. Obtain confirmatory serum testing, including TSH with FT4.

8. Measuring a thyroxine-binding globulin concentration when T4 is low but FT4 is normal may assist in distinguishing central hypothyroidism from thyroxine-binding globulin deficiency.

9. Infants with central CH should be evaluated, in consultation with a pediatric endocrinologist, for additional hypothalamic-pituitary dysfunction. Consideration should be given to the timing of this evaluation before starting L-T4 treatment, because such treatment may lower cortisol levels.

Further testing and imaging:

Once the thyroid function is confirmed as abnormal, treatment is started. Imaging is not essential unless we feel it will impact management. Radioisotope scanning or scintigraphy can be considered before the treatment is well established when the TSH is still high, ideally within 2-3 days of starting treatment-but don’t delay initiation of treatment for imaging purpose. Ultrasound of the thyroid gland could be considered but is less sensitive compared to scintigraphy.

Treatment of congenital hypothyroidism

Once treatment is indicated based on the results (as above), enteral L-T4 at a starting dose of 10 to 15 mcg/kg/day administered once daily is started. L-T4 tablets can be crushed and suspended by the parent or guardian in 2 to 5 ml (1 teaspoon) of human milk or water. The tablet is available in strengths of 25, 50 and 100 microgram strengths, and the dose prescribed should be taken as appropriate.

Repeat testing after starting treatment (in 2 weeks time) is important as dose adjustment is needed (to avoid both under and over treatment). We expect TSH to reduce and normalize over 2-3 weeks. A overly suppressed TSH (below 0.3) or a high free T4 might indicate overtreatment, and dose reduction is needed. Overtreatment could impact bone maturation and final height, and in some cases, symptoms of hyperthyroidism could develop. Whenever a dose adjustment is needed, a repeat test is needed after 2-3 weeks, while if stable, we could repeat after 3-4 weeks in the initial months and then less frequently as the child grows and is stable. It is recommended to delay the dose on the day of testing till after the sample is taken.

Monitoring of the growth and development is important as well. Parents should be well educated on the importance of compliance with treatment, as non-compliance could impact brain development and leave permanent damage. If treatment is initiated within the first 2-3 weeks of age, neurodevelopment is expected to be normal. Delayed initiation of treatment and longer time to normalization of thyroid function are associated with poorer outcomes. So, it is important to ensure newborn screening is done, and if the results are abnormal, the dose started should be appropriate (the higher the TSH or lower the free T4, the dose chosen should be at the higher end of the range of 10-15 microgm/kg/day). If the diagnosis is delayed for any reason, the possibility of developmental delay is significant and support for neurodevelopment is important.

Is the treatment lifelong?

Most parents have this question in their mind. The commonest cause of congenital hypothyroidism is an absent or poorly developed (hypoplastic) thyroid gland, and most of these babies need the treatment for life. The higher the TSH is at diagnosis, the more likely it is that the treatment would be long term. In some children, especially those with hypoplastic (small) glands or with mild enzyme defects, the dose required might be small, and we could consider a trial off treatment for a week once over 3 years of age, and decide based on the repeat results. But stopping treatment in the first 3 years is not advisable (as the brain development is rapid during this phase).

This write up doesn’t include hypothyroidism that develops in the older child (for example, related to immune factors). I have not discussed other situations like the transient hyperthyrotrophinemia in preterm babies. Do review the linked detailed lecture if you are interested in learning more.

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