Neonatal congenital hypothyroidism screening effective; questions remain for type, cutoff points

Congenital hypothyroidism is one of the most common endocrine disorders present at birth, as well as the most common treatable cause of mental retardation.

Before neonatal screening became standard in the United States during the past 40 years, congenital hypothyroidism often went unrecognized in many children.

“[The babies] used to all be missed because the signs and symptoms appear maybe months later, and by that time, often, treatment is less effective,” Samuel Refetoff, MD, professor of medicine and pediatrics and director of the endocrinology laboratory at The University of Chicago Pritzker School of Medicine, told Endocrine Today. “If treatment is not given in the first 6 months of life, then the damage is going to be severe.”

According to 2014 guidelines from the European Society for Paediatric Endocrinology, “The harmonization of diagnosis, management and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder.

“Individuals with [congenital hypothyroidism] require monitoring throughout their lives, particularly during early childhood and pregnancy,” according to the guidelines.

In a 2010 review published in the Orphanet Journal of Rare Diseases, researchers reported that the incidence of congenital hypothyroidism in the United States increased from one in 4,094 births in 1987 to one in 2,372 births in 2002.

According to the review, the incidence of preterm births has increased by nearly 20% during the past 20 years, which may be contributing to the overall increased incidence of congenital hypothyroidism. Another explanation may be a change in testing strategies.

“With increased sensitivity and accuracy of [thyroid-stimulating hormone] methods, many U.S. and other programs around the world have switched from a primary thyroxine follow-up TSH approach to a primary TSH test,” the researchers wrote. “If the TSH cutoff is lowered, more infants with milder congenital hypothyroidism will be detected.”

Endocrine Today interviewed several experts about the screening, infant characteristics and outcomes for congenital hypothyroidism.

Causes, types of congenital hypothyroidism

The most common underlying etiology of congenital hypothyroidism is thyroid dysgenesis, failure of the gland to develop or fully develop. According to Rosalind S. Brown, MD, CM, FRCP(C), senior associate physician in medicine and associate professor of pediatrics at Boston Children’s Hospital, thyroid dysgenesis accounts for 80% to 90% of cases.

“The thyroid gland starts its development in the fetus at the base of the tongue, and it has to migrate down to its normal location in the middle of the neck. If it does not migrate normally, it is referred to as an ectopic gland,” Stephen H. LaFranchi, MD, of the department of pediatrics, division of endocrinology at Oregon Health and Science University, told Endocrine Today. “All of those conditions — absent gland or hypoplasia or an ectopic gland — are grouped under thyroid dysgenesis, and that in a sense is a congenital malformation.”

The remaining 10% to 20% of cases are due to dyshormonogenesis, an abnormality in one of the steps necessary for thyroid hormone synthesis.

However, Refetoff said several less common conditions in which thyroid hormone deficiency is not implicated can give rise to congenital hypothyroidism.

In these instances, the thyroid hormone level is normal or even high, and neonatal screening will not pick up the problem, which can lead to severe symptoms later on. These are defects in the thyroid hormone cell transporter, metabolism and action at the receptor level.

“Children with cell transport defect never walk or talk, and there have been about 300 of these children identified so far,” he said.

According to a review published in the Orphanet Journal of Rare Diseases, there are two general types of congenital hypothyroidism: permanent congenital hypothyroidism and transient congenital hypothyroidism. Permanent congenital hypothyroidism is a persistent deficiency of thyroid hormone that requires lifelong treatment. Transient congenital hypothyroidism refers to a temporary deficiency of thyroid hormone that is discovered at birth but then recovers to normal thyroid hormone production. The recovery to euthyroidism typically occurs within the first few months or years of life.

According to LaFranchi, the chief intent of screening newborns is to detect permanent congenital hypothyroidism.

“At the time hypothyroidism is detected, it is impossible to tell if it is going to turn out to be permanent or transient,” LaFranchi said.

Detection as well as treatment of transient congenital hypothyroidism also is beneficial.

“We think that infants still benefit from detection and treatment because they may have a degree of hypothyroidism that is going to cause a problem, even though it gets better,” LaFranchi said. “There is still a temporary period of hypothyroidism where treatment may protect the brain.”

Brown added that thyroid hormone is critical for brain development within the first 3 years of life.

“We usually treat these transient cases, but there is controversy as to what to do,” Brown said. “A number of babies will have a normal thyroid hormone level, but their TSH level will be slightly elevated. There is disagreement as to when and if these babies have to be treated. Some people will wait for a few weeks to see if the levels are normalizing before treating, but nobody should wait very long because it is such a critical period for brain development.”

If congenital hypothyroidism is not detected through newborn screening, the major adverse impact on children would be in brain development.

“The developing brain in the fetus needs normal amounts of thyroid hormone produced by the thyroid to develop normally,” LaFranchi said. “With reduced levels of thyroid hormone, there are problems overall with brain development. The brain lacks the normal cell number and doesn’t have the normal morphology and myelination, which is important for function, so mental retardation is the main adverse effect of failure to detect congenital hypothyroidism.”

Screening, cutoff values

According to a 2013 report published in the Journal of Clinical Research in Pediatric Endocrinology, screening for newborn congenital hypothyroidism is “one of the major achievements of preventive medicine.”

“Since diagnosis based on clinical findings is delayed in most instances because of few symptoms and signs, hypothyroidism in the newborn period is almost always overlooked, and delayed diagnosis leads to the most severe outcome of congenital hypothyroidism, namely, mental retardation,” the report states.

According to Refetoff, screening was initially devised in Quebec, Canada, and was based on a measurement of thyroxine.

“That was the standard test for probably 5 or 10 years,” Refetoff said. “The problem is that there are a lot of false positives.”

Currently, every state undertakes screening for the disorder, but there is no gold standard for screening across the United States.

“The standard is to use whatever approach works best for you, that is each state, and the intent is to, again, detect babies with primary hypothyroidism,” LaFranchi told Endocrine Today.

One approach is measuring T₄ concentrations from a dried blood spot from the infant, and if the level is below a certain cutoff point, to then measure TSH. This strategy is referred to as a primary T₄ reflex TSH approach.

“The majority of states, initially, used this approach,” LaFranchi said. “Part of the issue was that TSH assays were just under development, and it was difficult to adapt testing to the small amount of blood available from the blood spot.”

When TSH testing accuracy improved, several screening programs in the United States switched to a primary TSH test.

“At present, about 40% of the states use the T₄ reflex TSH approach, 50% use TSH as the first test, and the other 10% actually do combined T₄ and TSH,” LaFranchi said. “Only programs that undertake the T₄-reflex TSH or the combined T₄ and TSH have the potential to detect secondary or central hypothyroidism.”

Screening should be done by age 48 hours to 4 days, although the European Society for Paediatric Endocrinology guideline states that the best window for screening is within age 48 to 72 hours. Samples that are collected in the first 24 to 48 hours of life may lead to false-positive TSH elevations.

The 2014 European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis and management of congenital hypothyroidism, which according to Susan R. Rose, MD, a professor in the division of endocrinology at Cincinnati Children’s Hospital Medical Center within the University of Cincinnati College of Medicine, included review from experts worldwide, including the United States, built on the 2006 American Academy of Pediatrics clinical report. The guideline recommends that treatment be started immediately after collection of confirmatory serum TSH and free T₄ if the dried blood spot TSH concentration is at least 40 mU/L of whole blood. However, if the concentration is less than 40 mU/L, the clinician may postpone treatment for 1 to 2 days pending serum results. Regardless of TSH concentration, treatment is recommended if free T₄ concentrations are below normal for the age of the infant. Further, if venous TSH concentration is persistently more than 20 mU/L, treatment should be started even if serum free T₄ concentration is normal.

“Some people have looked at a lower cutoff point and have found, naturally, that more children have TSH [concentrations] that are lower but still not as low as the cutoff point, and some are picked up to have true hypothyroidism but it is less severe,” Refetoff said. “The question is whether it is worth the effort or the cost to recall infants with lower TSH values; by lowering the cutoff points, clinicians will have to re-evaluate one of every 1,500 newborns instead of one of every 3,500.”

The guideline also suggests diagnostic imaging be performed to establish a definitive diagnosis when venous TSH concentration is between 6 mU/L and 20 mU/L and free T₄ concentration is within the normal limits for the newborn’s age.

“If the TSH [concentration] remains elevated more than a month, the children should be treated, but re-evaluated at 3 years of age by having them come off treatment and getting repeat thyroid level tests a month later,” Rose said. “The fact is that it may be transient, but it might not just last a couple of months, it may last 9 months. If you are waiting for it to resolve on its own, thinking it’s transient, then you have a long period of hypothyroidism that could lead to a loss of a few IQ points. We really don’t want that to happen, though. Treatment for 3 years is better than losing IQ points.”

Infant characteristics

Rose and colleagues evaluated data from the Ohio State Newborn Screening Program Database on 448,766 neonates to determine the variation in newborn screening false-positive rates for congenital hypothyroidism according to birth weight and gestational age.

Researchers found that although only 1.8% of participants were very low birth weight, they accounted for 18% of the false-positive results. False-positive rates were increased with decreasing birth weight and gestational age, and the rates were significantly increased in very low-birth-weight babies. Sixty-two percent of the false-positives in very low-birth-weight participants were due to thyrotropin/backup T₄ and 17-hydroxyprogesterone.

“Expanded [newborn screening false-positive rates] are inversely correlated to birth weight and gestational age,” the researchers wrote. “Waiting until 24 to 48 hours’ postnatal age to collect blood-spot specimens in nontransfused infants born at < 32 weeks’ gestation will potentially reduce [false-positive rates] for both thyrotropin and 17-hydroxyprogesterone analyte tests, which contribute to two-thirds of false-positive results in [very low-birth-weight] infants. A reduction in [false-positive rates] would potentially enhance screening efficiency, improve cost-effectiveness, and reduce parental anxiety associated with false-positive results.”

Rose told Endocrine Today that the absolute numerical values of thyroid levels are lower in preterm infants and that the levels actually decrease during the first week and then rise.

“Often, premature nurseries will get the screen right away; they try to do it before there’s any major illness,” Rose said. “Lots of preterm babies are not well, so they may do the screen earlier and before any transfusion. Illness itself will alter thyroid levels so it is possible to miss a diagnosis of congenital hypothyroidism because the TSH is blunted by the illness, so there are new recommendations to rescreen or do actual thyroid levels in the laboratory before the preterm infant goes home after they’re well enough, so we don’t miss a late rise in TSH.”

Brown said the rising survival of premature infants has “greatly complicated newborn screening.”

“Premature infants have immature thyroid glands, and therefore, their thyroid hormone levels are lower than those in term infants,” she said. “In addition, they’re frequently sick, they can be treated with medicines that affect the screening, they can be exposed to iodine, which can affect their thyroid function, and many programs believe that premature infants should be retested routinely, maybe at 2 weeks and then monthly until discharge to make sure that they don’t develop any abnormal thyroid function that needs to be treated. Premature infants have greatly increased the amount of screening that’s done.”

Lifelong treatment

The standard of care is essentially to replace the thyroid hormone that is missing and restore it to normal. According to the clinical report published by Rose and colleagues, initial levothyroxine doses of 10 µg/kg to 15 µg/kg — depending on disease severity — are recommended. The goal of treatment is to normalize T₄ within 2 weeks and TSH within 1 month. Free T₄ should be measured after 1 week of therapy to determine whether serum concentrations are increasing appropriately, and dose should be adjusted based on clinical response and serum free T₄ and TSH concentrations.

“Allowing the body to control the amount of thyroid hormone is ideal,” Refetoff said. “The adverse effect is either not enough is given or too much is given, and that’s not uncommon, especially later on in life when the children start taking care of themselves. When they’re teenagers they may not take their hormone properly or they take more before they go to the doctor because they’re afraid that the test will show that they haven’t been taking it.”

However, data presented at the Endocrine Society’s 98th Annual Meeting in April suggest that the recommended levothyroxine dosing level may be too high, and that some infants require a levothyroxine dose reduction because of iatrogenic hyperthyroxinemia when following guidelines for initiating therapy. In the study of 104 infants newly diagnosed with congenital hypothyroidism, 51% did not require a dose adjustment, 36.5% required a dose reduction and 12.5% required a dose increase. Fifty-seven percent of newborns with an initial dose of more than 12.5 µg/kg per day required a dose reduction at follow-up compared with 26.1% of those with a starting dose of 12.5 µg/kg per day or less (P = .007).

“A significantly large proportion of patients being treated for congenital hypothyroidism are requiring dose reduction on follow-up due to becoming hyperthyroid on laboratory evaluation, especially when dosed at the higher end of the dosage range,” Meghan Elizabeth Craven, MD, of Cohen Children’s Medical Center in New Hyde Park, New York, told Endocrine Today. “Further studies are needed, but we do advise practitioners to think carefully when dosing in the higher end of the dosage range and to make sure they are following laboratory values closely at the recommended 2-week mark.”

Rose added that the goal of treatment is to bring thyroid hormone levels into the optimal, normal range.

“If there is not adequate monitoring, then the thyroid hormone dose could lead to higher than the planned levels, and that could have side effects. If you don’t give a high enough dose, that can have side effects of undertreatment,” she said.

Rose said overtreatment can cause the infant to be jittery or have trouble sleeping.

“They kind of act like colics,” she said. “If you have a baby who has symptoms like this and you know that their levels are normal, you know that it’s not the thyroid hormone dose, you know it’s something else. Undertreatment could lead to poor growth and inadequate mental development.”

However, Brown added that although there can be side effects, thyroid hormone is really a replacement therapy.

“You’re just giving back what the body should be making itself,” she said. “It’s not a drug with side effects, per se. There have been some very mild abnormalities reported in some babies and some patients with congenital hypothyroidism, but it tends to relate to how early treatment was started, starting dose, how well thyroid function was maintained. It’s not a consequence of thyroid hormone, it’s a consequence of the deficiency or the treatment because of the deficiency.” – by Amber Cox

• References:
• Büyükgebiz A. J Clin Res Pediatr Endocrinol. 2013;doi:10.4274/jcrpe.845.
• Craven, MD, Frank GR. Poster Board FRI 047. Presented at: The Endocrine Society Annual Meeting; April 1-4, 2016; Boston.
• Léger J, et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-1891.
• Rastogi MV, LaFranchi SH. Orphanet J Rare Dis. 2010:doi:10.1186/1750-1172-5-17.
• Rose SR, et al. Pediatrics. 2006;doi:10.1542/peds.2006-0915.
• Slaughter JL, et al. Pediatrics. 2010;doi:10.1542/peds.2010-0943.
• For more information:
• Rosalind S. Brown, MD, CM, FRCP(C), can be reached at rosalind.brown@childrens.harvard.edu.
• Meghan Elizabeth Craven, MD, can be reached at meghan.craven@gmail.com.
• Stephen H. LaFranchi, MD, can be reached at lafranchs@ohsu.edu.
• Samuel Refetoff, MD, can be reached at srefetoff@uchicago.edu.
• Susan R. Rose, MD, can be reached at susan.rose@cchmc.org.

Disclosures: Brown, Craven, LaFranchi, Refetoff and Rose report no relevant financial disclosures.

Is there any need for the use of ultrasound or thyroid scan for thyroid conditions that will not show up by the standard measurements of T₄ and TSH?

Ultrasound imaging should not replace T₄-TSH testing.

Perhaps ultrasound should be employed in case there is an abnormal gland with T₄ and TSH. There are times when this is possible. If there is evidence of biochemical hypothyroidism that requires treatment, we frequently want to get some kind of confirmatory imaging studies. The advantage of the ultrasound is that it is very simple, painless and can easily be done. Ultrasound can also show some abnormalities, such as an ectopic thyroid gland, which will help make the diagnosis and can confirm the need for ongoing treatment. On the other hand, having a normal image does not exclude the possibility of hypothyroidism, and that’s why it needs to be taken in light of that.

The option for imaging would be thyroid scanning. Thyroid scanning gives some idea both about the location as well as the morphology of the gland. It also tells a little bit about functioning. The downside of imaging is that there are really no good normal values in infants. Goldis and colleagues discussed the use of imaging on this, along with possible advantages and disadvantages (Endocrinol Metab Clin North Am. 2016;doi:10.1016/j.ecl.2016.02.005). Imaging methods can help determine the anatomy and function of the thyroid gland, and although thyroid scan has been considered superior to ultrasound in detecting ectopic thyroid tissue, ultrasound can detect the presence of thyroid tissue not otherwise found in 15% of patients.

Robert Rapaport, MD, is professor of pediatrics and director of the division of pediatric endocrinology and diabetes at the Icahn School of Medicine at Mount Sinai. Disclosure: Rapaport reports no relevant financial disclosures.

It is time to act on the consensus recommendation to add imaging into the initial evaluation.

In 2014, experts from seven international pediatric endocrine societies published recommendations for the evaluation and management of congenital hypothyroidism (Léger J et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-1891). The authors recommended thyroid imaging as part of the initial evaluation, incorporating radioisotope scanning, ultrasonography or both. Despite these recommendations many providers continue to pursue a “simpler” approach of just starting levothyroxine rather than going through the process of trying to determine the etiology of congenital hypothyroidism.

Providers in favor of the “treat now and sort out later” approach suggest that the degree of elevation in TSH is an adequate predictor of etiology and prognosis. However, with lowering of cutoff levels to avoid missed cases, there are an increasing number of patients with borderline TSH values (5-20 mIU/L in the first month of life) placed on levothyroxine. In addition, even in infants with markedly elevated TSH — those typically considered overtly positive — there are a number of infants who will ultimately be found to have normal thyroid status secondary to transient factors, including maternal TSH receptor antibodies (TRAb) and iodine deficiency or excess.

The most common etiology of permanent congenital hypothyroidism is thyroid dysgenesis associated with ectopic tissue followed by dyshormonogenesis. Thyroid ultrasound has 100% sensitivity for identifying a eutopic gland, but is less sensitive for identifying ectopic tissue. Thyroid scan has high sensitivity for detecting ectopic tissue, with the exception of congenital hypothyroidism associated with a mutation in the sodium-iodine symporter or if secondary to maternal TRAb or exposure to excess iodine. Technetium-99m (99mTc) is less expensive than iodine-123, and imaging can be performed within 4 hours of administering the isotope, allowing one to obtain both an ultrasound and a thyroid scan on the same day if indicated. The reintroduction of the perchlorate discharge test would allow improved assessment for dyshormonogenesis.

The additional cost would be one hospital visit and approximately $2,000 to $2,500 to perform the tests, with many infants requiring only 99mTc because the most common etiology for permanent congenital hypothyroidism is thyroid dysgenesis/ectopy. Pursuing this approach does not (and should not) delay initiation of levothyroxine because the 99mTc scan can be performed up to 7 days from starting therapy. In contrast, if we continue to pursue the “treat now and sort out later” approach, the costs include the medication, monthly to every second or third month, laboratory testing, additional physician clinic visits, and the unknown impact of the stress and anxiety to the child and parent.

Our obligation is to ensure that we do not miss a diagnosis; however, it is time to reconsider that initial imaging may be less invasive and provide important data for appropriate care.

Andrew J. Bauer, MD, FAAP, is an endocrinologist and medical director of the Pediatric Thyroid Center at The Children’s Hospital of Philadelphia. Disclosure: Bauer reports no relevant financial disclosures.