Newborn Screening in the US May Miss Mild Persistent Hypothyroidism.

OBJECTIVE: To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life. STUDY DESIGN: All NBS programs in the US were contacted and asked to provide information on their NBS protocols, TSH cutoffs, and whether these cutoffs were age adjusted. RESULTS: Of 51 NBS programs, 28 request a repeat specimen if the initial eluted serum TSH concentration is mildly increased (between the cutoff and a median upper limit of 50 mU/L), whereas 14 programs perform a routine second screen in all infants. Although these specimens are typically collected between 1 week and 1 month of life, 16 of the 28 programs with a discretionary second test and 8 of 14 programs with a routine second test do not have age-adjusted TSH cutoffs after the first 48 hours of life. CONCLUSIONS: There is variation in NBS practices for screening for congenital hypothyroidism across the US, and many programs do not adjust the TSH cutoff beyond the first 2 days of life. Samples are processed when received from older infants, often to retest borderline initial results. This approach will miss congenital hypothyroidism in infants with persistent mild TSH elevations. We recommend that all NBS programs provide age-adjusted TSH cutoffs, and suggest developing a standard approach to screening for congenital hypothyroidism in the US.

Congenital Hypothyroidism: Screening and Management.

ABSTRACT: Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Congenital Hypothyroidism: Screening and Management.

Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Newborn screening (NBS) for CH should be performed in all infants. Prompt diagnosis by NBS leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet practiced in all countries globally. Seventy percent of neonates worldwide do not undergo NBS. The recommended initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and with free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding the detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth-weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism. NBS alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.

Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion.

We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized.

History of the Thyroid.

The history of the thyroid dates from 2697 BCE when the "Yellow Emperor" Hung Ti described the use of seaweed to treat goiter. The English name "thyroid" was coined by Thomas Wharton in 1656 from the Greek word for a shield. Bernard Courtois discovered iodine in 1811 when he noted a residual purplish ash while burning seaweed. Robert Graves is known for his classic 1835 report of "palpitations, goiter, and exophthalmos" in three women, but Caleb Parry observed the same clinical features in 1786. The clinical syndrome we now recognize as hypothyroidism was characterized as "myxoedema" in 1878 by William Ord at St. Thomas Hospital. In 1891, George Murray reported that injection of thyroid extract from sheep led to improvement in symptoms in a woman with myxedema. Thomas Kocher, who reported that patients with goiter who underwent complete thyroidectomy developed cachexia strumipriva, was awarded the Nobel Prize in Physiology and Medicine in 1909. Edward Kendall discovered "thyroxin" on Christmas day in 1914. Studies by David Marine that iodine treatment prevented endemic goiter led to salt iodination, which has largely eradicated endemic cretinism. In 1973, Jean Dussault reported detection of congenital hypothyroidism by screening newborn populations.

Thyroid Function in Preterm/Low Birth Weight Infants: Impact on Diagnosis and Management of Thyroid Dysfunction.

Maternal thyroid hormone crosses the placenta to the fetus beginning in the first trimester, likely playing an important role in fetal development. The fetal thyroid gland begins to produce thyroid hormone in the second trimester, with fetal serum T4 levels gradually rising to term. Full maturation of the hypothalamic-pituitary-thyroid (HPT) axis does not occur until term gestation or the early neonatal period. Postnatal thyroid function in preterm babies is qualitatively similar to term infants, but the TSH surge is reduced, with a corresponding decrease in the rise in T4 and T3 levels. Serum T4 levels are reduced in proportion to the degree of prematurity, representing both loss of the maternal contribution and immaturity of the HPT axis. Other factors, such as neonatal drugs, e.g., dopamine, and non-thyroidal illness syndrome (NTIS) related to co-morbidities contribute to the "hypothyroxinemia of prematurity". Iodine, both deficiency and excess, may impact thyroid function in infants born preterm. Overall, the incidence of permanent congenital hypothyroidism in preterm infants appears to be similar to term infants. However, in newborn screening (NBS) that employ a total T4-reflex TSH test approach, a higher proportion of preterm babies will have a T4 below the cutoff, associated with a non-elevated TSH level. In NBS programs with a primary TSH test combined with serial testing, there is a relatively high incidence of "delayed TSH elevation" in preterm neonates. On follow-up, the majority of these cases have transient hypothyroidism. Preterm/LBW infants have many clinical manifestations that might be ascribed to hypothyroidism. The question then arises whether the hypothyroxinemia of prematurity, with thyroid function tests compatible with either non-thyroidal illness syndrome or central hypothyroidism, is a physiologic or pathologic process. In particular, does hypothyroxinemia contribute to the neurodevelopmental impairment common to preterm infants? Results from multiple studies are mixed, with some randomized controlled trials in the most preterm infants born <28 weeks gestation appearing to show benefit. This review will summarize fetal and neonatal thyroid physiology, thyroid disorders specific to preterm/LBW infants and their impact on NBS for congenital hypothyroidism, examine treatment studies, and finish with comments on unresolved questions and areas of controversy.

Newborn screening strategies for congenital hypothyroidism: an update.

It is the purpose of this article to briefly review the initial development and subsequent evolution of newborn screening programs to detect infants with congenital hypothyroidism (CH) and then to provide an update of the advantages and disadvantages of the main test strategies. Pilot programs began screening newborn populations in North America in the mid-1970s using either primary thyroxine (T4)-follow-up thyroid stimulating hormone (TSH) or primary TSH testing. Many programs in the United States and around the world continue to prefer a primary T4-follow-up TSH test strategy. This approach has the advantage of detecting infants with primary CH, as well as cases of hypopituitary hypothyroidism, by follow-up of infants with a T4 below an absolute cutoff or with a persistently low T4 level, necessitating a higher recall rate. With increasing assay sensitivity and specificity, several programs in the United States and worldwide have elected to switch to a primary TSH test strategy. This test strategy has the advantage of detecting primary CH and subclinical hypothyroidism and at a lower recall rate. Programs considering switching to a primary TSH test strategy need to develop age-related TSH cutoffs to maintain an acceptable recall rate. Both test strategies have the potential to detect infants with CH characterized by "delayed TSH rise," but only if they collect a routine or discretionary second specimen, now recommended in low-birth-weight and acutely ill infants. Lastly, a lower TSH cutoff appears to be one of the explanations for the recently described increased incidence of CH.

Outcome of Newborn Screening for Congenital Adrenal Hyperplasia at Two Time Points.

BACKGROUND/AIMS: Screening newborns for congenital adrenal hyperplasia (CAH) is problematic owing to the dynamic changes in serum 17-hydroxyprogesterone (17-OHP) levels following birth. Our study objectives were to determine the accuracy of screening, severity of CAH, and biochemical and clinical outcomes of cases detected by our program which collects specimens at 2 time periods following birth. METHODS: We reviewed all CAH cases detected in the Northwest Regional Newborn Screening Program from 2003 through 2017. Comparison was made of screening and confirmatory serum 17-OHP, neonatal, maternal, and follow-up auxologic data, steroid treatment doses, and 21-hydroxylase genotype in cases detected on the first versus second test. RESULTS: Out of 164 cases of CAH, 25% were detected on the second screen. Infants detected on the second test had a lower screening 17-OHP (147 vs. 294 ng/mL), lower confirmatory serum 17-OHP (7,772 vs. 14,622 ng/dL), and were more likely to have simple virilizing CAH. There were no identifiable neonatal or maternal factors associated with detection on the second test. 21-Hydroxylase genotypes overlapped in first versus second screen cases. CONCLUSION: Early collection of specimens necessitated by early discharge resulted in milder CAH cases falling below the screening 17-OHP cutoff. In our program 25% of cases were detected on a routine second screen.

Should the levothyroxine starting dose be tailored to disease severity in neonates with congenital hypothyroidism?

Early levothyroxine treatment is crucial to minimize neurocognitive impairment associated with congenital hypothyroidism. In this Practice Point commentary, I discuss the findings, implications, and limitations of the study of Mathai et al. in which neonates with congenital hypothyroidism were treated with variable initial doses of levothyroxine. A high initial levothyroxine dose was used for newborn babies with athyreosis, an intermediate dose for those with ectopic glands, and a low dose for those with dyshormonogenesis. Serum free T(4) levels normalized within 2 weeks, but serum TSH levels within up to 4 weeks. A dose adjustment (mostly a dose reduction) was required in about half of the neonates in the first 2 weeks of life. As Mathai et al. carried out no neuropsychological tests, we do not know if their approach has a more beneficial effect on neurocognitive outcomes than other treatment strategies. Nevertheless, as tailoring the levothyroxine dose to severity rapidly normalized serum free T(4) levels, one would predict a beneficial effect of this approach on neurocognitive outcome.

How should we be treating children with congenital hypothyroidism?

Early detection by newborn screening and appropriate L-thyroxine treatment leads to normal or near-normal neurocognitive outcome in infants with congenital hypothyroidism. Many newborns with congenital hypothyroidism have some residual thyroid hormone production, and even in those with athyreosis, transplacental passage of maternal thyroid hormone offers some protection for a time. Given the serum T4 half-life of 6 days, the neonatal T4 level will fall and disappear over the first 2-3 weeks of life. Thus, there is a crucial 'window of opportunity' to correct the hypothyroidism and minimize the time the brain is exposed to hypothyroxinemia. While there are few truly prospective, randomized clinical trials investigating treatment parameters, studies measuring IQ outcome support a starting L-thyroxine dose of 10-15 microg/kg/day. Further, studies show that the most severely hypothyroid infants are at risk for a 5-20 point decrease in IQ. Such infants may benefit from a starting dose of 12-17 microg/kg/d, which has been shown to normalize T4 in 3 days and TSH in 2 weeks. Target serum T4 or free T4 levels appear to be higher in the first two weeks of treatment. Infants require more frequent laboratory monitoring, every 1-2 months in the first 6 months and every 3-4 months until age 3 years, as the developing brain has a critical dependence on thyroid hormone in the first 2-3 years of life.

Pediatric thyroid testing issues.

Thyroid problems are common in children. While serum thyroid function tests lead to an accurate diagnosis in most patients, unique patient situations can produce misleading results. Total T4 measurements can incorrectly suggest hypothyroidism in congenital thyroid binding globulin (TBG) deficiency and hyperthyroidism in TBG excess, as seen in high estrogen states. Free T4 (FT4) measurement techniques involve either physical separation of unbound thyroxine from serum binding proteins or estimation of FT4 levels in the presence of binding proteins. These estimation techniques are susceptible to under- or over-estimation of FT4 levels when binding proteins are low or high. Other complicating factors arise in the setting of prematurity or systemic non-thyroidal illness (NTI), simulating central hypothyroidism. Thyroid stimulating hormone (TSH) levels in children have a wider normal range than in adults and are affected by drugs and NTI. Additionally, heterophile and anti-T4 or anti-TSH antibodies can interfere with accurate T4 or TSH measurement.

Characterization of Thyroid Abnormalities in a Large Cohort of Children with Down Syndrome
.

BACKGROUND/AIMS: Thyroid disease is a common comorbidity in individuals with Down syndrome (DS), but historical studies have multiple limitations. We assessed thyroid abnormalities in a large cohort of children with DS. METHODS: Retrospective records review from a single institution. Calculated prevalence of common thyroid abnormalities and associations with common comorbidities. RESULTS: Among 508 patients, 120 (24%) had a thyroid-related diagnosis, the majority having elevated thyrotropin treated with levothyroxine. A Kaplan-Meier estimate projects that 50% have thyroid disorder by adulthood, with 20% of hypothyroidism diagnosed before the age of 6 months. When tested, approximately 50% had positive antithyroid antibodies, though this rate was 100% in overt hypothyroidism. There was no association between congenital or acquired hypothyroidism and common comorbidities. CONCLUSION: Thyroid disease in DS is more common and occurs earlier than in the general population, and is often transient. Thyroid disease is unrelated to gender, obesity, or other comorbidities. Apart from overt hypothyroidism, much of hypothyroidism in DS appears unrelated to autoimmunity; we recommend checking of antithyroid antibodies only in select cases. An additional screen for thyroid disease between the newborn screen and the 6-month well-child visit will detect early cases of hypothyroidism who passed their newborn screen.
.

Detecting Congenital Central Hypothyroidism by Newborn Screening: Difficulty in Distinguishing from Congenital Thyroxine-Binding Globulin Deficiency.

BACKGROUND/AIMS: Congenital central hypothyroidism (CH-C) can be detected on newborn screening (NBS) by programs using thyroxine (T4)-reflex thyroid-stimulating hormone (TSH) test approach. CH-C must be distinguished from T4-binding globulin (TBG) deficiency. We sought to determine whether thyroid function tests reliably separate CH-C from TBG deficiency. METHODS: We analyzed NBS and serum free and total T4, T3 resin uptake (T3RU) or TBG, and TSH for infants in the Northwest Regional NBS Program (NWRSP) between the years 2008 and 2015 with either CH-C or TBG deficiency. RESULTS: We discovered a significant overlap in T3RU and TBG levels amongst 21 cases of CH-C and 250 cases of TBG deficiency. Mean serum TBG levels were lower in CH-C cases (20.3 µg/mL, range 14.2-33.3) than what is reported in healthy infants (28.6 µg/mL, range 19.1-44.6). Serum free T4 was lower in CH-C cases than TBG deficiency but did not always differentiate between the two conditions. CONCLUSION: CH-C benefits from detection on NBS but must be distinguished from TBG deficiency. The diagnosis of CH-C rests solely on subnormal serum free T4, but is supported by the demonstration of other pituitary hormone deficiencies. As an overlap exists, serum TBG (or T3RU) levels do not play a role in the diagnosis of CH-C.

Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA.

BACKGROUND/AIMS: The newborn screening (NBS) program in Oregon, USA, collects two routine specimens in all infants. The aim of our study was to determine the incidence of permanent versus transient congenital hypothyroidism (CH) in infants detected on the first versus second screening test. METHODS: Thyroid function was determined in infants after the age of 3 years diagnosed with CH and born in Oregon between 2005 and 2011. Permanent hypothyroidism was defined as a TSH rise >10 mIU/ml after the first year on treatment or a TSH rise >6 mIU/ml with temporary discontinuation of l-thyroxine after the age of 3 years. RESULTS: Of the cases detected on the first test, 72 of 87 (83%) were permanent and 15 of 87 (17%) were transient, while of the cases detected on the second test, 5 of 22 (23%) were permanent and 17 of 22 (77%) were transient (OR 16.3, p < 0.001). There was a female preponderance detected on the first screen versus a male preponderance on the second screen. Blood spot and serum thyroid function tests at diagnosis, before treatment, were not meaningfully different between the two groups. The mean l-thyroxine dose at the age of 3 years was greater on the first screen: 61.2 versus 36.6 µg/day. CONCLUSIONS: Infants detected on the second NBS specimen have a higher incidence of transient CH. © 2016 S. Karger AG, Basel.

Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes?

A workshop entitled, "The Impact of Maternal Thyroid Diseases on the Developing Fetus: Implications for Diagnosis, Treatment, and Screening," was held in Atlanta, Georgia, January 12-13, 2004. This paper reports on the individual session that examined thyroid inadequacy during gestation as a risk factor for adverse pregnancy and developmental outcomes. For this session the following papers were presented: "Adverse Pregnancy Outcomes"; "Thyroid Physiology in the Fetus"; "New England Data: Cretinism Revisited-Preventing Fetal Brain Damage when Mothers Have Subclinical Hypothyroidism"; "Dutch Data: Pregnancy, Maternal Thyroid (Dys)function and Outcome of the Offspring"; and "Report on the Wales Controlled Antenatal Thyroid Screening Study (CATS); A Prospective RCT." These presentations were formally discussed by invited respondents well as others in attendance. Salient points from this session about which there was agreement include the following. Maternal hypothyroidism is associated with complications of pregnancy and adverse effects on the fetus. These risks are greater in women with overt hypothyroidism compared to subclinical hypothyroidism, and also appear to be increased in women with euthyroid autoimmune thyroid disease. If maternal hypothyroidism is treated adequately, this appears to reduce the risk for adverse outcomes. The demonstration of a pattern of ontogeny of fetal cerebral cortex deiodinases and thyroid hormone receptors, beginning by 7-8 weeks' gestation, is circumstantial evidence that thyroid hormone plays an important role in fetal neurodevelopment. Significant fetal thyroid hormone production and secretion does not begin until approximately 20 weeks' gestation. If there is a significant role for thyroid hormone in fetal neurodevelopment before 20 weeks' gestation, it likely is of maternal origin. Studies demonstrate low levels of thyroxine in the fetal coelomic fluid and blood prior to 12-14 weeks' gestation. Published data consistently document a relationship between maternal thyroid deficiency during pregnancy and problems with neuropsychological development of the offspring.

Androgen replacement in adolescents and young women with hypopituitarism.

The aim of this study was to test the hypothesis that young women with androgen deficiency due to hypopituitarism would benefit from androgen replacement in the form of dehydroepiandrosterone (DHEA). Five young women, age 15.2-23.1 years, with panhypopituitarism were studied in a 12-month double blind placebo-controlled crossover trial of DHEA replacement in a dose 50 mg/day (Belmar Pharmacy, Lakewood, CO). All had growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH) and antidiuretic hormone deficiencies. Gonadotropin deficiency was complete in three and partial in two. The patients were evaluated at baseline, 6 months and 12 months. Serum hormone levels, body composition, lumbar bone mineral density (BMD), exercise capacity and tests of psychological function were performed. DHEA replacement restored serum DHEA levels to normal, 359.8+/-337 ng/dl (12.5+/-11.7 nmol/l). The Life Situation Survey showed significantly better life satisfaction on DHEA than placebo (110 vs 102, p = 0.05). Trends for improved maximal oxygen uptake (VO2), and decreased percent body fat did not reach statistical significance. In conclusion, androgen replacement with DHEA should be considered in young women with panhypopituitarism. Further studies over longer periods in larger groups of patients are necessary to better evaluate the effects of DHEA replacement on BMD, muscle strength and body composition.

Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome.

The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg x d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. GH administration did not impact fasting ghrelin concentration.

Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome.

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.