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Clinical Monitoring Guidelines for Congenital Hypothyroidism: Laboratory Outcome Data in the First Year of Life
Clinical Monitoring Guidelines for Congenital Hypothyroidism: Laboratory Outcome Data in the First Year of Life Bharti Balhara, MD,* Madhusmita Misra, MD, MPH,* and Lynne L. Levitsky, MD Objective To examine whether current recommendations for thyroid status monitoring in children with congenital hypothyroidism (CH) (monthly in the first 6 months and every 3-4 months subsequently) are adequate, or whether monthly monitoring is necessary throughout the first year. Study design We reviewed charts of 70 children with CH for initial thyroid-stimulating hormone (TSH), frequency of follow-up, dose changes, and thyroxine (T4) and TSH levels in the first year. Need for monthly monitoring was determined on the basis of guidelines to maintain T4/free T4 in the upper half of the normal range and rapidly normalize TSH. Results Monthly monitoring was justified in 75% in the first 6 months and 36% in the next 6 months. Children requiring monthly monitoring in the second 6 months had higher baseline TSH (P = .02) and lower T4 (P = .01) than those not requiring monthly monitoring. Thyroid dysgenesis, starting levothyroxine dose, sex, and ethnicity did not predict requirement for monthly monitoring. Thirty percent of children in the first and second 6 months had $1 high TSH level, with a T4/free T4 not in the upper half of the normal range. Conclusion More than a third of children with CH require monthly monitoring between 6 to 12 months on the basis of study criteria. Current monitoring guidelines may need to be reexamined. (J Pediatr 2011;158:532-7). See editorial, p 525 and related article, p 538
C
ongenital hypothyroidism (CH) has a reported incidence of approximately one in 3000 to 4000 live births.1 Since the introduction of pilot screening programs in 1974, newborn screening for CH has become widely routine and represents a major advance in preventive medicine. It improves outcome by allowing intervention before the appearance of clinical hypothyroidism.2,3 The essential role of thyroid hormones for normal brain development during a critical period from fetal life to 24 to 36 months of age has been well described.4,5 Because children born with CH are at risk of poor cognitive development and behavioral problems, all infants with CH should be rendered euthyroid as promptly as possible.6-8 Clinical studies have suggested that factors that play an important role in determining long-term outcome include severity of hypothyroidism, age at which levothyroxine (L-T4) replacement is started, initial dose of L-T4, as well as time taken to achieve and maintain target ranges for thyroxine (T4) and thyroid-stimulating hormone (TSH).9-11 L-T4 supplementation (started within 2-3 weeks of age) is the standard of care for CH, and an initial dose of 10 to 15 mg/kg of L-T4 is recommended.12 Frequent evaluations of thyroid function (total T4 or free T4 [FT4] and TSH) are necessary to ensure optimal L-T4 dosage and compliance. The goal is to maintain total T4 or FT4 concentrations in the upper half of the reference range and to normalize serum TSH rapidly.13 The American Academy of Pediatrics (AAP) has issued 3 sets of guidelines for laboratory evaluations since 1987.13-15 The most recent of these13 suggest that T4 and TSH measurements should be performed at: (1) 2 and 4 weeks after starting treatment; (2) every 1 to 2 months during the first 6 months of life; (3) every 3 to 4 months between 6 months and 3 years; (4) every 6 to 12 months until growth is completed; and (5) at more frequent intervals when adherence is questioned, abnormal results are obtained, or dose or source has been changed; FT4 and TSH measurements should be repeated 4 weeks after any change in L-T4 dosage. There are few data supporting these recommendations. We performed a retrospective study to examine whether current guidelines for thyroid status monitoring are adequate in the first year or whether monthly monitoring is required throughout the first year of life, rather than just the first 6 months. AAP CH FT4 IQ L-T4 T4 TFT TSH
American Academy of Pediatrics Congenital hypothyroidism Free thyroxine Intelligence quotient Levothyroxine Thyroxine Thyroid function test Thyroid-stimulating hormone
From the Pediatric Endocrine Unit, Mass General Hospital for Children and Harvard Medical School; Boston, MA *Contributed equally to this work. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.10.006
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Methods We reviewed data on 98 children with CH who were followed up in the Pediatric Endocrine Unit at Massachusetts General Hospital between December 2003–September 2008. These data included infants diagnosed and subsequently monitored at Massachusetts General Hospital and those who were referred to our unit after undergoing the initial diagnostic evaluation elsewhere. Approval was obtained from the Partners HealthCare Institutional Review Board, and data were collected retrospectively and in compliance with the Health Insurance Portability and Accountability Act. In compliance with Institutional Review Board requirements, informed consent from parents was not obtained. Of 98 children identified with CH, 28 were excluded because: (1) adequate records were not available for the first year of age (n = 18); (2) poor adherence to therapy (n = 3); and (3) transiently abnormal thyroid function test (TFT) results (n = 7). The children with transiently abnormal TFT results had mild laboratory evidence of hypothyroidism that resolved spontaneously within 6 months and did not require replacement therapy. Four of 7 children had TSH values that were normal for age, one had an initial TSH level between 20 to 40 mU/mL (up to twice the upper limit of normal), and the remaining two children had TSH levels greater than twice the upper limit of normal (>40 mU/mL) at newborn screening. The remaining 70 children (28 males and 42 females) formed our referral base. Of these 70 children, 11 were preterm ranging in gestational age from 24.6 to 36.0 weeks. We obtained clinical information from a retrospective review of health records and collected information regarding ethnicity, family history of CH, and maternal intake of antithyroid drugs and hypothyroidism. We also collected anthropometric data at birth and follow-up visits and data regarding presence or absence of goiter, signs of hypothyroidism, and other associated congenital abnormalities if present. Data regarding the initial diagnostic workup, thyroid scan and bone age were collected when available. In addition, we collected data regarding age at onset of L-T4 replacement, initial dosage of L-T4, dose changes thereafter, the frequency of follow-up visits in the first year, and total T4, TSH, and FT4 results at each follow-up visit. Overall, the goals of therapy in our practice are early L-T4 supplementation and frequent evaluations of thyroid function to normalize TSH and to maintain T4 or FT4 in the upper half of the reference range. Levels of thyroid hormones rise soon after birth and then decrease slowly over the first few months of life to reach levels close to adult norms.13-16 Therefore after the first 3 months of life, we chose to use standard normative values from our laboratory: T4: 4.5-10.9 mg/dL, FT4: 0.9-1.8 ng/dL, TSH 0.4-5.0 mU/mL. TFTs (TSH, T4/ FT4) were obtained at each visit. The values of TFT results were interpreted as abnormal if total T4 or FT4 were not in the upper half of normal range or if TSH was not in the normal range. The dosage of L-T4 was adjusted at subsequent followup visits if needed depending on the clinical examination and
the thyroid function test results. The frequency of follow-up visits varied among subjects monitored by different physician members of the Pediatric Endocrine Unit. Our practice is to check TFT results monthly for the first 6 months of life and thereafter monthly or at least every other month for the second 6 months of life in contrast to the guidelines of the AAP, which recommend checking TFT results every 3 to 4 months for the second 6 months of life. For our study, we defined criteria indicating need for monthly monitoring during the first year in the following manner: (1) dose change within a month of a previous visit; (2) total/free T4 levels not in upper half of normal range within a month of the previous visit; (3) any elevated TSH level between 5 to 10 mU/mL (less than twice the upper limit of normal) within a month of previous visit associated with total/free T4 not in the upper half of normal range (to avoid inclusion of subjects with transient resistance to TSH sometimes reported in the first year of life in children with CH), except when these results were clearly a consequence of transient noncompliance until a few days preceding the blood test (as indicated by caregivers at the clinic visit during the course of careful history taking); (4) any elevated TSH >10 mU/mL (more than twice the upper limit of normal) within a month of the previous visit regardless of total/free T4 levels; and (5) any TSH less than 0.1 mU/mL. When monitoring was every other month, we considered a significantly elevated TSH level, that is, a TSH level more than twice the upper limit of normal as an indicator of need for more frequent monitoring regardless of total/free T4. Our predetermined assumption was that monthly monitoring in such cases would have picked up minor elevations in TSH, allowing earlier changes in L-T4 doses. Statistical Analysis The main study endpoint was the proportion of subjects in whom there appeared to be a need for monthly monitoring throughout the first year of life and to identify factors that could help predict such infants. We analyzed variables such as gestational age at birth, race, sex, birth weight, presence or absence of thyroid dysgenesis, initial dosage of L-T4 supplementation, age at start of therapy, and initial TSH and T4 levels as possible predictors of the need for monthly monitoring throughout the first year. Using our inclusion criteria, we identified subjects that did or did not appear to require monthly monitoring. A two sample t test was performed for each of the variables listed above for the two groups. TSH levels required log conversion to approximate a normal distribution. The results were expressed as the mean standard error. A P value of < .05 was considered significant.
Results Clinical and Treatment Characteristics of Subjects with CH Table I summarizes the clinical and treatment characteristics of the 70 patients. Of the 70 children, 60% were females, and 18.6% were born preterm. On initial confirmatory testing 533
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Table I. Clinical and treatment characteristics of children with congenital hypothyroidism treated with L-T4 (n = 70) Characteristic Ethnicity (n [%]) Hispanic Non-Hispanic Not reported Sex (n [%]) Male Female Gestational Age (n, %) Full Term (>37weeks) Pre Term (<37 weeks) Birth Weight (mean SE) (g) Positive family history of CH/maternal intake of antithyroid drugs Cause Dysgenesis (n [%]) No dysgenesis (n [%]) Not Reported (n [%]) Baseline TSH (mU/mL)* (Median [range]) Baseline Total T4 (mg/dL)* (Median [range]) Age at start of L-T4 therapy (days from birth)* (Median [range]) Initial dose of L-T4 (mean SE) (mg/kg body wt/day)
Study population 10 (14.3%) 23 (32.9%) 37 (52.9%) 28 (40.0%) 42 (60.0%) 57 (81.4%) 13 (18.6%) 3018 111 1 (1.4%) 40 (57.1%) 20 (28.6%) 10 (14.3%) 165.5 (23.0-1045) 6.80 (0.9-14.9) 9.0 (4.0-57.0) 11.9 0.4
SE, standard error. TSH and total T4 levels refer to confirmatory values obtained after notification of abnormal results on the newborn screen. *Data not normally distributed.
after notification from the newborn screen, nine children (12.9%) had TSH < 40 mU/mL, 34 (48.6%) had TSH between 40 to 200 mU/mL, and 27 (38.6%) had TSH > 200 mU/mL. The median age at onset of replacement therapy with L-T4 was 9 days (range 4-57 days), and mean initial L-T4 dose was 11.9 3.2 mg/kg body weight per day (after the first 3 days when a higher dose was often administered). Treatment Outcome on the Basis of Biochemical Test Results Monthly monitoring appeared to be necessary in 52 (74.3%) children in the first 6 months of life and in 25 (35.7%) children for the next 6 months of life on the basis of our chosen criteria. Thirty percent of children with CH in the first and second 6 months had a high TSH with a total T4 or FT4 not in the upper half of normal range. However, no child had total T4 or FT4 values below the normal range in the second 6 months. Seven children (two in the second 6 months of life) were classified as requiring monthly monitoring on the basis of a suppressed TSH level alone. All other children thus classified had either an elevated TSH or thyroid hormone levels in the lower half of the normal range. Table II shows illustrative examples of three children in whom dose changes were necessitated by alterations in TSH and total T4 or FT4 identified in the course of monthly monitoring in the second half of the first year of life. Table III summarizes the predictors for need for monthly monitoring in children with CH. Children requiring monthly monitoring in the second 6 months had higher baseline TSH 534
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Table II. Illustrative examples of three children with CH in whom dose changes in L-T4 were necessitated by alterations in TFT results picked up in the course of monthly monitoring in the second 6 months Month of life Example 1 6 7 8 9 Example 2 7 8 10 11 12 Example 3 6 7 8 9 10
TSH Levothyroxine Levothyroxine Total T4 Free T4 (mg/dL) (ng/dL) (mU/mL) dose (mg/kg) dose (mg) 1.8 1.5 1.4 1.4 10.5 8.5 9.1 10.4 12 1.4 1.3 1.4 1.5 1.4
0.2 2.1 23 12.9
4.0 4.0 4.5* 4.9*
25.0/37.5 25.0/37.5 37.5/44.0 44.0
10.7 5.8 7.9 1.6 1
4.0* 4.6* 5.9* 5.6 5.3
25.0/37.5 37.5 50.0 50.0 50.0
11.3 5.2 2.4 8 7.9
5.5* 6.1* 5.8 6.4* 7.7*
37.5 44.0 44.0 50.0 62.5
*Dose increased on the basis of laboratory results.
(326.2 59.1 vs 191.7 26 mU/mL, P = .02 after log conversion) and lower baseline total T4 (5.6 0.6 vs 7.8 0.6 mg/dL, P = .01) than those not requiring monthly monitoring. Similar results were obtained after excluding children classified as requiring monthly monitoring on the basis of a suppressed TSH alone. However, there was substantial overlap between the groups that did or did not appear to require monthly monitoring. Starting dose of L-T4, sex, and ethnicity did not predict requirement for monthly monitoring. In the second 6 months, 64% of children who appeared to require monthly monitoring and 76% not requiring monthly monitoring had thyroid dysgenesis (P not significant). We also examined predictors for need of monthly monitoring in children with thyroid dysgenesis and in children without thyroid dysgenesis (Table IV). In children without thyroid dysgenesis, baseline TSH was an important predictor of need for monthly monitoring, similar to the group as a whole.
Discussion The 2006 guidelines, issued jointly by the AAP, the American Thyroid Association, and the Lawson Wilkins Pediatric Endocrine Society, suggest checking thyroid function test results every 1 to 2 months for the first 6 months of life and every 3 to 4 months for the second 6 months.13 Although the guidelines also indicate that monitoring should be performed at more frequent intervals when adherence is questioned, abnormal results are obtained, or dose or source has been changed and that FT4 and TSH measurements should be repeated 4 weeks after any change in L-T4 dosage, no definite time point for monitoring is provided (except after a dose change). There is also the possibility that readers Balhara, Misra, and Levitsky
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Table III. Predictors for monthly monitoring between 6 to 12 months for all children with CH
Predictors
Monthly monitoring not necessary (n = 45)
Monthly monitoring necessary (n = 25)
P value
Baseline TSH (mU/mL) Baseline Total T4 (mg/dL) Baseline L-T4 dose (mg/k) Ethnicity (% white) Sex (% female) Preterm (%) Birth weight (k) Day of onset of L-T4 Dysgenesis (%)
191 26 7.8 0.6 12.1 0.5 87% 58% 30% 2.9 0.1 15.5 2.0 76%
326 59 5.6 0.6 11.6 0.6 79% 63% 9% 3.3 0.1 10.7 1.2 64%
.02* .01 .48 .43 .71 .06 .10 .05 .34
Mean standard error. *Student t test performed after log conversion.
may not get past the initial recommendations, which specify the frequency of monitoring more concretely. Our data indicate that monthly monitoring may be useful for as many as 74% of children studied in the first 6 months of life and in 36% in the second 6 months on the basis of our chosen criteria. Because no variable is clearly predictive of which child with CH requires monthly monitoring in the first year, with a significant overlap among children with even a high level of TSH or a low level of T4 at birth, more intensive evaluations may need to be performed in all children for this period until more data are available. Alternatively, certain children, namely those who at any particular visit meet any of the criteria that we used to indicate the need for frequent monitoring, may be selected for monthly monitoring in the first year of life. With screening and early initiation of LT4 supplementation, most children with CH experience normal growth and neurologic development and attain a normal intelligence quotient (IQ).9,17,18 Nevertheless, studies have shown that some children, particularly those with severe CH, are still vulnerable to persistent cognitive and motor deficits.19-22 Studies have also shown that early high-dose L-T4 treatment eliminates the negative impact of severity of CH on IQ.9,23 Data also suggest that infants with low normal serum T4 concentrations and high TSH concentration during the first year of life have lower IQ values than patients whose T4 concentra-
tions were held constant at higher concentrations,13,24 and 4 or more episodes of insufficiently suppressed TSH (>5 mU/ L) after the age of 6 months were associated with school delay.13,25 Significantly elevated TSH levels of >10 mU/mL would thus be even more concerning. In fact, Baloch et al25 suggest that on replacement therapy, TSH levels should be maintained between 0.5 and 2.0 mU/L during the first 3 years of life, a recommendation that is reiterated in the 2006 AAP guidelines.13 It may be particularly important to maintain T4 and TSH levels in the recommended range in the early years. We specifically looked at the first year of life in this study, given that growth rate is maximum and dose changes may be necessary more frequently. Importantly, given that adequacy of treatment is a predictor of neurocognitive and neurodevelopmental outcome, it is important to determine the optimal frequency of laboratory testing for TFTs to ensure that dosing of L-T4 is appropriate. Of concern, there is a paucity of literature behind the recent AAP recommendations for frequency of monitoring of TFTs in the first year of life. Given the possible risks associated with suboptimal levothyroxine replacement in the early years of neurologic development, and the fact that as many as 36% of infants appear to require monthly monitoring in the second 6 months of life, our data suggest that monthly monitoring should possibly continue throughout the first year in infants with CH. This is in contrast to the current guidelines and implies an increase in the number of tests per infant per year and an associated increase in cost. The lack of information regarding potential improvement of neurologic outcome by more frequent monitoring is a limitation of this study. However, avoidance of the potential for even subtle neurologic impairment by maintenance of normal levels of thyroid hormone seems reasonable. Prospective studies that incorporate neurologic outcome would be useful to determine whether suboptimal TFT results in the first year translate to suboptimal outcome and whether more frequent monitoring of TFT results and adjustment of L-T4 dose leads to improved neurodevelopmental outcome. Our study also indicates that an important factor predicting the need for monthly monitoring in the second 6 months is severity of hypothyroidism at birth. Those children who required monthly monitoring in our study had higher baseline
Table IV. Predictors for need of monthly monitoring between 6 to 12 months in subjects with and without dysgenesis Patients without dysgenesis Variables
Monthly monitoring not required
Monthly monitoring required
Baseline TSH (mU/mL) Baseline T4 (mg/dl) Baseline L-T4 dose (mg/k/d) Ethnicity (% white) Sex (% female) Birth weight (kg) Term birth (%) L-T4 start day
164 46 8.2 1.0 14.0 1.0 92 46 3.2 0.2 77 13.9 3.0
499 189 4.5 1.4 11.6 1.2 80 20 3.2 0.5 60 12.0 4.9
Patients with dysgenesis P value
Monthly monitoring not required
Monthly monitoring required
P value
.02* .07 .21 .49 .34 .99 .50 .74
217 35 7.0 0.8 11.6 0.6 91 78 3.3 0.1 89 10.9 1.3
261 53 6.6 0.6 11.6 0.8 81 75 3.4 0.1 100 10.5 1.0
.48* .76 .97 .37 .82 .49 .19 .84
Mean standard error. *Student t test performed after log conversion.
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TSH and lower baseline T4 levels than those not requiring monthly monitoring, although there was substantial overlap. Good adherence may explain the nonrequirement of monthly monitoring in some children with high baseline TSH or low T4 levels. Frequent monitoring appears desirable in all children in the second 6 months of life. Alternatively, at any visit after 6 months, criteria similar to those used in this study may be used to determine whether a child’s thyroid function test results should be monitored again within a month or 2 months, rather than in 3 to 4 months. The starting dose of L-T4 therapy did not predict the need for monthly monitoring in our subjects. Of note, the starting dose of L-T4 in our subjects (after the initial few days of higher dosing) was in the lower half of the recommended range of 10 to 15 mg/k, and it is certainly possible that a higher starting dose may have reduced the need for more frequent monitoring in the first 6 months. However, even though it is possible that a more prolonged higher starting dose of L-T4 might normalize TSH and T4 levels more quickly, it is unlikely that the impact of the starting dose would extend past the first 6 months of life. Importantly, recent data indicate that severity of hypothyroidism rather than the initial starting dose of L-T4 is predictive of long-term outcome.26 Data indicate that it is important to start L-T4 therapy within the first 2 weeks of life for optimal long-term outcome of children with CH. In our study, the median time to onset of L-T4 therapy was 9 days, with a wide range of 4 to 57 days. Children who were started on L-T4 past the first 2 weeks fell into one of three categories: (1) those born prematurely, in whom confirmation of CH required repeat newborn screening tests or in whom CH was diagnosed at a subsequent and not the initial screen (n = 7); (2) those with very mildly elevated TSH levels, in whom repeat testing was performed to confirm persistent elevations in TSH before beginning L-T4 replacement (n = 3); and (3) those whose initial bloodspot was inadequate and a second screen was necessary, causing delayed notification from the state laboratory (n = 3). In our subjects, age at initiation of L-T4 therapy did not predict the need for frequent monitoring. The limitations of this study include its retrospective nature, lack of data to support an improvement in outcome with more frequent monitoring compared with current guidelines, and lack of uniformity between physician practices regarding the frequency of follow-up visits. Normal laboratory test results during follow-up may not always indicate an excellent outcome, and indeed, Campos et al27 have reported that even children treated with low doses of levothyroxine who had mildly elevated TSH levels had good outcome, although other studies suggest that several mildly elevated TSH levels after 6 months of age may be associated with school delays.25 In addition, children who have an elevated TSH with total T4 or FT4 levels in the upper half of the normal range are a management dilemma given that these results may be consequent to either a transient pituitary resistance to thyroid hormones or transient noncompliance until a few days preceding the blood test. Whereas an elevated TSH level from transient pituitary resistance does not require an in536
Vol. 158, No. 4 crease in L-T4 dose and does not indicate the need for frequent monitoring, one may argue that a mildly elevated TSH (with total T4 and FT4 levels in the upper half of the normal range) may result from transient nonadherence and that these children would therefore benefit from more frequent monitoring. We did not consider this constellation of laboratory results to indicate a need for monthly monitoring except when there was evidence of noncompliance. However, confirmation of noncompliance can be difficult, and one may argue that these children should in fact be followed up more frequently given the possibility of noncompliance, to emphasize to families the importance of adherence to the treatment plan. Importantly, if we had included all children with a mildly elevated TSH and total or FT4 levels in the upper half of the normal range as indicative of a need for frequent monitoring, our numbers for this group would have been even higher. Our study provides preliminary data that suggest that current guidelines may need to be revisited. Further studies are required to define the optimal frequency of thyroid function monitoring during follow-up of children with CH, particularly with attention to long-term outcome. A multicenter study of CH would be useful in obtaining these data in a timely fashion, and it may be important to consider intensive monitoring throughout the first year of life until these data become available. n Submitted for publication May 13, 2010; last revision received Aug 31, 2010; accepted Oct 4, 2010. Reprint requests: Lynne L. Levitsky, MD, Room 539, 175 Cambridge St, Mass General Hospital for Children, Boston, MA 02114. E-mail: llevitsky@partners. org
References 1. Delange F. Neonatal screening for congenital hypothyroidism: results and perspectives. Horm Res 1997;48:51-61. 2. Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations. New England congenital hypothyroidism collaborative. Lancet 1981;2:1095-8. 3. Van Vliet G, Czernichow P. Screening for neonatal endocrinopathies: rationale, methods and results. Semin Neonatol 2004;9:75-85. 4. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. Pediatrics 1989;83:785-9. 5. Heyerdahl S. Long-term outcome in children with congenital hypothyroidism. Acta Paediatr 2001;90:1220-2. 6. Gruters A, Jenner A, Krude H. Long-term consequences of congenital hypothyroidism in the era of screening programmes. Best Pract Res Clin Endocrinol Metab 2002;16:369-82. 7. Oerbeck B, Sundet K, Kase BF, Heyerdahl S. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. Pediatrics 2003;112:923-30. 8. Rovet JF. Congenital hypothyroidism: an analysis of persisting deficits and associated factors. Child Neuropsychol 2002;8:150-62. 9. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J Clin Endocrinol Metab 1996;81:222-7. 10. Grant DB, Fuggle P, Tokar S, Smith I. Psychomotor development in infants with congenital hypothyroidism diagnosed by neonatal screening. Acta Med Austriaca 1992;19(Suppl. 1):54-6.
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April 2011 11. Heyerdahl S, Kase BF, Lie SO. Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 1991;118:850-7. 12. Revised guidelines for neonatal screening programmes for primary congenital hypothyroidism. Working Group on Neonatal Screening of the European Society for Paediatric Endocrinology. Horm Res 1999;52:49-52. 13. Rose SR, Brown RS, Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006;117:2290-303. 14. American Academy of Pediatrics, American Thyroid Association: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1987;80:745-9. 15. American Academy of Pediatrics AAP Section on Endocrinology and Committee on Genetics, and American Thyroid Association Committee on Public Health: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993;91:1203-9. 16. Elmlinger MW, Kuhnel W, Lambrecht HG, Ranke MB. Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH). Clin Chem Lab Med 2001;39:973-9. 17. Rovet JF, Ehrlich RM, Sorbara DL. Neurodevelopment in infants and preschool children with congenital hypothyroidism: etiological and treatment factors affecting outcome. J Pediatr Psychol 1992;17:187-213. 18. Tillotson SL, Fuggle PW, Smith I, Ades AE, Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ 1994;309:440-5. 19. Derksen-Lubsen G, Verkerk PH. Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data. Pediatr Res 1996;39:561-6.
ORIGINAL ARTICLES 20. Kempers MJ, van der Sluijs Veer L, Nijhuis-van der Sanden MW, Kooistra L, Wiedijk BM, Faber I, et al. Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab 2006;91:418-24. 21. Kooistra L, Laane C, Vulsma T, Schellekens JM, van der Meere JJ, Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment. J Pediatr 1994;124:903-9. 22. Simons WF, Fuggle PW, Grant DB, Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism. Arch Dis Child 1994;71:232-4. 23. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;136:292-7. 24. Heyerdahl S, Oerbeck B. Congenital hypothyroidism: developmental outcome in relation to levothyroxine treatment variables. Thyroid 2003;13:1029-38. 25. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13:3-126. 26. Selva KA, Harper A, Downs A, Blasco PA, Lafranchi SH. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005;147: 775-80. 27. Campos SP, Sandberg DE, Barrick C, Voorhess ML, MacGillivray MH. Outcome of lower L-thyroxine dose for treatment of congenital hypothyroidism. Clin Pediatr (Phila) 1995;34:514-20.
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C
ongenital hypothyroidism (CH) has a reported incidence of approximately one in 3000 to 4000 live births.1 Since the introduction of pilot screening programs in 1974, newborn screening for CH has become widely routine and represents a major advance in preventive medicine. It improves outcome by allowing intervention before the appearance of clinical hypothyroidism.2,3 The essential role of thyroid hormones for normal brain development during a critical period from fetal life to 24 to 36 months of age has been well described.4,5 Because children born with CH are at risk of poor cognitive development and behavioral problems, all infants with CH should be rendered euthyroid as promptly as possible.6-8 Clinical studies have suggested that factors that play an important role in determining long-term outcome include severity of hypothyroidism, age at which levothyroxine (L-T4) replacement is started, initial dose of L-T4, as well as time taken to achieve and maintain target ranges for thyroxine (T4) and thyroid-stimulating hormone (TSH).9-11 L-T4 supplementation (started within 2-3 weeks of age) is the standard of care for CH, and an initial dose of 10 to 15 mg/kg of L-T4 is recommended.12 Frequent evaluations of thyroid function (total T4 or free T4 [FT4] and TSH) are necessary to ensure optimal L-T4 dosage and compliance. The goal is to maintain total T4 or FT4 concentrations in the upper half of the reference range and to normalize serum TSH rapidly.13 The American Academy of Pediatrics (AAP) has issued 3 sets of guidelines for laboratory evaluations since 1987.13-15 The most recent of these13 suggest that T4 and TSH measurements should be performed at: (1) 2 and 4 weeks after starting treatment; (2) every 1 to 2 months during the first 6 months of life; (3) every 3 to 4 months between 6 months and 3 years; (4) every 6 to 12 months until growth is completed; and (5) at more frequent intervals when adherence is questioned, abnormal results are obtained, or dose or source has been changed; FT4 and TSH measurements should be repeated 4 weeks after any change in L-T4 dosage. There are few data supporting these recommendations. We performed a retrospective study to examine whether current guidelines for thyroid status monitoring are adequate in the first year or whether monthly monitoring is required throughout the first year of life, rather than just the first 6 months. AAP CH FT4 IQ L-T4 T4 TFT TSH
American Academy of Pediatrics Congenital hypothyroidism Free thyroxine Intelligence quotient Levothyroxine Thyroxine Thyroid function test Thyroid-stimulating hormone
From the Pediatric Endocrine Unit, Mass General Hospital for Children and Harvard Medical School; Boston, MA *Contributed equally to this work. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.10.006
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Methods We reviewed data on 98 children with CH who were followed up in the Pediatric Endocrine Unit at Massachusetts General Hospital between December 2003–September 2008. These data included infants diagnosed and subsequently monitored at Massachusetts General Hospital and those who were referred to our unit after undergoing the initial diagnostic evaluation elsewhere. Approval was obtained from the Partners HealthCare Institutional Review Board, and data were collected retrospectively and in compliance with the Health Insurance Portability and Accountability Act. In compliance with Institutional Review Board requirements, informed consent from parents was not obtained. Of 98 children identified with CH, 28 were excluded because: (1) adequate records were not available for the first year of age (n = 18); (2) poor adherence to therapy (n = 3); and (3) transiently abnormal thyroid function test (TFT) results (n = 7). The children with transiently abnormal TFT results had mild laboratory evidence of hypothyroidism that resolved spontaneously within 6 months and did not require replacement therapy. Four of 7 children had TSH values that were normal for age, one had an initial TSH level between 20 to 40 mU/mL (up to twice the upper limit of normal), and the remaining two children had TSH levels greater than twice the upper limit of normal (>40 mU/mL) at newborn screening. The remaining 70 children (28 males and 42 females) formed our referral base. Of these 70 children, 11 were preterm ranging in gestational age from 24.6 to 36.0 weeks. We obtained clinical information from a retrospective review of health records and collected information regarding ethnicity, family history of CH, and maternal intake of antithyroid drugs and hypothyroidism. We also collected anthropometric data at birth and follow-up visits and data regarding presence or absence of goiter, signs of hypothyroidism, and other associated congenital abnormalities if present. Data regarding the initial diagnostic workup, thyroid scan and bone age were collected when available. In addition, we collected data regarding age at onset of L-T4 replacement, initial dosage of L-T4, dose changes thereafter, the frequency of follow-up visits in the first year, and total T4, TSH, and FT4 results at each follow-up visit. Overall, the goals of therapy in our practice are early L-T4 supplementation and frequent evaluations of thyroid function to normalize TSH and to maintain T4 or FT4 in the upper half of the reference range. Levels of thyroid hormones rise soon after birth and then decrease slowly over the first few months of life to reach levels close to adult norms.13-16 Therefore after the first 3 months of life, we chose to use standard normative values from our laboratory: T4: 4.5-10.9 mg/dL, FT4: 0.9-1.8 ng/dL, TSH 0.4-5.0 mU/mL. TFTs (TSH, T4/ FT4) were obtained at each visit. The values of TFT results were interpreted as abnormal if total T4 or FT4 were not in the upper half of normal range or if TSH was not in the normal range. The dosage of L-T4 was adjusted at subsequent followup visits if needed depending on the clinical examination and
the thyroid function test results. The frequency of follow-up visits varied among subjects monitored by different physician members of the Pediatric Endocrine Unit. Our practice is to check TFT results monthly for the first 6 months of life and thereafter monthly or at least every other month for the second 6 months of life in contrast to the guidelines of the AAP, which recommend checking TFT results every 3 to 4 months for the second 6 months of life. For our study, we defined criteria indicating need for monthly monitoring during the first year in the following manner: (1) dose change within a month of a previous visit; (2) total/free T4 levels not in upper half of normal range within a month of the previous visit; (3) any elevated TSH level between 5 to 10 mU/mL (less than twice the upper limit of normal) within a month of previous visit associated with total/free T4 not in the upper half of normal range (to avoid inclusion of subjects with transient resistance to TSH sometimes reported in the first year of life in children with CH), except when these results were clearly a consequence of transient noncompliance until a few days preceding the blood test (as indicated by caregivers at the clinic visit during the course of careful history taking); (4) any elevated TSH >10 mU/mL (more than twice the upper limit of normal) within a month of the previous visit regardless of total/free T4 levels; and (5) any TSH less than 0.1 mU/mL. When monitoring was every other month, we considered a significantly elevated TSH level, that is, a TSH level more than twice the upper limit of normal as an indicator of need for more frequent monitoring regardless of total/free T4. Our predetermined assumption was that monthly monitoring in such cases would have picked up minor elevations in TSH, allowing earlier changes in L-T4 doses. Statistical Analysis The main study endpoint was the proportion of subjects in whom there appeared to be a need for monthly monitoring throughout the first year of life and to identify factors that could help predict such infants. We analyzed variables such as gestational age at birth, race, sex, birth weight, presence or absence of thyroid dysgenesis, initial dosage of L-T4 supplementation, age at start of therapy, and initial TSH and T4 levels as possible predictors of the need for monthly monitoring throughout the first year. Using our inclusion criteria, we identified subjects that did or did not appear to require monthly monitoring. A two sample t test was performed for each of the variables listed above for the two groups. TSH levels required log conversion to approximate a normal distribution. The results were expressed as the mean standard error. A P value of < .05 was considered significant.
Results Clinical and Treatment Characteristics of Subjects with CH Table I summarizes the clinical and treatment characteristics of the 70 patients. Of the 70 children, 60% were females, and 18.6% were born preterm. On initial confirmatory testing 533
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Table I. Clinical and treatment characteristics of children with congenital hypothyroidism treated with L-T4 (n = 70) Characteristic Ethnicity (n [%]) Hispanic Non-Hispanic Not reported Sex (n [%]) Male Female Gestational Age (n, %) Full Term (>37weeks) Pre Term (<37 weeks) Birth Weight (mean SE) (g) Positive family history of CH/maternal intake of antithyroid drugs Cause Dysgenesis (n [%]) No dysgenesis (n [%]) Not Reported (n [%]) Baseline TSH (mU/mL)* (Median [range]) Baseline Total T4 (mg/dL)* (Median [range]) Age at start of L-T4 therapy (days from birth)* (Median [range]) Initial dose of L-T4 (mean SE) (mg/kg body wt/day)
Study population 10 (14.3%) 23 (32.9%) 37 (52.9%) 28 (40.0%) 42 (60.0%) 57 (81.4%) 13 (18.6%) 3018 111 1 (1.4%) 40 (57.1%) 20 (28.6%) 10 (14.3%) 165.5 (23.0-1045) 6.80 (0.9-14.9) 9.0 (4.0-57.0) 11.9 0.4
SE, standard error. TSH and total T4 levels refer to confirmatory values obtained after notification of abnormal results on the newborn screen. *Data not normally distributed.
after notification from the newborn screen, nine children (12.9%) had TSH < 40 mU/mL, 34 (48.6%) had TSH between 40 to 200 mU/mL, and 27 (38.6%) had TSH > 200 mU/mL. The median age at onset of replacement therapy with L-T4 was 9 days (range 4-57 days), and mean initial L-T4 dose was 11.9 3.2 mg/kg body weight per day (after the first 3 days when a higher dose was often administered). Treatment Outcome on the Basis of Biochemical Test Results Monthly monitoring appeared to be necessary in 52 (74.3%) children in the first 6 months of life and in 25 (35.7%) children for the next 6 months of life on the basis of our chosen criteria. Thirty percent of children with CH in the first and second 6 months had a high TSH with a total T4 or FT4 not in the upper half of normal range. However, no child had total T4 or FT4 values below the normal range in the second 6 months. Seven children (two in the second 6 months of life) were classified as requiring monthly monitoring on the basis of a suppressed TSH level alone. All other children thus classified had either an elevated TSH or thyroid hormone levels in the lower half of the normal range. Table II shows illustrative examples of three children in whom dose changes were necessitated by alterations in TSH and total T4 or FT4 identified in the course of monthly monitoring in the second half of the first year of life. Table III summarizes the predictors for need for monthly monitoring in children with CH. Children requiring monthly monitoring in the second 6 months had higher baseline TSH 534
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Table II. Illustrative examples of three children with CH in whom dose changes in L-T4 were necessitated by alterations in TFT results picked up in the course of monthly monitoring in the second 6 months Month of life Example 1 6 7 8 9 Example 2 7 8 10 11 12 Example 3 6 7 8 9 10
TSH Levothyroxine Levothyroxine Total T4 Free T4 (mg/dL) (ng/dL) (mU/mL) dose (mg/kg) dose (mg) 1.8 1.5 1.4 1.4 10.5 8.5 9.1 10.4 12 1.4 1.3 1.4 1.5 1.4
0.2 2.1 23 12.9
4.0 4.0 4.5* 4.9*
25.0/37.5 25.0/37.5 37.5/44.0 44.0
10.7 5.8 7.9 1.6 1
4.0* 4.6* 5.9* 5.6 5.3
25.0/37.5 37.5 50.0 50.0 50.0
11.3 5.2 2.4 8 7.9
5.5* 6.1* 5.8 6.4* 7.7*
37.5 44.0 44.0 50.0 62.5
*Dose increased on the basis of laboratory results.
(326.2 59.1 vs 191.7 26 mU/mL, P = .02 after log conversion) and lower baseline total T4 (5.6 0.6 vs 7.8 0.6 mg/dL, P = .01) than those not requiring monthly monitoring. Similar results were obtained after excluding children classified as requiring monthly monitoring on the basis of a suppressed TSH alone. However, there was substantial overlap between the groups that did or did not appear to require monthly monitoring. Starting dose of L-T4, sex, and ethnicity did not predict requirement for monthly monitoring. In the second 6 months, 64% of children who appeared to require monthly monitoring and 76% not requiring monthly monitoring had thyroid dysgenesis (P not significant). We also examined predictors for need of monthly monitoring in children with thyroid dysgenesis and in children without thyroid dysgenesis (Table IV). In children without thyroid dysgenesis, baseline TSH was an important predictor of need for monthly monitoring, similar to the group as a whole.
Discussion The 2006 guidelines, issued jointly by the AAP, the American Thyroid Association, and the Lawson Wilkins Pediatric Endocrine Society, suggest checking thyroid function test results every 1 to 2 months for the first 6 months of life and every 3 to 4 months for the second 6 months.13 Although the guidelines also indicate that monitoring should be performed at more frequent intervals when adherence is questioned, abnormal results are obtained, or dose or source has been changed and that FT4 and TSH measurements should be repeated 4 weeks after any change in L-T4 dosage, no definite time point for monitoring is provided (except after a dose change). There is also the possibility that readers Balhara, Misra, and Levitsky
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Table III. Predictors for monthly monitoring between 6 to 12 months for all children with CH
Predictors
Monthly monitoring not necessary (n = 45)
Monthly monitoring necessary (n = 25)
P value
Baseline TSH (mU/mL) Baseline Total T4 (mg/dL) Baseline L-T4 dose (mg/k) Ethnicity (% white) Sex (% female) Preterm (%) Birth weight (k) Day of onset of L-T4 Dysgenesis (%)
191 26 7.8 0.6 12.1 0.5 87% 58% 30% 2.9 0.1 15.5 2.0 76%
326 59 5.6 0.6 11.6 0.6 79% 63% 9% 3.3 0.1 10.7 1.2 64%
.02* .01 .48 .43 .71 .06 .10 .05 .34
Mean standard error. *Student t test performed after log conversion.
may not get past the initial recommendations, which specify the frequency of monitoring more concretely. Our data indicate that monthly monitoring may be useful for as many as 74% of children studied in the first 6 months of life and in 36% in the second 6 months on the basis of our chosen criteria. Because no variable is clearly predictive of which child with CH requires monthly monitoring in the first year, with a significant overlap among children with even a high level of TSH or a low level of T4 at birth, more intensive evaluations may need to be performed in all children for this period until more data are available. Alternatively, certain children, namely those who at any particular visit meet any of the criteria that we used to indicate the need for frequent monitoring, may be selected for monthly monitoring in the first year of life. With screening and early initiation of LT4 supplementation, most children with CH experience normal growth and neurologic development and attain a normal intelligence quotient (IQ).9,17,18 Nevertheless, studies have shown that some children, particularly those with severe CH, are still vulnerable to persistent cognitive and motor deficits.19-22 Studies have also shown that early high-dose L-T4 treatment eliminates the negative impact of severity of CH on IQ.9,23 Data also suggest that infants with low normal serum T4 concentrations and high TSH concentration during the first year of life have lower IQ values than patients whose T4 concentra-
tions were held constant at higher concentrations,13,24 and 4 or more episodes of insufficiently suppressed TSH (>5 mU/ L) after the age of 6 months were associated with school delay.13,25 Significantly elevated TSH levels of >10 mU/mL would thus be even more concerning. In fact, Baloch et al25 suggest that on replacement therapy, TSH levels should be maintained between 0.5 and 2.0 mU/L during the first 3 years of life, a recommendation that is reiterated in the 2006 AAP guidelines.13 It may be particularly important to maintain T4 and TSH levels in the recommended range in the early years. We specifically looked at the first year of life in this study, given that growth rate is maximum and dose changes may be necessary more frequently. Importantly, given that adequacy of treatment is a predictor of neurocognitive and neurodevelopmental outcome, it is important to determine the optimal frequency of laboratory testing for TFTs to ensure that dosing of L-T4 is appropriate. Of concern, there is a paucity of literature behind the recent AAP recommendations for frequency of monitoring of TFTs in the first year of life. Given the possible risks associated with suboptimal levothyroxine replacement in the early years of neurologic development, and the fact that as many as 36% of infants appear to require monthly monitoring in the second 6 months of life, our data suggest that monthly monitoring should possibly continue throughout the first year in infants with CH. This is in contrast to the current guidelines and implies an increase in the number of tests per infant per year and an associated increase in cost. The lack of information regarding potential improvement of neurologic outcome by more frequent monitoring is a limitation of this study. However, avoidance of the potential for even subtle neurologic impairment by maintenance of normal levels of thyroid hormone seems reasonable. Prospective studies that incorporate neurologic outcome would be useful to determine whether suboptimal TFT results in the first year translate to suboptimal outcome and whether more frequent monitoring of TFT results and adjustment of L-T4 dose leads to improved neurodevelopmental outcome. Our study also indicates that an important factor predicting the need for monthly monitoring in the second 6 months is severity of hypothyroidism at birth. Those children who required monthly monitoring in our study had higher baseline
Table IV. Predictors for need of monthly monitoring between 6 to 12 months in subjects with and without dysgenesis Patients without dysgenesis Variables
Monthly monitoring not required
Monthly monitoring required
Baseline TSH (mU/mL) Baseline T4 (mg/dl) Baseline L-T4 dose (mg/k/d) Ethnicity (% white) Sex (% female) Birth weight (kg) Term birth (%) L-T4 start day
164 46 8.2 1.0 14.0 1.0 92 46 3.2 0.2 77 13.9 3.0
499 189 4.5 1.4 11.6 1.2 80 20 3.2 0.5 60 12.0 4.9
Patients with dysgenesis P value
Monthly monitoring not required
Monthly monitoring required
P value
.02* .07 .21 .49 .34 .99 .50 .74
217 35 7.0 0.8 11.6 0.6 91 78 3.3 0.1 89 10.9 1.3
261 53 6.6 0.6 11.6 0.8 81 75 3.4 0.1 100 10.5 1.0
.48* .76 .97 .37 .82 .49 .19 .84
Mean standard error. *Student t test performed after log conversion.
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TSH and lower baseline T4 levels than those not requiring monthly monitoring, although there was substantial overlap. Good adherence may explain the nonrequirement of monthly monitoring in some children with high baseline TSH or low T4 levels. Frequent monitoring appears desirable in all children in the second 6 months of life. Alternatively, at any visit after 6 months, criteria similar to those used in this study may be used to determine whether a child’s thyroid function test results should be monitored again within a month or 2 months, rather than in 3 to 4 months. The starting dose of L-T4 therapy did not predict the need for monthly monitoring in our subjects. Of note, the starting dose of L-T4 in our subjects (after the initial few days of higher dosing) was in the lower half of the recommended range of 10 to 15 mg/k, and it is certainly possible that a higher starting dose may have reduced the need for more frequent monitoring in the first 6 months. However, even though it is possible that a more prolonged higher starting dose of L-T4 might normalize TSH and T4 levels more quickly, it is unlikely that the impact of the starting dose would extend past the first 6 months of life. Importantly, recent data indicate that severity of hypothyroidism rather than the initial starting dose of L-T4 is predictive of long-term outcome.26 Data indicate that it is important to start L-T4 therapy within the first 2 weeks of life for optimal long-term outcome of children with CH. In our study, the median time to onset of L-T4 therapy was 9 days, with a wide range of 4 to 57 days. Children who were started on L-T4 past the first 2 weeks fell into one of three categories: (1) those born prematurely, in whom confirmation of CH required repeat newborn screening tests or in whom CH was diagnosed at a subsequent and not the initial screen (n = 7); (2) those with very mildly elevated TSH levels, in whom repeat testing was performed to confirm persistent elevations in TSH before beginning L-T4 replacement (n = 3); and (3) those whose initial bloodspot was inadequate and a second screen was necessary, causing delayed notification from the state laboratory (n = 3). In our subjects, age at initiation of L-T4 therapy did not predict the need for frequent monitoring. The limitations of this study include its retrospective nature, lack of data to support an improvement in outcome with more frequent monitoring compared with current guidelines, and lack of uniformity between physician practices regarding the frequency of follow-up visits. Normal laboratory test results during follow-up may not always indicate an excellent outcome, and indeed, Campos et al27 have reported that even children treated with low doses of levothyroxine who had mildly elevated TSH levels had good outcome, although other studies suggest that several mildly elevated TSH levels after 6 months of age may be associated with school delays.25 In addition, children who have an elevated TSH with total T4 or FT4 levels in the upper half of the normal range are a management dilemma given that these results may be consequent to either a transient pituitary resistance to thyroid hormones or transient noncompliance until a few days preceding the blood test. Whereas an elevated TSH level from transient pituitary resistance does not require an in536
Vol. 158, No. 4 crease in L-T4 dose and does not indicate the need for frequent monitoring, one may argue that a mildly elevated TSH (with total T4 and FT4 levels in the upper half of the normal range) may result from transient nonadherence and that these children would therefore benefit from more frequent monitoring. We did not consider this constellation of laboratory results to indicate a need for monthly monitoring except when there was evidence of noncompliance. However, confirmation of noncompliance can be difficult, and one may argue that these children should in fact be followed up more frequently given the possibility of noncompliance, to emphasize to families the importance of adherence to the treatment plan. Importantly, if we had included all children with a mildly elevated TSH and total or FT4 levels in the upper half of the normal range as indicative of a need for frequent monitoring, our numbers for this group would have been even higher. Our study provides preliminary data that suggest that current guidelines may need to be revisited. Further studies are required to define the optimal frequency of thyroid function monitoring during follow-up of children with CH, particularly with attention to long-term outcome. A multicenter study of CH would be useful in obtaining these data in a timely fashion, and it may be important to consider intensive monitoring throughout the first year of life until these data become available. n Submitted for publication May 13, 2010; last revision received Aug 31, 2010; accepted Oct 4, 2010. Reprint requests: Lynne L. Levitsky, MD, Room 539, 175 Cambridge St, Mass General Hospital for Children, Boston, MA 02114. E-mail: llevitsky@partners. org
References 1. Delange F. Neonatal screening for congenital hypothyroidism: results and perspectives. Horm Res 1997;48:51-61. 2. Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations. New England congenital hypothyroidism collaborative. Lancet 1981;2:1095-8. 3. Van Vliet G, Czernichow P. Screening for neonatal endocrinopathies: rationale, methods and results. Semin Neonatol 2004;9:75-85. 4. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. Pediatrics 1989;83:785-9. 5. Heyerdahl S. Long-term outcome in children with congenital hypothyroidism. Acta Paediatr 2001;90:1220-2. 6. Gruters A, Jenner A, Krude H. Long-term consequences of congenital hypothyroidism in the era of screening programmes. Best Pract Res Clin Endocrinol Metab 2002;16:369-82. 7. Oerbeck B, Sundet K, Kase BF, Heyerdahl S. Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults. Pediatrics 2003;112:923-30. 8. Rovet JF. Congenital hypothyroidism: an analysis of persisting deficits and associated factors. Child Neuropsychol 2002;8:150-62. 9. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, Van Vliet G. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J Clin Endocrinol Metab 1996;81:222-7. 10. Grant DB, Fuggle P, Tokar S, Smith I. Psychomotor development in infants with congenital hypothyroidism diagnosed by neonatal screening. Acta Med Austriaca 1992;19(Suppl. 1):54-6.
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April 2011 11. Heyerdahl S, Kase BF, Lie SO. Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 1991;118:850-7. 12. Revised guidelines for neonatal screening programmes for primary congenital hypothyroidism. Working Group on Neonatal Screening of the European Society for Paediatric Endocrinology. Horm Res 1999;52:49-52. 13. Rose SR, Brown RS, Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006;117:2290-303. 14. American Academy of Pediatrics, American Thyroid Association: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1987;80:745-9. 15. American Academy of Pediatrics AAP Section on Endocrinology and Committee on Genetics, and American Thyroid Association Committee on Public Health: Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993;91:1203-9. 16. Elmlinger MW, Kuhnel W, Lambrecht HG, Ranke MB. Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH). Clin Chem Lab Med 2001;39:973-9. 17. Rovet JF, Ehrlich RM, Sorbara DL. Neurodevelopment in infants and preschool children with congenital hypothyroidism: etiological and treatment factors affecting outcome. J Pediatr Psychol 1992;17:187-213. 18. Tillotson SL, Fuggle PW, Smith I, Ades AE, Grant DB. Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ 1994;309:440-5. 19. Derksen-Lubsen G, Verkerk PH. Neuropsychologic development in early treated congenital hypothyroidism: analysis of literature data. Pediatr Res 1996;39:561-6.
ORIGINAL ARTICLES 20. Kempers MJ, van der Sluijs Veer L, Nijhuis-van der Sanden MW, Kooistra L, Wiedijk BM, Faber I, et al. Intellectual and motor development of young adults with congenital hypothyroidism diagnosed by neonatal screening. J Clin Endocrinol Metab 2006;91:418-24. 21. Kooistra L, Laane C, Vulsma T, Schellekens JM, van der Meere JJ, Kalverboer AF. Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment. J Pediatr 1994;124:903-9. 22. Simons WF, Fuggle PW, Grant DB, Smith I. Intellectual development at 10 years in early treated congenital hypothyroidism. Arch Dis Child 1994;71:232-4. 23. Bongers-Schokking JJ, Koot HM, Wiersma D, Verkerk PH, de Muinck Keizer-Schrama SM. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;136:292-7. 24. Heyerdahl S, Oerbeck B. Congenital hypothyroidism: developmental outcome in relation to levothyroxine treatment variables. Thyroid 2003;13:1029-38. 25. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13:3-126. 26. Selva KA, Harper A, Downs A, Blasco PA, Lafranchi SH. Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH. J Pediatr 2005;147: 775-80. 27. Campos SP, Sandberg DE, Barrick C, Voorhess ML, MacGillivray MH. Outcome of lower L-thyroxine dose for treatment of congenital hypothyroidism. Clin Pediatr (Phila) 1995;34:514-20.
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