- Email: [email protected]
Initial treatment dose of L-thyroxine in congenital hypothyroidism
Initial treatment dose of L-thyroxine in congenital hypothyroidism Karin A. Selva, MD, Scott H. Mandel, MD, Leanne Rien, RN, BS, David Sesser, BS, Richard Miyahira, BS, Michael Skeels, PhD, MPH, Jerald C. Nelson, MD, and Stephen H. LaFranchi, MD Objectives: To determine the optimal initial treatment dose of L-thyroxine in congenital hypothyroidism (CH) by evaluating the time course of rise of thyroxine (T4) and free T4 concentrations into an established “target range” and normalization of thyroid-stimulating hormone (TSH) and to reevaluate the “target range” for T4 and free T4 concentrations during the first 2 weeks of CH treatment. Study design: Infants of birth weight 3 to 4 kg with CH (n = 47) detected by newborn screening were randomly assigned into three L-thyroxine treatment dose arms: 37.5 µg/day (group 1); 62.5 µg/day for 3 days, then 37.5 µg/day (group 2); and 50 µg/day (group 3). Serum T4, free T4, triiodothyronine (T3), free T3, and TSH were measured before treatment and at 3 days and 1, 2, 4, 8, and 12 weeks after treatment. Results: T4 and free T4 concentrations increased into the target range (10 to 16 µg/dL) by 3 days of therapy in infants in groups 2 and 3 and by 1 week in group 1; 50 µg/day (average 14.5 µg/kg/day) provided the most rapid normalization of TSH by 2 weeks. With the use of linear regression analysis of T4 versus TSH or free T4 versus TSH plots, the intercept at the lower range of normal for TSH (1.7 mU/L) showed T4 = 19.5 µg/dL and free T4 = 5.23 ng/dL. Conclusions: Initial dosing of 50 µg/day (12-17 µg/kg per day) raised serum T4 and free T4 concentrations to target range by 3 days and normalized TSH by 2 weeks of therapy. We recommend consideration of a somewhat higher “target range” of 10 to 18 µg/dL for T4 and 2 to 5.0 ng/dL for free T4 during the first 2 weeks of L-thyroxine treatment. After 2 weeks of treatment, the target range drops to 10 to 16 µg/dL for T4 and 1.6 to 2.2 for free T4. (J Pediatr 2002;141:786-92) Early detection and optimal treatment of congenital hypothyroidism (CH) provides the best neurodevelopmental
outcome. In the prescreening era, infants treated between ages zero and 3 months had intelligence quotients
From the Department of Pediatrics, Oregon Health and Sciences University, Oregon State Public Health Laboratories, and Northwest Kaiser Permanente, Portland, Oregon; and Quest Diagnostics, Inc, San Juan Capistrano, California.
Submitted for publication Nov 9, 2001; revisions received Mar 20, 2002, and July 8, 2002; accepted July 31, 2002. Reprint requests: Karin A. Selva, MD, Division of Pediatric Endocrinology, Oregon Health and Sciences University, 707 SW Gaines Rd CDRC-P, Portland, OR 97201. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/128887 doi:10.1067/mpd.2002.128887
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(IQS) significantly higher than those delayed in treatment until after 6 months.1 Newborn screening allows early detection and replacement of thyroxine in infants with CH; however, the optimal starting dose continues to undergo evaluation.
See editorial, p 752. The goal of the initial L-thyroxine dose is to raise the serum thyroxine (T4) concentration into the recommended target range of 10 to 16 µg/dL as rapidly as possible, limiting the impact of hypothyroidism on the developing central nervous system.2 Evidence has shown that serum T4 levels <10 µg/dL in the first year of life are associated with lower IQ levels than T4 concentrations >10 µg/dL.3 The rate of fall of thyroid-stimulating hormone (TSH) into the normal range is a second objective measure of treatment adequacy. It is equally important to avoid prolonged overtreatment.1 CH IQ TSH T4 T3
Congenital hypothyroidism Intelligence quotient Thyroid-stimulating hormone Thyroxine Triiodothyronine
Several investigations have described the time course of serum T4 rise and TSH normalization with initial thyroxine treatment dose. With doses of <10 µg/kg per day, T4 concentrations did not rise to >10 µg/dL until 1 to 3 months.4 In 1989, Fisher and Foley5 reported that initial dosing of 11 µg/kg per day (range, 10-15 µg/kg per day) raised T4 concentrations to the desired upper half of normal (10-16 µg/dL; mean, 13.8 µg/dL) within 3 weeks,
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VOLUME 141, NUMBER 6 Table I. Study onset: Birth weight, L-thyroxine dose, and screening and confirmatory thyroid function test results (mean ± SD) in the 3 treatment groups
No. of subjects Treatment dose(µg/day) Mean birth weight (kg) Mean dose (µg/kg/d) Screening T4 (µg/dL) Screening TSH (mU/L) Confirm. T4 (µg/dL) Confirm. Free T4 (ng/dL) Confirm. TSH (mU/L)
without evidence of overtreatment, whereas TSH concentrations remained elevated for 3 to 4 months. Germak and Foley6 reported the safety of initial dosing of 10 to 14 µg/kg per day, which raised T4 and free T4 concentrations to the target range within 1 week, without risk of overtreatment. Infants who had mild CH had TSH concentrations persistently elevated for 5 months, and those with severe disease had measurements above normal for 1 year.6 In a retrospective study comparing 3 initial L-thyroxine treatment doses, Salerno et al7 recently reported that infants receiving the highest dose of 13.4 µg/kg per day were able to normalize serum TSH by 1 month. The current American Academy of Pediatrics guidelines recommend initial dosing of 10 to 15 µg/kg per day for treatment of CH.3 Several investigations have reported that early, high-dose treatment corrects the untoward delay in rise of T4 in severely affected infants and consequently normalizes IQ when compared with ageand dose-matched counterparts with mild disease.7-10 A delay in rise in serum T4 concentration by as little as 1 week may result in lower IQ scores, by as much as 20 points, in children with severe forms of the disease.9 The first objective of our study was to determine the ideal replacement dose of L-thyroxine in infants with CH as judged by the time course of rise in T4 and free T4 and fall in TSH, by using 3 treatment arms. A second objective was
Group 1
Group 2
Group 3
P value
15 37.5 3.44 ± 0.22 10.9 4.8 ± 2.9 >200 ± 0 2.28 ± 2.1 0.37 ± 0.2 360 ± 223
15 62.5 – >37.5 3.53 ± 0.27 17.7 – >10.6 5.08 ± 2.9 194.3 ± 20 3.84 ± 4.1 0.53 ± 0.5 342 ± 243
17 50 3.45 ± 0.25 14.49 4.91 ± 3.4 >200 ± 0 2.99 ± 3.2 0.40 ± 0.3 357 ± 260
.97 .31 .49 .5 .96
to compare the rise in T4 and free T4 and fall in TSH between mild and severe cases of CH within each treatment group. A third objective was to reexamine the “target” T4 and free T4 range in the first 2 weeks of therapy, with the use of the above regimens, as judged by the corresponding TSH concentrations.
METHODS Screening Procedure Infants with CH were enrolled in the study after detection by The Northwest Regional Newborn Screening Program. Details of the screening procedures have been previously published.11 Briefly, an initial T4 is determined with TSH measurements in infants with T4 concentrations <10th percentile. Confirmatory venipuncture sampling is obtained on infants with any of the following filter paper results suggesting congenital hypothyroidism: (1) T4 < 10% for the assay on a given day and TSH > 25 mU/L (>60 mU/L for infants <24 hours of age); (2) T4 < 3.5 µg/dL, regardless of TSH, or (3) T4 <3rd percentile for the day in both first and second screening specimens, regardless of TSH level. Of note, screening TSH concentrations that are >200 mU/L are not further quantified.
Subjects and Treatment Arms Infants (birth weight 3 to 4 kg) diagnosed with CH (n = 47) between 1995 and 2001 were enrolled in and complet-
ed the study. To minimize the effects of L-thyroxine dose on a weight basis, only infants with birth weights between 3 and 4 kg were enrolled. All consecutive infants meeting the diagnostic criteria and birth weight were eligible to participate in the study. After obtaining informed consent, subjects were randomly assigned into 1 of 3 L-thyroxine replacement treatment groups: (1) 37.5 µg/d, n = 15; (2) loading dose of 62.5 µg/d for 3 days, followed by 37.5 µg/d, n = 17; and (3) 50 µg/d, n = 15.
Laboratory Evaluation Serum T4, free T4, T3, free T3, and TSH concentrations were measured at 0 (baseline, before onset of treatment) and 3 days and 1, 2, 4, 8, and 12 weeks after initiation of therapy. Instructions were given to obtain study blood samples before the daily treatment dose was administered. Thyroid function tests were performed by Quest Diagnostics, San Juan Capistrano, Calif, who also provided normal ranges for age.12 Free T4 was measured by direct dialysis method. To convert to SI units, multiply T4 (µg/dL) by 12.87 to find nmol/L, and T3, free T4, and free T3 (ng/dL) by 15.36 to find pmol/L.
Treatment Dosage Adjustments No changes were made in initial treatment dose for 2 weeks after starting therapy. Subsequently, dosages were adjusted to maintain T4 concentrations in the target range of 10 to 15 µg/dL by 787
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Table II. Twelve-week data: Average serum concentrations of T4, free T4,T3 and free T3, and TSH for period of 3 days to 12 weeks after initiation of therapy in 3 treatment groups Total T4 (µg/dL) Group 1 Group 2 Group 3 P value Free T4 ng/dL Group 1 Group 2 Group 3 P value Total T3 (µg/dL) Group 1 Group 2 Group 3 P value Free T3 (pg/dL) Group 1 Group 2 Group 3 P value TSH (mU/L) Group 1 Group 2 Group 3 P value
3d (7.0–16.6) 8.7 11.1 10.6 .30 3d (0.9-2.2) 1.46 2.1 2.31 .2111 3d (120– 240) 180.8 184.6 218.3 .43 3d (210– 440) 384.3 461.5 451.8 .6 3d (1.7–9.1) 305 226.13 206 .4736
1 wk (7.0–15) 13.2 13.1 17.9* .002* 1 wk (0.9 –2.2) 2.7 2.9 4.51 .057 1 wk (120– 240) 188.8 183.6 194.8 .8 1 wk (210– 440) 430.1 463.9 515.4 .23 1 wk (1.7-9.1) 110.2 65.4 40.6 .998
2 wk (7.0–15) 13.01 13.28 18.08* .0008* 2 wk (0.9– 2.2) 2.74 3.01 4.33* .0035* 2 wk (120– 240) 167.5 175.3 210.1* .01* 2 wk (210– 440) 441.3 471.5 571.5* .04 2 wk (1.7–9.1) 38.9 29.4 4.8 .171
4 wk (7.0–15) 11.58 11.46 15.17* .0001* 4 wk (0.9– 2.2) 2.33 2.44 3.18* .0092* 4 wk (120– 240) 167 178.1 198.5* .05* 4 wk (210– 440) 352.3 470.1 489* .002 4 wk (1.7–9.1) 23.4 28.34 2.33 .072
8 wk (7.0–15) 11.3 13.53 14.58* .016* 8 wk (0.9– 2.2) 2.04 2.66 2.81 .24 8 wk (120– 240) 179.8 212 213.4 .07 8 wk (210– 440) 408.7 513.5 467.9 .2 8 wk (1.7–9.1) 10.82 33.91 12.02 .229
12 wk (7.0–15) 12.96 12.03 12.64 .67 12 wk (0.9– 2.2) 2.29 1.93 2.86 .21 12 wk (120– 240) 186.9 211 204.2 .24 12 wk (210– 440) 411.1 427.4 444.5 .82 12 wk (1.7–9.1) 5.26 12.8 9.93 .476
Group 1 = 37.5 µg/day, group 2 = 62.5 µg/day 3 days, then 37.5 µg/day, and group 3 = 50 µg/day. Bold numbers represent those concentrations significantly higher than others. *P ≤ .05.
the following protocol: (a) if T4 < 8.5 µg/dL, increase dose by 12.5 µg/d, (b) if T4 between 8.5 and 9.9 µg/dL, increase dose by 6.25 µg/d, (c) if T4 between 15.1 and 16.5 µg/dL, decrease dose by 6.25 µg/d, and (d) if T4 > 16.5 µg/dL, decrease dose by 12.5 µg/d. Doses were given based on the currently available forms L-thyroxine, 25-µg and 50-µg tablets. Half-tablets were given in the same manner; however, to make changes of 6.25 µg/d, half- tablets were given every other day. Parents were instructed to give tablets mixed in water, at a time when the infant was not taking formula. Parents were also instructed to 788
not to mix L-thyroxine with iron-containing or soy formulas. This study was approved by the Institutional Review Board of the Oregon Health and Sciences University.
used to plot TSH versus T4 and TSH versus free T4 concentrations.
Statistical Analysis
Average age at the initial newborn screening test was 1.6 ± 1.4 days, with treatment initiated by age 10.9 ± 5.0 days (range 1 to 28 days, Table I). Pretreatment serum T4, free T4, and TSH concentrations were similar in the 3 treatment groups. The pretreatment serum T4 range was group 1, 0.4 to 14.0 µg/dL; group 2, 0.4 to 10.8 µg/dL, and group 3, 0.2 to 6.4 µg/dL.
Results are reported as means and standard deviations, except in Figs 1, 2, and 4, where they are means and standard errors of the mean. Serum T4, free T4, T3, free T3, and TSH concentrations are compared between treatment groups over time with the 1- way analysis of variance test to establish significance (P ≤ .05). Linear regression is
RESULTS Study Onset
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First 2 Weeks’ Data Infants in groups 2 and 3 reached mean serum T4 concentrations in the recommended target range (10 to 16 µg/dL) by 3 days of treatment, whereas infants in group 1 did so by 1 week of therapy (Fig 1). Subjects in groups 1 and 2 remained in the therapeutic range for weeks 1 and 2, whereas group 3 subjects surpassed the upper limit of 16 µg/dL, with concentrations significantly higher than the other two groups. Infants in all groups had serum free T4 concentrations in the normal range by day 3 of treatment. Subjects in all groups had concentrations above the upper limits of normal at 1 and 2 weeks. Group 3 infants demonstrated higher free T4 levels than those of the other groups at week 2. Serum total T3 concentrations rose to the normal range for age (120 to 240 µg/dL) in infants in all 3 treatment groups by 3 days of therapy and remained there for the first 2 weeks of the study. Although TSH fell with treatment, it remained elevated in infants in groups 1 and 2 for the first 2 weeks. Infants in group 3, however, had a normal mean TSH concentration of 4.8 ± 5.44 mU/L at 2 weeks (normal for age, 1.7 to 9.1 mU/L). Infants in group 1 normalized TSH by 12 weeks, whereas TSH never normalized in infants in group 2. Subjects were separated into severe and moderate CH categories on the basis of pretreatment serum T4 concentrations falling above or below the median for all subjects, 1.6 µg/dL. Serum T4 differences between severe and moderate CH were abolished in group 3 by 3 days and in groups 1 and 2 by 1 week. Thereafter, the T4 concentrations were similar in the severe and moderate categories within all treatment arms. There was no significant difference in TSH normalization between severe and moderate categories in any treatment group. At 1 and 2 weeks, we noted that serum T4 (group 3) and free T4 concentrations (all groups) were elevated compared with age-specific normal ranges, yet simultaneous TSH was elevated or
Fig 1. Two-week data. Average concentrations (± SEM) of serum T4, free T4,T3, and TSH for initial 2-week treatment period among treatment groups. Group 1 = 37.5 µg/day; group 2 = 62.5 µg/day 3 days, then 37.5 µg/day; and group 3 = 50 µg/day. Normal concentrations for age are shown in solid horizontal lines. 789
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Twelve-Week Data
Fig 2. Linear regression. Linear regression analysis showing 2-week total and free T4 concentrations versus corresponding TSH concentrations, selected for TSH <10 mU/L. Horizontal line indicates lower limit of normal for TSH concentration (1.7 mU/L). Data from all 3 treatment groups are plotted. r = 0.46 for T4 vs TSH; r = 0.49 for free T4 vs TSH; P < .05 for slope for both analyses. normal (Fig 2). For example, infants in group 3 (50 µg/d) had average T4 concentrations of 17.9 and 18.1 µg/dL, with corresponding TSH concentrations of 40.6 and 4.8 mU/L at weeks 1 and 2, respectively. Free T4 concentrations at these times were 4.51 and 4.33 ng/dL. We therefore carried out linear regression analysis to determine the T4 and 790
free T4 concentrations corresponding to TSH levels at the lower range of normal. When T4 and free T4 were plotted against TSH (using concentrations <10 mU/L) for all treatment groups, linear regression showed the T4 intercept at 19.5 µg/dL and free T4 at 5.23 ng/dL at the lower limit of normal for TSH (1.7 mU/L).
Mean T4 concentrations after 2 weeks of treatment ranged between 11.3 to 15.2 µg/dL among all 3 treatment groups (Table II). Infants in group 3 had significantly higher T4 concentrations for weeks 1 through 8, despite the fact that doses were adjusted after 2 weeks to maintain serum T4 concentrations between 10 and 15 µg/dL. By week 12, the average T4 was 12.53 µg/dL for all subjects and not different among the 3 groups. Subjects in groups 1 and 2 had mean free T4 concentrations higher than the normal range (0.9 to 2.2 ng/dL) at weeks 2 through 4, with group 1 normal at 8 weeks and group 2 normal at 12 weeks. Infants in group 3 had mean free T4 concentrations above normal from day 3 through week 12, though falling from 4.51 to 2.86 ng/dL. Group 3 concentrations were significantly higher than those of the other two groups for weeks 2 and 4. By 8 weeks after therapy, the free T4 concentrations were not significantly different from each other in the 3 groups. At week 12, the mean free T4 concentration, 2.36 ng/dL, was still above normal. Serum T3 concentrations generally were similar in all 3 treatment groups throughout the study, with the exception that subjects in group 3 had significantly higher T3 concentrations at weeks 2 and 4. Subjects in groups 2 and 3 demonstrated elevated mean free T3 concentrations from 3 days to 8 weeks of treatment, whereas group 1 infants generally had normal mean free T3 concentrations. Infants in group 3 had values significantly higher than those of the other two groups at 2 and 4 weeks. By week 12, only group 3 infants were slightly above normal. Throughout the study, there were no significant differences in TSH concentrations among the 3 treatment groups. Treatment group 3 infants normalized TSH quickest, falling to 4.8 mU/L by 2 weeks after treatment onset. The TSH concentration in this group remained in the normal range for 2 additional weeks
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VOLUME 141, NUMBER 6 and then increased to slightly higher than normal range for weeks 8 and 12. This reflects the dose adjustments made to keep serum T4 between 10 and 15 µ/dL per the study protocol. Infants in group 1 reached normal TSH concentrations at week 12, whereas group 2 never achieved normal concentrationsof TSH but approached this goal with a value of 12.8 mU/L by 12 weeks.
Dose Changes Doses of L-thyroxine in each treatment arm were unchanged for the first 2 weeks of the study. After 2 weeks, the dosages were adjusted to keep the serum T4 in the upper half of normal range (10 to 15 µg/dL). By week 4, the mean L-thyroxine doses were not statistically different from one another. At week 12, the mean L-thyroxine treatment dose for all groups was 36.7 µg/d, ~6 µg/kg per day.
DISCUSSION The goals of treatment of CH are to raise the serum T4 concentration as quickly as possible, thereby decreasing TSH concentrations into the normal range and to maintain normal growth and development without overtreatment. A retrospective study reported in 2001 by Henwood-Storto et al13 revealed that initial doses of L-thyroxine of >11.7 µg/kg per day were required to safely and rapidly raise serum T4 and free T4 concentrations into the upper half of the normal range and/or normalize TSH, when compared with other doses given. In another retrospective study, Salerno et al7 reported IQ outcomes at age 4 years in 83 children with CH divided into 3 initial L-thyroxine dose groups: 6 to 8 µg/kg per day, 8.1 to 10 µg/kg per day, and 10.1 to 15 µg/kg per day. IQ was positively correlated with thyroxine dosage and free T4 concentrations and negatively correlated with TSH concentrations measured after 1 month of treatment. Infants started on the highest dose (mean 13.4
µg/kg per day) had a mean T4 of 14.9 µg/dL and TSH of 2.4 mU/L after 1 month of treatment.7 It has been reported that TSH can remain elevated in infants with CH for months despite apparent adequate treatment with T4 concentrations in the normal range. This is thought to be secondary to an abnormal negative feedback set point in TSH sensitivity to T4, which has been shown to persist in 10% of children with CH.11 Heyerdahl and Kase,14 however, have shown that elevated serum TSH concentrations (>10 mU/L) were associated with both lower dosage of L-thyroxine and serum thyroxine concentrations after 6 weeks of therapy. Our study shows that 50 µg/d or 14.5 µg/kg per day normalized serum TSH within 2 weeks, the earliest time period reported to date. These results suggest that TSH will normalize by 2 weeks in most infants if a high enough treatment dose is used. One may argue that such dosing produces serum T4 and free T4 concentrations in the hyperthyroid range. On the other hand, these T4 and free T4 concentrations are similar to those normally seen in the first week of life. It may be that such levels are necessary for normal setting of the pituitary-thyroid feedback relation. Linear regression plotting total T4 and free T4 against TSH for this time period shows a T4 intercept of 19.5 µg/dL and a free T4 of 5.23 ng/dL when the TSH concentration is the lower range of normal for this age group, 1.7 mU/L. Thus one may need to consider increasing the “target” range of T4 and free T4 concentrations for the first 2 weeks of therapy, as TSH remained normal, not suppressed, with these corresponding T4 and free T4 concentrations. In a comparison of severe versus moderate CH, we also found that the higher dose of 50 µg abolished the T4 difference by 3 days, whereas the other two doses abolished this difference by 1 week. This aspect is important as previous studies have shown that delayed rise in T4 levels in children with severe
forms of CH is associated with lower IQS later in life.8,9 Some authors have recommended using T3 combined with L-thyroxine in the treatment of congenital hypothyroidism, as this is the more biologically active hormone. Our results show that supplementation with T3 is unnecessary because both T3 and free T3 concentrations normalized or were slightly above normal by 3 days of therapy, regardless of the dose of L-thyroxine used, and remained normal for the 12 weeks of the study. A loading thyroxine dose, in theory, would meet the treatment goals of CH by quickly raising the T4 levels into normal range, then subsequently maintaining such levels in the target range with lower dosage. Our study used a loading dose of 62.5 µg/d for 3 days followed by 37.5 µg/d. This regimen was successful in raising the T4 and free T4 concentrations into the target range by 3 days of therapy; however, TSH never normalized. Perhaps a loading dose, if used for a longer period, for example, 1 week instead of 3 days, might have normalized TSH. Interestingly, however, 37.5 µg/d alone did achieve TSH normalization by 12 weeks of therapy. This phenomenon most likely is a reflection of dose adjustments made after 2 weeks of treatment. In accordance with the American Academy of Pediatrics guidelines to keep serum T4, free T4, and TSH concentrations approximating normal range, without overtreating CH, the Lthyroxine dose administered to enrolled subjects was adjusted after week 2. By 4 weeks, there were no significant differences between all 3 treatment groups in doses for the remainder of the study. The average dose for all 3 groups at 12 weeks was 36.7 µg/day (~6 µg/kg/day). Thus, the dose required for optimal treatment appears to drop quickly on a weight basis from a starting dose of 14 µg/kg/day to 6 µg/kg per day at 3 to 4 months of age. One may question whether an increase of serum T4 and free T4 into the target range by 3 days versus 7 days 791
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and normalization of serum TSH by 2 weeks, as was seen with the 50-µg/day dose, is likely to have an effect on psychometric outcome. In infants with mild CH, any of the three doses worked well. However, in infants with severe CH, starting at a lower serum T4 concentration, the higher dose may have such an effect. As reported by BongersSchokking et al,9 a lower dose (<9.5 µg/kg/day) combined with later onset of therapy (>13 days of life) resulted in a 20-point lowering of IQ compared with a higher dose (>9.5 µg/kg/day) started earlier (<13 days) in infants judged to have severe CH. Based on our results, we recommend consideration of a somewhat higher “target” range of 10 to 18 µg/dL for T4 and 2 to 5.0 ng/dL for free T4 during the first 2 weeks of L-thyroxine treatment. After 2 weeks of treatment, the target range would drop to 10 to 16 µg/dL for T4 and 1.6 to 2.2 for free T4. Careful follow-up evaluation of growth and neurodevelopment of infants treated with our higher dose is required to determine whether this new “target” range is safe and beneficial.
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REFERENCES 1. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and treatment. Thyroid 1999;9:735-40. 2. Fisher D. The importance of early management in optimizing IQ in infants with congenital hypothyroidism [letter]. J Pediatr 2000;126:273-4. 3. American Academy of Pediatrics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993;91:1203-9. 4. LaFranchi S. Congenital hypothyroidism: a newborn screening success story? The Endocrinologist 1994;4:477-86. 5. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. Pediatrics 1989;5:785-9. 6. Germak JA, Foley TP. Longitudinal assessment of L-thyroxine treatment for congenital hypothyroidism. J Pediatr 1990;117:211-9. 7. Salerno M, Militerni R, Bravaccio C, Micillo M, Capalbo D, Di Maio S, et al. Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism. Thyroid 2002;12:45-52. 8. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, Vliet GV. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine replace-
9.
10.
11.
12.
13.
14.
ment. J Clin Endocrinol Metab 1996; 81:222-7. Bongers-Schokking JJ, Koot HM, Wierserma D, Verkerk PH, de Muinck Keizer-Schrama SMPF. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;126:292-7. 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. Fisher DA, Schoen EJ, LaFranchi SH, Mandel SH, Nelson JC, Carlton EI, et al. The hypothalamic pituitary thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000;85:2722-7. Nelson JC, Clark SJ, Borut DL, Tomei RT, Carlton EI. Age related changes in serum free thyroxine during childhood and adolescence. J Pediatr 1993;123: 899-905. Henwood-Storto MJ, Rossi WC, Post EM. Customizing the dose of L-thyroxine for treating congenital hypothyroidism [abstract]. Pediatr Res 2001; 49:104. Heyerdahl S, Kase BF. Significance of elevated serum thyrotropin during treatment of congenital hypothyroidism. Acta Paediatr 1995;84:634-8.
outcome. In the prescreening era, infants treated between ages zero and 3 months had intelligence quotients
From the Department of Pediatrics, Oregon Health and Sciences University, Oregon State Public Health Laboratories, and Northwest Kaiser Permanente, Portland, Oregon; and Quest Diagnostics, Inc, San Juan Capistrano, California.
Submitted for publication Nov 9, 2001; revisions received Mar 20, 2002, and July 8, 2002; accepted July 31, 2002. Reprint requests: Karin A. Selva, MD, Division of Pediatric Endocrinology, Oregon Health and Sciences University, 707 SW Gaines Rd CDRC-P, Portland, OR 97201. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/21/128887 doi:10.1067/mpd.2002.128887
786
(IQS) significantly higher than those delayed in treatment until after 6 months.1 Newborn screening allows early detection and replacement of thyroxine in infants with CH; however, the optimal starting dose continues to undergo evaluation.
See editorial, p 752. The goal of the initial L-thyroxine dose is to raise the serum thyroxine (T4) concentration into the recommended target range of 10 to 16 µg/dL as rapidly as possible, limiting the impact of hypothyroidism on the developing central nervous system.2 Evidence has shown that serum T4 levels <10 µg/dL in the first year of life are associated with lower IQ levels than T4 concentrations >10 µg/dL.3 The rate of fall of thyroid-stimulating hormone (TSH) into the normal range is a second objective measure of treatment adequacy. It is equally important to avoid prolonged overtreatment.1 CH IQ TSH T4 T3
Congenital hypothyroidism Intelligence quotient Thyroid-stimulating hormone Thyroxine Triiodothyronine
Several investigations have described the time course of serum T4 rise and TSH normalization with initial thyroxine treatment dose. With doses of <10 µg/kg per day, T4 concentrations did not rise to >10 µg/dL until 1 to 3 months.4 In 1989, Fisher and Foley5 reported that initial dosing of 11 µg/kg per day (range, 10-15 µg/kg per day) raised T4 concentrations to the desired upper half of normal (10-16 µg/dL; mean, 13.8 µg/dL) within 3 weeks,
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VOLUME 141, NUMBER 6 Table I. Study onset: Birth weight, L-thyroxine dose, and screening and confirmatory thyroid function test results (mean ± SD) in the 3 treatment groups
No. of subjects Treatment dose(µg/day) Mean birth weight (kg) Mean dose (µg/kg/d) Screening T4 (µg/dL) Screening TSH (mU/L) Confirm. T4 (µg/dL) Confirm. Free T4 (ng/dL) Confirm. TSH (mU/L)
without evidence of overtreatment, whereas TSH concentrations remained elevated for 3 to 4 months. Germak and Foley6 reported the safety of initial dosing of 10 to 14 µg/kg per day, which raised T4 and free T4 concentrations to the target range within 1 week, without risk of overtreatment. Infants who had mild CH had TSH concentrations persistently elevated for 5 months, and those with severe disease had measurements above normal for 1 year.6 In a retrospective study comparing 3 initial L-thyroxine treatment doses, Salerno et al7 recently reported that infants receiving the highest dose of 13.4 µg/kg per day were able to normalize serum TSH by 1 month. The current American Academy of Pediatrics guidelines recommend initial dosing of 10 to 15 µg/kg per day for treatment of CH.3 Several investigations have reported that early, high-dose treatment corrects the untoward delay in rise of T4 in severely affected infants and consequently normalizes IQ when compared with ageand dose-matched counterparts with mild disease.7-10 A delay in rise in serum T4 concentration by as little as 1 week may result in lower IQ scores, by as much as 20 points, in children with severe forms of the disease.9 The first objective of our study was to determine the ideal replacement dose of L-thyroxine in infants with CH as judged by the time course of rise in T4 and free T4 and fall in TSH, by using 3 treatment arms. A second objective was
Group 1
Group 2
Group 3
P value
15 37.5 3.44 ± 0.22 10.9 4.8 ± 2.9 >200 ± 0 2.28 ± 2.1 0.37 ± 0.2 360 ± 223
15 62.5 – >37.5 3.53 ± 0.27 17.7 – >10.6 5.08 ± 2.9 194.3 ± 20 3.84 ± 4.1 0.53 ± 0.5 342 ± 243
17 50 3.45 ± 0.25 14.49 4.91 ± 3.4 >200 ± 0 2.99 ± 3.2 0.40 ± 0.3 357 ± 260
.97 .31 .49 .5 .96
to compare the rise in T4 and free T4 and fall in TSH between mild and severe cases of CH within each treatment group. A third objective was to reexamine the “target” T4 and free T4 range in the first 2 weeks of therapy, with the use of the above regimens, as judged by the corresponding TSH concentrations.
METHODS Screening Procedure Infants with CH were enrolled in the study after detection by The Northwest Regional Newborn Screening Program. Details of the screening procedures have been previously published.11 Briefly, an initial T4 is determined with TSH measurements in infants with T4 concentrations <10th percentile. Confirmatory venipuncture sampling is obtained on infants with any of the following filter paper results suggesting congenital hypothyroidism: (1) T4 < 10% for the assay on a given day and TSH > 25 mU/L (>60 mU/L for infants <24 hours of age); (2) T4 < 3.5 µg/dL, regardless of TSH, or (3) T4 <3rd percentile for the day in both first and second screening specimens, regardless of TSH level. Of note, screening TSH concentrations that are >200 mU/L are not further quantified.
Subjects and Treatment Arms Infants (birth weight 3 to 4 kg) diagnosed with CH (n = 47) between 1995 and 2001 were enrolled in and complet-
ed the study. To minimize the effects of L-thyroxine dose on a weight basis, only infants with birth weights between 3 and 4 kg were enrolled. All consecutive infants meeting the diagnostic criteria and birth weight were eligible to participate in the study. After obtaining informed consent, subjects were randomly assigned into 1 of 3 L-thyroxine replacement treatment groups: (1) 37.5 µg/d, n = 15; (2) loading dose of 62.5 µg/d for 3 days, followed by 37.5 µg/d, n = 17; and (3) 50 µg/d, n = 15.
Laboratory Evaluation Serum T4, free T4, T3, free T3, and TSH concentrations were measured at 0 (baseline, before onset of treatment) and 3 days and 1, 2, 4, 8, and 12 weeks after initiation of therapy. Instructions were given to obtain study blood samples before the daily treatment dose was administered. Thyroid function tests were performed by Quest Diagnostics, San Juan Capistrano, Calif, who also provided normal ranges for age.12 Free T4 was measured by direct dialysis method. To convert to SI units, multiply T4 (µg/dL) by 12.87 to find nmol/L, and T3, free T4, and free T3 (ng/dL) by 15.36 to find pmol/L.
Treatment Dosage Adjustments No changes were made in initial treatment dose for 2 weeks after starting therapy. Subsequently, dosages were adjusted to maintain T4 concentrations in the target range of 10 to 15 µg/dL by 787
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Table II. Twelve-week data: Average serum concentrations of T4, free T4,T3 and free T3, and TSH for period of 3 days to 12 weeks after initiation of therapy in 3 treatment groups Total T4 (µg/dL) Group 1 Group 2 Group 3 P value Free T4 ng/dL Group 1 Group 2 Group 3 P value Total T3 (µg/dL) Group 1 Group 2 Group 3 P value Free T3 (pg/dL) Group 1 Group 2 Group 3 P value TSH (mU/L) Group 1 Group 2 Group 3 P value
3d (7.0–16.6) 8.7 11.1 10.6 .30 3d (0.9-2.2) 1.46 2.1 2.31 .2111 3d (120– 240) 180.8 184.6 218.3 .43 3d (210– 440) 384.3 461.5 451.8 .6 3d (1.7–9.1) 305 226.13 206 .4736
1 wk (7.0–15) 13.2 13.1 17.9* .002* 1 wk (0.9 –2.2) 2.7 2.9 4.51 .057 1 wk (120– 240) 188.8 183.6 194.8 .8 1 wk (210– 440) 430.1 463.9 515.4 .23 1 wk (1.7-9.1) 110.2 65.4 40.6 .998
2 wk (7.0–15) 13.01 13.28 18.08* .0008* 2 wk (0.9– 2.2) 2.74 3.01 4.33* .0035* 2 wk (120– 240) 167.5 175.3 210.1* .01* 2 wk (210– 440) 441.3 471.5 571.5* .04 2 wk (1.7–9.1) 38.9 29.4 4.8 .171
4 wk (7.0–15) 11.58 11.46 15.17* .0001* 4 wk (0.9– 2.2) 2.33 2.44 3.18* .0092* 4 wk (120– 240) 167 178.1 198.5* .05* 4 wk (210– 440) 352.3 470.1 489* .002 4 wk (1.7–9.1) 23.4 28.34 2.33 .072
8 wk (7.0–15) 11.3 13.53 14.58* .016* 8 wk (0.9– 2.2) 2.04 2.66 2.81 .24 8 wk (120– 240) 179.8 212 213.4 .07 8 wk (210– 440) 408.7 513.5 467.9 .2 8 wk (1.7–9.1) 10.82 33.91 12.02 .229
12 wk (7.0–15) 12.96 12.03 12.64 .67 12 wk (0.9– 2.2) 2.29 1.93 2.86 .21 12 wk (120– 240) 186.9 211 204.2 .24 12 wk (210– 440) 411.1 427.4 444.5 .82 12 wk (1.7–9.1) 5.26 12.8 9.93 .476
Group 1 = 37.5 µg/day, group 2 = 62.5 µg/day 3 days, then 37.5 µg/day, and group 3 = 50 µg/day. Bold numbers represent those concentrations significantly higher than others. *P ≤ .05.
the following protocol: (a) if T4 < 8.5 µg/dL, increase dose by 12.5 µg/d, (b) if T4 between 8.5 and 9.9 µg/dL, increase dose by 6.25 µg/d, (c) if T4 between 15.1 and 16.5 µg/dL, decrease dose by 6.25 µg/d, and (d) if T4 > 16.5 µg/dL, decrease dose by 12.5 µg/d. Doses were given based on the currently available forms L-thyroxine, 25-µg and 50-µg tablets. Half-tablets were given in the same manner; however, to make changes of 6.25 µg/d, half- tablets were given every other day. Parents were instructed to give tablets mixed in water, at a time when the infant was not taking formula. Parents were also instructed to 788
not to mix L-thyroxine with iron-containing or soy formulas. This study was approved by the Institutional Review Board of the Oregon Health and Sciences University.
used to plot TSH versus T4 and TSH versus free T4 concentrations.
Statistical Analysis
Average age at the initial newborn screening test was 1.6 ± 1.4 days, with treatment initiated by age 10.9 ± 5.0 days (range 1 to 28 days, Table I). Pretreatment serum T4, free T4, and TSH concentrations were similar in the 3 treatment groups. The pretreatment serum T4 range was group 1, 0.4 to 14.0 µg/dL; group 2, 0.4 to 10.8 µg/dL, and group 3, 0.2 to 6.4 µg/dL.
Results are reported as means and standard deviations, except in Figs 1, 2, and 4, where they are means and standard errors of the mean. Serum T4, free T4, T3, free T3, and TSH concentrations are compared between treatment groups over time with the 1- way analysis of variance test to establish significance (P ≤ .05). Linear regression is
RESULTS Study Onset
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First 2 Weeks’ Data Infants in groups 2 and 3 reached mean serum T4 concentrations in the recommended target range (10 to 16 µg/dL) by 3 days of treatment, whereas infants in group 1 did so by 1 week of therapy (Fig 1). Subjects in groups 1 and 2 remained in the therapeutic range for weeks 1 and 2, whereas group 3 subjects surpassed the upper limit of 16 µg/dL, with concentrations significantly higher than the other two groups. Infants in all groups had serum free T4 concentrations in the normal range by day 3 of treatment. Subjects in all groups had concentrations above the upper limits of normal at 1 and 2 weeks. Group 3 infants demonstrated higher free T4 levels than those of the other groups at week 2. Serum total T3 concentrations rose to the normal range for age (120 to 240 µg/dL) in infants in all 3 treatment groups by 3 days of therapy and remained there for the first 2 weeks of the study. Although TSH fell with treatment, it remained elevated in infants in groups 1 and 2 for the first 2 weeks. Infants in group 3, however, had a normal mean TSH concentration of 4.8 ± 5.44 mU/L at 2 weeks (normal for age, 1.7 to 9.1 mU/L). Infants in group 1 normalized TSH by 12 weeks, whereas TSH never normalized in infants in group 2. Subjects were separated into severe and moderate CH categories on the basis of pretreatment serum T4 concentrations falling above or below the median for all subjects, 1.6 µg/dL. Serum T4 differences between severe and moderate CH were abolished in group 3 by 3 days and in groups 1 and 2 by 1 week. Thereafter, the T4 concentrations were similar in the severe and moderate categories within all treatment arms. There was no significant difference in TSH normalization between severe and moderate categories in any treatment group. At 1 and 2 weeks, we noted that serum T4 (group 3) and free T4 concentrations (all groups) were elevated compared with age-specific normal ranges, yet simultaneous TSH was elevated or
Fig 1. Two-week data. Average concentrations (± SEM) of serum T4, free T4,T3, and TSH for initial 2-week treatment period among treatment groups. Group 1 = 37.5 µg/day; group 2 = 62.5 µg/day 3 days, then 37.5 µg/day; and group 3 = 50 µg/day. Normal concentrations for age are shown in solid horizontal lines. 789
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Twelve-Week Data
Fig 2. Linear regression. Linear regression analysis showing 2-week total and free T4 concentrations versus corresponding TSH concentrations, selected for TSH <10 mU/L. Horizontal line indicates lower limit of normal for TSH concentration (1.7 mU/L). Data from all 3 treatment groups are plotted. r = 0.46 for T4 vs TSH; r = 0.49 for free T4 vs TSH; P < .05 for slope for both analyses. normal (Fig 2). For example, infants in group 3 (50 µg/d) had average T4 concentrations of 17.9 and 18.1 µg/dL, with corresponding TSH concentrations of 40.6 and 4.8 mU/L at weeks 1 and 2, respectively. Free T4 concentrations at these times were 4.51 and 4.33 ng/dL. We therefore carried out linear regression analysis to determine the T4 and 790
free T4 concentrations corresponding to TSH levels at the lower range of normal. When T4 and free T4 were plotted against TSH (using concentrations <10 mU/L) for all treatment groups, linear regression showed the T4 intercept at 19.5 µg/dL and free T4 at 5.23 ng/dL at the lower limit of normal for TSH (1.7 mU/L).
Mean T4 concentrations after 2 weeks of treatment ranged between 11.3 to 15.2 µg/dL among all 3 treatment groups (Table II). Infants in group 3 had significantly higher T4 concentrations for weeks 1 through 8, despite the fact that doses were adjusted after 2 weeks to maintain serum T4 concentrations between 10 and 15 µg/dL. By week 12, the average T4 was 12.53 µg/dL for all subjects and not different among the 3 groups. Subjects in groups 1 and 2 had mean free T4 concentrations higher than the normal range (0.9 to 2.2 ng/dL) at weeks 2 through 4, with group 1 normal at 8 weeks and group 2 normal at 12 weeks. Infants in group 3 had mean free T4 concentrations above normal from day 3 through week 12, though falling from 4.51 to 2.86 ng/dL. Group 3 concentrations were significantly higher than those of the other two groups for weeks 2 and 4. By 8 weeks after therapy, the free T4 concentrations were not significantly different from each other in the 3 groups. At week 12, the mean free T4 concentration, 2.36 ng/dL, was still above normal. Serum T3 concentrations generally were similar in all 3 treatment groups throughout the study, with the exception that subjects in group 3 had significantly higher T3 concentrations at weeks 2 and 4. Subjects in groups 2 and 3 demonstrated elevated mean free T3 concentrations from 3 days to 8 weeks of treatment, whereas group 1 infants generally had normal mean free T3 concentrations. Infants in group 3 had values significantly higher than those of the other two groups at 2 and 4 weeks. By week 12, only group 3 infants were slightly above normal. Throughout the study, there were no significant differences in TSH concentrations among the 3 treatment groups. Treatment group 3 infants normalized TSH quickest, falling to 4.8 mU/L by 2 weeks after treatment onset. The TSH concentration in this group remained in the normal range for 2 additional weeks
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VOLUME 141, NUMBER 6 and then increased to slightly higher than normal range for weeks 8 and 12. This reflects the dose adjustments made to keep serum T4 between 10 and 15 µ/dL per the study protocol. Infants in group 1 reached normal TSH concentrations at week 12, whereas group 2 never achieved normal concentrationsof TSH but approached this goal with a value of 12.8 mU/L by 12 weeks.
Dose Changes Doses of L-thyroxine in each treatment arm were unchanged for the first 2 weeks of the study. After 2 weeks, the dosages were adjusted to keep the serum T4 in the upper half of normal range (10 to 15 µg/dL). By week 4, the mean L-thyroxine doses were not statistically different from one another. At week 12, the mean L-thyroxine treatment dose for all groups was 36.7 µg/d, ~6 µg/kg per day.
DISCUSSION The goals of treatment of CH are to raise the serum T4 concentration as quickly as possible, thereby decreasing TSH concentrations into the normal range and to maintain normal growth and development without overtreatment. A retrospective study reported in 2001 by Henwood-Storto et al13 revealed that initial doses of L-thyroxine of >11.7 µg/kg per day were required to safely and rapidly raise serum T4 and free T4 concentrations into the upper half of the normal range and/or normalize TSH, when compared with other doses given. In another retrospective study, Salerno et al7 reported IQ outcomes at age 4 years in 83 children with CH divided into 3 initial L-thyroxine dose groups: 6 to 8 µg/kg per day, 8.1 to 10 µg/kg per day, and 10.1 to 15 µg/kg per day. IQ was positively correlated with thyroxine dosage and free T4 concentrations and negatively correlated with TSH concentrations measured after 1 month of treatment. Infants started on the highest dose (mean 13.4
µg/kg per day) had a mean T4 of 14.9 µg/dL and TSH of 2.4 mU/L after 1 month of treatment.7 It has been reported that TSH can remain elevated in infants with CH for months despite apparent adequate treatment with T4 concentrations in the normal range. This is thought to be secondary to an abnormal negative feedback set point in TSH sensitivity to T4, which has been shown to persist in 10% of children with CH.11 Heyerdahl and Kase,14 however, have shown that elevated serum TSH concentrations (>10 mU/L) were associated with both lower dosage of L-thyroxine and serum thyroxine concentrations after 6 weeks of therapy. Our study shows that 50 µg/d or 14.5 µg/kg per day normalized serum TSH within 2 weeks, the earliest time period reported to date. These results suggest that TSH will normalize by 2 weeks in most infants if a high enough treatment dose is used. One may argue that such dosing produces serum T4 and free T4 concentrations in the hyperthyroid range. On the other hand, these T4 and free T4 concentrations are similar to those normally seen in the first week of life. It may be that such levels are necessary for normal setting of the pituitary-thyroid feedback relation. Linear regression plotting total T4 and free T4 against TSH for this time period shows a T4 intercept of 19.5 µg/dL and a free T4 of 5.23 ng/dL when the TSH concentration is the lower range of normal for this age group, 1.7 mU/L. Thus one may need to consider increasing the “target” range of T4 and free T4 concentrations for the first 2 weeks of therapy, as TSH remained normal, not suppressed, with these corresponding T4 and free T4 concentrations. In a comparison of severe versus moderate CH, we also found that the higher dose of 50 µg abolished the T4 difference by 3 days, whereas the other two doses abolished this difference by 1 week. This aspect is important as previous studies have shown that delayed rise in T4 levels in children with severe
forms of CH is associated with lower IQS later in life.8,9 Some authors have recommended using T3 combined with L-thyroxine in the treatment of congenital hypothyroidism, as this is the more biologically active hormone. Our results show that supplementation with T3 is unnecessary because both T3 and free T3 concentrations normalized or were slightly above normal by 3 days of therapy, regardless of the dose of L-thyroxine used, and remained normal for the 12 weeks of the study. A loading thyroxine dose, in theory, would meet the treatment goals of CH by quickly raising the T4 levels into normal range, then subsequently maintaining such levels in the target range with lower dosage. Our study used a loading dose of 62.5 µg/d for 3 days followed by 37.5 µg/d. This regimen was successful in raising the T4 and free T4 concentrations into the target range by 3 days of therapy; however, TSH never normalized. Perhaps a loading dose, if used for a longer period, for example, 1 week instead of 3 days, might have normalized TSH. Interestingly, however, 37.5 µg/d alone did achieve TSH normalization by 12 weeks of therapy. This phenomenon most likely is a reflection of dose adjustments made after 2 weeks of treatment. In accordance with the American Academy of Pediatrics guidelines to keep serum T4, free T4, and TSH concentrations approximating normal range, without overtreating CH, the Lthyroxine dose administered to enrolled subjects was adjusted after week 2. By 4 weeks, there were no significant differences between all 3 treatment groups in doses for the remainder of the study. The average dose for all 3 groups at 12 weeks was 36.7 µg/day (~6 µg/kg/day). Thus, the dose required for optimal treatment appears to drop quickly on a weight basis from a starting dose of 14 µg/kg/day to 6 µg/kg per day at 3 to 4 months of age. One may question whether an increase of serum T4 and free T4 into the target range by 3 days versus 7 days 791
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and normalization of serum TSH by 2 weeks, as was seen with the 50-µg/day dose, is likely to have an effect on psychometric outcome. In infants with mild CH, any of the three doses worked well. However, in infants with severe CH, starting at a lower serum T4 concentration, the higher dose may have such an effect. As reported by BongersSchokking et al,9 a lower dose (<9.5 µg/kg/day) combined with later onset of therapy (>13 days of life) resulted in a 20-point lowering of IQ compared with a higher dose (>9.5 µg/kg/day) started earlier (<13 days) in infants judged to have severe CH. Based on our results, we recommend consideration of a somewhat higher “target” range of 10 to 18 µg/dL for T4 and 2 to 5.0 ng/dL for free T4 during the first 2 weeks of L-thyroxine treatment. After 2 weeks of treatment, the target range would drop to 10 to 16 µg/dL for T4 and 1.6 to 2.2 for free T4. Careful follow-up evaluation of growth and neurodevelopment of infants treated with our higher dose is required to determine whether this new “target” range is safe and beneficial.
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REFERENCES 1. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis, and treatment. Thyroid 1999;9:735-40. 2. Fisher D. The importance of early management in optimizing IQ in infants with congenital hypothyroidism [letter]. J Pediatr 2000;126:273-4. 3. American Academy of Pediatrics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics 1993;91:1203-9. 4. LaFranchi S. Congenital hypothyroidism: a newborn screening success story? The Endocrinologist 1994;4:477-86. 5. Fisher DA, Foley BL. Early treatment of congenital hypothyroidism. Pediatrics 1989;5:785-9. 6. Germak JA, Foley TP. Longitudinal assessment of L-thyroxine treatment for congenital hypothyroidism. J Pediatr 1990;117:211-9. 7. Salerno M, Militerni R, Bravaccio C, Micillo M, Capalbo D, Di Maio S, et al. Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism. Thyroid 2002;12:45-52. 8. Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, Vliet GV. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine replace-
9.
10.
11.
12.
13.
14.
ment. J Clin Endocrinol Metab 1996; 81:222-7. Bongers-Schokking JJ, Koot HM, Wierserma D, Verkerk PH, de Muinck Keizer-Schrama SMPF. Influence of timing and dose of thyroid hormone replacement on development in infants with congenital hypothyroidism. J Pediatr 2000;126:292-7. 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. Fisher DA, Schoen EJ, LaFranchi SH, Mandel SH, Nelson JC, Carlton EI, et al. The hypothalamic pituitary thyroid negative feedback control axis in children with treated congenital hypothyroidism. J Clin Endocrinol Metab 2000;85:2722-7. Nelson JC, Clark SJ, Borut DL, Tomei RT, Carlton EI. Age related changes in serum free thyroxine during childhood and adolescence. J Pediatr 1993;123: 899-905. Henwood-Storto MJ, Rossi WC, Post EM. Customizing the dose of L-thyroxine for treating congenital hypothyroidism [abstract]. Pediatr Res 2001; 49:104. Heyerdahl S, Kase BF. Significance of elevated serum thyrotropin during treatment of congenital hypothyroidism. Acta Paediatr 1995;84:634-8.