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Starting Dose of Levothyroxine for the Treatment of Congenital Hypothyroidism
A Systematic Review
Ihor Hrytsiuk, MB, ChB;
Ruth Gilbert, MD, MSc(Epid), FRCPCH;
Stuart Logan, MB, ChB, MSc(Epid), FRCPCH;
Sima Pindoria, MSc(Med Stats);
Charles G. D. Brook, MD, FRCP, FRCPCH
Arch Pediatr Adolesc Med. 2002;156:485-491.
ABSTRACT
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Objective To determine the effect of levothyroxine sodium starting dose on cognitive
development, growth, or behavior in children with congenital hypothyroidism
identified by neonatal screening.
Design Systematic review of cohort studies. Two analyses were performed: a
between-study comparison of mean starting dose with mean developmental score
and an analysis of the within-study effects of starting dose on cognitive
development, growth, or behavior.
Results The between-study comparison (14 cohort studies based on 1321 patients)
found that the standardized mean IQ or developmental quotient scores ranged
from 90 to 115 but were not associated with the mean starting dose of levothyroxine
(P = .48). The within-study comparison of 4 cohort
studies (based on 558 patients) that reported the effect of the starting dose
of levothyroxine on cognitive development found no consistent effects. There
was weak evidence for an effect of starting dose on growth (1 study) and on
behavior problems (1 study).
Conclusions The evidence for an effect of starting dose of levothyroxine on cognitive
development, growth, or behavior is too weak to justify recommendations in
favor of high- or standard-dose regimens. More reliable information, based
on a randomized controlled trial of starting dose or a meta-analysis of the
individual patient data currently available, is required to inform treatment
policies.
INTRODUCTION
NEONATAL screening for congenital hypothyroidism was introduced in the
early 1970s in response to the finding that children who were diagnosed based
on symptoms of congenital hypothyroidism had better developmental outcomes
the earlier treatment was started.1-3
The screening test involves the detection of raised levels of thyroid-stimulating
hormone (TSH) and/or low levels of thyroxine (T4) in filter paper
blood samples collected shortly after birth. The sensitivity of these screening
tests is 90% to 100% depending on the method used.4-5
Confirmation of the diagnosis is based on sequential analysis of serum levels
of free thyroxine and TSH to rule out transient hypothyroidism.
Although early studies clearly support the treatment of children with
hypothyroidism, evidence to support specific dose regimens is lacking. Replacement
therapy for congenital hypothyroidism was initially determined empirically
and was based on the use of desiccated thyroid.6
In the early 1970s, children were treated with a combination of triiodothyronine
(50 µg/m2 per day)7 and standardized
preparations from desiccated thyroid or levothyroxine sodium (100 µg/kg
per day), and later with levothyroxine sodium alone at doses of approximately
100 µg/m2 per day (4-8 µg/kg per day).8-9
The starting dose of levothyroxine sodium has gradually increased since the
introduction of neonatal screening, and current regimens vary from 5 to 10
µg/kg per day in some centers10-11
(standard-dose regimen) to 10 to 15 µg/kg per day (or 50 µg/d
as a uniform dose) (high-dose regimen) in others.12-15
Starting doses of 10 to 15 µg/kg per day have been reported to result
in normalization of total thyroxine levels within a few days16
to 3 weeks,13-15,17
whereas doses of less than 8 µg/kg per day result in normalization within
6 to 8 weeks.18-19 However, there
is a lack of evidence that earlier normalization of biochemical markers improves
developmental outcome or growth after taking into account the severity of
hypothyroidism at diagnosis. In addition, there are possible adverse effects
of high-dose regimens and elevated T4 levels on temperament and
behavior in later childhood.19-22
We aimed to systematically evaluate the evidence of an effect of levothyroxine
starting dose on development, growth, and behavior. Because to our knowledge
there have been no controlled trials comparing starting doses of levothyroxine
treatment, we first compared mean population standardized developmental scores
in cohorts with different mean starting doses of levothyroxine (between-study
comparison). An underlying assumption in this ecologic analysis was that the
spectrum of patients identified by screening would be similar, and population
differences in mean developmental scores might therefore be attributable to
differences in the starting dose. In the second analysis, we sought studies
that compared development, growth, or behavior in children treated with different
starting doses of levothyroxine within a cohort (within-study comparison).
We stipulated that studies included in the within-study comparison had to
address the potential confounding effects of severity of hypothyroidism at
diagnosis.23
METHODS
LITERATURE SEARCH
We conducted searches of the Cochrane Trials Register, Medline, and
EMBASE (to June 1999), using the terms "congenital," "hypothyroid," "myxedem*,"
"cretin*," "levothyrox*," "l-thyrox*," "drug," "therap*," "treatm*," "manag*)."
(An asterisk symbol is used to include all terms that contain the preceding
word or word part.) There were no language restrictions. In addition, we hand-searched
reference lists in review articles, relevant textbooks, and expert committee
reports. Forward citation searches were conducted for all studies that met
the inclusion criteria up to March 2000.
STUDY SELECTION
One reviewer (I.H.) scanned the titles and abstracts of all studies
generated by the search. Hard copies of all potentially relevant articles
were retrieved. These were assessed by 2 independent reviewers (R.G. and Tessa
Parsons, PhD) to determine whether they met the inclusion criteria.
The inclusion criteria for the between-study comparison required that
participants were children with congenital hypothyroidism identified by neonatal
screening whose global development or cognitive development had been assessed
using a population-standardized measure. For the within-study comparison,
inclusion criteria required that the study must (1) be a cohort study of children
with congenital hypothyroidism identified by neonatal screening and (2) either
include an analysis of the relationship between starting dose and any measure
of global or cognitive development or growth, adjusted for severity of hypothyroidism
at diagnosis based on serum T4 levels or bone age or include an analysis of
the relationship between individual starting dose and any measure of behavior.
DATA EXTRACTION
Two reviewers (I.H. and R.G.) independently extracted the data. For
the between-study comparison, we recorded the mean starting dose of levothyroxine,
the number of patients identified with congenital hypothyroidism, the number
of patients excluded from the developmental assessment and reasons for this,
the number undergoing testing for IQ or developmental quotient (DQ), and the
mean IQ or DQ score at each age of assessment. We preferentially recorded
the Full-Scale IQ or Global Developmental Assessment scores rather than subscales.
For the within-study comparison, we preferentially reported results
for associations between starting dose and Full-Scale IQ or Global DQ unless
results were only reported for subscales. We preferentially used adjusted
measures of association between the starting dose of levothyroxine and IQ
or DQ obtained using continuous measures for starting dose, severity of hypothyroidism,
and any other confounding variables. In the event of uncertainty about whether
analyses represented crude or adjusted measures of association, we contacted
the authors. We also recorded results from studies that examined the relationship
between starting dose and any measure of growth, after adjusting for severity
of hypothyroidism at diagnosis. We sought any reports that examined the relationship
between starting dose and behavior because behavioral problems have been reported
to be an adverse effect of high-dose levothyroxine. Because the evidence for
an association between severity of hypothyroidism at diagnosis and later behavior
is inconsistent,18, 24 we included
reports regardless of whether they took account of severity of hypothyroidism.
ANALYSIS
Between-Study Comparison
Our aim was to determine whether the mean IQ or DQ for the cohort was
correlated with the mean starting dose of levothyroxine. We ranked studies
according to the mean or median (when the mean was not available) starting
dose. For the UK [United Kingdom] II study, only a range of total daily doses
during the first 6 months was given but was reported to be the same as the
starting dose. We used the mean starting dose of 7 µg/kg per day quoted
in the UK I study. We plotted the mean IQ or DQ with 95% confidence intervals
for each study at each age in order of starting dose to visualize any relationship
between starting dose and outcome (Figure
1). Because of potential biases due to loss to follow-up at older
ages, we also plotted the mean scores for the youngest age of assessment (Figure 2). Confidence intervals were derived
from the SDs for the tests in the normative population and the sample size.
The association between starting dose and mean IQ or DQ was investigated in
a weighted linear regression analysis after allowing for between-cohort variation,
using a random effects model. Studies were weighted by the inverse of the
variance, and the model included terms for the proportion of children followed-up
and age at assessment. Because the mean starting dose in the UK II study was
not known for certain, we carried out sensitivity analyses, imputing doses
between 0 and 20 µg/d. These were applied to the measurements at the
youngest and oldest age of assessment separately. All analyses were performed
using STATA software (Stata Corp, College Station, Tex).25
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Figure 1. Mean developmental score for cohorts
at every age of assessment. Cohorts are ranked according to mean starting
dose of levothyroxine. UK indicates United Kingdom.
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Figure 2. Mean developmental score for cohorts
at youngest age of assessment. Cohorts are ranked according to mean starting
dose of levothyroxine. UK indicates United Kingdom.
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Within-Study Comparison
We did not attempt a quantitative analysis of the effect of starting
dose on development due to the lack of consistency in the measures used for
starting dose and other covariates and in the measures of association.
RESULTS
One thousand one hundred sixty-six articles (excluding duplicates) were
retrieved from the electronic databases and 106 from additional search methods,
including hand-searches of textbooks, committee reports, and the forward citation
search. We did not find any randomized controlled trials. Thirty-three potentially
relevant studies were evaluated against the inclusion criteria (references
available).
BETWEEN-STUDY COMPARISON
Characteristics of Studies Included
We identified 14 studies, involving 1321 patients, described in 31 articles11-12,18, 20-21,26-51
for the between-study comparison. All of these studies enrolled children whose
hypothyroidism was identified by neonatal screening (Table 1). Six more cohort studies identified by the searches failed
to meet all of the inclusion criteria because mean development scores were
not given13, 52 or there was no
information on the starting dose.10, 53-57
All 14 studies excluded children with transient hypothyroidism. Most studies
excluded children because of language difficulties and the largest studies
(UK II, New England, Quebec I, and Toronto) excluded children with comorbid
conditions likely to affect development (eg, Down syndrome). The age at final
assessment ranged from 1 to 14 years. The number of children lost to follow-up
or refusing to participate increased with age at assessment. Between 26% (Quebec
I) and 88% (Norway) of the original cohort underwent the final developmental
assessment.
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Table 1. Studies Reporting Cognitive or Global Development in Children
With Congenital Hypothyroidism Used in the Between-Study Comparison*
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Relationship Between Mean Starting Dose of Levothyroxine and IQ or
DQ
We found no evidence for an effect of mean starting dose on mean IQ
or DQ score at the youngest age of assessment (P
= .48) after adjusting for age at assessment or percentage of children followed-up.
In a sensitivity analysis, variation of the mean starting dose in the UK II
study did not produce an effect that was significant at the 5% level. Similar
results were observed at the oldest age assessed.
WITHIN-STUDY COMPARISON
Characteristics of Studies
Five studies20, 38, 42, 51, 58
met the inclusion criteria. Twelve studies11-13,18, 26-36,39-40,43-50,52
were excluded because the authors had not determined the effect of the starting
dose of levothyroxine on development, growth, or behavior, or had not allowed
for severity of hypothyroidism at diagnosis.
Development
Four studies examined the effect of the starting dose of levothyroxine
on development20, 38, 42, 51, 59
(Table 2). The results were inconsistent.
The largest study42 (n = 361) was based on
a national UK register of children with congenital hypothyroidism. There was
no evidence for an association (P = .6) between average
levothyroxine dose during the first 6 months of life and Full-Scale IQ at
age 5 years after adjusting for serum T4 level at diagnosis (measured
as a continuous variable), socioeconomic status (categorized as manual or
nonmanual), and age at the start of treatment (measured as a continuous variable).
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Table 2. Studies Reporting the Association Between Starting Dose of
Levothyroxine and Cognitive Development or Growth Analyzed in the Within-Study
Comparison*
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In the Norwegian study38 (n = 45), the
initial dose of levothyroxine was associated with verbal IQ at age 6 years
(accounting for 12% of the variance; P<.05). No
association was detected between starting dose and the Mental Development
Index (MDI) at age 2 years. The analysis adjusted for serum T4
level at diagnosis (measured as a continuous variable) and socioeconomic status
(measurement not specified).
The Toronto study19 was based on 91 children
and reported an association between starting dose of levothyroxine and Full-Scale
IQ. Starting dose was divided into 2 groups using a cutoff of 7.7 µg/kg
per day. The authors did not assess T4 levels at diagnosis but
reported results stratified by bone age at diagnosis (above and below 36 weeks
of gestational age). No justifications were given for the cutoffs used and
no other confounding factors were included in the analysis.
Finally, the Dutch study51 involved 61
children and found no direct association between starting dose and MDI or
Psychomotor Developmental Index (PDI) measured between age 10 months and 2.5
years after adjusting for serum thyroxine levels at diagnosis. However, the
authors did report a significant effect of a combined variable (defined as
the initial levothyroxine dose / log of the age at onset of treatment [measured
as continuous variables]), MDI (P = .03), and PDI
(P = .006). Dose and age explained only 7.5% and
3.4% of the variance, respectively.
Growth
Four cohort studies10, 32, 58, 60-61
reported growth in children with congenital hypothyroidism but only 258, 61 examined the effect of starting dose
on growth and only one58 took account of the
severity of hypothyroidism at diagnosis. Heyerdahl et al58
compared serial growth measurements in children whose hypothyroidism was categorized
as mild (T4  3.1 ng/dL [40 nmol/L]) or severe (T4
< 3.1 ng/dL [40 nmol/L]). There was an inverse correlation (r = -0.40; P = .02) between the starting
dose of levothyroxine and the age at onset of the childhood component of growth
in children with severe hypothyroidism (n = 34) but not in those with mild
hypothyroidism (n = 42). The age at onset of the childhood component of growth
is derived from serial growth measurements up to age 3 years and represents
the onset of the slow deceleration in linear growth that occurs between the
ages of 6 and 12 months in normal children. This change probably reflects
the start of the influence of growth hormone on linear growth.62
Behavior
Although behavior was assessed in several cohort studies,11, 18-19,21-22,59, 63
the effect of the starting dose of levothyroxine on behavior was only reported
in the Toronto study. Clinician-assessed behavior indices (social withdrawal,
internalizing problems, somatic complaints, social problems, thought problems,
delinquency, and aggression on the Child Behavior Checklist and the Conner's
Parent hyperactivity scale) measured in 88 children at age 8 years were increased
in children who began receiving high-dose (>7.7 µg/kg per day) compared
with low-dose ( 7.7 µg/kg per day) levothyroxine therapy (P<.05).19 A subsequent report of
83 children from the same cohort59 assessed
by parents and teachers at mean ages of 8.8 and 11.8 years, respectively,
reported more internalizing (P<.05) and externalizing
(P<.05) behavior problems in the high-dose group.
The analyses did not adjust for the severity of hypothyroidism at diagnosis
or other potential confounding factors.
Adverse Effects Other Than Behavior
Two studies12, 16 each reported
a single episode of thyrotoxicosis. Both involved children with mild forms
of hypothyroidism receiving high doses of levothyroxine.
COMMENT
Although neonatal screening for hypothyroidism has been in operation
for more than 20 years, we found no randomized controlled trials comparing
the effects of different starting doses on clinical outcomes. We analyzed
the available cohort data using 2 approaches and found no clear evidence for
an effect of starting dose of levothyroxine on cognitive or global development,
growth, or behavior.
The results of the between-study comparison should be interpreted with
caution since an association between mean development scores and the starting
dose of levothyroxine may have been masked by other center-specific characteristics.
These include differential loss to follow-up, the spectrum of severity of
hypothyroidism, the types of children refusing or excluded from participation,
the performance of the IQ or DQ assessment, and secular trends in IQ score.63
Within-study examination of the relationship between starting dose and
outcome is less susceptible to bias but nonetheless may be affected by confounding.
Analysis of starting dose as a categorical variable runs the risk of obscuring
a real effect or, if not decided a priori, may produce spurious associations.
Similarly, analysis of serum T4 level as a categorical variable reduces the
power of the study to control adequately for confounding. Only 2 studies,
UK II42 and the Netherlands,51
analyzed the starting dose of levothyroxine and serum T4 level
(a measure of the severity of hypothyroidism) as continuous variables. Neither
study reported an association between starting dose and developmental outcome.
The report by Bongers-Schokking et al51 of
a weak association between a composite measure (dose divided by log age at
the start of treatment) and developmental outcome up to 2.5 years, should
be interpreted as a chance finding unless confirmed in independent data sets.
Similarly, the weak associations between starting dose and IQ reported in
the Toronto and Norwegian studies were based on categorizations of data, which
were not justified a priori and may have occurred by chance.
The relevance of the weak correlation, found in the Norwegian-Swedish
study, between starting dose and the onset of childhood component of growth
for growth in later childhood and final adult height is uncertain. We found
weak evidence for increased behavior problems in children given a high starting
dose of levothyroxine. This important, potentially adverse effect of a high
starting dose needs to be confirmed in other studies that adjust for possible
confounding by severity of hypothyroidism at diagnosis and social factors.
The limitations of the evidence found do not support clinical recommendations
of high or standard starting doses of levothyroxine. Although higher-dose
regimens lead to more rapid normalization of biochemical indices, we found
no clear evidence for an effect on cognitive or global development. Our findings
may be partly due to poor study methods and do not exclude a moderate but
clinically important effect. More reliable information on the effect of high
vs standard-dose regimens on development, particularly in severely affected
infants, might be provided by combining several large cohort studies in a
meta-analysis of individual patient data. Alternatively or in addition, unbiased
estimates of the effect of starting dose of levothyroxine on development,
growth, and behavior in the long term could be determined by undertaking a
multicenter randomized controlled trial.
| What This Study Adds
Compared with standard dosage regimens, a higher starting dose of levothyroxine
for treatment of congenital hypothyroidism results in more rapid normalization
of biochemical indices but the effect on development or growth is uncertain.
We found no clear evidence that high-dose regimens improve development or
growth. Weak evidence for an association between high starting dose and adverse
behavior at 8 years indicates that further study is necessary.
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AUTHOR INFORMATION
Accepted for publication January 17, 2002.
This study was supported in part by the Department of Health Directorate
of Research and Development, London, England.
We thank Leanne Jones, MSc, for help with searching, Tim Cole for help
with statistical analysis, Tessa Parsons, PhD, for independent assessment
of eligible studies, Peter Hindmarsh, and an anonymous reviewer for helpful
comments on the manuscript.
Corresponding author and reprints: Ruth Gilbert, MD, MSc, FRCPHCH,
Department of Paediatric Epidemiology and Biostatistics, Institute of Child
Health, 30, Guilford St, London, WC1N 1EH, England (e-mail: r.gilbert{at}ich.ucl.ac.uk).
From the Department of Paediatric Endocrinology, the Middlesex Hospital,
University College London (Drs Hrytsiuk and Brook); Systematic Reviews Training
Unit, Department of Paediatric Epidemiology and Biostatistics, Institute of
Child Health (Drs Gilbert and Logan and Mr Pindoria), London, England.
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