Freund Publishing House Ltd.

, London

Journal of Pediatric Endocrinology & Metabolism, 20, 559-578 (2007)

How Should We Be Treating Children

with Congenital Hypothyroidism?
Stephen H. LaFranchi and Juliana Austin
Department of Pediatrics, Division of Endocrinology,
Oregon Health & Science University, Portland, OR, USA
ABSTRACT

KEY WORDS

Early detection by newborn screening and

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

congenital hypothyroidism, newborn screening,

thyroid
dysgenesis,
dyshormonogenesis,
Lthyroxine, neurocognitive outcome, IQ

Reprint address:
Stephen H. LaFranchi, M.D.
Department of Pediatrics [CDRCP]
Oregon Health & Science University
707 SW Gaines St.
Portland, OR 97239, USA
e-mail: lafrancs@ohsu.edu
VOLUME 20, NO. 5, 2007

INTRODUCTION

Delay in diagnosis or suboptimal treatment of

congenital hypothyroidism results in variable
mental retardation, whereas early detection and
appropriate L-thyroxine hormone replacement leads
to normal or near-normal neurocognitive outcome.
The developing brain has a critical dependence on
thyroid hormone, beginning before birth and
extending through the first 2-3 years of life. There
is accumulating evidence that maternal thyroid
hormone that crosses to the fetus is important for
normal brain development, even before onset of
significant fetal thyroid hormone production1.
Thyroid hormone receptor mRNAs (TR1, TR2,
and TR1) are present from 7-8 weeks gestation in
the fetal brain2,3. Type 2 or 5-deiodinase (5-D2)
mRNA is measurable from 7-8 weeks gestation3.
5-D2, which converts T4 to the biologically active
T3, increases with hypothyroidism. While significant fetal thyroid hormone production and
secretion does not begin until approximately 20
weeks, T4 can be demonstrated in the coelomic
cavity as early as 6 weeks gestation4. The
concentration of coelomic fluid T4 correlates
positively with maternal serum T4 levels5. Thus, if
there is a significant role for thyroid hormone in
fetal brain development before 20 weeks gestation,
it is likely of maternal origin. In addition, it would
appear that normal maternal thyroid function is
important for fetal neurodevelopment6.
Based on cord T4 levels in infants with total
organification defects or thyroid agenesis, approxi559

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S.H. LaFRANCHI AND J. AUSTIN

mately one-third of maternal T4 crosses to the fetus

at birth7. Further, most infants with congenital
hypothyroidism have some residual thyroid tissue
(the most common etiology of congenital hypothyroidism is an ectopic gland), so they are able to
produce some thyroid hormone. Although the
combination of the maternal thyroid hormone
contribution and fetal thyroid hormone production
is still subnormal, it likely explains why the
majority of newborns with congenital hypothyroidism are normally grown and lack obvious clinical
manifestations of hypothyroidism. Given the serum
T4 half-life of approximately 6 days, the maternal
contribution will fall and disappear over the first 23 weeks of life. Thus, there is a crucial window of
opportunity to detect this disorder and start treatment within this time frame. Further, it is critical to
raise the serum T4 into the target range as rapidly
as possible, to minimize the time the brain is
exposed to hypothyroidism. Experience has shown
that this requires higher starting L-thyroxine doses
than were initially recommended by newborn
screening programs. In addition, frequent monitoring of thyroid function tests in the first 2-3 years of
life is also important, to assure that thyroid function
remains in the target range during this time of
continued brain dependence on thyroid hormone.
HISTORICAL PERSPECTIVE: CONGENITAL
HYPOTHYROIDISM IN THE PRE-SCREENING ERA

Prior to the onset of screening programs, a

comprehensive survey in Sweden reported that the
incidence of congenital hypothyroidism during the
1969-1975 period was 1:6,9008. The authors stated
that in spite of an efficient National Health Care
Program for infants, the diagnosis was delayed
until after an age of three months in 52% of the
cases. Klein et al. from Pittsburgh Childrens
Hospital examined the effect of age at clinical
diagnosis and treatment on IQ9. If thyroid hormone
treatment was started before 3 months of age, the
mean IQ was 89 (see Table 1). If treatment was
started between 3 and 6 months, mean IQ fell to 71,
while if treatment was started after 6 months of
age, the mean IQ dropped to 54. Several studies
indicate an inverse relationship between the age of
clinical diagnosis and treatment and IQ outcome.

Even if treatment is started before 3 months of age,

there appears to be a small decrement in IQ. In the
1960s, most infants were treated with dessicated
thyroid (porcine thyroid, containing both T4 and
T3), with recommended starting doses in the range
of 15-30 mg daily10. Most experts began
recommending sodium L-thyroxine in the 1970s; at
this time and even in the early 1980s, the
recommended starting dose was 6-8 g/kg/day11.
TABLE 1

Inverse relationship between age at clinical diagnosis

of congenital hypothyroidism and IQ outcome9
Age of treatment
(months)

IQ
mean

range

0-3

89

64-107

3-6

71

35-96

>6

54

25-80

Congenital hypothyroidism is not usually a

heritable disorder; the majority of cases are
sporadic. Thus, it is not possible to identify a
population of pregnant women who are at high-risk
for delivering a newborn with hypothyroidism, and,
short of fetal cord blood sampling, no reliable
prenatal test has been developed. As described
above, the clinical manifestations are often subtle,
non-specific, or even absent at birth, so that most
cases are not suspected or diagnosed clinically in
the neonatal period. For these reasons, when
technology allowed the measurement of T4 and
TSH in the small volume of blood obtained for
newborn screening (eluted from filter paper specimens obtained by heel-prick), testing for congenital
hypothyroidism was added by programs starting in
the mid-1970s12-14.
TREATMENT OF INFANTS WITH CONGENITAL
HYPOTHYROIDISM DETECTED BY
NEWBORN SCREENING

Newborn screening programs for the detection

of congenital hypothyroidism have been in place in
many countries for approximately 30 years (Canada
and the United States, most countries in Europe,
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TREATING CONGENITAL HYPOTHYROIDISM

Israel, Japan, Australia and New Zealand), and they

have been developed more recently in parts of
Mexico, several countries in South America and
some in Asia and the Middle East. The incidence of
congenital hypothyroidism ranges from 1:3,000 to
1:4,000 newborns in most reports. In the year 2000
survey of United States screening programs, 1,635
cases of permanent primary hypothyroidism were
detected among 4,125,135 infants, for an incidence
of 1:2,52315. The incidence from newborn screening programs is approximately twice that from the
pre-screening era. Most likely, this is the result of
detection of cases of transient hypothyroidism,
milder cases of congenital hypothyroidism, or cases
that would have been diagnosed later in childhood
and so thought to represent acquired hypothyroidism.
The advent of newborn screening has resulted
in dramatic improvement in the neurocognitive
outcome of infants with congenital hypothyroidism.
That said, it is the experience of many programs
that undertake follow-up psychometric testing that
infants tend to have a slight, 5-10 IQ point deficit
compared to appropriate control groups16, and that
they have an increased likelihood of having subtle
learning problems, such as difficulty with vocabulary, reading comprehension, arithmetic, and
memory17. It is therefore incumbent to examine
ways in which we can improve treatment of infants
detected with congenital hypothyroidism.
The overall goals of treatment are to assure
normal growth and development, with neurocognitive outcome similar to the childs genetic
potential. Investigators have carried out studies of
the components of treatment to examine which
leads to the best neurocognitive outcome. Such
investigations include examining the effect of
different starting L-thyroxine doses on the timecourse of normalization of serum thyroid function
tests and on psychometric outcome. In addition,
studies have examined the effects of severity of
congenital hypothyroidism and the age of initiation
of treatment on psychometric outcome. The
following sections address several components of
treatment.

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561

L-THYROXINE TABLETS; T4 VS T4 + T3;

ADMINISTRATION, AND INHIBITORS

L-Thyroxine: tablet vs liquid

At present, only L-thyroxine tablets should be

used; there are no U.S. Food and Drug Administration (FDA)-approved liquid preparations. LThyroxine suspensions that may be prepared by
individual pharmacists may lead to unreliable
dosage. There is a report of a liquid T4 preparation
from Europe (manufactured by Henning Berlin; 1
drop [50 l] = 5 g)18. Using a median starting
dose of 12.3 g/kg/d, serum TSH normalized
within 2 weeks, while using a slightly higher
median dose of 12.7 g/kg/d resulted in TSH
normalization within 1 week. Infants treated with
this liquid L-T4 for up to 2 years appeared to do
well, although follow-up psychometric testing has
yet to be reported. Further studies leading to FDA
approval should be carried out before this liquid T4
preparation is used by physicians in the United
States.
T4 vs T4 + T3
L-T4 is the treatment of choice. As T3 is the
biologically active thyroid hormone, there has been
recent interest in T4 + T3 combination treatment of
hypothyroidism. While there is some evidence that
T4 treatment alone may not normalize intracellular
T3 levels in all tissues19, the majority of brain T3 is
derived from local monodeiodination of T420.
Further, the correct dose of T3 or the exact ratio of
T4 and T3 in children has yet to be worked out. At
present, the only T4 + T3 preparations available
are Armour dessicated thyroid, which may have
variable potency, and thyrolar, a dessicated T4 and
synthetic T3 combination. Given the priority of
protecting the brain from thyroid deficiency and the
years of experience using L-thyroxine with good
results, T4 remains the treatment of choice.

Administration

The T4 tablet should be crushed (for example,

between two spoons, or using a mortar and pestle)
and mixed with liquid (e.g., water, expressed breast
milk, or formula) to prepare each days dose. The
daily dose can be drawn up in a plastic syringe and

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S.H. LaFRANCHI AND J. AUSTIN

squirted into the infants cheek pad. Another

method is to add the daily suspension to an open
bottle nipple and offer it just before a feeding. The
crushed T4 tablet should not be added to a full
bottle for feeding, as some of the L-T4 may stick to
the bottle wall or settle at the bottom and so may
not be consumed.
Substances/disorders inhibiting gastrointestinal
(G-I) absorption

Approximately 60-80% of ingested L-T4 is

absorbed from the G-I tract, primarily from the
small intestine21. Several substances are reported to
bind thyroxine and interfere with its absorption;
these are listed in Table 2. Soy formula has been
the best studied in infants with congenital hypothyroidism22. In a retrospective analysis, after
initiation of T4 treatment, infants fed soy formula
took much longer to achieve a serum TSH <10
mU/l than those on non-soy formula (median of
150 vs 40 days)23. In infants in whom soy formula
is deemed necessary, L-T4 should be given half
way between soy feedings. Thyroid function should
be monitored carefully, and the dose of T4
increased as necessary to achieve desired FT4 and
TSH levels. In addition, disorders associated with
malabsorption, including celiac disease and Heliobacter pylori infection, are associated with a need
for a higher T4 dose. Lastly, prolonged heat
exposure of the L-T4 tablets may reduce
bioactivity.

TABLE 2

Substances that interfere with L-thyroxine absorption

Soy protein

Iron (concentrated)

Calcium (concentrated)

Aluminum hydroxide

Cholestyramine and other resins

Fiber supplements

Sucralfate

L-THYROXINE STARTING DOSE; TAILORING TO

SEVERITY OF DISEASE; EFFECT OF TIMING, AND
INITIAL TREATMENT GOALS

L-T4 starting dose

The current recommended starting dose is 10-15

g/kg/day (American Academy of Pediatrics,
2006)24. There is an inverse correlation between the
starting L-T4 dose and the time to achieve the
desired serum T4 concentration (see Table 3).
Guidelines recommend raising the T4 or FT4 level
into the upper half of the normal range for age: T4
= 10-16 g/dl (130-206 nmol/l), FT4 = 1.4-2.3
ng/dl (18-30 pmol/l)24. Studies showed that the
historical starting dose of 6 g/kg/d took 45-90
days to raise the serum T4 to >10 g/dl25, dropping
to an average of 31 days at 10 g/kg/d28, while
using a dose of 10-14 g/kg/d, the desired T4 was
reached in 7 days29. In a study from Oregon of
three starting treatment doses, the highest dose (50
g/ day = 12-17 g/kg/d) raised the serum T4 to
>10 g/dl by 3 days and normalized the TSH by 2
weeks of treatment31. The intermediate dose (37.5
g/day = 9.4-12.4 g/kg/d) or a loading dose
followed by the intermediate dose (62.5 g/d for 3
days followed by 37.5 g/d), took 1 week to raise
the serum T4 to >10 g/dl, while the serum TSH
was normalized at 12 weeks of treatment31. Infants
who took longer than 2 weeks to normalize their
thyroid function had significantly lower cognitive,
attention, and achievement scores than those who
achieved normal thyroid function by 1 or 2 weeks
after starting therapy32. These studies show that the
current recommended starting L-T4 dose of 10-15
g/kg/d leads to the most rapid normalization of
thyroid function.
Early reports of psychometric outcome using
the recommended starting L-T4 dose of 6-8 g/kg/d
reported that global IQs were similar to control
infants.
The
New
England
Congenital
Hypothyroidism Collaborative reported a verbal IQ
score of 109, a performance IQ of 107, and a full
scale IQ of 109 at six years of age33. However,
other programs have reported that infants started on
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TREATING CONGENITAL HYPOTHYROIDISM

the lower T4 dose did not do as well as control

infants. In the Toronto program, a comparison was
made of infants started on a dose of 6.4 g/kg/d vs
9.0 g/kg/d34. Verbal IQ was 98.6 vs 106.3 (p
<0.01),

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S.H. LaFRANCHI AND J. AUSTIN

performance IQ was 103.8 vs 108.2 (p = NS), and

full scale IQ was 100.0 vs 107.6 (p <0.01) in the
low vs high dose infants. A report from Italy
compared psychometric outcome in infants started
on a low (6-8 g/kg/d), intermediate (8.1-10
g/kg/d) or high (10.1-15 g/kg/d) dose of T430.
The verbal IQs in the three treatment groups were
92, 94 and 98, respectively (NS), but the performance IQs were 85, 95, and 98, while the full scale
IQs were 88, 94, and 98, respectively (both p
<0.01). In another report, the Norwegian neonatal
screening program reported psychometric testing
in young adults with congenital hypothyroidism
detected by newborn screening, also correlating
outcome with L-T4 starting dose35. Compared with
control subjects, adults with congenital hypothyroidism had a lower verbal IQ (102.4 vs 110.2),
performance IQ (101.1 vs 110.2), and total IQ
(102.4 vs 111.4). A higher initial L-T4 dose correlated with higher verbal IQ, language tests, and
arithmetic screening skills. The starting L-T4 dose
in school completers was 9.2 g/kg/d, higher than
in non-completers, 7.1 g/kg/d. In the study from
Oregon quoted above, patients starting on the
higher T4 dose (50 g/d = 12-17 g/kg/d) had full
scale IQ scores 11 points higher than those started
on the lower dose (37.5 g/d = 9.4-12.4 g/kg/d)32.

In our review of the literature, we found ten

studies examining the effect of different starting LT4 doses on psychometric outcome (see Table 4).
Of these, two reported no effect, while six reported
that lower starting doses on average correlated with
a 12.3 point drop in IQ. Two studies actually
reported that a lower T4 starting dose led to a better
IQ (average 8.6 points) as compared to the higher
dose. On balance, however, most studies found that
children started on the currently recommended
starting L-T4 dose of 10-15 g/kg/d have a better
neurocognitive outcome than children started on
the dose used when newborn screening programs
were initiated, 6-8 g/kg/d.
Tailoring L-thyroxine dose to severity of disease

Several programs have investigated psychometric outcome in infants judged to have more
severe congenital hypothyroidism. The screening
program in England, Wales and Northern Ireland
reported that infants with pre-treatment serum T4
<3.3 g/dl (<42.8 nmol/l) had a global IQ 11.6
points lower than infants with serum T4 >3.3 g/
dl43. The Quebec Screening Network compared IQ
outcome in a cohort of severely affected and
moderately affected infants, as judged by a serum
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TREATING CONGENITAL HYPOTHYROIDISM

T4 <2 g/dl or >2 g/dl and an epiphyseal surface

area <0.05 cm2 or >0.05 cm2, respectively, both
treated with a starting L-T4 dose of 6 g/kg/d44.
Serial psychometric testing up to age 12 years
showed a global scale IQ 16 points lower in the
severely affected cohort. Subsequently, the Quebec
group reported that using a starting L-T4 dose of
11.6 g/kg/d narrowed the gap, such that IQs
were not statistically different between the moderate and severe groups (110 vs 107)45.
The Dutch newborn screening program
investigated both the effect of initial starting dose
(<9.5 or >9.5 g/kg/d) and age of onset of
treatment (<13 or >13 days of age) in infants
judged by thyroid scan results to have mild (pretreatment mean FT4 = 0.67 ng/dl) or severe (pretreatment FT4 = 0.21 ng/dl) hypothyroidism40. In
the infants with more severe hypothyroidism,
testing at 10-30 months of age showed IQ 21-27
points lower in the groups treated with the lower
dose and/or treated at a later age; the group treated
with a high dose and at an early age had the best
outcome (IQ = 125). On the other hand, all the
infants with mild hypothyroidism did well, except
the group treated with a low dose and at a later age,
which had an IQ 22-25 points below the other
groups. Re-evaluation at 6 years of age showed
improvement, with a global IQ score of 104.7 for
the entire group, similar to the control group of
children, 107.541. The mild groups IQ was 108.5,
while the severe groups IQ was 99.4, but this
difference was not statistically significant. However, the visuomotor scores were higher in the mild
vs severe group (96.5 vs 86.3, p = 0.048).
In the study from Oregon described above,
infants classified as having moderate hypothyroidism had an IQ 11 points higher than those
with severe hypothyroidism, 100 vs 89 (p = 0.05)32.
In our review of the literature, we found 30
studies comparing psychometric outcome in infants
with more severe vs moderate or mild congenital
hypothyroidism (see Table 5). Of these, nine reported no difference in IQ, while 21 reported a 5.523 point decrease in IQ in the more severely
affected infants. As described above, doses in the
upper end of the recommended 10-15 g/kg/d
range lead to more rapid normalization of thyroid

VOLUME 20, NO. 5, 2007

565

function. Based on the studies comparing outcome

with severity of disease, we conclude that it is
important to use the higher end of the dosage
range, perhaps even extending it to 12-17 g/kg/d,
in those infants judged to have more severe hypothyroidism (e.g., serum T4 <5 g/dl).
Initial biochemical goals

Guidelines recommend raising the serum T4 or

free T4 into the upper half of the normal range for
age and normalizing the serum TSH level24.
As reviewed above, it is important to normalize
thyroid function as rapidly as possible to achieve
the best neurocognitive outcome. Given the current
recommendation to use starting L-T4 doses of 1015 g/kg/d, and perhaps even higher doses for the
most severely affected infants, 12-17 g/kg/d, the
Oregon program reported that even higher serum
T4 or FT4 levels may be seen before TSH
normalizes. Using a linear regression analysis of
T4 or FT4 vs TSH plot, the intercept at the lower
range of normal for TSH (1.7 mU/l) showed T4 =
19.5 g/dl and FT4 = 5.23 ng/dl31. The Oregon
program recommended a higher target range for
the
first
2 weeks of L-T4 treatment:
T4 10-18 g/dl (130-232 nmol/l)
FT4 2.0-5.0 ng/dl (25.7-64 pmol/l)
TSH 1.7-9.1 mU/l
While these levels are high, they are similar to
the normal, high ranges seen in the first few weeks
after birth64, so that, in a sense, high-dose treatment
would be duplicating the hyperthyroxinemia seen
with the postnatal TSH surge. Also, bear in mind
that these ranges are only for the first 2 weeks after
starting treatment; after the first 2 weeks, the target
ranges drop (see below).
Studies examining the age of onset of treatment
and psychometric outcome emphasize the importance of starting treatment at as early an age as
possible, with frequent monitoring. In our review
of the literature, of 11 studies comparing starting
treatment at an earlier age (range 12-30 days of
life) vs at a later age, infants starting at the earlier
age averaged 15.7 IQ points higher than those
infants started at a later age (see Table 6).

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TREATING CONGENITAL HYPOTHYROIDISM

MONITORING L-THYROXINE TREATMENT:

THYROID FUNCTION TESTS; FREQUENCY;
BIOCHEMICAL AND CLINICAL OBJECTIVES;
AVOIDING PROLONGED OVER-TREATMENT

Thyroid function tests

T4 or FT4
TSH
Measurement of serum TSH is the single most
sensitive test to monitor L-T4 treatment. However,
a TSH test alone is not adequate to monitor
treatment of congenital hypothyroidism. After
initiation of L-T4, serum TSH may take several
weeks or longer to fall into the normal range. Some
infants may manifest a persistently elevated TSH
level, despite other evidence, both clinical and
biochemical, that the T4 dose is correct (see below,
patients with altered hypothalamic-pituitarythyroid axis feedback). Thus, in general it is safest
to measure both T4 or FT4 and TSH levels to make
correct decisions about dose adjustments. It is
important to compare the result to the normal range
for age. Measurement of serum T3 or free T3 (FT3)
is not useful in monitoring treatment, as these tests
may be normal, despite a low T4 or FT4 and
elevated TSH level.
Frequency of monitoring thyroid function tests

When treating infants with congenital hypothyroidism, it is important to carry out thyroid
function tests more frequently than in, for example,
older children with acquired hypothyroidism. Infants
undergo rapid growth and development in the first
2-3 years of life, and more frequent dose changes
may be necessary. Further, during this time of

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567

critical brain dependence on normal thyroid levels,

it is important to try to prevent prolonged periods
of either under- or over-treatment. Whereas the
effects of under- or over-treatment are reversible in
adolescents, they may have permanent effects in
infancy. The current guidelines for frequency of
monitoring thyroid tests are presented in Table 7.
Testing may need to be carried out at more frequent
intervals when compliance is questioned, abnormal
values are obtained, or the source of thyroid
hormone is changed, e.g., from one brand to
another brand, to a generic, or from one generic to
another generic L-thyroxine.
Biochemical and clinical objectives of treatment

As before, the biochemical goals are to keep the

serum T4 or FT4 in the upper half of the normal
range for age, with the TSH now suppressed to the
lower half of the normal range. After the first two
weeks of treatment, serum thyroid test target range
guidelines are24:
T4 10-16 g/dl (130-206 nmol/l)
FT4 1.4-2.3 ng/dl (18-30 pmol/l)
TSH 0.5-2.0 mU/l
As stated previously, the overall goal of treatment is to assure normal growth and development.
The treatment dose does not appear to be as critical
for growth, as essentially all studies show normal
growth of infants with congenital hypothyroidism
detected by newborn screening programs. Salerno
et al. from Italy reported that, while onset and
progression of puberty were normal in girls and
boys, girls started on an initial L-T4 dose >8
g/kg/d entered puberty a year earlier, with

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S.H. LaFRANCHI AND J. AUSTIN

menarche also a year earlier, as compared to girls

started on a lower dose65. However, all the children
in the study (boys and girls) reached a similar adult
height (0.1 1.1 SDS), which was actually greater
than mid-parental target height (-0.9 0.9 SDS).
No significant correlation was found between adult
height and specific etiology or severity of congenital hypothyroidism or initial starting T4 dose.
Avoiding prolonged over-treatment

Prolonged over-treatment, typically presenting

as a serum T4 or FT4 above the normal range
accompanied by a suppressed TSH level, may lead
to adverse effects. Animal studies report that
prolonged over-treatment accelerates the tempo of
brain development, resulting in premature completion of brain development with fewer neurons and
disordered myelination66. In infancy, overtreatment has been associated with premature
fusion of the skull bones and craniosynostosis.
Behavior issues, including problems with
temperament67 and short attention span68, have
been reported. With appropriate monitoring and T4
dose adjustments, these adverse effects are
generally avoided or reversible.
PATIENTS WITH ALTERED HYPOTHALAMICPITUITARY-THYROID AXIS FEEDBACK
(THYROID HORMONE RESISTANCE)
VS COMPLIANCE ISSUES

Under normal conditions, there is a log-linear

relationship between serum FT4 and TSH69. Some
treated children with congenital hypothyroidism,
however, manifest a persistently elevated serum
TSH level, typically in the 10-20 mU/l range,
despite FT4 or T4 in the upper half of the normal
range. If the T4 dose is raised to normalize the TSH
level, the serum FT4 or T4 is elevated above the
normal range and some patients will manifest
hyperthyroid symptoms. This mild pituitary-thyroid
resistance is speculated to be a result of a resetting
of the hypothalamic-pituitary-thyroid feedback
axis70. This abnormal feedback threshold was seen
in 43% of infants <1 year of age, decreasing to
10% of children by age 10 years70. It appears to be
a characteristic of congenital hypothyroidism, as it
was not found in children with acquired hypo-

thyroidism71. If there is evidence for an abnormal

feedback threshold, we recommend using primarily
the serum FT4 or T4 and clinical assessment to
adjust the L-T4 dose, allowing the serum TSH to
remain slightly elevated. Most cases resolve with
time.
Some treated children with congenital hypothyroidism will manifest an elevated serum TSH
with FT4 or T4 in the upper half of the normal
range as a result of irregular compliance. Such
children will typically have had normalization of
the serum TSH and FT4 in the past, evidence that
they do not have a feedback axis abnormality. The
explanation for these findings appears to be
irregular administration of T4 until just before an
appointment and blood testing, when missed doses
are quickly made up. Under these circumstances,
serum FT4 or T4 will increase quickly, over 24 h,
while serum TSH may take several weeks to fall
into the normal range69.
PERMANENT VS TRANSIENT
CONGENITAL HYPOTHYROIDISM

Some patients detected by newborn screening

will have a transient form of hypothyroidism. In
North America, it is estimated that 10-20% of cases
are transient15, while in Europe the frequency
appears to be higher, primarily a result of transient
cases in infants born in areas of iodine deficiency72.
Some clinicians elect to carry out thyroid scintigraphy or ultrasonography at the time of detection
by newborn screening. If such imaging studies
show an ectopic gland, or absent thyroid uptake,
confirmed by ultrasonography, a permanent form
of hypothyroidism is present. If an inborn error of
thyroid hormone biosynthesis is suspected, for
example, with a goiter and elevated radioiodine
uptake, this is evidence for a permanent defect.
Permanent hypothyroidism can also be assumed if
the serum TSH concentration rises to >10 mU/l
after 6 months of life, as the infant outgrows the T4
replacement dose or there are issues with compliance.
If permanent hypothyroidism has not been
established, guidelines recommend stopping T4
treatment sometime after 3 years of age, waiting
4 weeks, and then checking serum FT4 or T4 and
JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TREATING CONGENITAL HYPOTHYROIDISM

TSH24. If the TSH is elevated and FT4 or T4 is

low, permanent hypothyroidism is confirmed. On
the other hand, if thyroid function tests are normal,
transient hypothyroidism is presumed. If results are
inconclusive (e.g., normal FT4 or T4 and slightly
elevated TSH), careful follow-up and retesting are
indicated.
In cases of transient congenital hypothyroidism,
one may sometimes not be sure whether there truly
was transient hypothyroidism, or whether the infant
had false positive thyroid screening tests. Fortunately, studies of infants with transient congenital
hypothyroidism, treated for anywhere from 6
weeks to 2 years, showed normal growth and
development out to 6-14 years of age73.
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572

S.H. LaFRANCHI AND J. AUSTIN

TABLE 3

Time course of thyroid function with initial L-T4 treatment dose

Screening program

Quebec25
Toronto

26

27

France

New England

28
29

US (Pennsylvania)
Italy

30
31

US (Oregon)

T4 dose
(g/kg/d)

Time to serum
T4 >10 g/dl
(days)

Time to serum
TSH <9.1 mU/l
(days)

45-90

7-9

74

15

10

31

10-14

150

10-15

30

30

12-17

14

60

TABLE 7

Frequency of monitoring serum T4 or FT4 and TSH24

2 and 4 weeks after initiation of L-T4 treatment

Every 1 to 2 months in the first 6 months of life

Every 3 to 4 months between 6 months and 3 years

Every 6 to 12 months until growth is completed

4 weeks after any change in L-T4 dose

JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM

TABLE 4

Studies comparing different starting L-thyroxine doses and effect on IQ

Study by
location

No. of
patients

L-T4 dose

Age of psychometric test

Type of test

Results
FSIQ 101.9 vs 98.1 (NS)

<8 g/kg/d vs >8 g/kg/d

Australia
Connelly et al.36
2001

VIQ 103.3 vs 98.9 (NS)

8 yr

95

WISC-R

<10 g/kg/d vs >10 g/kg/d

PIQ 99.5 vs 98.4 (NS)

FSIQ 101.8 vs 95.9 (p=0.05)
VIQ 103.2 vs 96.4 (p=0.04)
PIQ 99.9 vs 97.0 (NS)
FSIQ 100 vs 107.6 (p=0.01)

Toronto, Canada
Rovet & Ehrlich34
1995

91

7 yr

<6.0 g/kg/d vs 6.2-7.8 g/kg/d

vs 8.2-12.3 g/kg/d
<6.0 g/kg/day vs
8.2-12.3 g/kg/d

VIQ 98.6 vs 106.3 (p=0.01)

PIQ 103.8 vs 108.2 (NS)

7.7 g/kg/d vs 7.8 g/kg/d

88

Toronto, Canada
Rovet37
2005

WISC-R
McCarthy Memory

46.6 vs 53.8 (p=0.01)

8 yr

Woodcock Reading
Mastery-Revised

50.1 vs 59.3 (P=0.05)

6, 7, or 9 yr

McCarthy, WISC-R

95.9 vs 102.5 vs 109.3 (NS)

95.9 vs 109.3 (p<0.05)
GIQ 112.1 vs 117.3 (p<0.03)

<6 g/kg/d vs 6 g/kg/d

France
Boileau et al.38
2004

VIQ 109.1 vs 112.8 (NS)

PIQ 112.8 vs 117.3 (p<0.02)

131
<5 g/kg/d vs 5-7 g/kg/d vs
7 g/kg/d

7 yr

WISC-R and WISC-III

GIQ 110.2 vs 114.2 vs 116.9 (NS)

VIQ 107.3 vs 111.0 vs 112.7 (NS)
PIQ 110.9 vs 115.0 vs 117.6 (NS)

76
55
Italy
Salerno et al.39
1995

47

< 21 days: GIQ 116.4 vs 118.4 (NS)

<6 g/kg/d vs 6 g/kg/d

<7 g/kg/d vs 7 g/kg/d

> 21 days: GIQ 108.0 vs 113.0 (NS)

7 yr

Stanford-Binet test

96 vs 94 (NS)

Study by
location

No. of
patients
83

Italy
Salerno et al.30
2002

L-T4 dose

Age of psychometric test

Results
FSIQ 88 vs 94 vs 98 (p=0.009)

6-8 g/kg/d vs 8.1-10 g/kg/d

vs 10.1-15 g/kg/d

VIQ 92 vs 94 vs 98 (NS)
4 yr

32

Type of test

WPPSI-R

6-8 g/kg/d vs 10.1-15 g/kg/d

PIQ 85 vs 95 vs 98 (p<0.0001)
FSIQ 84 vs 97 (p<0.05)
VIQ 89 vs 98 (NS)
PIQ 80 vs 96 (p<0.05)

The Netherlands
BongersSchokking et al.40
2000

The Netherlands
BongersSchokking &
de Muinck KeizerSchrama41
2005

34

Early/Low vs Late/Low vs
Early/High vs Late/High

27

Early/Low vs Late/Low vs
Early/High vs Late/High

21.7 mo

Bayley Test: Mental

Development Index
(MDI) and
Psychomotor
Development Index
(PDI)

Mild: MDI 124 vs 110 vs 125 vs 122 (p=0.016)

PDI 123 vs 111 vs 120 vs 117 (NS)
Severe: MDI 103 vs 97 vs 124 vs 99 (p=0.035)
PDI 109 vs 113 vs 123 vs 101 (p=0.001)
Early (<13 days): Rakit 106.5 vs 104.6 (NS)

19

Low (<9.5 g/kg/d) vs

72.5 mo

26

High (>9.5 g/kg/day)

Rakit; Beery-Buktenica
Developmental Test for
Visual-Motor
Integration; Language
Test for Children

VMI 89.0 vs 96.3 (NS)

Verbal Score 92.7 vs 91.0 (NS)
Late (>13 days): Rakit 100.1 vs 108.2 (NS)
VMI 90.9 vs 93.3 (NS)
Verbal Score 64.3 vs 99.4 (p=0.001)
FSIQ 109 vs 98 (NS)

Kansas City, MO
Schwartz et al.42
1994

14

<7.5 g/kg/d vs >7.5 g/kg/d

(1 to 3 mo)

9.6 yr

WISC-R; Beery VMI;

WRAT-R

Language 105.6 vs 96.2 (NS)

Visuomotor 108.9 vs 95.2 (p=0.035)
Perceptual/Numerical 103.3 vs 98.1 (NS)

Portland, OR
Selva et al.32
2005

31

37.5 g/day (10.9 g/kg/d) vs

Mullen Scales of Early

Learning (<4 yr)

FSIQ 89.5 vs 95.3 vs 100.6 (p<0.05, low vs

high dose)

62.5 g/day x 3 days,

then 37.5 g/day

WPPSI-R (4-6 yr)

VIQ NS

50 g/day (14.5 g/kg/d)

WISC-III and WRATIII (>6 yr)

PIQ NS

TABLE 5

Studies comparing severity of congenital hypothyroidism and effect on IQ

Study by
Location

No. of
patients

Criterion

Age of psychometric Test

Type of test

Results
FSIQ 96.1 vs 101.1 vs 101.5 (NS)

119

athyreosis vs
dyshormonogenesis vs ectopia

VIQ 95.8 vs 99.4 vs 102.8 (NS)

PIQ 97.7 vs 101.2 vs 100.0 (NS)

Victoria, Australia
Connelly et al.36
2001

FSIQ 96.7 vs 103.0 (p=0.03)

106

TT4 <3.1 vs >3.1 g/dl

8 yr

WISC-R

VIQ 96.9 vs 103.7 (p=0.03)

PIQ 97.4 vs 101.6 (NS)
FSIQ 97.5 vs 101.8 (NS)

88

BA 36 wk vs >36 wk

VIQ 98.2 vs 101.8 (NS)

PIQ 97.9 vs 101.2 (NS)

Brazil
Kreisner et al.46
2004

FSIQ 91.4 vs 102.73 (NS)

31

T4 2.5 g/dl vs >2.5 g/dl

>4 yr

WPPSI (4-6 yr),

WISC (6 yr-15 yr 11 mo)

VIQ 91.75 vs 104.55 vs (p=0.030)

PIQ 92.70 vs 99.64 (NS)
GIQ 86 vs 102 (p<0.001)

T4 <2 g/dl and bone surface

<0.05 cm2 vs T4 >2 g/dl and/or
bone surface 0.05 cm2

9 yr

T4 <2 g/dl and bone surface

<0.05 cm2 vs T4 >2 g/dl and/or
bone surface 0.05 cm2

12 yr

45

Area of the knee epiphyses

<0.05 cm2 vs 0.05 cm2

18 mo

Griffiths Scales

107 vs 110 (NS)

18

Area of the knee epiphyses

<0.05 cm2 vs 0.05 cm2

5 yr 9 mo

McCarthy Scale

General Cognitive Index 102 vs 102 (NS)

Quebec, Canada
Glorieux et al.25
1988

19

Quebec, Canada
Glorieux et al.44
1992

27

Quebec, Canada
Dubuis et al.45
1996
Quebec, Canada
Simoneau-Roy et
al.47 2004

WISC-R

VIQ 83 vs 99 (p<0.001)
NVIQ 92 vs 107 (p<0.001)
GIQ 89 vs 104 (p<0.007)

WISC-R

VIQ 84 vs 99 (p<0.009)
NVIQ 96 vs 109 (p<0.02)

Study by
Location

No. of
patients

Criterion

Age of psychometric Test

Type of test

Results
FSIQ 97.8 vs 109.2 (p=0.02)

WPPSI

PIQ 96.8 vs 109.1 (p=0.01)

VIQ 9.9 vs 11.9 (p=0.04)

Toronto, Canada
Rovet et al.48
1987

34

BA 36 wk vs >36 wk

5 yr

Beery-Buktenica
Developmental Test of
Visual Motor Integration

42.3 vs 72.4 (p=0.02)

McCarthy Scale

45.5 vs 53.9(p=0.02)

Reynell Developmental
Language Scales (Revised)

-0.233 vs 0.692 (p=0.02)

FSIQ 103.4 vs 106.7 vs 107.1 (NS)

Toronto, Canada
Rovet et al.49
1992

95

Toronto, Canada
Song et al.51
2001
Toronto, Canada
Rovet37
2005
France
Boileau et al.38
2004

VIQ 102.9 vs 110 vs 105.1 (NS)

5 yr

108
Toronto, Canada
Rovet50
1999

athyreosis vs
dyshormonogenesis vs ectopia
WPPSI

BA 36 wk vs >36 wk

FSIQ 104 vs 109.8 (p=0.045)

T4 <4.0 g/dl vs >4.0 g/dl

48

athyreosis vs dyshomonogenesis
vs ectopia

62

athyreosis vs
dyshormonogenesis vs ectopia

PIQ 10.2 vs 10.7 vs 11.3 vs 12.1 (NS)

NS

>13 yr

WISC-III

97.1 vs 106.3 vs 102.1 (NS)

FSIQ 91.6 vs 98.1 vs 102.9 (p=0.05)

8.8 yr

WISC-III

VIQ 94.9 vs 96.4 vs 101.6 (NS)

PIQ 89.3 vs 97.8 vs 106.2 (p=0.01)

33

BA 36 wk vs >36 wk

T4 <3.5 g/dl vs >3.5 g/dl

131

athyreosis vs
dyshormonogenesis vs ectopia

97.5 vs 105.9 (NS)

6, 7, or 9 yr

McCarthy, WISC-R

102.2 vs 103.1 (NS)

GIQ 111.5 vs 118.4 vs 113.1 (NS)

7 yr

WISC-R and WISC-III

VIQ 108.0 vs 116.8 vs 109.3 (NS)

PIQ 113.0 vs 117.0 vs 114.1 (NS)

Study by
Location
Italy
Salerno et al.39
1995
Italy
Salerno et al.52
1999

No. of
patients
27

47

Criterion

Age of psychometric Test

Type of test

T4 1.1 g/dl and BA 31.5 wk vs

93 vs 99 (p<0.05)

T4 6.3 g/dl and BA 40.1 wk

T4 <2 g/dl vs >2 g/dl;
BA 33.1 wk
vs 36.8 wk (p<0.01)

Results

7 yr

Stanford-Binet test
92 vs 98 (p<0.02)
FSIQ 78.5 vs 90.8 (p=0.02)

40

athyreosis vs other

12.25 yr

WISC-R

VIQ 83.6 vs 95.6 (p=0.04)

PIQ 76.4 vs 87.0 (p<0.04)
6-8 mg/kg/day:

42

FSIQ 84 vs 92 (p<0.05)
VIQ 89 vs 95 (NS)
PIQ 80 vs 87 (p<0.05)

Italy
Salerno et al.30
2002

8.1-10 mg/kg/day: FSIQ 93 vs 95 (NS)

21

T4 <3.1 g/dl vs 3.1 g/dl

4 yr

WPPSI-R

VIQ 94 vs 94 (NS)
PIQ 92 vs 98 (NS)
10.1-15 mg/kg/day: FSIQ 97 vs 99 (NS)

20

VIQ 98 vs 98 (NS)
PIQ 96 vs 100 (NS)

Italy
Chiovato et al.53
1991

19

hypoplasia/aplasia vs ectopia

3 yr

Stanford Binet Scales

Pisa, Italy
Bargagna et al.54
2000

24

T4 <2 g/dl vs >2 g/dl

7 yr

WISC-R

97 vs 105 (NS)

101.7 vs 107.7 (NS)

GIQ 91.8 vs 99.1 (NS)

46
The Netherlands
Kooistra et al.55
1994

athyreosis vs other

VIQ 93.1 vs 96.8 (NS)

9 yr

61

T4 <3.9 g/dl vs 3.9 g/dl

WISC-R

PIQ 92.1 vs 101.8 (NS)

GIQ 94.8 vs 101.4 (p<0.01)
VIQ 93.9 vs 98.6 (p<0.01)
PIQ 97.0 vs 104.5 (NS)

Study by
Location

No. of
patients

Criterion

Age of psychometric Test

Type of test

MDI 106 vs 118 (p=0.002)

61

PDI 111 vs 117 (NS)

Low/Late:

16
The Netherlands
BongersSchokking et al.40
2000

16

severe (athyreosis/total
dyshomonogenesis) vs mild
(dystopic gland/partial
dyshormonogenesis)

21.7 mo

Bayley Test: Mental

Development Index (MDI)
and Psychomotor
Development Index (PDI)

12

PDI 113 vs 111(NS)

Low/Early:

MDI 103 vs 124 (p<0.005)

PDI 109 vs 123 (p<0.005)

High/Late:

MDI 99 vs 122 (p<0.005)

High/Early: MDI 124 vs 125 (NS)

PDI 123 vs 120 (NS)
Rakit

45

MDI 97 vs 110 (NS)

PDI 101 vs 117 (p<0.005)

17
The Netherlands
BongersSchokking & de
Muinck KeizerSchrama41 2005

Results

severe vs mild (see above)

72.5 mo

Beery-Buktenica
Developmental Test for
Visual-Motor Integration
Language Test for Children

99.4 vs 108.5 (NS)

86.3 vs 96.5 (p=0.048)
82.8 vs 88.4 (NS)
FSIQ 91.3 vs 99.1 vs 101.3
(severe vs mild p=0.043)

The Netherlands
Kempers et al.56
2006

70

T4 <2.3 g/dl vs 2.3 g/dl

4.7 g/dl vs 4.7 g/dl

21.5 yr

WISC-III

VIQ 92.9 vs 97.8 vs 101.8 (NS)

PIQ 90.4 vs101.3 vs 100.4
(severe vs moderate p=0.031,
severe vs mild p=0.037)

Zurich,
Switzerland
Illig et al.57
1986

Taipei, Taiwan
Hsiao et al.58
2001

athyreosis vs ectopia

NS
7 yr

The German version of

WPPSI (HAWIVA)

13

prenatal BA vs normal
skeletal maturation

62

T4 <2 g/dl vs 2 g/dl

95 vs106 (p<0.05)

48

<3 vs 3 ossification centers

91 vs 104 (p<0.05)

36

femoral epiphysis area

<0.1 cm2 vs 0.1 cm2

62

athyreosis vs
dyshormonogenesis vs ectopia

3.8 yr

Chinese Fourth Revision of

Binet-Simon Scales

NS

92 vs 106 (p<0.05)
95 vs 97 vs 103 (NS)

Study by
Location
UK
Murphy et al.59
1986
UK
Murphy et al.60
1990
UK
Fuggle et al.61
1991
UK
Simons et al.62
1994

UK
Tillotson et al.43
1994

No. of
patients

Criterion

36

T4 <1.6 g/dl vs >4.7 g/dl

35

T3 130 ng/dl vs >130 ng/dl

37

BA <30 wk vs >30 wk

51

athyreosis vs other

Age of psychometric Test

Type of test

3 yr

McCarthy Scale

3 yr

McCarthy Scale

94 vs 106 (p=0.013)
93 vs 105 (p<0.01)
93 vs 103 (p=0.03)

T4 <1.6 g/dl vs 1.6-4.7 g/dl

vs >4.7 g/dl
57

Results

89.5 vs 103.2 (NS)

FSIQ 100.4 vs 109.3 vs 115.4

5 yr

WPPSI

TSH >500 mU/l vs 250-500

mU/l vs <250 mU/l

FSIQ 108.1 vs 107.4 vs 110.9 (NS)

FSIQ 104.7 vs 114.6 (p<0.05)

59

T4 3.1 g/dl vs >3.1 g/dl

10 yr

WISC-R

VIQ 105.4 vs 114.2 (p<0.05)

PIQ 103.1 vs 112.0 (p<0.05)

325

T4 0.1-0.9 g/dl vs 1.0-1.6 vs

1.6-2.3 vs 2.4-3.1 vs 3.2-4.7 vs
4.7-6.2 vs 6.3-18.5 g/dl

186

T4 <3.3 g/dl vs 3.3 g/dl

(manual and unemployed)

159

T4 <3.3 g/dl vs 3.3 g/dl

(non-manual)

101.5 vs 100.6 vs 103.3 vs 103.1 vs 112 vs

110.3 vs 111.5 (linear trend p=0.003, analysis
of variance p<0.0001)
5 yr

WPPSI

97.5 vs 109.1
107.6 vs 115.5
FSIQ 95.9 vs 106.8 (NS)

15
Buffalo, NY
Campos et al.63
1995

BA 32 wk vs >32 wk

PIQ 95.9 vs 105.8 (NS)

5 yr

16

WPPSI-R

T4 <2 g/dl vs >2 g/dl

VIQ 96.7 vs 106.1 (p=0.05)

FSIQ 95.5 vs 105.0 (NS)
PIQ 96.5 vs 103.5 (NS)
VIQ 95.5 vs 105.2 (p=0.04)

Portland, OR
Selva et al.32
2005

30

T4 <1.6 g/dl vs 1.6 g/dl

Mullen Scales of Early

Learning (< 4 yr), WPPSI-R
(4-6 yr), WISC-III and
Wide-Range achievement
Test Revision 3 (WRAT-III)
(> 6 yr)

FSIQ 89 vs 100.3 (p=0.05)

VIQ 4.8 difference (NS)
PIQ 9.2 difference (NS)

TABLE 6

Studies comparing timing of onset of L-thyroxine therapy and effect on IQ

Study by location

No. of
patients

Age of onset of
treatment

Age of psychometric test

Type of test

FSIQ 98.1 vs 99.6 (NS)

Victoria, Australia
36

Connelly et al.

109

>14 days vs 14 days

8 yr

WISC-R

2001

VIQ 98.2 vs 100.4 (NS)

PIQ 98.3 vs 99.3 (NS)
FSIQ 91.67 vs 103.30 (NS)

Brazil
Kreisner et al.46

Results

31

>30 days vs 30 days

>4 yr

2004

WPPSI (4-6 yrs),

WISC (6 yrs-15 yrs 11 mos)

VIQ 93.48 vs 102.20 (NS)

PIQ 91.43 vs 103.00 (p=0.036)

Toronto, Canada
Rovet37

>12 days vs <12 days

6, 7, or 9 yr

McCarthy, WISC-R

105.1 vs 100.5 (NS)

2005
GIQ 108.6 vs 117.1 (p<0.01)
>21 days vs 21 days
France

VIQ 105.4 vs 113.5 (p<0.017)

PIQ 109.7 vs 117.6 (p<0.008)

131
>30 days vs 22-30 days
vs 15-21 days
vs <15 days

Boileau et al.38
2004
95

7 yr

WISC-R and WISC-III

GIQ 109.8 vs 107.7 vs 115.3 vs 119.2 (p=0.0008)

VIQ 106.3 vs 104.7 vs 111.6 vs 115.8 (p=0.007)
PIQ 110.4 vs 109.1 vs 116.5 vs 118.8 (p=0.0009)
<6 mg/kg/day: GIQ 108.0 vs 116.4 (p=0.0009)

>21 days vs 21 days

>6 mg/kg/day: GIQ 113.0 vs 118.4 (NS)

36
Italy
Salerno et al.39

24

42.4 vs 18.3 days

7 yr

Stanford-Binet test

98 vs 95 (NS)

1995
8.1-10 mg/kg/day:
21

FSIQ 91 vs 96 (NS)
VIQ 93 vs 98 (NS)

Italy

PIQ 90 vs 95 (NS)

Salerno et al.30

>21 days vs <21 days

4 yr

WPPSI-R
10.1-15 mg/kg/day:

2002
20

FSIQ 98 vs 98 (NS)
VIQ 98 vs 98 (NS)
PIQ 98 vs 99 (NS)

Study by location

The Netherlands

No. of
patients

Age of onset of
treatment

34

late/low vs late/high vs
early/low vs early/high

Bongers-Schokking et
27

Type of test

Results
Severe:

21.7 mo

al.40
2000

Age of psychometric test

late/low vs late/high vs
early/low vs early/high

Bayley Test: Mental Development

Index (MDI) and Psychomotor
Development Index (PDI)

MDI 97 vs 99 vs 103 vs 124 (p=0.035)

PDI 113 vs 101 vs 109 v. 123 (p=0.001)

Mild:

MDI 110 vs 122 vs 124 vs 125 (p=0.016)

PDI 111 vs 117 vs 123 vs 120 (NS)

Low (<9.5 mg/kg/day): Rakit 100.1 vs 106.5 (NS)

The Netherlands

21

Bongers-Schokking &
de Muinck KeizerSchrama41
2005

late (13 days) vs

early (<13 days)

72.5 mo

24

Rakit; Beery-Buktenica
Developmental Test for VisualMotor Integration; Language Test
for Children

VMI 90.9 vs 89.0 (NS)

Verbal Score 64.3 vs 92.7 (p=0.001)
High (>9.5 mg/kg/day): Rakit 108.2 vs 104.6 (NS)
VMI 93.3 vs 96.3 (NS)
Verbal Score 99.4 vs 91.0 (NS)

Taipei, Taiwan
Hsiao et al.58

62

30 days vs <30 days

3.8 yr

Chinese Fourth Revision of BinetSimon Scales

57

>30 days vs 22-30 days

vs 0-21 days

5 yr

WPPSI

FSIQ 104.5 vs 109.6 vs 111.7

361

26-173 vs 21-25 vs 16-20

vs 11-15 vs 1-10

5 yr

WPPSI

106.3 vs 110.7 vs 105.9 vs 104.5 vs 104.2 (NS)

2001
UK
Fuggle et al.61
1991
UK
Tillotson et al.43
1994

102 vs 101 (NS)