The American Academy
of Pediatrics (AAP) recommends an initial L-thyroxine dose of 10 to 15
mcg/kg/d for the treatment of congenital hypothyroidism (CH). Several
studies have shown that early high dose therapy which quickly produces
serum T-4 levels within the “normal” neonatal range may be associated
with the development of near normal IQ scores, whereas therapy with
lower dosages are associated with a delay in achieving normal T-4
concentrations by as little as 1 week may result in lower IQ scores.
Thus, pediatricians and pediatric endocrinologists need to be familiar
with treatment regimes that achieve the T-4 goal with as little delay as
possible, yet do not produce untoward side effects such as
craniosynostosis.
Selva and colleagues
present data obtained in 47 congenitally hypothyroid neonates (BW 3-4kg)
using a prospective randomized study of 3 different L-thyroxine dosing
regimens (Group 1 – 37.5mcg/d; Group 2- loading dose 62.5mcg/d x 3d,
then 37.5mcg/d; Group 3 – 50mcg/d). Serum T-4, free T-4, T-3, free T-3,
and TSH were measured at baseline, 3 days, and 1, 2, 4, 8, and 12 weeks
after starting treatment. No changes in treatment dose were made for 2
weeks. At that time, dosages were altered using the following important
algorithm to maintain serum T–4 concentrations between 10 – 15 mcg/dL;
a)T-4 < 8.5mcg/dL, increase dose by 12.5mcg/d, b) T-4 between 8.5 and
9.9mcg/dL, increase dose by 6.25mcg/d, c) T-4 between 15.1 and 16.5mcg/dL,
decrease dose by 6.25mcg/d, d) T-4 greater than 16.5mcg/dL, decrease
dose by 12.5mcg/d.
Pre-treatment
thyroid levels were similar in all three groups. Infants in Groups 2 and
3 achieved target T-4 levels by 3 days, while infants in Group 1 did so
by 1 week of age. Subjects in Group 3 had T-4 levels above 16mcg/dL by 1
week, while the others were in the target range at both 1 and 2 weeks.
TSH remained elevated in Groups 1 and 2 for the first 2 weeks. After 2
weeks, serum T-4 remained within the target range in all three groups,
but doses were adjusted as outlined above. At 12 weeks, mean
L-thyroxine dose was 36.7 mcg/d (approximately 6mcg/kg/d) in all groups,
which was associated with ideal target levels of T4, T3, and TSH. Free
T-4 levels rose above normal by 1 week and remained above normal at 12
weeks in all age groups. There were no significant differences in TSH
concentrations at 12 weeks among the groups.
When patients were
divided into severe and moderate CH categories based on serum T-4 above
or below the median value, the differences in initial T-4 levels were
abolished by 3 days for Group 3 infants and by 1 week for the others.
The authors state
that their data shows that a loading dose of 62.5mcg/d x3 days followed
by a dose of 37.5mcg/d raises serum T-4 levels quickly but does not
normalize TSH levels. However, the sustained dose of L-thyroxine
(50mcg/d – Group 3) normalized TSH levels within 2 weeks and abolished
any difference in serum T-4 levels between severe and moderate CH
infants by 3 days. Consequently, they recommend the use of a higher
target range of 10 to 18mcg/dL for T-4 for the first 2 weeks of therapy
to insure that the benefits of therapy are maximized.
Selva K, et al.
J Pediatr 2002:141:786-792.
Editor’s Comment:
It may seem surprising to read a paper dealing with the “correct”
L-thyroxine dose for treating infants with CH, when most neonatal
screening programs have been in place for approximately 20 years and
have been highly successful in identifying these infants and seeing that
they receive what has been considered “appropriate” treatment. However,
the medical community, despite well-delineated guidelines from the AAP,
has yet to define “appropriate” treatment. The article by Selva et al
helps clarify three different treatment regimens. They are to be
commended for the prospective randomized protocol followed. It is
interesting that they refrain from “recommending” a single or favorite
regimen. Indeed all three regimens work well if the goal is to normalize
serum T-4 within 1 week. Quicker attainment of the target range requires
a loading dose for three days. The accompanying algorithm for adjusting
L-thyroxine doses is helpful and all of these data and recommendations
need to be disseminated to those caring for neonates.
William L. Clarke,
MD
Second Editor’s
Comment:
This detailed analytical study is accompanied by a detailed analytical
report pointing out that several groups have demonstrated as much as a
20 point IQ deficit in severely affected CH infants who did not have
rapid and complete conversion of serum hormonal levels of T4, T3, free
T4 and T3, and TSH to normal. The article convinced me that a treatment
protocol as used for group 3 is currently the best available.
In an accompanying
editorial by Dr. Nancy Hopwood1 of the
University
of Michigan,
emphasis is given to the importance of using only tablets of T4 because
liquid preparations may be unreliable. She also points out that
persistent TSH elevation can result from faulty absorption of T4 in
patients with milk allergy, malabsorption of various causes, with soy
formulas, iron therapy, and with acidic juices in children of all ages.
The article by Selva et al and the editorial by Dr. Hopwood fit together
splendidly.
Reference
1.
Hopwood NJ. J Pediatr 2002;141:752-4.
Robert M. Blizzard,
MD
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