Nature Reviews Endocrinology 6, 537-538 (October 2010)
Shiao Y. Chan
Thyroid gland: Early adjustment of levothyroxine treatment in pregnancy
Abstract
The THERAPY trial investigators conclude that, when pregnancy is confirmed
in adequately treated women with hypothyroidism, doubling the dose of
prepregnancy levothyroxine on 2 days each week safely prevents maternal
hypothyroidism in the first trimester of pregnancy in most cases. Is this
really the best strategy to adopt?
The maintenance of biochemical euthyroidism during pregnancy in women
previously diagnosed as having hypothyroidism can normalize obstetric and
neonatal outcomes.1, 2 In the majority of cases, this normalization can only
be achieved by increases in levothyroxine dosages from very early on during
gestation.3 The recent THERAPY (Thyroid Hormone Early
Adjustment in Pregnancy) trial4 describes an effective and safe strategy to achieve
biochemical euthyroidism throughout pregnancy that attempts to minimize the
risks of both hypothyroidism and hyperthyroidism.
...thyroid function
tests could be timed to coincide with routine antenatal appointments 
Over the past decade, reports that even maternal subclinical hypothyroidism
(defined as an elevated TSH level in the presence of normal concentrations of
free T3 and T4) is associated with miscarriage, preterm
delivery,1 placental abruption,5 as well as adverse neurodevelopmental sequelae in
the offspring,2 have prompted renewed interest in the issue of
levothyroxine treatment in pregnancy. Whilst controversy around the universal
screening for and treatment of previously undiagnosed subclinical
hypothyroidism awaits resolution by several ongoing clinical trials, the
widespread consensus is that concerted efforts should be made to avoid even
mild hypothyroidism during pregnancy in women previously diagnosed as having
hypothyroidism. The most critical time for euthyroidism is believed to be the
first trimester of pregnancy, which is prior to the onset of endogenous fetal
thyroid hormone production and when fetoplacental development is, thus,
entirely reliant upon the supply of maternal thyroid hormones. Maternal
euthyroidism in the first trimester can also minimize the risk of miscarriage.1
The investigators of the THERAPY trial recruited 60 stably treated women
with hypothyroidism and normal prepregnancy thyroid function and compared two
strategies for dose increases starting from the time pregnancy was first
confirmed. The women either doubled their prepregnancy levothyroxine intake on
2 days (29% levothyroxine increase; group A) or on 3 days (43% levothyroxine
increase; group B) of the week. The researchers recommend the first approach,
accompanied by thyroid function testing and appropriate dose adjustments every
4 weeks until 20 weeks of gestation. This strategy successfully prevented
maternal hypothyroidism in 85% of women in the first trimester with minimal
risk of marked TSH suppression and resulted in a close replication of normal
physiological changes in circulatory TSH concentrations with gestation.
The investigators titrated levothyroxine adjustments to TSH levels, not free
T4 concentrations, as the former is a more sensitive marker of
thyroid status in pregnancy in the context of iodine sufficiency. TSH assays
are also less affected by the normal physiological changes of pregnancy
compared with assays for free T4. For titration of the levothyroxine
dosages, the study protocol used TSH reference ranges derived from euthyroid,
nonpregnant women (0.5–5.0 mIU/l). The data were subsequently re-analyzed using
trimester-specific reference ranges, which have a lower TSH limit of 0.1 mIU/l
and upper limits of 2.5 mIU/l in the first trimester and 3.0 mIU/l in the
second and third trimesters.6 With these trimester-specific reference ranges, 40%
of the women in group A displayed isolated incidences of elevated TSH levels (over
one-third occurred in the first trimester), and 8% had a markedly low TSH level
<0.1 mIU/l. By comparison, only 17% of women in group B had isolated
episodes of elevated TSH concentration, but 26% had isolated incidences of
markedly low TSH levels. However, a substantial proportion of incidences of
markedly low TSH levels occurred in thyroid cancer patients (where TSH levels
were deliberately kept on the lower side of the reference range) and in the
first trimester, when biochemical hyperthyroidism is found in 3% of healthy
pregnant women. Encouragingly, none of the women had clinical signs and
symptoms of hyperthyroidism and both strategies were well-tolerated. If the
study protocol had been designed using the trimester-specific reference ranges,
dose increases or decreases would have been triggered at lower TSH
concentrations than those actually used. Moreover, the aim was to prevent
derangement in TSH concentrations; thus, dose increases should have been
instituted when TSH levels were at the upper end of the normal range rather
than when they had become abnormal. With the adoption of both of these
suggestions some of the incidences of TSH elevations might have been avoided.
The speed with which increased thyroxine demand occurs at the start of
pregnancy was emphasized, as 30% of previously adequately treated women were
already hypothyroid at recruitment (median 5.5 weeks gestation). Furthermore,
92% of these women had a TSH level <2.5 mIU/l before conception, which is
the recommendation of the consensus clinical guidelines of 2007.6 This strategy of maintaining a TSH level in the
lower part of the normal range prior to conception offers only limited
protection from early pregnancy hypothyroidism and reinforces the need for
early levothyroxine increases in pregnancy. Doubling levothyroxine dosages on
specific days of the week is easily understood; with prepregnancy counseling,
women could implement treatment changes themselves immediately following a
positive pregnancy test without a visit to a physician or the need for a new
prescription. This simplicity is pertinent, given that most pregnant women in
the Western world do not access professional antenatal care until the late
first trimester of pregnancy.
Sustained elevations in maternal free T4 concentrations over
several months of pregnancy are associated with fetal growth restriction;
however, a large retrospective study found no increased adverse obstetric
outcomes with subclinical hyperthyroidism.7 Thus, the risks of transient mild hyperthyroidism
in pregnancy are probably minimal. One could argue that isolated incidences of
TSH suppression may be more acceptable than isolated incidences of elevated TSH
levels. Therefore, dose-doubling three times a week could be favored over the
twice-weekly regimen, especially in women who do not have risk factors for
marked TSH suppression, such as a prepregnancy TSH level <1.5 mIU/l, a
prepregnancy levothyroxine dosage of more than 100 µg daily or athyreosis.
The strategy of front-loading levothyroxine therapy in anticipation of an
increased T4 demand in pregnancy necessitates regular monitoring of
thyroid function. Not only did a substantial proportion of women require
further dose increases, but dose reductions during pregnancy were also not
uncommon, occurring in nearly half of the women and sometimes in the first
trimester. Testing of thyroid function every 4 weeks, up to 20 weeks gestation,
would identify over 90% of abnormal TSH values. These thyroid function tests
could be timed to coincide with routine antenatal appointments. If women sought
antenatal care as soon as pregnancy is confirmed, they could be first seen at
about 6–7 weeks gestation, then at 10–12 weeks for an ultrasound scan to date
the pregnancy, at 15–16 weeks for serum screening for Down syndrome (if this is
opted for) and at 20 weeks for a midtrimester fetal anomaly scan.
Doubling levothyroxine
twice a week is safely applicable to all women with hypothyroidism
The importance of continued biochemical euthyroidism in the late third
trimester has been suggested by reports of increased incidence of breech
presentation at term associated with TSH levels in the upper end of the normal
range at 36 weeks gestation8 and increased instrumental and cesarean deliveries
secondary to malrotation of the fetal head in labor associated with lower free
T4 concentrations.9 Thus, further thyroid function tests at week 28 and
34 of gestation may be more useful than a single test at 30 weeks gestation as
performed in the THERAPY trial, especially as some studies have found that
further dose adjustments are required in the third trimester.10
In conclusion, the THERAPY trial demonstrates a simple, yet effective
approach to adjust levothyroxine dosage from early pregnancy in women with
hypothyroidism. Despite the drawback of using reference ranges of nonpregnant
women that resulted in an overly cautious study protocol, subsequent
re-analysis using trimester-specific reference ranges have yielded highly
useful information for guiding clinical practice. Doubling levothyroxine twice
a week is safely applicable to all women with hypothyroidism. Nevertheless, the
more aggressive regimen of doubling levothyroxine three times weekly may be
more appropriate in women who are not at high risk of TSH suppression.
Re-evaluation of these treatment strategies using trimester-specific references
ranges within a routine antenatal care setting is called for. Increased
understanding of the mechanisms underlying the complications of maternal
hypothyroid disease will enable refinement of treatment strategies that could
take into account gestational milestones at which critical developmental
processes dependent on thyroid hormones occur.
Practice point
- The empirical increase in levothyroxine dosage in women
with hypothyroidism when pregnancy is first confirmed could prevent
maternal hypothyroidism in the first trimester of pregnancy in the
majority of cases
- Monthly thyroid function testing until 20 weeks of
pregnancy could detect over 90% of abnormal TSH values
- Subsequent need for further dose increments and dose
reductions in levothyroxine occurred in almost half of the cases
- Risk factors for marked TSH suppression were a
prepregnancy TSH level <1.5 mIU/l, a prepregnancy levothyroxine dosage
of more than 100 µg daily and being athyreotic
Competing interests statement
The author declares no competing interests.
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Author affiliations
S. Y. Chan
The School of Clinical and Experimental Medicine, College of Medical and Dental
Sciences, University of Birmingham, Level 3, Academic Department, Birmingham
Women's Hospital, Metchley Park Road, Edgbaston, Birmingham, West Midlands B15
2TG, UK.
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