DRUGS IN PREGNANCY
Hypothyroidism in Pregnancy
Marilyn Sutandar, MD, Facundo Garcia-Bournissen, MD, Gideon Koren, MD
The Motherisk Program, Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto ON
J Obstet Gynaecol Can 2007;29(4):354–356
Hypothyroidism is a relatively common illness in preg-
nancy. Between 2.2% and 2.5% of women have been
found to have serum thyroid stimulating hormone (TSH)
levels of 6 mU/L or greater at 15 to 18 weeks’ gestation.1,2
OF MATERNAL HYPOTHYROIDISM
Maternal hypothyroidism may place the mother at an
increased risk of adverse obstetrical outcomes. Untreated
hypothyroidism is associated with increased risk for
preeclampsia, low birth weight, placental abruption, miscar-
riage, and perinatal mortality.3,4 Recently, Idris et al. found
that in addition to an increased risk of low birth weight,
hypothyroidism (as defined by increased serum TSH) early
and late in pregnancy may also increase the rate of Caesar-
ean section (CS).5Raised maternal serum TSH in the
second trimester is also associated with an increased rate of
fetal death after 16 weeks’ gestation.2Recent studies have
found that although women treated for hypothyroidism
may have higher rates of preeclampsia6and CS7than
euthyroid women, they are not at any higher risk for adverse
outcomes such as fetal anomalies, fetal demise, or preterm
birth. In a study of 419 hypothyroid women, Tan et al.
observed that women who are treated with levothyroxine
(L-T4) in pregnancy were not at increased risk of maternal
or neonatal morbidity.8
NEONATAL AND LONG-TERM COMPLICATIONS
OF MATERNAL HYPOTHYROIDISM
In addition to adverse obstetrical outcomes, maternal
hypothyroidism is associated with adverse neonatal
outcomes. As the fetus does not begin to produce its own
thyroid hormones until approximately 12 weeks’ gestation,
it is solely dependent on maternal thyroxine (T4) during
early gestation.9,10 After 12 weeks, thyroid hormone in the
fetus continues to be partly supplied by the mother.11
Neuropsychological deficits in the offspring from as early
as 3 weeks to 9 years of age have been observed. Recently,
Kooistra et al. studied 108 neonates born to mothers with
serum free thyroxine (fT4) levels below the 10th percentile
at 12 weeks’ gestation. Compared with control subjects,
these infants had decreased neonatal behavioural
assessment scores at three weeks of age.12 Pop et al. studied
220 healthy infants and found that having maternal serum
fT4 levels below the 10th percentile at 12 weeks’ gestation
was a significant risk for impaired psychomotor develop-
ment at 10 months of age.13 A similar result was observed
by Kasatkina et al.14 The finding of a low maternal serum
fT4 level at five to nine weeks’ gestation correlated signifi-
cantly with a lower coefficient of mental development
(which is thought to represent neuropsychological develop-
ment) at 6, 9, and 12 months of age.14 In a study of 63 cases
with matched controls, mothers with low serum fT4 at
12 weeks’ gestation who continued to have low levels at
weeks 24 and 32 were at risk of having a child with delays in
mental and motor development at one and two years of age.
This neurodevelopmental delay was even more profound
when the mothers had a continuing decrease in serum fT4
as pregnancy progressed.15 Children born to women who
were not treated for thyroid deficiency during pregnancy (as
defined by increased serum TSH) had average IQ scores at
354 lAPRIL JOGC AVRIL 2007
DRUGS IN PREGNANCY
Key Words: Pregnancy, thyroid disease, hypothyroidism, therapy
seven to nine years of age that were 7 points lower than
those of controls.16
Fortunately, treatment of maternal hypothyroidism
decreases the risk of neurodevelopmental deficits in the off-
spring. The stage of development during which the lack of
T4 in the fetus is most detrimental for neurodevelopment is
thought to be the first trimester.17 However, Pop et al.
showed that maternal treatment at a later stage in pregnancy
is also beneficial for neonatal outcome. In this study, the
offspring of women who had an ongoing increase in mater-
nal serum fT4 from 12 to 32 weeks’ gestation showed
neurodevelopment at one and two years of age that was not
significantly different from that of controls.15 Other investi-
gators have noted similar benefits with treatment of
maternal hypothyroidism. The offspring of mothers who
had correction of serum fT4 by week nine of gestation using
L-T4 had the same level of neurodevelopment at one year
of age as control subjects.14 Interestingly, Haddow et al.
observed that even when pregnant women were insuffi-
ciently treated for hypothyroidism (based on serum TSH
measurements), the IQ scores of their offspring were not
significantly different from those of controls.16
Given the increased risk for adverse obstetrical and neona-
tal outcomes in untreated patients, it is prudent to treat all
pregnant women who have hypothyroidism. Levothyroxine
is the treatment drug of choice. As LT-4 is a synthetic drug,
the hormonal content is standardized and more reliable.4It
is considered safe to use in pregnancy and has not been
shown to have teratogenic potential.18,19 Clinicians should
also bear in mind that some medications, including iodine,
lithium, carbamazepine, phenytoin, rifampin, amiodarone,
aluminum hydroxide, cholestyramine, sucralfate, gluco-
corticoids, and propanolol have the potential to interfere
with L-T4 requirements. Mechanisms involved include
inhibition of thyroid hormone synthesis or release, inhibi-
tion of T4 conversion to T3, increase of thyroxine clear-
ance, interference with binding of T4 or T3 to transport
proteins, and interference with intestinal absorption of
L-T4.4,20 As many pregnant women take vitamin
supplementation, it is also important to note that ferrous
sulfate21 and calcium carbonate22 can each reduce the
absorption of L-T4 if taken concurrently.
It is evident that treatment of maternal hypothyroidism dur-
ing pregnancy greatly improves both obstetrical6–8 and
neonatal14–16 outcomes. In fact, treating maternal hypo-
thyroidism is beneficial to the offspring, even if treatment is
insufficient.16 Nonetheless, women should be made
euthyroid as quickly as possible after the diagnosis of
hypothyroidism, and all attempts should be made to
maintain thyroid balance. The dose of L-T4 usually needs to
be increased as pregnancy progresses.5,23–25 This increase
can be as great as 47% of the pre-pregnancy dosage.24 Some
authors have even suggested that women who are taking
L-T4 prior to conception should increase the dosage (by
30–60%) once pregnancy is confirmed.5,20,23,24 Because of
this increased requirement of L-T4, thyroid status should be
monitored frequently throughout pregnancy.
There is no consensus about whether it is better to monitor
the serum level of fT4 or TSH in maternal hypothyroidism,
as it is not clear which of these better represents the T4 sup-
ply to the fetus.26 Several investigators have suggested that
TSH levels should be monitored to assess the adequacy of
thyroid hormone replacement during pregnancy4,24,27;
Montoro et al. have even suggested the time intervals at
which TSH should be measured (at 6–8 weeks, at 16–20
weeks, and at 28–32 weeks).4However, others have argued
that serum fT4 levels should be monitored, because these
more closely reflect the hormone available to cross the
Currently there are also no clear reference ranges for serum
levels of fT4 and TSH in pregnancy.26 This deficiency is
complicated by the fact that human chorionic gonadotropin
(hCG) is a weak thyroid stimulator and thus will cause
maternal serum TSH levels to decline.29 Additionally, iodine
insufficiency may cause a decrease in serum fT4 levels with-
out a measurable change in TSH.10 In a review, Soldin has
presented some trimester-specific reference ranges for
serum levels of both TSH and fT4.20 However, more
research in larger populations is required to confirm these
reference ranges as valid.24 Several placebo-controlled ran-
domized trials are currently in progress to evaluate the fetal
effects of L-T4 in pregnant women who have an increased
level of serum TSH without clinical signs of
hypothyroidism. At present, it is left to the clinician to
decide the ideal serum levels of fT4 and TSH during preg-
nancy. That being said, the correction of an isolated low
level of fT4 (without elevation of TSH) has more potential
for benefit than harm, given the adverse obstetrical and
neonatal outcomes of maternal hypothyroidism.26
Treatment of maternal hypothyroidism is essential, because
adverse outcomes for both mother and baby are greatly
reduced, if not eliminated, when patients are treated. Even
when treatment is initiated later in pregnancy or is insuffi-
cient to restore a euthyroid state, the babies of treated
mothers will show more normal neurodevelopment than
the babies of non-treated mothers. Clinicians must follow
Hypothyroidism in Pregnancy
APRIL JOGC AVRIL 2007 l355
hypothyroid women closely during pregnancy and increase
the dose of L-T4 as required.
Neurodevelopmental follow-up of the babies of hypothy-
roid mothers is also recommended in order to identify
cognitive deficiencies as early as possible and provide
The preparation of this manuscript was supported by a
grant from the Canadian Institute for Health Research.
Facundo Garcia-Bournissen has received funding from the
Clinician Scientist Training Program, which is funded, fully
or in part, by the Ontario Student Opportunity Trust
Fund–Hospital for Sick Children Foundation Student
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