Download Thyroid function in pregnancy

Published Online December 23, 2010
Thyroid function in pregnancy
John H. Lazarus *
Centre for Endocrine and Diabetes Sciences, Cardiff University School of Medicine,
University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK
Keywords: thyroid function testing/hyperthyroid/hypothyroid/screening/
neurodevelopment
Accepted: November 29, 2010
Introduction
*Correspondence address.
Centre for Endocrine and
Diabetes Sciences, Cardiff
University School of
Medicine, University
Hospital of Wales, Heath
Park, Cardiff CF14 4XN, UK.
E-mail: [email protected]
During the last 20 years, it has been appreciated that thyroid physiology changes significantly during gestation.1 Advances in the assessment of thyroid function also have indicated that interpretation of
thyroid function tests depend on the stage of pregnancy. Thyroid disorders are prevalent in women of child-bearing age and for this reason
commonly present in pregnancy and the puerperium.2 Uncorrected
thyroid dysfunction in pregnancy has adverse effects on foetal and
maternal well-being. The deleterious effects of thyroid dysfunction also
British Medical Bulletin 2011; 97: 137–148
DOI:10.1093/bmb/ldq039
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Advances in understanding the physiology of thyroid function in normal
pregnancy have highlighted the importance of the consequences of
abnormal function on obstetric outcome and foetal well-being. Pubmed
search was done using the terms thyroid and pregnancy. Areas of agreement
are the following: gestational normative reference ranges for thyroid
function tests are required for proper interpretation of any abnormalities.
Measurement of thyroid-stimulating antibodies and antithyroid peroxidase
antibodies is useful for diagnosis of thyroid disease in pregnancy. Treatment
of Graves’ hyperthyroidism should be done with propylthiouracil for first
trimester only, then carbimazole or methimazole. Patients on levothyroxine
require an increase in dosage during gestation. Areas of controversy are the
following: total thyroxine (TT4) versus Free T4 (FT4) assays in pregnancy.
Screening for thyroid function in early gestation: should it be routinely
performed on everyone? What tests are appropriate? Growing points are the
following: physiology of thyroxine delivery to the foetus. Establishment of
gestational thyroid hormone reference ranges. Evaluation of strategies to
screen thyroid function in early pregnancy. Areas timely for developing
research are the following: placental thyroid hormone physiology, thyroid
hormone therapy and screening thyroid function.
J. H. Lazarus
extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child.
This review will focus on thyroid function in pregnancy followed by
a discussion of thyroid dysfunction and its effects.
Thyroid physiology and function in normal pregnancy
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Pregnancy has an appreciable effect on thyroid economy.1 There is
an increased excretion of iodine in the urine accounting for the
increase in thyroid volume in areas of moderate and severe
deficiency but not in iodine-sufficient regions. Iodine deficiency
during pregnancy is associated with maternal goitre and reduced
maternal thyoxine (T4) level, which is seen in areas of endemic cretinism.3 A recommended daily iodine intake of 250 mg/day
(suggested by a WHO consultation) represents an increase from the
previous figure of 200 mg/day. In the pregnant woman, a median
urinary iodine (UI) of 150 mg/l is regarded as insufficient, an
excretion of 150 –249 as adequate, that of 250– 499 as more than
adequate and 500 as excessive.4
Thyroid hormone transport proteins particularly thyroxine-binding
globulin (TBG) increase due to enhanced hepatic synthesis and a
reduced degradation rate due to oligosaccharide modification. Serum
concentration of thyroid hormones has been reported to be decreased,
increased or unchanged during gestation by different groups depending
on the assays used. Assays employing total T4 show a result approximately 1.5 times the non-pregnant value. There is general consensus
that there is a transient rise in FT4 in the first trimester due to the relatively high circulating human chorionic gonadotrophin (hCG) concentration and a decrease of FT4 in the second and third trimester albeit
within the normal reference range.5 Changes in free triiodothyronine
(FT3) concentration are also seen in which they broadly parallel the
FT4, again within the normal range. The precise reason for the decline
in free thyroid hormones is not clear but the interaction of thyroidstimulating hormone (TSH), oestrogen and thyroid-binding proteins is
of importance.1 In iodine deficient areas, hypothyroxinaemia with preferential T3 secretion may occur accompanied by a rise in median TSH
and serum thyroglobulin (Fig. 1).
It is probable that the changes in thyroid hormone during gestation
relate to the necessity of delivering thyroxine to the foetal cells, particularly neuronal cells. Adequate concentrations of T4 are essential for
neural development and this T4 can only be maternally derived from,
at least during the first trimester. The placenta plays an important role
in T4 transport, although details are still unclear.
Thyroid function in pregnancy
The placenta secretes hCG, a glycoprotein hormone sharing a
common alpha subunit with TSH but having a unique beta subunit,
which confers specificity. hCG, or a molecular variant, acts as a TSH
agonist so that elevated levels contribute to the cause of gestational
transient hyperthyroxinaemia seen in about 0.3% of pregnancies.
Hyperemesis gravidarum, which sometimes requires hospitalization
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Fig. 1 Gestational variation in thyroid function in normal women. Data from 606 normal
pregnancies showing the rise in TBG (top panel) accompanied by the changes in FT4 and
FT3 concentrations throughout gestation in a mildly iodine deficient area (Brussels). The
lower 2 panels show the relationship between serum TSH and hCG as a function of gestational age and the relation between FT4 and hCG in the first half of gestation. Adapted
from Glinoer, DG (1997)1 with permission.
J. H. Lazarus
because of the development of dehydration and ketosis, may be associated with hyperthyroidism due to excess hCG stimulation and
hyperthyroidism is also seen in some cases of hydatiform mole where
excess hCG is secreted.
Thyroid function tests in pregnancy
It is essential therefore to have reliable accurate tests of thyroid function in pregnancy as maternal thyroid dysfunction may affect maternal
health, foetal health and obstetric outcome. Gestational thyroid physiology affects thyroid tests (Table 1) and it is becoming clear that normative gestational related reference ranges for thyroid hormones are
required for diagnosis.6
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Fig. 1 Continued.
Thyroid function in pregnancy
Table 1 Physiologic changes in pregnancy that influence thyroid function tests from Brent
19975.
Physiologic change
Thyroid function test change
Thyroid binding globulin (TBG)
Serum total T4 and T3 concentration
First trimester hCG elevation
Free T4 and TSH
Plasma volume
T4 and T3 pool size
Type III 5-deiodinase (inner ring deiodination) due to T4 and T3 degradation resulting in
increased hormone placental mass
requirement for increased production
Thyroid enlargement (in some women)
Serum thyroglobulin
Iodine clearance
Hormone production in iodine deficient areas
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Circulating T4 and T3 are at equilibrium with free- and proteinbound hormones. The majority of thyroid hormones (.99%) are
bound to transport proteins, mainly to TBG and to a lesser extent to
transthyretin and albumin. Protein binding may prevent thyroid hormones from entering cells to exert their biological effects and also
provide a storage reservoir. In contrast, the free hormones are present
at much lower concentrations ( picomolar compared with the nanomolar concentrations of total hormones) and are biologically active.
Due to their increased serum concentrations, it has been technically
easier to develop assays for total thyroid hormones and these are more
accurate and valid than free hormone assays.7 However, the rise in
TBG causes total T4 to increase to 1.5 times the concentration typical
in the non-pregnant individual. Total T4 assays generally agree quite
well resulting in better-defined reference intervals in adults. Due to the
changes in serum concentrations in pregnancy gestation-specific reference intervals for total thyroid hormones need to be defined and used.
However, in most clinical laboratories total T4 testing has been
replaced with free hormone assays. In general, commercial FT4 immunoassays are affected to variable degrees by the physiological increase
in the TBG that occur in pregnancy. For this reason, there is significant
method-dependant variation in FT4 measurement in pregnancy.
Therefore, it is necessary to use method- and gestation-specific reference intervals for the interpretation of various laboratory results during
pregnancy.6 Furthermore, it is becoming increasingly recognized that
iodine status of the reference population, as well as the background
thyroid autoimmunity should be taken into account and that the
reference population be iodine sufficient.8
Serum TSH concentrations usually provide the first clinical indicator
for thyroid dysfunction in the non-pregnant patient. Due to the loglinear relationship between TSH and FT4, very small changes in T4
concentrations will result in very large changes in serum TSH.
However, in early gestation, TSH is suppressed by 20 –50% by week
10 due to the steep increase in hCG concentrations (Fig. 1) and its
J. H. Lazarus
Thyroid dysfunction in pregnancy
Hyperthyroidism
Hyperthyroidism occurs in 2 /1000 pregnancies , the commonest cause
(85%) being Graves’ hyperthyroidism, due to thyroid stimulation by
thyrotropin receptor antibodies (TRabs).14 Transient gestational thyrotoxicosis (due to thyroid stimulation by hCG) seen in the first trimester, is more common in Asians than Europeans.
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measurement at this time does not provide a good indicator for either
the diagnosis or the control of treatment of thyroid dysfunction.9
Therefore, it is essential to rely on T4 and T3 (either bound or free) to
assess thyroid status in early gestation, although TSH will be significantly elevated in overt hypothyroidism. Later in gestation (from about
16 weeks on) TSH is more reflective of thyroid status.
Although the measurement of thyroid antibodies (thyroid peroxidize
antibodies, TPOAbs and TSH receptor antibodies, TSHRAbs) does not
give any indication of thyroid status, their presence does have important implications for the pregnancy. TPO antibodies are a marker for
an increased risk of infertility, miscarriage and preterm delivery.10
TPOAbs are found in around 10% of women in early pregnancy and
are also associated with decreased thyroid functional reserve during
gestation with possible development of hypothyroidism.11 Their presence at 32 weeks gestation has also resulted in a significant IQ decrement in children even when the mothers were euthyroid.12 It should
also be remembered that the finding of TPOAbs in early pregnancy
imparts a 50% risk for the development of postpartum thyroid dysfunction and the whole spectrum of postpartum thyroiditis.13 TSH
receptor antibodies are present only rarely in gestation (,1%) but do
signify the presence of Graves’ disease.14
Changes in thyroid function and thyroid antibodies during gestation
must be viewed against the backdrop of the immune changes that
occur during and immediately after pregnancy.15 It is beyond the scope
of this review to discuss these in detail. (For recent review see
Weetman16). Important facts to note include the presence of a Th2
state during pregnancy switching abruptly to Th1 at delivery. These
changes as well as the development of postpartum thyroiditis are
thought to be related to the actions of T regulatory cells ( phenotypically CD4 þ CD25þ) in maintaining peripheral tolerance thus preventing autoimmune disease. Clinically, many autoimmune diseases
including Graves’ disease show a remission during pregnancy only to
relapse postpartum.
Thyroid function in pregnancy
Table 2 Management of Graves’ hyperthyroidism in pregnancy.
Confirm diagnosis
Discuss treatment with patient
effect on patient
effect on foetus
breast feeding
Start propylthiouracil—use for first trimester only
Render patient euthyroid—continue with low dose carbimazole or MMI up to and during labour
Monitor thyroid function regularly throughout gestation (4 –6 weeks)
Adjust ATD if necessary
Serial ultrasonography of the foetus
Check TRAbs at 30 –36 weeks
Inform paediatrician
Review postpartum—check for exacerbation
Check infant for thyroid dysfunction if indicated
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The Th2 status of pregnancy may be the reason why there is usually
an amelioration of the severity of Graves’ hyperthyroidism (and other
autoimmune diseases) after the first trimester: deterioration in the first
trimester may be due to increasing TRabs together with high levels of
hCG.
It is critical to interpret thyroid function tests correctly so as not to
miss the diagnosis as there are significant maternal complications
including miscarriage, placenta abruptio and preterm delivery and preeclampsia. One to 5% of neonates of mothers with Graves’ disease
have hyperthyroidism due to the transplacental passage of maternal stimulating TRAbs (even though the mother may be euthyroid and has
received previous treatment for Graves’ disease). Neonatal hyperthyroidism may also be due to an activating mutation of the TSH receptor
dominantly inherited from the mother. Transient neonatal central
hypothyroidism is due to poorly controlled Graves’ disease leading to
suppression of the foetal pituitary thyroid axis due to placental transfer
of T4.17
Ideally a woman who is known to have hyperthyroidism should seek
pre-pregnancy advice; appropriate education should allay fears that are
commonly present in these women. She should be referred for specialist
care for frequent checking of her thyroid status, thyroid antibody
evaluation and close monitoring of her medication needs.18
At all stages of pregnancy, the use of antithyroid drugs (ATDs) is the
preferred treatment option. Radioiodine is contra-indicated and
surgery requires pretreatment with antithyroid drugs to render the
patient euthyroid. Important aspects of management are outlined in
Table 2.
The thionamide drugs carbimazole (CMI), methimazole (MMI) and
propylthiouracil (PTU) are all effective in inhibiting thyroidal biosynthesis of thyroxine during pregnancy. PTU is the preferred drug in the
J. H. Lazarus
Hypothyroidism
In contrast to hyperthyroidism, hypothyroidism is quite common in
pregnancy.21 The incidence of subclinical hypothyroidism (raised TSH
and normal or low normal T4) is at least 2.5% and these women have
no clinical features and are often asymptomatic, but 50 –60% will have
evidence of autoimmune thyroid disease ( positive TPOAbs and or thyroglobulin antibodies, TgAbs) in iodine-sufficient areas. It should be
noted however that endemic iodine deficiency is the most common
cause of hypothyroidism seen in pregnant women worldwide. Overt
hypothyroidism occurs in only about 5% of all women who have a
high TSH. To make the diagnosis of hypothyroidism in the first trimester, it is necessary to employ a gestation-related normative reference
range for TSH (as this will be reduced by hCG at this time). For
example, the upper limit for TSH in the non-pregnant woman (commonly 4.5 or 5 mIU/L) may be reduced to 3.5 mIU/L.
During the last decade, it has become apparent that untreated
maternal hypothyroidism and subclinical hypothyroidism in pregnancy
is associated with adverse foetal and obstetric outcomes,22,23 which
can be ameliorated by adequate levo-thyroxine therapy.24 These events
include miscarriages, anaemia in pregnancy, preeclampsia, abruptio
placenta and post-partum haemorrhage while premature birth, low
birth weight and increased neonatal respiratory distress have been
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first trimester pregnancy due to the possibility (albeit rare) of teratogenic effects of carbimazole and MMI (aplasia cutis and MMI embryopathy). The latter malformation may be extremely severe requiring
surgical management. In women already receiving CMI before conception they should also be switched to PTU either before the planned
gestation or as soon as possible on confirmation of pregnancy.
However, there are recent data suggesting an increase in hepatotoxicity
with PTU19 so CMI or MMI should be given in the second and third
trimesters. Maternal FT4 levels should be kept in the upper third of the
normal non-pregnant reference range to avoid foetal hypothyroidism,
as with this management serum-free T4 levels are normal in more than
90% of neonates. Although these patients may have received antithyroid drugs, surgery or radioiodine therapy and be euthyroid on or off
thyroxine therapy, neonatal hyperthyroidism may still occur. TRAbs
should be measured early in pregnancy in a euthyroid pregnant women
previously treated by either surgery or radioiodine20 TRAb antibodies
should be measured again in the last trimester (at about 32 weeks) and
if positive the neonate needs to be checked for hyperthyroidism following delivery.
Thyroid function in pregnancy
Table 3 Aspects of thyroxine treatment of hypothyroidism in pregnancy (adapted from
Abalovich et al.40).
Preconception: optimise therapy in patients with pre-existing disease
On confirmation of pregnancy, increase dose by 30 –50% of preconception dose
Check thyroid function early in first trimester
Aim for TSH ,2.5 mU/l in the first trimester and ,3 mU/l in later pregnancy
Monitor thyroid function 4 –6 weeks and further adjust dose
Higher dose requirement in post-ablative and post-surgical hypothyroidism
After delivery reduce thyroxine to preconception dose
Recheck thyroid function at 6 weeks postpartum
Note drug interactions:
(a) Drugs which impair thyroxine absorption: iron supplements, cholestyramine, calcium carbonate,
soy milk
(b) Drugs which increase thyroxine clearance: carbamazepine, rifampicin, valproate
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described in babies born to mothers with hypothyroidism.25 There is a
greater prevalence of subclinical hypothyroidism in women with delivery before 32 weeks and there is even an association between thyroid
autoimmunity and adverse obstetric outcome, which is independent of
thyroid function.26 Higher maternal TSH levels even within the normal
reference range are associated with an increased risk of miscarriages,
foetal and neonatal distress27 as well as preterm delivery.28 Of equal or
even greater importance than the above is the detrimental effect of
gestational maternal hypothyroidism on foetal brain development. The
availability of thyroxine to the developing foetal neurones is vital for
their maturation and proper function.29 Either due to iodine deficiency
or autoimmune thyroid disease reduction of circulating maternal thyroxine has been shown to result in lower IQ in infants and young children in retrospective30 and prospective31 studies.
Isolated hypothyroxinaemia (low FT4 and normal TSH) has been
found not to be associated with adverse perinatal outcomes,32 although
other studies have shown it to be associated with reduced motor and
intelligence performance in neonates33 and in children aged 25– 30
months in a Chinese population.34
The strength of evidence relating maternal hypothyroidism to low IQ
in children suggests strongly that screening thyroid function in early
gestation with L-thyroxine intervention in appropriate women would
be beneficial. There is evidence that such a strategy would be costeffective35,36 but at present there are no prospective controlled trials of
this strategy assessing child IQ. Preliminary results from a prospective
randomized trial of L-T4 treatment in women screened prior to 16
weeks gestation (compared with control women not screened and
therefore not treated with L-T4), the CATS study, are now available.
The mean IQ of the two groups of children (screen and control) was
not different. However, an on-treatment analysis showed that the
number of children with IQ ,85 born to women with subclinical
J. H. Lazarus
hypothyroidism who were considered to have been compliant with
their T4 treatment was significantly less (9%) than in the control
group (15%).
Conclusion
Funding
Supported by The Wellcome Trust Grant number 065143/A/01/2.
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There is agreement that pregnancy imposes a stress on the thyroid
which is greater in areas of iodine deficiency. Changes in thyroid function characterized by a fall in TSH and a rise in total and free T4 levels
associated with the rise in hCG are well established. The variation in
assay methodology indicates the necessity of establishing normative
gestational-related reference ranges for thyroid hormones.
Hyperthyroidism in pregnancy, usually due to Graves’ disease, is
uncommon but has deleterious effects on mother and foetus and requires
therapy. Thionamide antithyroid drug therapy (propylthiouracil in the
first trimester then carbimazole/MMI) is the treatment of choice.
Hypothyroidism, usually subclinical, is common and should be
treated with L-thyroxine to reduce obstetric and foetal complications.
Women already receiving thyroxine require an increase in dose during
gestation37 (Table 3).
There is current controversy relating to the validity of free thyroxine
assays in pregnancy as measured by ‘kits’.
Controversy also exists relating to the advisability of screening all
women in early pregnancy for thyroid dysfunction. Current guidelines
recommend a targeted approach38 but studies have demonstrated that
such a strategy may exclude 30 –50% of women with significant
thyroid dysfunction.39,40 As foetal brain development requires adequate
thyroxine delivery to foetal neurones, it seems reasonable to treat
mothers with hypothyroidism with thyroxine to prevent IQ decrement
as well as for obstetric reasons. However, preliminary results from the
recently completed CATS study suggest caution and a degree of uncertainty relating to this approach.
There is a need for more data concerning transfer of thyroid
hormone from mother to foetus. The role of the placenta in this
process is unclear at present. Correction of worldwide iodine deficiency
continues to be required and monitored. Further prospective trials of
screening thyroid function in pregnancy with measurable developmental outcomes are required.
Thyroid function in pregnancy
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