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SUPPLEMENT TO JAPI JANUARY 2011 VOL. 59

Thyroid Disorders in Pregnancy


Samar Banerjee

Introduction

ver the past several years it has been proved that maternal
thyroid disorder influence the outcome of mother and
fetus, during and also after pregnancy. The most frequent
thyroid disorder in pregnancy is maternal hypothyroidism. It is
associated with fetal loss, placental abruptions, pre-eclampsia,
preterm delivery and reduced intellectual function in the
offspring.1 In pregnancy, overt hypothyroidism is seen in 0.2%
cases2 and sub clinical hypothyroidism in 2.3% cases3. Fetal loss,
fetal growth restriction, pre-eclampsia and preterm delivery are
the usual complications of overt hyperthyroidism (low TSH
and high T3, T4) seen in 2 of 1000 pregnancies whereas mild or
sub clinical hyperthyroidism (suppressed TSH alone) is seen in
1.7% of pregnancies and not associated with adverse outcomes4.
Autoimmune positive euthyroid pregnancy shows doubling
of incidence of miscarriage and preterm delivery. Worldwide
more than 20 million people develop neurological sequel due
to intra uterine, iodine deprivation5. Other problems of thyroid
disorders in pregnancy are post partum thyroiditis, thyroid
nodules and cancer, hyper emesis gravidarum etc. Debates and
disputes persist regarding several protocol and management
plan in this specific spectrum of diseases. An attempt is made
hereby to formulate an acceptable and applicable guideline in
the scenario of country, based on evidences and background
knowledge.

Physiology of Thyroid in Pregnancy


T hy ro i d h ormon e s c o n s i s t o f t h y r o x i n (T 4 ) and
triiodothyronine (T3) of which active forms are the free portions
(fT3, fT4) consisting of 1% of total hormones. The fT3 fraction is
biologically more significant and derived from conversion of
fT4 at liver, kidney and muscle. The fT3 hormone acts through
specific nuclear receptors of fT3, situated in most of the tissues.
TSH secreted from anterior pituitary act as negative feedback
from fT3 levels. Dietary iodine is essential for this thyroid
hormone synthesis.
Fetal aspects
In pregnancy, fetus receives
iodine from maternal
source in all
the trimesters. Fetus receives thyroxin from
mother up to 12 weeks through placental circulation but not
TSH or fT3. Thyroxin is partially converted to fT3 and combines
with receptors in fetal brain and responsible for fetal brain
development. From 12th week, placental changes resist T4
passage to fetus and fetal pituitary thyroid axis start functioning
Table 1: Median values of trimester specific thyroid
hormones (rounded to nearest 0.5)
Reference
range used
1st
2nd
3rd
for nonTrimesters Trimesters Trimesters
pregnant
population
fT4 (pmol/L) 9 26
10-16
9 15.5
8 -14.5
fT3 (pmol/L) 2.60 - 5.7
3-7
3 5.5
2.5 5.5
TSH (mu/L) 0.3 4.2
0-5.5
0.5 3.5
0.5 - 4
Professor, Department of Medicine, Vivekananda Institute of Medical
Sciences, Kolkata; Ex Professor and Head Department of Medicine,
In-Charge, Diabetic Clinic, N.R.S. Medical College, Kolkata

like adult.5
Maternal aspects
1.

In pregnancy, half life of Thyroxin Binding Globulin (TBG)


increases from 15min to 3days and concentration becomes
3 times by 20weeks due to the effect of oestrogen driven
glycosylation, which increases the level of T3 and T4
making its estimation non reliable. But fT3 and fT4 remain
unaffected, and are of choice for estimating the thyroid
function during pregnancy.

2. HCG and TSH due to structural similarity produce


hormone spillover syndrome in 1st trimester, manifested
as stimulation of TSH receptors by HCG and biochemical
hyperthyroidism. This is common in multiple pregnancy,
hyper emesis gravidarum and trophoblastic diseases.
Diagnosis of false hyperthyroidism should be avoided in
these cases.
3.

Depletion of iodine can occur due to increased glomerular


filtration and greater thyroidal uptake due to higher T4
concentration. In several maternal iodine deficiency,
compensation if fails can lead to cretinism in the offspring.

4.

Concentration of the enzyme deiodinase III (which converts


T4 to T3 and further breakdown) is increased in placenta
and reduces thyroxin transfer.5

About 2 to 5% of pregnant woman suffer from any variety of


thyroid disorders and timely intervention can be done if detected
early.6 Because of physiological changes values of thyroid
hormones during pregnancy differ from non-pregnant values.
Values in pregnancy also vary from trimester to trimester and
no consensus about this value has been made yet. Coutez C et
al., established the following value as shown in table 1.7
In 2008, Marwaha RK et al, first time presented the trimester
specific thyroid function values in Indian Woman.8 These are
shown in table 2.

Recommendations
Screening: Screening should be with minimum TSH only
and if necessary fT3 and fT4 may be tested. Universal screening
or screening of high risk woman is to be practiced is not yet
settled. Majority is of the opinion, that evidence is insufficient
in favor of routine screening. But the message from the study
of Vaidya et al9 should also be given due consideration, who
commented that most pregnant woman with thyroid disease
would be diagnosed by case finding but at least 30% will remain
undetected. But we will have to wait till the report of Controlled
Antenatal Thyroid screening Study (CATS)10 by John Lazarus,
is completed. This is a prospective randomized study directly
testing the value of screening for thyroid disease and treating
woman with TSH elevations. Probably at present moment we
Table 2: Trimester wise median values of thyroid hormones
in Indian women

fT4 (pmol/L)
fT3 (pmol/L)
TSH (mu/L)

Nonpregnant
normal
valves
3.7 7.2
12.0 23
0.27 42

1st
Trimesters
0.37 6.58
8.04 22
0.04 10.8

2nd
Trimesters

3rd
Trimesters

2.7 7.69
2.93 5.92
9.26 22.12 9.54 27.02
0.026 10.85 0.2 9.55

SUPPLEMENT TO JAPI JANUARY 2011 VOL. 59

would only screen the high group woman who should be tested
definitely are the following.11
Screening of pregnant women
1. History of hypo / hyperthyroidism or thyroid lobectomy
or post partum thyroiditis
2.

Family history of thyroiditis

3. Goiter
4.

Thyroid auto-antibodies

5. Symptoms, signs or biochemical markers suggestive of


thyroid disease
6.

Type 1 diabetes

7.

Other autoimmune disorders

8. Infertility
9.

Previous head or neck irradiation

10. History of miscarriage or preterm delivery


Routine screening in pregnancy and neonates
The problem of thyroid disease in pregnancy is receiving
increasing attention from many scientific concerns. Thyroid
function in pregnancy is characterized by a T4 surge at 12
weeks which declines subsequently. There is a fall in the
serum thyroid hormone concentrations in the second half of
pregnancy. However, data shows that some women may have
thyroid hormone levels within reference ranges even in the
second half of pregnancy. Development of the fetal brain is
dependent on T4 transportation to the fetus, which eventually
depends upon adequate maternal iodine supply. There is current
concern that adequate iodisation is not present in large parts
of India and other countries. A growing amount of evidence
suggests that thyroid autoimmunity is associated with fetal
loss, however, the mechanism remains unclear and carefully
conducted studies are required to elucidate optimal therapy.
The incidence of hyperthyroidism in pregnancy is uncommon,
but effects on both mother and child are critical if untreated.
Substantial evidence also exists which shows that low maternal
T4 (or high TSH) during pregnancy have deleterious effects on
child IQ. Many genetic causes of congenital hypothyroidism
have been elucidated with the advancement of molecular
biology. However, further research is required in order to
elucidate the etiologies of majority of cases, which still remain
unclear. About 10% of pregnant women have TPO antibodies
early during gestation and are at increased risk of developing
subclinical hypothyroidism during pregnancy and thyroid
dysfunction post-partum. The latter condition occurs in 5-9%
of women and 25-30% progress to permanent hypothyroidism.
This review suggests that routine screening for thyroid function
in early pregnancy to detect maternal overt or subclinical
thyroid disorders should be considered but evidence is awaited.
Screening for both thyroid dysfunction and thyroid antibodies
ideally at a preconception clinic but certainly in early gestation is
recommended. Neonates born of mothers with thyroid disorders
must undergo routine thyroid screening.

Guideline for
Treatment of Thyroid Disorders
Hypothyroidism and pregnancy
1. Both maternal and fetal hypothyroidism exert serious
adverse effects on the fetus, so maternal hypothyroidism
should be avoided by early diagnosis at the first prenatal
visit or at diagnosis of pregnancy

33

2. In cases of hypothyroidism diagnosed before pregnancy,


adjust the preconception T4 dose to reach a TSH level not
higher than 2.5m/ml before pregnancy.
3. By 4-6 weeks of gestation, the T4 dosage needs to be
increased by about 30-50%.
4. If overt hypothyroidism is diagnosed during pregnancy,
thyroid function should be normalized as rapidly as
possible. The target is to achieve and maintain TSH
concentrations below 2.5mU/ml in the first trimester (or 3m
U/ml in the second and third trimesters) or to trimesterspecific normal TSH ranges. This can be achieved by rapidly
titrating the T4 dosage to reach and maintain the target TSH
levels. A reassessment of the thyroid function should be
carried out within 30 to 40 days.
5. Women who have thyroid antibodies in the early stages
of their pregnancy but are otherwise euthyroid, should be
monitored for elevations of TSH above the normal range
because they are risk of developing hypothyroidism.
6. Sub clinical hypothyroidism: Recommend T4 replacement
as T4 treatment has been shown to improve obstetrical
outcome, though do not modify long-term neurological
development in the offspring.
7. After delivery, dose of T4 need to be decreased in most
hypothyroid women.11
Maternal hypothyroidism
1. If a below normal serum TSH level is detected,
hyperthyroidism must be distinguished from both
normal physiology during pregnancy and hyperemesis
gravidarum. Presence of autoimmunity, a goiter, and
TRAb can differentiate Graves disease from gestational
thyrotoxicosis.
2.

In cases of frank hyperthyroidism due to Graves disease or


toxic nodules, Anti Thyroid Drug (ATD) therapy should be
either initiated (for those with new diagnoses) or adjusted
(for those with a prior history) to maintain the maternal
thyroid hormone levels for free T4 in the upper nonpregnant
reference range.

3. ATD Propylthiouracil is of choice than methimazole (may


be associated with congenital anomalies), especially during
first-trimester the time for organogenesis.

In case of non-availability of or intolerance to or adverse


events with propylthiouracil, methimazole can be
prescribed.

4.

Subtotal thyroidectomy is indicated in cases of

Severe adverse reaction to ATD therapy,

Persistently high doses of ATD requirement,

Patient noncompliance.

The optimal timing of surgery is in the second trimester.

5.

Pregnant patients with subclinical hyperthyroidism should


not be treated without evidence to show that treatment
improves pregnancy outcome, keeping in mind the potential
of adverse effects on fetal outcome.

6. TRAb (either TSH receptor-stimulating or binding


antibodies) freely cross the placenta and can stimulate the
fetal thyroid. Women with Graves disease or with a history
of Graves disease or treatment with 131I or thyroidectomy,
or with a previous newborn with Graves disease should
undergo measurements of TRAb antibodies either prior to
becoming pregnant or by the end of the second trimester.

34

Women who have a negative TRAb and do not require ATD


have a very low risk of fetal or neonatal thyroid dysfunction.
7.

131
Iodine should be avoided in a woman who is or may be
pregnant. 131I should not be used in a pregnant woman.
However, on inadvertent use, the patient should be
promptly informed about the danger of radiation to the
fetus and about thyroid destruction if the patient has been
treated after the 12th week of gestation. There are no data
for or against recommending termination of pregnancy after
131
Iodine exposure.

SUPPLEMENT TO JAPI JANUARY 2011 VOL. 59

3. Asymptomatic women with PPT who have a TSH above


the reference range but less than 10mU/ml and who are not
planning a subsequent pregnancy do not necessarily require
intervention but should, if untreated, be re-monitored in
48 weeks. Symptomatic women and women with a TSH
above normal and who are attempting pregnancy should
be treated with levothyroxine.
4. Women with postpartum depression should be screened
for hypothyroidism and appropriately treated

Conclusions

8. Pregnant women with TRAb or those treated with ATD


should have a fetal ultrasound to detect fetal thyroid
dysfunction. This may include growth restriction, hydrops,
presence of goiter, and cardiac failure.

Uncontrolled or inadequate control of thyroid dysfunction


in pregnancy is associated with adverse fetal and maternal
outcomes

9. Evaluate newborns of mothers with Graves disease for


thyroid dysfunction and treated if indicated.

Hyperthyroidism in pregnancy requires careful control of


maternal disease whilst avoiding fetal hypothyroidism

Gestational hyperemesis and hyperthyroidism

Propylthiouracil is the preferred antithyroid drug in


pregnancy although methimazole can be used where
propylthiouracil is unavailable

Synthetic levothyroxine is the treatment of choice in


hypothyroidism

Patients with pre-existing hypothyroidism usually require


an increase in thyroxine dose in pregnancy

Universal screening for anti thyroid antibodies and possible


treatment cannot be recommended as there are very few reports
regarding positive association between the presence of thyroid
antibodies and pregnancy loss.

Most patients with postpartum thyroiditis will require


treatment during the hypothyroid phase

Long-term follow-up of patients with this syndrome is


essential owing to the risk of permanent hypothyroidism

Thyroid nodules and cancer

1. Fine-needle aspiration (FNA) cytology, preferably


Ultrasound-guided should be advised if thyroid nodules
larger than 1 cm are detected in pregnancy.

Subclinical hypothyroidism in pregnancy requires


replacement treatment

Excellent maternal and fetal outcomes can be achieved


with appropriate management of thyroid dysfunction in
pregnancy.

1.

Abalovich M, Gutierrex S, Alcaraz G, et al. Overt and subclinical


hypothyroidism complicating pregnancy Thyroid 2002;12:638.

2.

Casey BM, Leveno KJ Thyroid disease in pregnancy. Obstet Gynecol


2006;108:128392.

3.

Biondi B, Cooper DS The clinical significance of subclinical thyroid


dysfunction. Endocr Rev 2008;29:7613 .

4.

Casey BM, Dashe JS, Wells CE, Subclinical hyperthyroidism and


pregnancy outcomes. Obstet Gynecol 2006;107:337341.

5.

Girling J, Thyroid disease in pregnancy. Obstet, Gynec and Reprod


Medicine 2008;18:10.

6.

Glinoer D, Soto MF, Bourdoux P, et al. Pregnancy in patients with


mild thyroid abnormalities: maternal and neonatal repercussions.
J Clin Endocrinol Metab 1991;73:4217.

7.

Cotzias C, Wong SJ, Taylor E et al. A study to establish gestationspecific reference intervals for thyroid function tests in normal
singleton. Eur J Obstet & Gynecol and Reprod Biol 2008;137:616.

8.

Marwaha RK, Chopra S, Gopalakrishnan S et al. Establishment of


reference range for thyroid hormones in normal pregnant Indian
women, BJOG An Int J Obstet and Gynaec 2008;602-6.

9.

Vaidya B, Anthony S, Bilous M et al. Detection of thyroid


dysfunction in early pregnancy: universal screening or targeted
high-risk case finding. J Clin Endocrinol Metab 2007;92:2037.

1. Measure Thyroid function tests in all patients with


hyperemesis gravidarum
2. ATD treatment to be given to overt hyperthyroidism
due to coincident Graves disease and few women with
hyperemesis gravidarum
Autoimmune and thyroid disease and miscarriage

2.

Pregnancy should not be interrupted and surgery should be


offered in the second trimester before fetal viability when
nodules discovered in the first or early second trimester are
malignant. Women found to have cytology indicative of
papillary cancer or follicular neoplasm without evidence of
advanced disease and who prefer to wait until the delivery,
they that can be counseled that most well differentiated
thyroid cancers are slow growing and surgical treatment
soon after delivery is unlikely to adversely affect prognosis.

3. In pregnant women with a previously treated thyroid


cancer, a positive FNA for cancer or suspicion of cancer,
and those who elect to delay surgery until postpartum,
treatment with thyroid hormone to achieve suppressed but
detectable TSH is advisable.
4. 131Iodine should not be given to lactating women. Pregnancy
should be avoided for 6 months to 1 yr in them.
Iodine nutrition during pregnancy
Increase daily iodine intake to 250 mg on average during
pregnancy and breastfeeding by encouraging the use of iodized
salt.
Postpartum thyroiditis (PPT)
1. TSH estimation at 3 and 6 months in women known to be
thyroid peroxidase antibody positive, for women with type
1 diabetes mellitus (PPT 3-fold greater).
2.

Women with a history of PPT have a markedly heightened


risk of developing permanent primary hypothyroidism
within 5 to 10 years, should undergo annual TSH
assessments.

References

10. Brent GA. Diagnosing Thyroid Disease in Pregnant Women J Clin


Endocrinol Metab 2007;92:3941.
11. Abalovich M, Amino N, Barbour LA et al. Green. Management
of Thyroid Dysfunction during Pregnancy and Postpartum: An
Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab
2007;92:S147.