CLINICAL SCIENCE SESSION

HYPERTHYROIDISMS IN PREGNANCY

Compiled by :
Ridha Hayyu Nisa
Nandini Nur Annisa

Penguji :
dr. Bogie Prabowo R, Sp.OG

BAGIAN OBSTETRI DAN GINEKOLOGI

FAKULTAS KEDOKTERAN UNIVERSITAS PADJADJARAN
RSUP DR. HASAN SADIKIN
BANDUNG
2018
 DAFTAR ISI

DAFTAR ISI ........................................................................................................... i

I. INTRODUCTION.......................................................................................... 1

II. EPIDEMIOLOGY ........................................................................................ 2

III. PHYSIOLOGICAL CHANGES OF THYROID FUNCTION DURING

PREGNANCY ................................................................................................ 2

3.1 Hormone Changes ........................................................................................ 2

3.2 Size Changes ................................................................................................. 3

IV. ETIOLOGY AND PATHOGENESIS.......................................................... 3

V. PATHOPHYSIOLGY .................................................................................. 6

5.1 Pregnancy outcome ...................................................................................... 6

5.2 Fetal and neonatal thyroid dysfunction ..................................................... 6

VI. SIGNS AND SYMPTOMS ........................................................................... 8

VII. DIAGNOSIS............................................................................................... 8

VIII. TREATMENT OF HYPERTHYROIDISM IN PREGNANCY ......... 9

8.2 Fetal surveillance ....................................................................................... 12

8.3 Postpartum period ...................................................................................... 13

8.3.1 Breast feeding ............................................................................................. 13

IX. PROGNOSIS ............................................................................................... 14

DAFTAR PUSTAKA .......................................................................................... 15

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I. INTRODUCTION

Pregnancy has a profound impact on the thyroid gland and thyroid

function. The gland increases 10%-40% in size during pregnancy. Production of

thyroxine (T4) and triiodothyronine (T3) increases by 50%. The range of

thyrotropin (TSH), under the impact of placental human chorionic gonadotropin

(hCG), is decreased throughout pregnancy, the level is higher in the first trimester

and reduced along the reduction of beta hCG through the 2nd and 3rd trimester.

Hyperthyroidism most likely happened in pregnant women with hyperemesis

gravidarum1.

Hyperthyroidism occurs in 2/1000 pregnancies in the United Kingdom.

Graves’ hyperthyroidism (defined as hyperthyroidism that is the result of

stimulation of the thyroid by thyrotrophin receptor stimulating antibodies (TRAb))

is the commonest cause of hyperthyroidism in young women (about 85% of cases)

in the United Kingdom. In areas of mild iodine deficiency the prevalence is

higher1,2.

In addition to true hyperthyroidism, the more common clinical entity of

transient gestational hyperthyroidism may be seen particularly in the first

trimester, with a prevalence in Europeans of 2-3% but a much higher prevalence

in South Asian populations. Hyperthyroidism does not often arise for the first time

in early pregnancy1.

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 II. EPIDEMIOLOGY

Mestmann JH in his study said that the prevalence of hyperthyroidism in

pregnancy is about 0.2% and the most common cause is Graves' disease. This

study is along with the study done by ATA which said the prevalence of

hyperthyroidism in pregnancy in USA is 0,1-0,4% with the common etiology is

grave disease. Globally hyperthyroidism happens ini 0,05-3% in all pregnancies

over the world2,3.

III. PHYSIOLOGICAL CHANGES OF THYROID FUNCTION

DURING PREGNANCY

3.1 Hormone Changes

A normal pregnancy results in a number of important physiological and

hormonal changes that alter thyroid function. Thyroid function tests change

during pregnancy due to the influence of two main hormones: human chorionic

gonadotropin (hCG) and estrogen. HCG can weakly turn on the thyroid and the

high circulating hCG levels in the first trimester may result in a slightly low TSH

(called subclinical hyperthyroidism). When this occurs, the TSH will be slightly

decreased in the first trimester and then return to normal throughout the duration

of pregnancy1.

Estrogen increases the amount of thyroid hormone binding proteins in the

serum which increases the total thyroid hormone levels in the blood since >99%

of the thyroid hormones in the blood are bound to these proteins. However,

measurements of “Free” hormone (that not bound to protein, representing the

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active form of the hormone) usually remain normal. The thyroid is functioning

normally if the TSH, Free T4 and Free T3 are all normal throughout pregnancy.

3.2 Size Changes

The thyroid gland can increase in size during pregnancy (enlarged thyroid

= goiter). However, pregnancy-associated goiters occur much more frequently in

iodine-deficient areas of the world. It is relatively uncommon in the United States,

which is thought to be relatively iodine-sufficient. If very sensitive imaging

techniques (ultrasound) are used, it is possible to detect an increase in thyroid

volume in some women. This is usually only a 10-15% increase in size and is not

typically apparent on physical examination by the physician. However, sometimes

a significant goiter may develop and prompt the doctor to measure tests of thyroid

function.

IV. ETIOLOGY AND PATHOGENESIS

Overall, the most common cause (80-85%) of maternal hyperthyroidism

during pregnancy is Graves’ disease and occurs in 1 in 1500 pregnant patients

(website).

Graves’ disease is an autoimmune disease that leads to a generalized

overactivity of the entire thyroid gland. Graves’ disease is triggered by a process

in the body’s immune system. Sometimes the immune system can be tricked into

making antibodies that cross-react with proteins on our own cells. In many cases

these antibodies can cause destruction of those cells. In Graves’ disease these

antibodies (called the thyrotropin receptor antibodies (TRAb) or thyroid

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stimulating immunoglobulins (TSI) do the opposite – they cause the cells to work

overtime. The antibodies in Graves’ disease bind to receptors on the surface of

thyroid cells and stimulate those cells to overproduce and release thyroid

hormones. This results in an overactive thyroid (hyperthyroidism)1–3.

In addition to other usual causes of hyperthyroidism (box 1) (jurnal bmj),

very high levels of hCG, seen in severe forms of morning sickness (hyperemesis

gravidarum), may cause transient hyperthyroidism. During pregnancy, the

hormone HCG (human chorionic gonadotropin) is produced. hCG can act like

TSH and crank up the function of the thyroid gland. Beta hCG can cause

hyperthyroidism because the molecular structure of these two hormones. As it

turns out, hCG and TSH are rather similar to each other. Both are composed of

two different protein subunits. One of those protein subunits is called "alpha" and

the other "beta." The alpha subunits of hCG and TSH are identical but the beta

subunits are a different; but not by much. The beta subunits of hCG and TSH are

about 40 percent identical. When present a very high concentrations, such as in

situations of multiple pregnancies (twins, triplets) HCG levels are even higher,

and symptoms can be more pronounced. Temporary subclinical (no apparent

symptoms) hyperthyroidism occurs in 10-20% of normal pregnant women during

this period, and these women typically do not require treatment. hCG can actually

stimulate the thyroid gland sending it a message to go into over-drive. In other

words, hCG can sometimes act like TSH. Fortunately, this doesn't happen unless

the amount of hCG in the blood gets to be very, very elevated. In one study an

hCG threshold of 400,ooo IU/L was identified as the concentration above which

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actual symptoms of hyperthyroidism could occur. The lower hCG concentration

of 200,000 IU/L was identified as the threshold above which a majority of women

demonstrated biochemical signs of hyperthyroidism (i.e. decreased TSH) but they

did not have actual symptoms of hyperthyroidism until the hCG increased to twice

that amount1,2,4.

In addition to other usual causes of hyperthyroidism

Tabel 1. Causes of Hyperthyroidism in pregnancy

The diagnosis of hyperthyroidism can be somewhat difficult during

pregnancy, as 123I thyroid scanning is contraindicated during pregnancy due to

the small amount of radioactivity, which can be concentrated by the baby’s

thyroid. Consequently, diagnosis is based on a careful history, physical exam and

laboratory testing.

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V. PATHOPHYSIOLGY

5.1 Pregnancy outcome

Pre-eclampsia, heart failure, fetal loss, premature labour, and having a low

birthweight baby are more likely to occur in untreated or poorly controlled

thyrotoxic women than in those receiving adequate treatment. A retrospective

review of 11 reports documented a 5.6% incidence of fetal death or stillbirth in

249 pregnancies and a further 5% incidence of fetal and neonatal abnormalities. A

study of 60 cases of hyperthyroidism in pregnancy over a 12 year period found

that metabolic status at delivery correlated with pregnancy outcome.Preterm

delivery, perinatal mortality, and maternal heart failure were more common in

women who remained thyrotoxic despite treatment or whose hyperthyroidism was

first diagnosed during pregnancy.

Women with thyroid hormone resistance (where thyroid hormone and

thyrotrophin concentrations are inappropriately high—that is, not due to

autoimmunity) also have a high miscarriage rate, indicating a direct toxic effect of

thyroid hormones on the fetus.

5.2 Fetal and neonatal thyroid dysfunction

Improvement of Graves’ hyperthyroidism during a woman’s pregnancy is

often associated with a reduction in the titre of maternal serum TRAb

concentrations and a change from stimulatory to blocking antibodies. If antibodies

do not decline they will cross the placenta and stimulate the fetal thyroid,

evidenced by signs of fetal hyperthyroidism such as tachycardia, intrauterine

growth retardation, cardiac failure, and the development of fetal goitre.

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 Of the babies born to women with Graves' disease, about 1% will have

hyperthyroidism at birth. The cause is the transfer of antibodies that stimulate the

TSH receptor across the placenta to the baby. These antibodies then stimulate the

baby's thyroid gland. These antibodies should be measured in the mother during

her second trimester of pregnancy, because values that are greater than five times

normal have been associated with hyperthyroidism in the baby at birth. Before the

baby is born, a high fetal heart rate (greater than 160 beats/min), a goiter in the

fetus noted during ultrasound, poor growth, and bony abnormalities are

indications of hyperthyroidism in the baby.

One to five percent of neonates of mothers with Graves’ disease have

hyperthyroidism as a result of the transplacental passage of maternal TRAb

concentrations. Presentation of neonatal hyperthyroidism may be delayed as

antithyroid drugs administered to the mother are cleared more rapidly from the

fetal circulation than maternal stimulating antibodies.

Maternal euthyroidism is particularly important in the later stages of

pregnancy, as poorly controlled hyperthyroidism can lead to suppression of the

fetal pituitary thyroid axis resulting from placental transfer of thyroxine. A case-

control study noted a low thyrotrophin concentration with a thyrotrophin releasing

hormone test, and low serum thyroxine concentration in a group of neonates

whose mothers had had poorly controlled hyperthyroidism in the third trimester of

pregnancy. The condition may last up to six months.

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VI. SIGNS AND SYMPTOMS

Symptoms of hyperthyroidism may mimic those of normal pregnancy,

such as an increased heart rate, sensitivity to hot temperatures, and fatigue. Other

symptoms of hyperthyroidism include the following:

 Irregular heartbeat

 Nervousness

 Severe nausea or vomiting

 Slight tremor

 Trouble sleeping

 Weight loss or low weight gain for a typical pregnancy

VII. DIAGNOSIS

History Taking

 Anxiety

 Irritability or moodiness

 Nervousness, hyperactivity

 Sweating or sensitivity to high temperatures

 Hand trembling (shaking)

 Hair loss

Physical Examination

• Heart rate : tachycardia

• Irregular heartbeat

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Laboratory Test

• high levels of thyroid hormones, T3 and T4 (the gold standard is using

quilibrium dialysis coupled with mass spectrometry)

• low level of thyroid stimulating hormone (TSH)

Radiologic Examination

• USG

• Mass

VIII. TREATMENT OF HYPERTHYROIDISM IN PREGNANCY

a. Patients already treated for hyperthyroidism caused by Graves’

disease

Although patients who have already been treated for hyperthyroidismmay

have received antithyroid drugs, had surgery, or had radioiodine therapy and be

euthyroid (whether receiving thyroxine or not), neonatal hyperthyroidism may

still occur. TRAb concentration should be measured early in pregnancy in a

euthyroid pregnant women who has previously had surgery or radioiodine

therapy. If the concentration is high at this time, the fetus should be evaluated

carefully during gestation (with serial ultrasonography) and the antibodies

measured again in the third trimester. If the TRAb concentration is high at 36

weeks, the neonate needs to be checked for hyperthyroidism after delivery.

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The main elements in managing hyperthyroidism in a pregnant woman :

Tabel 2. Management of hyperthyroidism in pregnancy

At all stages of pregnancy antithyroid drugs are the preferred treatment

Tabel 3. Drugs used in hyperthyroidism

Radioiodine is contraindicated because of fetal radiation risk. Surgery

requires pretreatment with antithyroid drugs to render the patient euthyroid. The

thionamides carbimazole, methimazole (the metabolite of carbimazole), and

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propylthiouracil are all effective in inhibiting thyroidal biosynthesis of thyroxine

during pregnancy. Propylthiouracil is the preferred drug in pregnancy as

carbimazole and methimazole are (albeit rarely) associated with teratogenic

effects. An early study also reported less placental transfer of propylthiouracil

than of methimazole, but results of a more recent study measuring

propylthiouracil and methimazole concentrations and examining placental

perfusion in vitro have not shown any advantage for propylthiouracil in relation to

placental transport. This use of propylthiouracil as the initial preferred drug for

maternal hyperthyroidism is an expert consensus recommendation of the

Endocrine Society.

The starting dose of propylthiouracil is relatively high, 300-450 mg a day,

up to 600 mg daily if necessary, given in two to three divided doses. Some

improvement is usually seen after one week of treatment with antithyroid drugs,

but four to six weeks may be needed for a full effect. Once the hyperthyroidism

has been controlled, the dose needs to be gradually reduced by a quarter to a third

every three to four weeks, typically to 50-100 mg twice daily.

The main principle of treatment is to administer the lowest dose of

antithyroid drugs needed for controlling clinical symptoms, with the aim of

restoring normal maternal thyroid function but ensuring that fetal thyroid function

is minimally affected.

The administration of levothyroxine together with propylthiouracil as a

“block and replace” regimen is not advisable in pregnancy as the amount of

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antithyroid drug may be excessive in proportion to the amount of thyroxine that

crosses the placenta, resulting in fetal goitre and hypothyroidism.

No consensus has been reached on the duration of antithyroid drug

treatment during pregnancy as no good level of evidence exists. Some authorities

suggest stopping the drug in the third trimester or after four to 12 weeks of

treatment with subsequent close monitoring.

Medications to slow the mother's heart rate down may also be necessary.

The class of drugs recommended is called beta-blockers (metoprolol, propranolol)

may be used for a few weeks to ameliorate the peripheral sympathomimetic

actions of excess thyroid hormone. While these drugs are not thought to be

dangerous to the fetus (teratogenic), there have been associations with growth

retardation, but prolonged use can result in restricted fetal growth, impaired

response to hypoxic stress, postnatal bradycardia, respiratpry problems and

hypoglycaemia.

Since radiation therapy is not safe for the baby in pregnancy, surgery may

be the only other option for women who cannot tolerate medicine treatments.

Surgery itself is associated with an increased risk of premature delivery and

spontaneous abortion (miscarriage).

8.2 Fetal surveillance

Because of the risk of fetal thyroid dysfunction in women with raised

TRAb concentration or those taking antithyroid drugs, serial ultrasound scans of

the fetus should be performed. Ultrasound evidence of fetal thyroid disease

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includes intrauterine growth restriction, tachycardia, cardiac failure, hydrops,

advanced bone age, and goitre. If fetal hyperthyroidism is diagnosed, treatment

involves modulation of maternal antithyroid drugs. If fetal hypothyroidism has

resulted from administration of antithyroid drugs to the mother, this treatment

should be decreased or stopped and administration of intra-amniotic thyroxine

considered. Early delivery may need to be considered in the case of fetal thyroid

dysfunction, depending on the gestation at diagnosis and the severity of fetal

symptoms.

8.3 Postpartum period

8.3.1 Breast feeding

Propylthiouracil and methimazole are secreted in human milk, however,

only limited quantities of propylthiouracil and carbimazole are now knownto be

concentrated into milk. As long as the doses of methimazole or propylthiouracil

can be kept moderate (propylthiouracil <250-300 mg a day, methimazole <20 mg

a day), the risk for the infant is negligible, and no evidence based argument exists

to advise mothers against breast feeding when they take an antithyroid drug. It is

prudent to monitor periodically the infant’s thyroid function while the mother is

taking antithyroid drugs, although a recent reassuring study showed that thyroid

function in breastfed infants was not affected, even when antithyroid drugs

induced maternal hypothyroidism.

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IX. PROGNOSIS

Although untreated hyperthyroidism has potentially serious adverse effects

on the mother and fetus, when treated promptly and monitored appropriately, the

outcome for mother and fetus can be excellent.

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 DAFTAR PUSTAKA

1. Stagnaro-green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro

R, et al. Guidelines of the American Thyroid Association for the Diagnosis

and Management of Thyroid Disease. 2011;21(10).

2. Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy.

2008;336(March):663–7.

3. Pearce EN, Brent GA, Alexander EK, Brown RS, Chen H, Dosiou C, et al.

2017 Guidelines of the American Thyroid Association. 2017;27(3).

4. Ruchi Mathur MD. Hyperthyroidism and Pregnancy.

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