Transcript Thyroid Disease in Pregnancy

Hyperthyroid in Pregnancy
Dr. n mohammadi
Fellowship of fetal medicine
Normal physiology
• The hypothalamic pituitary axis
• Thyrotropin-releasing hormone (TRH)
– Produced in a tonic fashion in the paraventricular
nucleus of the hypothalamus.
• TSH has an α and β subunit;β subunit confers
specificity.
• TSH secretion regulated by negative feedback
from circulating thyroid hormone, dopamine, and
somatostatin.
• TSH then stimulates the thyroid gland to
produce, as well as secrete, thyroxine(T4) and
triiodothyronine (T3).
Physiologic adaptation during pregnancy
• increase in thyroid-binding globulin
– secondary to an estrogenic stimulation of TBG
synthesis and reduced hepatic clearance of TBG ;two
to threefold
– levels of bound proteins, total thyroxine, and total
triiodothyronine are increased and resin
triiodothyronine uptake (RT3U) is decreased
– begins early in the first trimester, plateaus during
midgestation, and persists until shortly after delivery
– decrease in its hepatic clearance,estrogen-induced
sialylation
• free T4 and T3 increase slightly during the first trimester
in response to elevated hCG. decline to nadir in third
trimester
• human chorionic gonadotropin (hCG)
– intrinsic thyrotropic activity
– begins shortly after conception, peaks around
gestational week 10,declines to a nadir by about
week 20
– directly activate the TSH receptor
– partial inhibition of the pituitary gland (by crossreactivity of the α subunit)
• transient decrease in TSH between Weeks 8 and 14
• mirrors the peak in hCG concentrations
– 20% of normal women, TSH levels decrease to less
than the lower limit of normal
TSH
hCG
• A decrease in basal TSH of 0.1 mU/L was
observed for every 10,000 IU/L increment in
hCG
• reduction in plasma iodide
– fetal :monodeiodinase types II and III in the placenta
– increased maternal glomerular filtration rate-increased renal clearance of iodide throughout
pregnancy
• transplacental passage of T4 and iodide and
placental metabolism of iodothyronines
– stimulate the maternal thyroid ; depleting the maternal
circulation of thyroid hormone and its precursors
EFFECTS OF PREGNANCY ON THYROID
PHYSIOLOGY
Physiologic Change
Thyroid-Related Consequences
↑ Serum thyroxine-binding globulin
↑ Total T4 and T3; ↑ T4 production
↑ Plasma volume
↑ T4 and T3 pool size; ↑ T4
production; ↑ cardiac output
D3 expression in placenta and (?) uterus
↑ T4 production
First trimester ↑ in hCG
↑ Free T4; ↓ basal thyrotropin; ↑ T4
production
↑ Renal I- clearance
↑ Iodine requirements
↑ T4 production; fetal T4 synthesis during
second and third trimesters
↑ Oxygen consumption by fetoplacental
unit, gravid uterus, and mother
↑ Basal metabolic rate; ↑ cardiac
output
Screening for Thyroid Disease in Pregnancy
A 24-year-old woman was just diagnosed with
her first pregnancy. She enjoys good general
health. There is no h/o thyroid disease or Rx.
Q: Should she have screening TFT?
Thyroid 21:1081-1125, 2011
Screening for Thyroid Disease in Pregnancy
Although the benefits of universal screening for thyroid
dysfunction may not be justified at this time, selected
screening for the following should be done:
• Positive FHx
• Other autoimmune
thyroid disease
disease
• Goiter
• TPOAb+
• Symptoms
• Type 1 DM
• Miscarriage
Thyroid 2011
• Infertility
• Morbid obesity
• >30 years
TSH in Pregnancy
A 28-year-old woman who is 6 weeks
pregnant has a routine serum TSH
level of 4.1 mIU/L & FT4 1.3 ng/dL
Q: Is this TSH normal?
Guidelines for Serum TSH During Pregnancy
• Recommendation 1
Trimester-specific reference ranges for TSH, as
defined in populations with optimal iodine intake,
should be applied
• Recommendation 2
If trimester-specific reference ranges for TSH
are not available in the laboratory, the following
references ranges are recommend:
1st trimester, 0.1-2.5 mIU/L; 2nd trimester,
0.2-3.0 mIU/L; 3rd trimester, 0.3-3.0 mIU/L
Hyperthyroidism and pregnancy
• 0.2% of pregnancies
• prevalence 0.1% to 0.4%, with 85% Graves’
disease
– Single toxic adenoma, multinodular toxic goiter, and
subacute thyroiditis
– gestational trophoblastic disease,viral thyroiditis and
tumors of the pituitary gland or ovary (struma ovarii)
• TSH is depressed and fT4 and fT3 are
increased.
• The RT3U that normally is decreased in
pregnancy is increased in hyperthyroidism.
Hyperthyroidism and pregnancy
• serum TSH value <0.01 mU/L and also a high
serum free T4 value
• may be difficult to determine the cause
– thyroid radionuclide imaging is contraindicated in pregnant
women.
• Measurement of thyrotropin receptor antibody (thyroid
stimulating immunoglobulins)  Graves' disease during
pregnancy
• transient hyperthyroidism in hyperemesis gravidarum
and gestational transient thyrotoxicity (GTT)
Causes of Low TSH in Pregnancy
Trimester
1
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3
High hCG
Gestational Transient Thyrotoxicosis
Graves’ Hyperthyroidism
Subacute thyroiditis
Toxic adenomatous goitre
Toxic Multinodular goitre
Nodular goitre
Mutant TSH Receptor
Molar pregnancy
TSH assay error
Factitious (eg T4 addiction)
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Hyperthyroid manifestations
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Nonspecific symptoms;
_Tachycardia
_Heat intolerance
_Increased perspiration
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Additional symptoms:
_Anxiety
_Hand tremor
_Weigh loss despite a normal or increased
appetite
Specific findings:
• Goiter
• ophthalmopathy
Hyperthyroidism and pregnancy
• Severe maternal hyperthyroidism
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increased risk of stillbirth
preterm delivery
intrauterine growth restriction
Preeclampsia
heart failure
spontaneous abortion
Fetal thyroid hyperfunction or hypofunction caused by
TSHRAbs
Fetal goiter from excessive antithyroid drug treatment
Neonatal thyrotoxicosis
Increased perinatal and maternal mortality
Decreased IQ of offspring because of excessive use
of antithyroid drugs
Transient hyperthyroidism during pregnancy &
gestational transient thyrotoxicity (GTT)
• hyperemesis gravidarum
– severe nausea and vomiting leading to a 5% loss of body weight,
dehydration, and ketosis.
– absence of goiter and ophthalmopathy, and absence of the common
symptoms and signs of hyperthyroidism
– higher serum hCG and estradiol concentrations
– 60% have a subnormal serum TSH level (< 0.4 mU/L),50% have
an elevated serum free T4 concentration
– Severity positively correlated with maternal free T4 levels but not
to thyroid function.
• 12% elevated free T3 index
– believed to be related to hCG stimulation of the thyroid gland
– Normalization of T4 levels by midgestation.
– Treatment is supportive care
• GTT
– first trimester
– related to hCG stimulation of the thyroid gland
– symptoms of hyperthyroidism and elevated free T4
levels.
– The thyroid gland usually is not enlarged
– resolution of symptoms parallels the decline in hCG
levels
– usually resolves spontaneously by 20 weeks’
gestation
– beyond 20 weeks,repeat evaluation for other causes
Trophoblastic hyperthyroidism
• hydatidiform mole (molar pregnancy) &
choriocarcinoma.
– high serum hCG concentrations and abnormal hCG
isoforms
• 55 to 60 percent had clinically evident
hyperthyroidism
• normal thyroid gland and few symptoms of
thyroid hormone excess.
• some :findings of hyperthyroidism and a diffuse
goiter
– ophthalmopathy is not present
• Nausea and vomiting may predominate
Trophoblastic hyperthyroidisem
• Women with symtomatic moderate to
severe hyperthyroidisem due to
trophoblastic diseases require treatment.
• This include women with total T4 and total
T3> 1.5 times the upper limit of
nonpregnant women, require antithyroid
therapy.
subclinical hyperthyroidism
• Low TSH and normal free T4.
• associated with osteoporosis
cardiovascular morbidity, and progression
to overt thyrotoxicosis and thyroid failure.
• not associated with adverse pregnancy
outcomes
• does not warrant treatment.
Graves’ disease
• 95% of thyrotoxicosis during pregnancy.
• activity level fluctuate during gestation, with
– exacerbation during the first trimester
– gradual improvement during the latter half.
– exacerbation shortly after delivery
• clinical scenarios.
– stable Graves’ disease receiving thionamide therapy
with exacerbation during early pregnancy.
– in remission with a relapse of disease.
– without prior history diagnosed with Graves’ disease
de novo during pregnancy.
Graves’ disease
• Diagnosis
– difficult :hypermetabolic symptoms in normal
pregnancy
– thyroid examination: goiter (with or without bruit)
– suppressed serum TSH level and usually elevated
free and total T4 serum concentrations.
– TSH receptor antibodi
• autoantibodies mimic TSH can cross the
placenta and cause neonatal Graves’ disease
Graves’ disease
• Pregnancy outcome
• preterm labor
– untreated (88%)/partially treated(25%) /adequately treated (8%) [
• preeclampsia
– untreated twice
• stillbirth
– untreated (50%) /partially treated (16%) /adequately treated (0%)
• small for gestational age
• congenital malformations unrelated to thionamide therapy
• Mother may have thyroid-stimulating hormone-binding inhibitory
immunoglobulin (TBII),
– cause transient neonatal hypothyroidism
– fetal bradycardia, goiter,and growth restriction
Graves’ disease
• Neonatal thyrotoxicosis :
– 1% of infants
– occur in euthyroid mother or has had surgical or
radioactive 131I treatments before pregnancy
– fetal ultrasound to exclude evidence of fetal
thyrotoxicosis (eg, an anterior fetal neck mass) or
fetal tachycardia.
– fetal goiter, advanced bone age, poor growth, and
craniosynostosis, Cardiac failure and hydrops
– Fetal blood sampling — Fetal blood for thyroid
function tests by percutaneous umbilical vein
sampling after 20 weeks of gestation
• High maternal TSH receptor-stimulating antibody levels Fetal
signs suggestive of thyroid disease History of a prior baby
with hyperthyroidism
Thyroid storm
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obstetric emergency
extreme metabolic state
10% of pregnant women with hyperthyroidism
high risk of maternal cardiac failure.
fever, change in mental status, seizures, nausea,
diarrhea, and cardiac arrhythmias.
• inciting event (eg, infection, surgery, labor/delivery) and
a source of infection
• treatment immediately, even if serum free T4, free T3,
and TSH levels are not known.
• untreated thyroid storm can be shock, stupor, and coma.
Guidelines for clinical management of maternal
hyperthyroidism during pregnancy
• 1. Use the lowest dosage of thionamide
(preferably PTU) to maintain maternal total T4
concentrations in the upper one third of normal
to slightly elevated range for pregnancy.
– Normal range of total T4 during pregnancy is
estimated to be 1.5 times the nonpregnant state
• 2. Monitor maternal total T4 serum concentration
every 2–4 weeks, and titrate thionamide as
necessary.
– Monitoring serum TSH may become useful later.
Guidelines for clinical management of maternal
hyperthyroidism during pregnancy
• 3. Measure TSH receptor antibodies (thyroidstimulating immunoglobulins or TSH receptor
binding inhibitory immunoglobulins) at 26–28
weeks to assess risk of fetal/neonatal
hyperthyroidism.
– TSH receptor antibody measurement is crucial in
hypothyroid levothyroxine-treated women with a prior
history of Graves’ disease, who do not appear
thyrotoxic.
• 4. Perform fetal ultrasound at weeks 26–28 to
assess potential fetal response to thionamide
treatment and effect of TSH receptor antibodies
on fetal thyroid function
Treatment
• Thionamides
• propylthiouracil (PTU) and methimazole(MMI)
• Both cross the placenta with equal transfer
kinetics.
• Both can cause fetal goiter and hypothyroidism,
usually mild and transient & dose-dependent
• median time to normalization of maternal thyroid
function
– 7 weeks with PTU and 8 weeks with MMI
• PTU more highly bound to albumin
– theorize that MMI crosses the placenta in higher
concentrations
Treatment
• Thionamides
• maternal :rash
• rare birth defects in MMI: aplasia cutis, choanal
atresia,esophageal atresia, and minor dysmorphic
features
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Low thyroid function at birth ½ neonates whose mothers received PTU or
MMI and had serum T4 concentrations within the normal (non-pregnant)
range
– normal IQ scores
• Graves’ disease may ameliorate
– thionamide discontinued in 30% during the final weeks
– fall in serum TSH receptor-stimulating antibody concentrations and a
rise in TSH receptor-blocking antibodies.
• Graves' hyperthyroidism can worsen postpartum
• do not recommend the use of T4 with thionamide therapy during
pregnancy.
Treatment
• β-Adrenergic blockers
• weaned as soon as the hyperthyroidism is controlled
• occasional cases of neonatal growth restriction,
hypoglycemia, respiratory depression, and bradycardia
• increased frequency of first-trimester miscarriages
• avoiding in the first trimester
• Iodides
• past reports of neonatal hypothyroidism after exposure
to iodine
• low-dose potassium iodide may be considered
– Preparation for thyroidectomy
– thionamide-intolerant patients refusing surgery.
Treatment
• Surgery
• Subtotal thyroidectomy :
– persistently high dosages of thionamides (PTU > 600 mg/d, MMI > 40
mg/d) are required to control maternal disease
– allergic or intolerant of both thionamides
– noncompliant with medical therapy
– compressive symptoms
• second trimester, before gestational week 24
• prepared with a β-adrenergic blocking agent and a 10- to 14-day
course of potassium iodide
Treatment
• Radioactive iodine therapy
• contraindicated
• fetal thyroid gland begins to concentrate iodine after
gestational week 10, Fetal thyroid tissue is present by 10
to 12 weeks
– predisposing to congenital hypothyroidism
• Nursing
• Breast feeding in mothers taking PTU or MMI is safe
• Thyroid function in newborn infants is unaffected
• PTU is preferred because it is less concentrated in
breast milk
Up to date_ATA
• Suggest that PTU use be limited to first
trimester only.
• In the second trimester,switching from
PTU to MMI
• Initial lowest dose: PTU 50 mg two or
three times daily and MMI 5 to 10 mg
daily.
PTU associated liver failure:
• Sudden onset- rapidly progressive
• Routine monitoring of LFT is not
recommended.
• Malaise weakness nausea vomiting
jundice dark urine light-colored stools.
A 32-year-old woman pregnant 10 weeks
presents with nausea, vomiting, and a 2 kg
weight loss; her first pregnancy 2 years
earlier was uncomplicated
On exam she is dehydrated, euthyroid,
without a goiter and has normal eyes
TSH 0.01 (<2.5)
FT4 2.1 (0.8-1.8)
FT4I 20 (5-12)
Hyperthyroidism & Pregnancy
Conclusions
• Hyperemesis gravidarum is HCG-induced,
reversible, and dosent requires ATD.
• Measure TSH receptor Ab (TRAb),TBII assay
• and TOTAL T3 to distinguish from Graves’
disease.
Hyperthyroidism & Pregnancy
• Recommendation 22
When serum TSH is suppressed (<0.1) in
the 1st trimester, FT4 should be obtained;
TT3 & TRAb may also be helpful
• Recommendation 26
ATDs are not recommended for Rx of
gestational hyperthyroidism
Hyperthyroidism & Pregnancy
A 32-year-old woman is 8 weeks pregnant;
she reports palpitations, anxiety, heat
intolerance and an 8 lb weight loss for 6
months
On exam she is nervous, slightly
hyperthyroid, has lid lag, and thyroid is x2
enlarged
TSH 0.01
FT4 2.8
FT4I 16 (5-12)
Postpartum thyroid disease
• Postpartum thyroiditis
– Dx: documenting abnormal TSH (elevated or
suppressed) levels during the first year postpartum in
the absence of positive TSI or a toxic nodule
– hypo- or hyperthyroidism
– classic presentation :
– transient hyperthyroid phase that occurs 6 weeks to 6
months postpartum
– followed by a hypothyroid phase that lasts for up to 1
year postpartum
Postpartum thyroiditis
• autoimmune disorder with a self-limited hyperthyroid phase
• within one year after parturition.
• Presentations
– Transient hyperthyroidism alone
– Transient hypothyroidism alone
– Transient hyperthyroidism followed by hypothyroidism
and then recovery.
• can also occur after spontaneous or induced
abortion
• 3 to 16 percent
– higher, up to 25 percent, in women with type 1 diabetes mellitus
,and in women with positive antithyroid antibodies (normal
thyroid function)
Postpartum thyroiditis
• like painless thyroiditis
– variant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis).
• high serum concentrations of anti-peroxidase antibodies
• many eventually become hypothyroid or have a goiter
• high serum antithyroid antibody concentrations early in pregnancy
– decline later (as immunologic tolerance increases during pregnancy)
– rise again after delivery
• subclinical thyroid autoimmune disease early in pregnancy and soon
after
• Progression to permanent hypothyroidism
– related to higher TSH concentrations and the antiperoxidase antibody
titer
– maternal age and female sex of the infant
• Postpartum thyroiditis is likely to recur after subsequent pregnancies
• distinguished from Graves' hyperthyroidism,
– hyperthyroidism in postpartum thyroiditis is usually
mild (both clinically and biochemically),
– thyroid enlargement is minimal
– Graves' ophthalmopathy is absent.
– by reevaluation in three to four weeks: postpartum
thyroiditis improved
• lymphocytic hypophysitis,
– TSH normal or low, low free T4
– postpartum thyroiditis, TSH elevated with decreased
FT4.
Postpartum thyroiditis
• antithyroids :no role.
• Hypothyroid :may require treatment and some
• significant rate of residual hypothyroidism
– Recommend:maintain thyroxine until childbearing is complete,
with an attempt to wean off medication 1 year after the last
delivery
• Postpartum--signs/symptoms of thyroid dysfunction
– symptoms mimic normal postpartum changes
• TSH, free T4, and antithyroid antibodies levels
• postpartum depression and postpartum thyroiditis
Postpartum Graves’ disease
• 60% Graves’ disease in the reproductive
years; postpartum onset
• euthyroid patients with Graves’ disease
with TSI
– increased risk of developing recurrent Graves’
disease if antithyroid medication was withheld
• TSIs differentiate postpartum Graves’
disease from postpartum thyroiditis with a
hyperthyroid component.
Thyroid cancer
• Thyroid tumors ;most common endocrine neoplasms.
• thyroid cancer accounts for 1% of all cancers. ¾ women; 1/2
reproductive years.
• biopsy ,Serum TSH and free T4 levels,ultrasonography & Fine
needle aspiration
• Radionucleotide scanning is contraindicated during pregnancy
• malignant or suspicious for papillary cancer, surgery at the earliest
safe period
• no evidence that pregnancy causes a reactivation of thyroid cancer
or that exposure to radioactive iodine poses a risk to future
pregnancies
• maintained on thyroid replacement therapy with monitoring of TSH
and free T4 levels every 8 weeks.
Euthyroidism with autoimmune
thyroid disease
• increased risk for spontaneous
miscarriage, subclinical hypothyroidism,
and postpartum thyroiditis
• Increase in serum TSH levels
– most normal
• presence of antithyroid antibodies
– lack of thyroidal reserve in response to the
stimulatory effects of pregnancy.
Euthyroidism with autoimmune
thyroid disease
• recommend initiating levothyroxine therapy in
women with antithyroid antibodies
– before pregnancy
– TSH level greater than 2.5 mU/L.
• Serum TSH should be monitored throughout
pregnancy in all antithyroid antibody–positive
women
• maintain the TSH concentration at 2.5 mU/L or
less.
CLINICAL PRACTICE GUIDELINE
Management of Thyroid Dysfunction during Pregnancy
and Postpartum: An Endocrine Society Clinical
Practice Guideline
• 1. HYPOTHYROIDISM AND PREGNANCY: MATERNAL
• AND FETAL ASPECTS
• 1.1.1. maternal hypothyroidism should be avoided.Targeted case
finding is recommended at the first prenatalvisit or at diagnosis of
pregnancy
• 1.1.2. If hypothyroidism diagnosed before pregnancy, adjust
preconception T4 dose to reach a TSH ≤2.5 U/ml before pregnancy.
• 1.1.3. T4 dose incremented by 4–6 wk gestation and 30–50%
increase in dosage.
• 1.1.4. If overt hypothyroidism is diagnosed during pregnancy, thyroid
function tests should be normalized as rapidly as possible.
– The T4 dosage should be titrated to rapidly ,maintain serum TSH ≤ 2.5
U/ml in the first trimester (or 3 U/ml in the second and third trimesters)
or to trimester-specific normal TSH ranges.
– Thyroid function tests remeasured within 30–40 d.
• 1.1.5. Women with thyroid autoimmunity who are
euthyroid in the early stages of pregnancy are at risk of
developing hypothyroidism and should be monitored for
elevation of TSH above the normal range
• 1.1.6. Subclinical hypothyroidism ;associated with an
• adverse outcome for both the mother and offspring.
– T4 treatment - improve obstetrical outcome but has not been
proved to modify long-term neurological development in the
offspring.
– Recommends T4 replacement in women with subclinical
hypothyroidism.
• 1.1.7. After delivery, most hypothyroid women need a
• decrease in the T4 dosage they received during
pregnancy
• 3. GESTATIONAL HYPEREMESIS AND
HYPERTHYROIDISM
• 3.1. Thyroid function tests should be measured in all
patients with hyperemesis gravidarum (5% weight loss,
dehydration, and ketonuria)
• 3.2. Few women with hyperemesis gravidarum will
require ATD treatment.
• Overt hyperthyroidism believed due to coincident
Graves’ disease should be treated with ATD.
• Gestational hyperthyroidism with clearly elevated thyroid
hormone levels (free T4 above the reference range or
total T4 150% of top normal pregnancy value and TSH
0.1 U/ml) and evidence of hyperthyroidism may require
treatment as long as clinically necessary
• 4. AUTOIMMUNE THYROID DISEASE AND
MISCARRIAGE
• 4.1. universal screening for antithyroid antibodies and
possible treatment cannot be recommended at this time.
• 6. IODINE NUTRITION DURING PREGNANCY
• 6.1. Women of childbearing age ; average iodine intake 150 g/d.
• pregnancy and breastfeeding women should increase intake to 250
g
• 6.2. Iodine intake during pregnancy and breastfeeding should not
exceed twice the daily recommended nutritional intake for iodine, i.e.
500 g iodine per day
• 6.3. To assess the adequacy of the iodine intake during pregnancy
in a population, urinary iodine concentration should be measured in
a cohort of the population.
– Urinary iodine concentration should ideally range between 150 and 250
g/liter.
• 6.4. To reach the daily recommended nutrient intake for iodine,
multiple means must be considered, tailored to the iodine intake
level in a given population.
– 1) countries with iodine sufficiency and/or with a well established
universal salt iodization (USI) program,
– 2) countries without a USI program or an established USI program
where the coverage is known to be only partial, and finally
– 3) remote areas with no accessible USI program and difficult
socioeconomic conditions.
• 8. SCREENING FOR THYROID
DYSFUNCTION DURING PREGNANCY
• 1. Women with a history of hyperthyroid or
hypothyroid disease, PPT, or thyroid lobectomy.
• 2. Women with a family history of thyroid
disease.
• 3. Women with a goiter.
• 4. Women with thyroid antibodies (when known).
• 5. Women with symptoms or clinical signs
suggestive of thyroid underfunction or
overfunction, including anemia,elevated
cholesterol, and hyponatremia.
• 6. Women with type I diabetes.
• 7. Women with other autoimmune disorders.
• 8. Women with infertility who should have
screening with TSH as part of their infertility
work-up.
• 9. Women with previous therapeutic head or
neck irradiation.
• 10. Women with a history of miscarriage or
preterm delivery.