1. Hyperthyroid in Pregnancy
Dr. n mohammadi
Fellowship of fetal medicine

4. 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).

6. 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

7. 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 cross-reactivity 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

8. hCG
TSH

9. reduction in plasma iodide
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

10. 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

12. 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: , 2011

13. 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 thyroid disease
Goiter
TPOAb+
Symptoms
Type 1 DM
Miscarriage
Other autoimmune disease
Infertility
Morbid obesity
>30 years
Thyroid 2011

14. 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?

15. 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, mIU/L; 2nd trimester, mIU/L; 3rd trimester, mIU/L

16. 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.

17. 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)

19. Hyperthyroid manifestations
Nonspecific symptoms;
_Tachycardia
_Heat intolerance
_Increased perspiration
Additional symptoms:
_Anxiety
_Hand tremor
_Weigh loss despite a normal or increased appetite

20. Specific findings:
Goiter
ophthalmopathy

21. Hyperthyroidism and pregnancy
Severe maternal hyperthyroidism
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

22. 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

23. 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

24. 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

25. 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.

26. 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.

27. 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.

28. 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

29. Graves’ disease Pregnancy outcome preterm labor preeclampsia
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

30. 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

31. Thyroid storm 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.

32. 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.

33. Guidelines for clinical management of maternal hyperthyroidism during pregnancy
3. Measure TSH receptor antibodies (thyroid-stimulating 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

34. 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

35. Treatment Thionamides maternal :rash
rare birth defects in MMI: aplasia cutis, choanal atresia,esophageal atresia, and minor dysmorphic features
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.

36. Treatment β-Adrenergic blockers Iodides
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.

37. 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

38. Treatment Radioactive iodine therapy Nursing 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

39. 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.

40. 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.

41. 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 ( )
FT4I 20 (5-12)
Q: Does she require antithyroid Rx?

42. 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.

43. 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

44. 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) TRAb 75% (<16%)
Q: How do you manage?

45. 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

46. 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)

47. 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

48. 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.

49. 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

50. 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.

51. 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.

53. 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.

54. 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.

55. 1. HYPOTHYROIDISM AND PREGNANCY: MATERNAL AND FETAL ASPECTS
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
maternal hypothyroidism should be avoided.Targeted case finding is recommended at the first prenatalvisit or at diagnosis of pregnancy
If hypothyroidism diagnosed before pregnancy, adjust preconception T4 dose to reach a TSH ≤2.5 U/ml before pregnancy.
T4 dose incremented by 4–6 wk gestation and 30–50% increase in dosage.
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.

56. 1.1.6. Subclinical hypothyroidism ;associated with an
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
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.
After delivery, most hypothyroid women need a
decrease in the T4 dosage they received during pregnancy

57. 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.

58. 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.

59. 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.

60. 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.