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 globulinsecondary to an estrogenic stimulation of TBG synthesis and reduced hepatic clearance of TBG ;two to threefoldlevels of bound proteins, total thyroxine, and total triiodothyronine are increased and resin triiodothyronine uptake (RT3U) is decreasedbegins early in the first trimester, plateaus during midgestation, and persists until shortly after deliverydecrease in its hepatic clearance,estrogen-induced sialylationfree 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 activitybegins shortly after conception, peaks around gestational week 10,declines to a nadir by about week 20directly activate the TSH receptorpartial inhibition of the pituitary gland (by cross-reactivity of the α subunit)transient decrease in TSH between Weeks 8 and 14mirrors the peak in hCG concentrations20% of normal women, TSH levels decrease to less than the lower limit of normal
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 hCGreduction in plasma iodidefetal :monodeiodinase types II and III in the placentaincreased maternal glomerular filtration rate-- increased renal clearance of iodide throughout pregnancytransplacental passage of T4 and iodide and placental metabolism of iodothyroninesstimulate the maternal thyroid ; depleting the maternal circulation of thyroid hormone and its precursors
10 EFFECTS OF PREGNANCY ON THYROID PHYSIOLOGY Physiologic ChangeThyroid-Related Consequences↑ Serum thyroxine-binding globulin↑ Total T4 and T3; ↑ T4 production↑ Plasma volume↑ T4 and T3 pool size; ↑ T4 production; ↑ cardiac outputD3 expression in placenta and (?) uterus↑ T4 productionFirst 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 diseaseGoiterTPOAb+SymptomsType 1 DMMiscarriageOther autoimmune diseaseInfertilityMorbid obesity>30 yearsThyroid 2011
14 TSH in PregnancyA 28-year-old woman who is 6 weeks pregnant has a routine serum TSH level of 4.1 mIU/L & FT4 1.3 ng/dLQ: 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 appliedRecommendation 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 pregnanciesprevalence 0.1% to 0.4%, with 85% Graves’ diseaseSingle toxic adenoma, multinodular toxic goiter, and subacute thyroiditisgestational 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 valuemay be difficult to determine the causethyroid radionuclide imaging is contraindicated in pregnant women.Measurement of thyrotropin receptor antibody (thyroid stimulating immunoglobulins) Graves' disease during pregnancytransient hyperthyroidism in hyperemesis gravidarum and gestational transient thyrotoxicity (GTT)
21 Hyperthyroidism and pregnancy Severe maternal hyperthyroidismincreased risk of stillbirthpreterm deliveryintrauterine growth restrictionPreeclampsiaheart failurespontaneous abortionFetal thyroid hyperfunction or hypofunction caused by TSHRAbsFetal goiter from excessive antithyroid drug treatmentNeonatal thyrotoxicosisIncreased perinatal and maternal mortalityDecreased IQ of offspring because of excessive use of antithyroid drugs
22 Transient hyperthyroidism during pregnancy & gestational transient thyrotoxicity (GTT) hyperemesis gravidarumsevere 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 hyperthyroidismhigher serum hCG and estradiol concentrations60% have a subnormal serum TSH level (< 0.4 mU/L),50% have an elevated serum free T4 concentrationSeverity positively correlated with maternal free T4 levels but not to thyroid function.12% elevated free T3 indexbelieved to be related to hCG stimulation of the thyroid glandNormalization 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 enlargedresolution of symptoms parallels the decline in hCG levelsusually resolves spontaneously by 20 weeks’ gestationbeyond 20 weeks,repeat evaluation for other causes
24 Trophoblastic hyperthyroidism hydatidiform mole (molar pregnancy) & choriocarcinoma.high serum hCG concentrations and abnormal hCG isoforms55 to 60 percent had clinically evident hyperthyroidismnormal thyroid gland and few symptoms of thyroid hormone excess.some :findings of hyperthyroidism and a diffuse goiterophthalmopathy is not presentNausea 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 outcomesdoes not warrant treatment.
27 Graves’ disease 95% of thyrotoxicosis during pregnancy. activity level fluctuate during gestation, withexacerbation during the first trimestergradual improvement during the latter half.exacerbation shortly after deliveryclinical 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 pregnancythyroid examination: goiter (with or without bruit)suppressed serum TSH level and usually elevated free and total T4 serum concentrations.TSH receptor antibodiautoantibodies mimic TSH can cross the placenta and cause neonatal Graves’ disease
30 Graves’ disease Neonatal thyrotoxicosis : 1% of infants occur in euthyroid mother or has had surgical or radioactive 131I treatments before pregnancyfetal 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 hydropsFetal blood sampling — Fetal blood for thyroid function tests by percutaneous umbilical vein sampling after 20 weeks of gestationHigh 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 hyperthyroidismhigh 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 infectiontreatment 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 state2. 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-dependentmedian time to normalization of maternal thyroid function7 weeks with PTU and 8 weeks with MMIPTU more highly bound to albumintheorize 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 featuresLow thyroid function at birth ½ neonates whose mothers received PTU or MMI and had serum T4 concentrations within the normal (non-pregnant) rangenormal IQ scoresGraves’ disease may amelioratethionamide discontinued in 30% during the final weeksfall in serum TSH receptor-stimulating antibody concentrations and a rise in TSH receptor-blocking antibodies.Graves' hyperthyroidism can worsen postpartumdo not recommend the use of T4 with thionamide therapy during pregnancy.
36 Treatment β-Adrenergic blockers Iodides weaned as soon as the hyperthyroidism is controlledoccasional cases of neonatal growth restriction, hypoglycemia, respiratory depression, and bradycardiaincreased frequency of first-trimester miscarriagesavoiding in the first trimesterIodidespast reports of neonatal hypothyroidism after exposure to iodinelow-dose potassium iodide may be consideredPreparation for thyroidectomythionamide-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 diseaseallergic or intolerant of both thionamidesnoncompliant with medical therapycompressive symptomssecond trimester, before gestational week 24prepared 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 weekspredisposing to congenital hypothyroidismNursingBreast feeding in mothers taking PTU or MMI is safeThyroid function in newborn infants is unaffectedPTU is preferred because it is less concentrated in breast milk
39 Up to date_ATASuggest that PTU use be limited to first trimester only.In the second trimester,switching from PTU to MMIInitial 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 progressiveRoutine 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 uncomplicatedOn exam she is dehydrated, euthyroid, without a goiter and has normal eyesTSH 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 assayand 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 helpfulRecommendation 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 monthsOn exam she is nervous, slightly hyperthyroid, has lid lag, and thyroid is x2 enlargedTSH 0.01 FT4 2.8FT4I 16 (5-12) TRAb 75% (<16%)Q: How do you manage?
45 Postpartum thyroid disease Postpartum thyroiditisDx: documenting abnormal TSH (elevated or suppressed) levels during the first year postpartum in the absence of positive TSI or a toxic nodulehypo- or hyperthyroidismclassic presentation :transient hyperthyroid phase that occurs 6 weeks to 6 months postpartumfollowed by a hypothyroid phase that lasts for up to 1 year postpartum
46 Postpartum thyroiditis autoimmune disorder with a self-limited hyperthyroid phasewithin one year after parturition.PresentationsTransient hyperthyroidism aloneTransient hypothyroidism aloneTransient hyperthyroidism followed by hypothyroidism and then recovery.can also occur after spontaneous or induced abortion3 to 16 percenthigher, 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 thyroiditisvariant form of chronic autoimmune thyroiditis (Hashimoto's thyroiditis).high serum concentrations of anti-peroxidase antibodiesmany eventually become hypothyroid or have a goiterhigh serum antithyroid antibody concentrations early in pregnancydecline later (as immunologic tolerance increases during pregnancy)rise again after deliverysubclinical thyroid autoimmune disease early in pregnancy and soon afterProgression to permanent hypothyroidismrelated to higher TSH concentrations and the antiperoxidase antibody titermaternal age and female sex of the infantPostpartum 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 minimalGraves' ophthalmopathy is absent.by reevaluation in three to four weeks: postpartum thyroiditis improvedlymphocytic hypophysitis,TSH normal or low, low free T4postpartum thyroiditis, TSH elevated with decreased FT4.
49 Postpartum thyroiditis antithyroids :no role.Hypothyroid :may require treatment and somesignificant rate of residual hypothyroidismRecommend:maintain thyroxine until childbearing is complete, with an attempt to wean off medication 1 year after the last deliveryPostpartum--signs/symptoms of thyroid dysfunctionsymptoms mimic normal postpartum changesTSH, free T4, and antithyroid antibodies levelspostpartum depression and postpartum thyroiditis
50 Postpartum Graves’ disease 60% Graves’ disease in the reproductive years; postpartum onseteuthyroid patients with Graves’ disease with TSIincreased risk of developing recurrent Graves’ disease if antithyroid medication was withheldTSIs 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 aspirationRadionucleotide scanning is contraindicated during pregnancymalignant or suspicious for papillary cancer, surgery at the earliest safe periodno evidence that pregnancy causes a reactivation of thyroid cancer or that exposure to radioactive iodine poses a risk to future pregnanciesmaintained 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 thyroiditisIncrease in serum TSH levelsmost normalpresence of antithyroid antibodieslack 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 antibodiesbefore pregnancyTSH level greater than 2.5 mU/L.Serum TSH should be monitored throughout pregnancy in all antithyroid antibody–positive womenmaintain 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 Guideline1. HYPOTHYROIDISM AND PREGNANCY: MATERNALAND FETAL ASPECTSmaternal hypothyroidism should be avoided.Targeted case finding is recommended at the first prenatalvisit or at diagnosis of pregnancyIf 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 rangeSubclinical hypothyroidism ;associated with anadverse 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 adecrease 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 necessary4. AUTOIMMUNE THYROID DISEASE AND MISCARRIAGE4.1. 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 g6.2. Iodine intake during pregnancy and breastfeeding should not exceed twice the daily recommended nutritional intake for iodine, i.e. 500 g iodine per day6.3. 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 finally3) 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.