Endocrine Pathology associated with pregnancydr. Yunus Tanggo Sp.PD. PhDDepartment of Internal Medicine, Universitas Kristen Indonesia General Hospital, Jakarta, Indonesia

HYPER and HYPOTHYROIDISM DURING PREGNANCY

INTRODUCTIONThyroid diseases are more prevalent in women relatively common in pregnancy

Pregnancy may affect the course of thyroid disorders conversely.. Thyroid diseases may affect the course of pregnancy

Thyroid disorders & their management may affect the mother & fetus

Control of Thyroid FunctionBy a negative-feedback loop:The hypothalamus releases TRHTRH acts on the pituitary to release TSHTSH acts on the thyroid gland to release T3 and T4 , that regulate metabolismTRH and TSH concentrations are inversely related to the level of T3 & T499% circulating T3 & T4 is bound to TBG. 1% circulate in the Free form, (only the free forms are biologically active)

NORMAL CHANGES IN THYROID FUNCTION ASSOCIATED WITH PREGNANCYThyroid function tests change during pregnancy due to the influence of two main hormones: human chorionic gonadotropin (hCG), the hormone that is measured in the pregnancy test and estrogen, the main female hormone.

The high circulating hCG levels in the first trimester may result in a slightly low TSH. The TSH will be slightly decreased in the first trimester and then return to normal throughout the duration of pregnancy.

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.

Thyroid function in normal pregnancy Following conception, circulating total T4 (TT4) and T4 binding globulin (TBG) concentrations increase by 68 weeks and remain high until delivery.

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

Levels of T4,and T3 gradually increase in the fetus between the second and third trimester, reflecting the rising contribution of the fetal thyroid

Results of Thyroid Testsin Different Clinical SituationsAnti-TPO = antithyroid peroxidase antibodies; FT3 = free triiodothyronine; FT4 = free thyroxine; TSH = thyroid stimulating hormon; TSI = thyroid stimulating immunoglobulins; TT4 = total thyroxine

TT4TT3FT4 FT3 TSHAnti-TPOTSI NonpregnantNNNNN( - )N Normal pregnancyNNN( - )N Hyperthyroidism( +)? Gestasional Transient Thyrotoxicosis (GTT)( - )N HypothyroidismNN( +)N Subclinical hypothyroidismNNNN( +)N Chronic thyroiditisNNNNN( +)N

THYROTOXICOSIS & PREGNANCYCauses:Graves diseaseTMNG, toxic adenomaThyroiditisHydatiform moleGestational hCG-asscociated ThyrotoxicosisHyperemesis gravidarum hCG60% TSH, 50% FT4Resolves by 20 wks gestationOnly Rx with ATD if persists > 20 wk

SIGNS AND SYMPTOMS OF HYPERTHYROIDISMBulging Eyes/Unblinking StareMenstrual Irregularities or Light PeriodExcessive Vomiting in PregnancyFirst-Trimester MiscarriageFamily History of Thyroid Disease or DiabetesNervousnessIrritabilityDifficulty SleepingSwelling (Goiter)Frequent Bowel MovementsWarm, Moist Palms

Hoarseness or Deepening of VoiceDifficulty SwallowingRapid or Irregular Heartbeat InfertilityWeight LossHeat IntoleranceIncreased SweatingPersistentSore or Dry Throat

THYROTOXICOSIS & PREGNANCYRisks:Maternal: stillbirth, preterm labor, preeclampsia, CHF, thyroid storm during laborFetal: SGA, possibly congenital malformation (if 1st trimester thyrotoxicosis), fetal tachycardia, hydrops fetalis, neonatal thyrotoxicosisMeasure:TSH, FT4, FT3, T4, T3, thyroid antibodies?Examine: goitre? orbitopathy? pretibial myxedema?

Pregnant & Suppressed TSHTSH < 0.1TSH 0.1 0.4Recheck in 5 wksFT4, FT3, T4, T3Thyroid AbsExamineNormalizesStill suppressed Very High TFTs: TSH undetectable very high free/total T4/T3 hyperthyroid symptoms no hyperemesis TSH-R ab + orbitopathy goitre, nodule/TMNG pretibial myxedemaTreat Hyperthyroidism (PTU)Hyperemesis GravidarumAbnormal TFTs past 20 wkDont treat with PTU

TREATMENT GUIDELINES FOR GRAVES' DISEASE DURING PREGNANCY Monitor Pulse, weight gain, FT4 , TSH every 2-4 weeks Titrate ATD as necessaryATD: PTU is usually preferred to MTZ, but both types can be used. Use the lowest dosage of that will maintain the patient in a euthyroid or mildly hyperthyroid state. Usually the ATD dose can be adjusted downward after 1st trim. often discontinued during the 3rd trimester ATD will often need to be reinstituted or increased after delivery.Do not attempt to normalize serum TSH -- TSH 0.1 - 0.4 mU/L are appropriateCommunicate regularly with obstetric providers, Especially fetal pulse & growth in the 2nd half of gestation

THYROTOXICOSIS & PREGNANCYTREATMENTPTUStart 100 mg tid, titrate to lowest possible doseMonitor qmos on Rx: T4, T3, FT4, FT3TSH less useful (lags, hCG suppression)Aim for high-normal to slightly elevated hormone levelsT4 150-230 nM, T3 3.8-4.6 nM, FT4 26-32 pM3rd trimester: titrate PTU down & d/c prior to delivery if TFTs permit to minimize risk of fetal goitreConsider fetal U/S wk 28-30 to R/O fetal goitre

If allergy/neutropenia on PTU: 2nd trimester thyroidectomy

HYPOTHYROIDISM IN PREGNANCY MAY BE DIFFICULT TO DIAGNOSESigns and symptoms (weight gain, fatigue) can overlap with common pregnancy complaintsAmong pregnant hypothyroid patients: 1/3 have few or no symptoms 1/3 have moderate symptoms 1/3 have classical presentation of hypothyroidism

Overt Hypothyroidism: symptomatic patient TSH level FT4 & FT3. Subclinical hypothyroidism: asymptomatic TSH normal FT4 & FT3 LABORATORY TESTS

RISK FACTORS FOR HYPOTHYROIDISM IN PREGNANT WOMENPrevious therapy for hyperthyroidismPrevious external neck irradiation Goiter , Autoimmune disorderFamily history of thyroid disease

FETAL THYROID FUNCTION

During early gestationThe Fetus needs T4 for brain / neurologic development Fetal Thyroid development begin at 10 -12 ws, Fetus does not produce its own T4 until 12 ws, Fetus relies on Maternal T4 : Exclusively (until 12 ws)

By 20 weeks gestational ageThe fetal thyroid is fully responsive to Thyroid stimulating immunoglobulin (TSI) Antithyroid drugs Maternal T4, T3 & TSH pass across the placenta in small and decreasing amounts as gestation progress, but TSI, Iodides are readily transferred to the fetus

CONSEQUENCES OF HYPOTHYROIDISM IN PREGNANCYMiscarriagePreterm deliveryAnemiaPlacental abruptionFetal complicationsThe impact -- depends on the severity of the condition.

CONSEQUENCES OF HYPOTHYROIDISM IN PREGNANCYCongenital cretinism: Growth failure, Mental retardation, Other neuropsychologic deficits If cretinism is identified & treated in the first 3 months of life: near-normal growth and intelligence can be expected. newborn screening for congenital hypothyroidism !!

THERAPY OF HYPOTHYROIDISMChoice of medicationAdjustment of therapyFollow-up care

GESTATIONAL DIABETESThis diagnosis is given when a woman, who has never had diabetes before, gets diabetes or has high blood sugar, when she is pregnant. In pregnant women not previously known to have diabetes, screen for GDM at 24-28 weeks gestation, using a 75-g OGTT It occurs in about 5% of all pregnancies (200,000 cases each year)If not treated, gestational diabetes can cause health problems for the mother and the fetus.

RISK FACTORS: for first trimester screening> 35 yrsBMI > 30 Previous diagnosis of GDMDelivery of a mascrosomic babyMember of a high-risk population (Aboriginal, Hispanic, South Asian, Asian, African)Acanthosis nigricansCorticosteroid usePCOS

ADA and WHO Criteria for the Diagnosis of GDMADA ADA WHO 100-g OGTT 75-g OGTT 75-g OGTTFasting (mg/dl) 95 95 1261-hour (mg/dl) 180 180 2-hour (mg/dl) 155 155 1403-hour (mg/dl) 140 For the ADA criteria, two or more of the values from either the 100- or 75-g OGTT must be met or exceeded to make the diagnosis of GDM. For the WHO criteria, one of the two values from the 75-g OGTT must be met or exceeded to make the diagnosis of GDM

PATHOPHYSIOLOGY (1)Characterized by progressive insulin resistance that begins near midpregnancy and progresses through the third trimesterIn late pregnancy, insulin sensitivity falls by until 50%Two main contributors to insulin resistance includeincreased maternal adiposityinsulin desensitizing effects of hormones produced by theplacentaPlacenta produces human chorionic somatomammotropin (HCS, formerly called human placental lactogen), bound and free cortisol, estrogen, and progesterone

PATHOPHYSIOLOGY (2)

HCS stimulates pancreatic secretion of insulin in the fetus and inhibits peripheral uptake of glucose in the motherIn non diabetic pregnant women, the first- and second phase insulin responses compensate for this reduction in insulin sensitivity, and this is associated with -cell hypertrophy and hyperplasiaHowever, women who have a deficit in this additional insulin secretory capacity develop GDM-Cell dysfunction in women diagnosed withGDM may fall into one of three major categories: 1) autoimmune, 2) monogenic, 3) occurring on a background of insulin resistance (as is most common).

PATHOPHYSIOLOGY (3)The loss of the first-phase insulin response leads to postprandial hyperglycemia, whereas impaired suppression of hepatic glucose production is responsible for fasting hyperglycemia when present.Because insulin does not cross the placenta, the fetus is exposed to the maternal hyperglycemiaThe fetal pancreas is capable of responding to this hyperglycemiaThe fetus thus becomes hyperinsulinemic, which in turn promotes growth and subsequent macrosomia.

Why isnt insulin doing its jobThe placenta is a system of vessels that passes nutrients, blood, and water from mother to fetus.The placenta makes certain hormones that may prevent insulin from working the way that it should.When this condition happens, it is referred to as insulin resistance.In order to keep metabolism normal during pregnancy, the body has to make three times more insulin than normal to offset the hormones made by the placenta.

COMPLICATIONS

Maternal complications Antepartum morbidity in women with GDM mostly consists of higher risk for development of hypertensive disorders and preeclampsiaGDM increases the risk of cardiovascular disease (CVD) increased risk of cesarean deliveryGDM have an increased risk of developing diabetes after pregnancy compared to the general population

COMPLICATIONSFetal complications MacrosomiaNeonatal hypoglycemiaPerinatal mortalityCongenital malformationHyperbilirubinemia,Polycythemia, hypocalcemia,Respiratory distress syndrome.

Refer patients for nutritional counseling with registered dietitian familiar with pregnancyMNT is based on standard nutritional recommendations during pregnancy, with customization based on: HeightWeightNutritional assessmentLevel of glycemic control3,4,5Goals: Provide a nutritionally adequate diet for pregnancyAchieve normoglycemia

MEDICAL NUTRITION THERAPY (MNT)1. Castorino K, Jovanovic L. Clin Chem. 2011;57(2):221-30. 2. Kitzmiller JL, et al. Diabetes Care. 2008;31(5):1060-79. 3. Jovanovic L, et al. Mt Sinai J Med. 2009;76(3):269-80. 4. ADA. Diabetes Care. 2004;27(suppl 1):S88-90. 5. National Academy of Sciences, Institute of Medicine, Food and Nutrition Board, Committee on Nutritional Status in Pregnancy and Lactation, Nutrition During Pregnancy: http://www.iom.edu/Reports/1990/Nutrition-During-Pregnancy-Part-I-Weight-Gain-Part-II-Nutrient-Supplements.aspx, 1990. Accessed: April 26, 2012.

Target Glucose Levels for Normoglycemia3Preprandial glucose 95 mg/dL (5.3 mmol/L)1-hour postprandial glucose 140 mg/dL (7.8 mmol/L) or 2-hour postprandial glucose 120 mg/dL (6.7 mmol/L)

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