Thyroid Disorders in PregnancyProf. Md. Farid UddinFounder Chairman & Course Co-ordinatorDepartment of EndocrinologyBSMMU, Dhaka

Thyroid function during normal Pregnancy

Gestational weekTSH and hCG during Gestation

Thyroid hormone changes in different trimester

Hormone1sttrimester2ndtrimester3rdtrimesterTSHNormal or decreaseNormalNormal

Free T4NormalNormalNormal

Free T3NormalNormalNormal

Total T4HighHighHighTotal T3HighHighHigh

Pregnancy and Thyroid Disease - FactsGestationalHyperthyroidism0.24%Hypothyroidism (TSH) 2-2.5%Thyr Antibodies [antiTPO] 10%PostpartumPPTD 5-9%PP depression 30% [ vs 20%]PP Graves up to 40% of Graves

Fetal Mortality and Morbidityin Pregnant Hyperthyroid PatientsNumber of reports 11(1954-1983)Number of pregnancies3 - 41Total number of pregnancies249Fetal death and stillbirth14 (5.6%)Fetal and neonatal abnormality15 (5%)

NB:Incidence of Hyperthyroidism in pregnancy app 0.24%

Outcome of Poorly Treated Hyperthyroidism in PregnancyMATERNAL

MiscarriagePlacenta abruptioPreterm deliveryCongestive Ht failureThyroid StormPre-eclampsiaFETAL

HyperthyroidismNeonatal hyperthyroidismPrematurityIUGRFetal death /stillbirthFetal abnormalities

Causes of Thyrotoxicosis in PregnancyGraves diseaseTMNG, toxic adenomaThyroiditisHydatiform moleGestational hCG-asscociated ThyrotoxicosisHyperemesis gravidarum hCG60% TSH, 50% FT4Resolves by 20 wks gestationOnly Rx with ATD if persists > 20 wk

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 of Hyperthyroidism in PregnancyAim for high-normal to slightly elevated hormone levelsT4 150-230 nM, T3 3.8-4.6 nM, FT4 26-32 pM

Confirm diagnosis

No RAI ever (destroy fetal thyroid)

Start propylthiouracil or other ATD

Render patient euthyroid - continue with low dose ATD up to and including labour

Monitor thyroid function regularly throughout gestation (4-6wkly).Adjust ATD if necessary

Treatment of Hyperthyroidism in Pregnancycontinued.Check TSAb at 36 wks. Gestation

Discuss treatment with patient [effect on patient, effect on fetus, breast feeding]

If allergy/Neutrogena on PTU: 2nd trimester thyroidectomy

Review postpartum - check for exacerbation

Effect of Antithyroid Drugsin Pregnancy on OffspringMesser et al Acta Endoc. 1990, 123:311-316SStudied 17 children of 13 hyperthyroid mothers (ATD) and 25 children of 15 euthyroid mothers 7-11 years after birthNo differences between groups in clinical/mental psychological development

Similar to data from1) McCarrol et al. Arch Dis Child 1976, 51:532-5362) Burrow et al. Yale J Biol Med 1978, 51: 151-156

Thyrotoxicosis & LactationATD generally dont get into breast milk unless at higher doses:PTU > 450-600 mg/dMTZ > 20 mg/dGenerally safeTake ATD dose just after breast-feedingShould provide 3-4h interval before lactates again

Patterns of Thyroid Function Post PartumFrom AMINO

Post Partum Graves Disease

Immune rebound phenomenon TSHR Ab decrease during pregnancy - rebound in postpartum (Gonzalez-Jimenez et al 1993) 37/92 patients of child bearing age had onset postpartum i.e. 40% (Tada et al 1994)

But PP Graves often de novo presentation

Of 96 episodes postpartum hyperthyroidism - silent thyroiditis was seen occasionally coincidental with Graves (Momotani et al 1994).

Indications for TestingThyroid Function in PregnancyOn T4 prior to gestation

History of autoimmune thyroid disease+ve thyroid autoantibodiesPrevious postpartum thyroiditisGraves disease in remission

+ve FH autoimmune thyroid disease

Type 1 DM and/ other autoimmune disease

Previous neck irradiation/ partial thyroidectomy [decreased thyroid reserve]

Epidemiology

Prevalence : Overt Hypothyroid (OH) : 0.3 % 0.5 %TSH >10 and Free T4: Low

Sub-Clinical Hypothyroid (SCH): 2 % - 3 %TSH: High >5 but

Thyroid Autoimmunity (TAI) & causes of hypothyroid in pregnancy

Thyroid autoantibodies : 5 % - 15 % in child bearing age , even with normal thyroid function. Associated with increased rate of pregnancy loss.Dr. A. Hasanat, Prof. M.N. Alam et al (1997).... 135/397(34 % with different thyroid disease in Bangladesh)

Chronic autoimmune thyroiditis is the leading cause of hypothyroidism in pregnancy.Iodine deficiency (UIE < 10 g/dl) by WHOLymphocytic hypophysitis

Thyroid function in the Fetus :

TSH appears at 10 12 weeks.Little hormone synthesis until 18 20 th weeks.At term TSH is much higher FT4 is lower.Soon after birth TSH is ~ 50 80 mIU/literComes down to 10 -15 mIU/liter within 48 hours.

Congenital hypothyroid is not related to maternal thyroid dysfunction. Iodine deficiency may contribute.

Clinical features :

Usually not very prominent symptomsMay have wt gain, cold intolerance, lethargy, constipation, edema etc.Asymptomatic

Lab Investigations

Free T4TSHAntithyroid antibody : TPO (Thyroid peroxidase) TG (Thyroglobulin)Total T4 and T3 level is increased (~ 1.5 folds) due to increased TBG. TBG is increased about 2 folds.No change in Free T4 or FT3

Patients may present as

Diagnosed Hypothyroid on Replacement became pregnant Newly diagnosed Hypothyroid during pregnancy (OH or SCH)

Diagnostic criteria : during pregnancy

Still controversial .Trimester specific reference ranges1 of FT4 and TSH is coming up.TSH is Lowest in first trimester , highest in third trimester andIn between in the second trimesterNormal Ref. Range is 0.4 mIU/liter 4.0 mIU/liter

1. Deshe et al.J Clin Endocrinol Metab. August 2007, 92(8)(Suppl): S8

Some of the Authors if

TSH > 2.3 in first trimester andTSH > 3.5 in the Second and Third TrimesterWith normal Free T4

Should be considered as Subclinical Hypothyroidism Obstet gynecol 2005;106:753-757

Evidence :Repercussion of Hypothyroid: Maternal aspect InfertilityAbortionAnemiaHypertension (Gestational)Placental abruptionPPHJ Med Screen 7:127-130

Repercussion of Hypothyroid: Fetal aspect

Premature birthLBW (30 %)ARDSCognitive impairment of the babyAbnormal brain developmentIncreased perinatal mortality (12 %)Psychoneurological impairment, Low I.Q. etc J Med Screen 7:127-130Endocrine Clinics of North America 2006

The maternal and fetal repercussion depends on ..

Severity of hypothyroidism (in case of OH is more than SCH) Time of onset ( First trimester is more important) Adequacy of treatment (under treatment is associated with Increased adverse outcome)

Therapeutic Aspects :

Levothyroxin 30 % - 50 % above preconception doseNon Pregnant 1.7 2.0 g/kg/day, increased upto 2.0 -2.4 g/kg/day New onset hypothyroid should be initiated with higher dose100 150 g per day or titrate according to B.W.

Dose adjustment every 4-6 weeks.Those who are already on thyroxin, may increase the dose by 25 % as soon as pregnancy is confirmed.10 % - 20 % may not need to increase the dose. Hypothyroid due to other causes (Surgery, Post ablative, Congenital agenesis ) requires greater increment than H.T.Aim is to maintain normal FT4 and TSHDose increment may be difficult in hyperemesis

Treatment to target TSH 0.3 2.5 in First Trimester and 0.5 3.0 in the Second or Third trimester1

FT4 should be kept either at trimester specific target or above the median of the Laboratory Reference Range. eg. Normal Range 9 23 pmol/l , keep above 16 .

Target of TSH and FT4 :1. US Preventive Study Task Force

Whom to screen ?Universal screening not yet recommended except by AACE.High risk subjects should be screened : - H/O thyroid disease - F/H of thyroid disorders - Known case of TAI ( Antibody +) -Other autoimmune disease - High degree of suspicion - Bad obstetric history - Obese or Rapidly gaining weight

Recommendations:

Both OH and SCH should be treatedTreatment is very safe and Effective. Drug interactionwith Calcium and Ferrous Sulfate ( absorption)Usually life longNew onset SCH subjects may be re-evaluated after stopping the drug for 6 wks.

Continue throughout pregnancy and Lactation (Do not stop to see any reason )

Increase dose during pregnancy ( 30 50 %)

Normal delivery or as per obstetric indication

Target TSH and FT4 must be achieved

After delivery mostly need to decrease the dose

Close monitoring by Endocrinologist and Obstetrician & Gynecologist for better outcome.

Dependable Laboratory support

Neonatal screeningCH is one of the major causes of mental and physical retardation. (1:4000)

The condition is reversible if detected in first few weeks of life and treatment starts

Unfortunately the clinical manifestation is often late

Neonatal screening is now a well established program throughout the world for detection of CH

Procedure of screeningFew drops of blood are collected in filter paper, dried and sent to laboratory for analysis

The blood is collected from cord at birth or from heel prick after 72 hrs of birth

For detection of CH TSH is estimated

The screening positive babies are recalled and confirmed by serum T4 & TSH

SCH INMU Experience

Period of screen--ingNo. of babies screen-edNo. of positive babiesNo. of babies detectedIncidence of CH1999-2008983141094381:2587

Thank You

20.19 Thyroid disease in pregnancy Normal pregnancy Trimester-specific normal ranges: should be used to interpret thyroid function test results in pregnancy. In the first trimester, TSH is lower and free free T4 and T3 higher, in part due to thyroid stimulation by human chorionic gonadotrophin (hCG). In later pregnancy, free T4 and T3 are lower. Binding globulin levels are induced by oestrogen, so total T4 and T3 levels are invariably high. Iodine requirements: increased in pregnancy. The World Health Organization (WHO) recommends minimum intake of 200 g/day. Screening of thyroid function and autoantibodies: not recommended for every woman, but should be performed in first trimester in those with a personal or family history of thyroid disease, goitre, other autoimmune disease including type 1 diabetes, or when there is clinical suspicion of thyroid dysfunction. Thyrotoxicosis Hyperemesis gravidarum: associated with thyrotoxic biochemistry, sometimes requiring antithyroid drugs. Subclinical thyrotoxicosis: not usually treated, to avoid fetal hypothyroidism. Anti-thyroid drugs: propylthiouracil is first choice. Hypothyroidism Preterm labour and impaired cognitive development in the offspring: may be associated with even subclinical hypothyroidism. Thyroxine replacement therapy dose requirements: increase by 30-50% from early in pregnancy. Monitoring to maintain TSH results within the trimester-specific reference range is recommended in early pregnancy and at least once in each trimester. Post-partum thyroiditis Screening: not recommended for every woman, but thyroid function should be tested 4-6 weeks post-partum in those with a personal history of thyroid disease, goitre or other autoimmune disease including type 1 diabetes, those known to have positive anti-thyroid peroxidase antibodies, or when there is clinical suspicion of thyroid dysfunction.

************