Thyroid Disorders in PregnancyThyroid Disorders in Pregnancy

Prof. Md. Farid UddinProf. Md. Farid UddinFounder Chairman & Course Co-ordinatorFounder Chairman & Course Co-ordinator

Department of EndocrinologyDepartment of Endocrinology

BSMMU, DhakaBSMMU, Dhaka

Thyroid function during normal Pregnancy

Gestational week

TSH and hCG during Gestation

Thyroid hormone changes in different trimesterThyroid hormone changes in different trimester

HormoneHormone 11ststtrimestertrimester 22ndndtrimestertrimester 33rdrdtrimestertrimester

TSHTSH Normal or Normal or decreasedecrease

NormalNormal NormalNormal

Free T4Free T4 NormalNormal NormalNormal NormalNormal

Free T3Free T3 NormalNormal NormalNormal NormalNormal

Total T4Total T4 HighHigh HighHigh HighHigh

Total T3Total T3 HighHigh HighHigh HighHigh

Pregnancy and Thyroid Disease - FactsPregnancy and Thyroid Disease - Facts

GestationalGestationalHyperthyroidismHyperthyroidism 0.24%0.24%Hypothyroidism (TSH) Hypothyroidism (TSH) 2-2.5%2-2.5%Thyr Antibodies [antiTPO] Thyr Antibodies [antiTPO] 10%10%

PostpartumPostpartumPPTDPPTD 5-9%5-9%PP depression PP depression 30% [ vs 20%]30% [ vs 20%]PP Graves’ PP Graves’ up to 40% of Graves’up to 40% of Graves’

Fetal Mortality and MorbidityFetal Mortality and Morbidityin Pregnant Hyperthyroid Patientsin Pregnant Hyperthyroid Patients

Number of reportsNumber of reports 11(1954-1983)11(1954-1983)Number of pregnanciesNumber of pregnancies 3 - 413 - 41Total number of pregnanciesTotal number of pregnancies 249249Fetal death and stillbirthFetal death and stillbirth 14 (5.6%)14 (5.6%)Fetal and neonatal abnormalityFetal and neonatal abnormality 15 (5%)15 (5%)

NB:Incidence of Hyperthyroidism in pregnancy app 0.24%NB:Incidence of Hyperthyroidism in pregnancy app 0.24%

Outcome of Poorly Treated Hyperthyroidism Outcome of Poorly Treated Hyperthyroidism in Pregnancyin Pregnancy

MATERNALMATERNAL

MiscarriageMiscarriage

Placenta abruptioPlacenta abruptio

Preterm deliveryPreterm delivery

Congestive Ht failureCongestive Ht failure

Thyroid StormThyroid Storm

Pre-eclampsiaPre-eclampsia

FETALFETAL

HyperthyroidismHyperthyroidismNeonatal Neonatal hyperthyroidismhyperthyroidismPrematurityPrematurityIUGRIUGRFetal death Fetal death /stillbirth/stillbirthFetal abnormalitiesFetal abnormalities

Causes of Thyrotoxicosis in PregnancyCauses of Thyrotoxicosis in Pregnancy

Graves’ diseaseGraves’ disease TMNG, toxic adenomaTMNG, toxic adenoma ThyroiditisThyroiditis Hydatiform moleHydatiform mole Gestational hCG-asscociated ThyrotoxicosisGestational hCG-asscociated Thyrotoxicosis

Hyperemesis gravidarum Hyperemesis gravidarum hCG hCG 60% 60% TSH, 50% TSH, 50% FT4 FT4 Resolves by 20 wks gestationResolves by 20 wks gestation Only Rx with ATD if persists > 20 wkOnly Rx with ATD if persists > 20 wk

Pregnant & Suppressed TSH

TSH < 0.1 TSH 0.1 – 0.4

Recheck in 5 wks

FT4, FT3, T4, T3Thyroid Ab’sExamine

NormalizesStill suppressed

• Very High TFT’s:• TSH undetectable• very high free/total T4/T3• hyperthyroid symptoms • no hyperemesis

• TSH-R ab +• orbitopathy• goitre, nodule/TMNG• pretibial myxedema

Treat Hyperthyroidism (PTU)

Hyperemesis Gravidarum

Abnormal TFT’s past 20 wk

Don’t treat with PTU

Treatment of Hyperthyroidism in PregnancyTreatment of Hyperthyroidism in PregnancyAim for high-normal to slightly elevated hormone levelsAim for high-normal to slightly elevated hormone levels

T4 150-230 nM, T3 3.8-4.6 nM, FT4 26-32 pMT4 150-230 nM, T3 3.8-4.6 nM, FT4 26-32 pM

Confirm diagnosisConfirm diagnosis

No RAI ever (destroy fetal thyroid)No RAI ever (destroy fetal thyroid)

Start propylthiouracil or other ATDStart propylthiouracil or other ATD

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

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

Treatment of Hyperthyroidism in PregnancyTreatment of Hyperthyroidism in Pregnancycontinued….continued….

Check TSAb at 36 wks. GestationCheck TSAb at 36 wks. Gestation

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

If allergy/Neutrogena on PTU: 2If allergy/Neutrogena on PTU: 2ndnd trimester trimester thyroidectomythyroidectomy

Review postpartum - check for exacerbationReview postpartum - check for exacerbation

Effect of Antithyroid DrugsEffect of Antithyroid Drugsin Pregnancy on Offspringin Pregnancy on Offspring

Messer et al Acta Endoc. 1990, 123:311-316SMesser et al Acta Endoc. 1990, 123:311-316S

Studied 17 children of 13 hyperthyroid mothers Studied 17 children of 13 hyperthyroid mothers (ATD) and 25 children of 15 euthyroid mothers 7-(ATD) and 25 children of 15 euthyroid mothers 7-11 years after birth11 years after birth

No differences between groups in clinical/mental No differences between groups in clinical/mental psychological developmentpsychological development

Similar to data fromSimilar to data from1) McCarrol et al. Arch Dis Child 1976, 51:532-5361) McCarrol et al. Arch Dis Child 1976, 51:532-5362) Burrow et al. Yale J Biol Med 1978, 51: 151-1562) Burrow et al. Yale J Biol Med 1978, 51: 151-156

Thyrotoxicosis & LactationThyrotoxicosis & Lactation

ATD generally don’t get into breast milk ATD generally don’t get into breast milk unless at higher doses:unless at higher doses:

PTU > 450-600 mg/dPTU > 450-600 mg/d MTZ > 20 mg/dMTZ > 20 mg/d

Generally safeGenerally safe Take ATD dose just after breast-feedingTake ATD dose just after breast-feeding

Should provide 3-4h interval before lactates Should provide 3-4h interval before lactates againagain

Patterns of Thyroid Function Post Partum

From 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 TestingIndications for TestingThyroid Function in PregnancyThyroid Function in Pregnancy

On T4 prior to gestationOn T4 prior to gestation

History of autoimmune thyroid diseaseHistory of autoimmune thyroid disease+ve thyroid autoantibodies+ve thyroid autoantibodiesPrevious postpartum thyroiditisPrevious postpartum thyroiditisGraves’ disease in remissionGraves’ disease in remission

+ve FH autoimmune thyroid disease+ve FH autoimmune thyroid disease

Type 1 DM and/ other autoimmune diseaseType 1 DM and/ other autoimmune disease

Previous neck irradiation/ partial Previous neck irradiation/ partial thyroidectomy [decreased thyroid reserve]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 <10 mIu/liter, Free t4 : Normal

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 µg/dl) by WHO

•Lymphocytic 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/liter

Comes 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 symptoms

•May have wt gain, cold intolerance, lethargy, constipation, edema etc.

•Asymptomatic

Lab Investigations

Free T4

TSH

Antithyroid 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 and

In between in the second trimester

Normal 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 and

TSH > 3.5 in the Second and Third Trimester

With normal Free T4

…Should be considered as Subclinical Hypothyroidism

Obstet gynecol 2005;106:753-757

Evidence :

Repercussion of Hypothyroid: Maternal aspect

• Infertility

•Abortion

•Anemia

•Hypertension (Gestational)

•Placental abruption

•PPH

J Med Screen 7:127-130

Repercussion of Hypothyroid: Fetal aspect

•Premature birth

•LBW (30 %)

•ARDS

•Cognitive impairment of the baby

•Abnormal brain development

•Increased perinatal mortality (12 %)

•Psychoneurological impairment, Low I.Q. etc

J Med Screen 7:127-130

Endocrine 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 dose

•Non Pregnant 1.7 – 2.0 µg/kg/day, increased upto

2.0 -2.4 µg/kg/day

•New onset hypothyroid should be initiated with higher dose

•100 – 150 µg 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 TSH

•Dose 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 treated

•Treatment is very safe and Effective. Drug interaction

with Calcium and Ferrous Sulfate ( ↓ absorption)

•Usually life long

•New 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 screeningNeonatal screening

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

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

Unfortunately the clinical manifestation is often Unfortunately the clinical manifestation is often latelate

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

Procedure of screeningProcedure of screening

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

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

For detection of CH TSH is estimatedFor detection of CH TSH is estimated

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

SCH – INMU ExperienceSCH – INMU Experience

Period of Period of screen-screen-

-ing-ing

No. of No. of babies babies screen-edscreen-ed

No. of No. of positive positive babiesbabies

No. of No. of babies babies detecteddetected

Incidence of Incidence of CHCH

1999-1999-20082008

9831498314 10941094 3838 1:25871:2587

Thank YouThank You

20.19 20.19 Thyroid disease in pregnancyThyroid disease in pregnancy Normal pregnancyNormal pregnancy Trimester-specific normal Trimester-specific normal ranges:ranges: should be used to interpret thyroid function test results in pregnancy. In the first should be used to interpret thyroid function test results in pregnancy. In the first trimester, TSH is lower and free free Ttrimester, TSH is lower and free free T44 and T and T33 higher, in part due to thyroid stimulation by higher, in part due to thyroid stimulation by human chorionic gonadotrophin (hCG). In later pregnancy, free Thuman chorionic gonadotrophin (hCG). In later pregnancy, free T44 and T and T33 are lower. Binding are lower. Binding globulin levels are induced by oestrogen, so total Tglobulin levels are induced by oestrogen, so total T44 and T and T33 levels are invariably high. levels are invariably high.

Iodine requirements:Iodine requirements: increased in pregnancy. The World Health Organization (WHO) increased in pregnancy. The World Health Organization (WHO) recommends minimum intake of 200 μg/day. recommends minimum intake of 200 μg/day.

Screening of thyroid function and autoantibodies:Screening of thyroid function and autoantibodies: not recommended for every woman, not recommended for every woman, but should be performed in first trimester in those with a personal or family history of thyroid 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 disease, goitre, other autoimmune disease including type 1 diabetes, or when there is clinical suspicion of thyroid dysfunction. suspicion of thyroid dysfunction.

ThyrotoxicosisThyrotoxicosis Hyperemesis gravidarum:Hyperemesis gravidarum: associated with thyrotoxic biochemistry, associated with thyrotoxic biochemistry, sometimes requiring antithyroid drugs. sometimes requiring antithyroid drugs.

Subclinical thyrotoxicosis:Subclinical thyrotoxicosis: not usually treated, to avoid fetal hypothyroidism. not usually treated, to avoid fetal hypothyroidism. Anti-thyroid drugs:Anti-thyroid drugs: propylthiouracil is first choice. propylthiouracil is first choice. HypothyroidismHypothyroidism Preterm labour and impaired cognitive development in the offspring:Preterm labour and impaired cognitive development in the offspring:

may be associated with even subclinical hypothyroidism. may be associated with even subclinical hypothyroidism. Thyroxine replacement therapy dose requirements:Thyroxine replacement therapy dose requirements: increase by 30-50% from early in increase by 30-50% from early in

pregnancy. Monitoring to maintain TSH results within the trimester-specific reference range is pregnancy. Monitoring to maintain TSH results within the trimester-specific reference range is recommended in early pregnancy and at least once in each trimester. recommended in early pregnancy and at least once in each trimester.

Post-partum thyroiditisPost-partum thyroiditis Screening:Screening: not recommended for every woman, but thyroid function 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, 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 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. anti-thyroid peroxidase antibodies, or when there is clinical suspicion of thyroid dysfunction.