thyroid and pituitary disease in pregnancy · 2014-09-18 · thyroid disease in pregnancy catherine...

Thyroid diseaseThyroid disease

in pregnancyin pregnancy

Catherine NelsonCatherine Nelson--PiercyPiercy

Consultant Obstetric PhysicianConsultant Obstetric Physician

Guy’s & St Thomas’ Trust &Guy’s & St Thomas’ Trust &

Queen Charlotte’s HospitalQueen Charlotte’s Hospital

London, UKLondon, UK

Thyroid disorders in pregnancyThyroid disorders in pregnancy

Physiological adaptationPhysiological adaptation

Interpretation of TFTs in pregnancyInterpretation of TFTs in pregnancy

HypothyroidismHypothyroidism

ThyrotoxicosisThyrotoxicosis

Postpartum thyroiditisPostpartum thyroiditis

Physiological adaptationPhysiological adaptation

2 x increase in urinary iodine excretion2 x increase in urinary iodine excretion

3 x increase in iodine uptake by the thyroid3 x increase in iodine uptake by the thyroid

Diversion of iodine to fetoDiversion of iodine to feto--placental unitplacental unit

Increased maternal iodine requirementsIncreased maternal iodine requirements

Increase in thyroid volumeIncrease in thyroid volume

Fetus dependent on maternal thyroxine < 12 Fetus dependent on maternal thyroxine < 12

weeksweeks

Normal thyroid function in pregnancy

Maternal TBG means total T3 and T4

hCG results in TSH in 1st trimester

T4 in 2nd and 3rd trimester

Normal ranges for fT4 (pmol/L) and TSH (mu/l)

Non-pregnant 9-23 0-4

1st trimester 10-24 0.-1.6

2nd trimester 9-19 0.1-1.8

3rd trimester 7-15 0.7-7.3

Biochemical thyrotoxicosisBiochemical thyrotoxicosis Biochemical thyrotoxicosisBiochemical thyrotoxicosis

Suppressed TSHSuppressed TSH

High fTHigh fT4 4 & fT& fT33

Correlates with severity of hyperemesisCorrelates with severity of hyperemesis

Goodwin et al. AJOG 1992; 167: 648Goodwin et al. AJOG 1992; 167: 648

Abnormal TFTs in 40Abnormal TFTs in 40--60% with HG60% with HG

Correlates with hCGCorrelates with hCG

Increased oestradiol in HG vs controlsIncreased oestradiol in HG vs controls

Goodwin et al. J Clin End Metab 1992; 75: 1333Goodwin et al. J Clin End Metab 1992; 75: 1333

Gestational thyrotoxicosis vs GravesGestational thyrotoxicosis vs Graves

Graves / HyperthyroidismGraves / Hyperthyroidism

Symptoms pre date Symptoms pre date

pregnancypregnancy

Thyroid stimulating Thyroid stimulating

antibodiesantibodies

GoitreGoitre

TremorTremor

Thyroid eye diseaseThyroid eye disease

Gestational /HyperemesisGestational /Hyperemesis

Onset first trimesterOnset first trimester

Improves with treatment of Improves with treatment of

hyperemesishyperemesis

No thyroid stimulating No thyroid stimulating

antibodiesantibodies

No preNo pre--pregnancy thyroid pregnancy thyroid

diseasedisease

Free T4 v highFree T4 v high

HypothyroidismHypothyroidism Affects around 1% of Affects around 1% of Pregnancies in EuropeansPregnancies in Europeans

TSH Screening studies TSH Screening studies (subclinical hypo(subclinical hypo--thyroidism) thyroidism)

0.3% Japan0.3% Japan

2.2% Europe2.2% Europe

2.5% USA2.5% USA

Usually identified and treated Usually identified and treated prepre--pregnancypregnancy

Usually due to Hashimoto’s Usually due to Hashimoto’s thyroiditis or treated thyroiditis or treated Thyrotoxicosis Thyrotoxicosis (surgery / (surgery / radioiodine / drugs)radioiodine / drugs)


Majority have antithyroid antibodiesMajority have antithyroid antibodies

Thyroid microsomal (peroxidase) antibodiesThyroid microsomal (peroxidase) antibodies

Women with antibodies convert from subclinical to clinical Women with antibodies convert from subclinical to clinical

hypothyroidism at 5%/yearhypothyroidism at 5%/year

Important to monitor for hypothyroidismImportant to monitor for hypothyroidism

Type 1 diabetes high incidence of subclinical hypothyroidism Type 1 diabetes high incidence of subclinical hypothyroidism

so monitor in pregnancyso monitor in pregnancy

Of 82 type 1 diabetics 22.5% in T1 and 18.4% in T3 had Of 82 type 1 diabetics 22.5% in T1 and 18.4% in T3 had

thyroid dysfunction (usually subclinical hypothyroidism)thyroid dysfunction (usually subclinical hypothyroidism)

Gallas et al 2002Gallas et al 2002


Clinically overt hypothyroidism rare in pregnancy Clinically overt hypothyroidism rare in pregnancy due to subfertilitydue to subfertility

Symptoms and signs similar to nonSymptoms and signs similar to non--pregnantpregnant

Fatigue, weakness, cold intolerance, Fatigue, weakness, cold intolerance, constipation, dry skin etcconstipation, dry skin etc

Overt hypothyroidism increased risk of Overt hypothyroidism increased risk of miscarriage, premiscarriage, pre--eclampsia, FGReclampsia, FGR

Monitor fetal growthMonitor fetal growth

Hypothyroidism in pregnancyHypothyroidism in pregnancy

Good controlGood control normal maternal course normal maternal course

thyroid function test in each trimesterthyroid function test in each trimester

if euthyroid, T4 requirements usually stableif euthyroid, T4 requirements usually stable

monitor fetus/ neonatemonitor fetus/ neonate

Overt maternal hypothyroidismOvert maternal hypothyroidism intellectual impairment in childhood intellectual impairment in childhood

prepre--eclampsiaeclampsia

FGR, abruption, prematurityFGR, abruption, prematurity

fetal deathfetal death

J Clin Endocrinol Metab. 2012

U.S. Preventive Service Task Force (USPSTF)

I’m hypothyroid. Should I continue to take my levothyroxine during my pregnancy?I’m hypothyroid. Should I continue to take my levothyroxine during my pregnancy?

Yes! In factYes! In fact

, of your pregnancy. Check with your GP., of your pregnancy. Check with your GP.

I’m hyperthyroid and take I’m hyperthyroid and take carbimazolecarbimazole. Is this okay during pregnancy?. Is this okay during pregnancy?

PropylthiouracilPropylthiouracil is the medication of choice during pregnancy for the first trimester only in is the medication of choice during pregnancy for the first trimester only in

hyperthyroid (overactive) patients. hyperthyroid (overactive) patients. CarbimazoleCarbimazole is the drug used during the rest of is the drug used during the rest of

pregnancy.pregnancy.

I have been treated with radioiodine for an overactive thyroid. Will this harm the baby?I have been treated with radioiodine for an overactive thyroid. Will this harm the baby?

You should not get pregnant for 6 months after this treatment. If you are in doubt check You should not get pregnant for 6 months after this treatment. If you are in doubt check

with your GPwith your GP

I have Graves’ disease treated by surgery and am taking levothyroxine. Are there any I have Graves’ disease treated by surgery and am taking levothyroxine. Are there any

problems for the baby?problems for the baby?

. There is also a . There is also a

very small chance that the baby could be born with an overactive thyroid but if so it would very small chance that the baby could be born with an overactive thyroid but if so it would

only last for about one month and can be treated easily. A blood test during the later part only last for about one month and can be treated easily. A blood test during the later part

of pregnancy will indicate if there is a high risk of this.of pregnancy will indicate if there is a high risk of this.

Studies of maternal hypothyroxinaemia Studies of maternal hypothyroxinaemia

and subsequent IQ of their offspringand subsequent IQ of their offspring

Haddow et al. Haddow et al. NEJMNEJM 1999; 341: 5491999; 341: 549--555555 25,216 women screened in 2nd trimester

62 with highest TSH compared with 124

controls

2/15 psychometric tests in the offspring aged

7-9 yrs showed impaired outcome

effect more marked if not taking thyroxine

i.e. impaired function in 8 tests and 7

point in IQ

Studies of maternal hypothyroxinaemia and

subsequent IQ of their offspring

Pop et al. Clin Endo 2003; 59: 282-288 prospective 3 year follow-up study

compared 57 cases with FT4 <10th percentile

and normal TSH at 12/40 with 58 controls

thyroid function test in each trimester

Bayley scales of infant development aged 1 and 2

children had delayed mental and motor function

BUT if maternal FT4 increased at 24 and

32/40 the scores did not differ from controls

Kooistra et al. Pediatrics 2006; 117: 161-167 studied 1361 pregnant women with normal TSH

compared 108 neonates of mothers with FT4 <10th

percentile, and 96 from controls

Neonatal Behavioural Assessment Scale used at 3 wks

Regression analysis showed that T1 maternal FT4 was

a significant predictor of NBAS score

Did not find any effect for TSH or FT4 later in gestation

Studies of maternal hypothyroxinaemia and

subsequent IQ of their offspring

Management of treated hypothyroidismManagement of treated hypothyroidism

No evidence for No evidence for routineroutine increase in thyroxine increase in thyroxine

during pregnancyduring pregnancy Monitor and adjust dose of T4 as requiredMonitor and adjust dose of T4 as required

50/100 required dose increase (Kothari & Girling, 2008)50/100 required dose increase (Kothari & Girling, 2008) 11 diagnosed just before pregnancy11 diagnosed just before pregnancy

9 raised TSH before conception9 raised TSH before conception

8 sub8 sub--optimal complianceoptimal compliance

Other studies range from 20Other studies range from 20--75% 75% Girling JC & de Swiet M. BJOG Girling JC & de Swiet M. BJOG

1992; Mandel NEJM 1990; 1992; Mandel NEJM 1990;

Little thyroxine crosses the placentaLittle thyroxine crosses the placenta

Does thyroxine requirement increase in Does thyroxine requirement increase in

pregnant women with hypothyroidism?pregnant women with hypothyroidism?

Alexander et al. Alexander et al. NEJMNEJM 2004; 351: 2412004; 351: 241--249249 prospective measurement of TFT, HCG, prospective measurement of TFT, HCG,

estradiol preestradiol pre--conception and in 1conception and in 1stst trimester trimester

20 pregnancies in 19 women20 pregnancies in 19 women

thyroxine dose thyroxine dose if TSH > 5.0if TSH > 5.0U/mlU/ml

6 cases had Ca 6 cases had Ca -- if TSH > 0.5if TSH > 0.5U/mlU/ml

Results:Results: 17/20 (85%) pregnancies required 17/20 (85%) pregnancies required

increased thyroxineincreased thyroxine

mean thyroxine requirement mean thyroxine requirement by 47%by 47%

Does inadequate Does inadequate thyroxinethyroxine replacement influence replacement influence

subsequence intelligence of the offspring?subsequence intelligence of the offspring?

Lazarus et al. – NEJM 2012; 366:493-501

21846 women screened at 12/40

Randomly allocated to screened (results revealed and thyroxine

given if TSH > 97.5th C or fT4 < 2.5th C) or control

390 screened; 404 control: no diff in IQ or RR of low IQ at 3 years of

age

Sensible to screen all women with hypothyroidism at booking

and before conception to ensure TSH is normal and FT3 and FT4

are not low

Ideally aim for fT4 level at the upper end of the normal range

(gestation specific)

there are no studies to show that T4 treatment in pregnancy

will influence subsequent long-term intelligence

Hypothyroidism Summary:Hypothyroidism Summary:

Practical managementPractical management

PrepregnancyPrepregnancy

Good control and reassure re safetyGood control and reassure re safety

AntenatallyAntenatally

Monitor fT4 / TSH at first visit and in each trimester Monitor fT4 / TSH at first visit and in each trimester

(more frequently if inadequate replacement)(more frequently if inadequate replacement)

Increase dose of T4 if required…Remember to avoid Increase dose of T4 if required…Remember to avoid

taking T4 with antacids or irontaking T4 with antacids or iron

PostpartumPostpartum

Review treatment and repeat TFTsReview treatment and repeat TFTs

Hyperthyroidism in pregnancyHyperthyroidism in pregnancy

In poorly / uncontrolled patients increased risk of In poorly / uncontrolled patients increased risk of preeclampsia, FGR, preterm preeclampsia, FGR, preterm labourlabour, high output cardiac , high output cardiac failurefailure

Study of 19 patients with uncontrolled thyrotoxicosis Study of 19 patients with uncontrolled thyrotoxicosis ((MontoroMontoro and and MestmanMestman 1981)1981)

15 preterm delivery15 preterm delivery

5 neonatal deaths5 neonatal deaths

5 severe neonatal morbidity5 severe neonatal morbidity

Often improves in second / third trimestersOften improves in second / third trimesters

Graves Graves ophthalmopathyophthalmopathy not affected by pregnancynot affected by pregnancy


Encountered in about Encountered in about

0.2% of pregnancies and 0.2% of pregnancies and

1% of women in 1% of women in

reproductive age groupreproductive age group

Most commonly Graves Most commonly Graves

disease rather than toxic disease rather than toxic

(multi)nodular goitre(multi)nodular goitre

Graves: Thyroid Graves: Thyroid

stimulating antibodiesstimulating antibodies

Often diagnosed in 1st Often diagnosed in 1st

year after deliveryyear after delivery


Pregnancy mimics hyperthyroidismPregnancy mimics hyperthyroidism

Heat intolerance,palpitationsHeat intolerance,palpitations

Emotional disturbanceEmotional disturbance

Bowel disturbanceBowel disturbance

Goitre, palmar erythemaGoitre, palmar erythema

Increased total T4, decreased TSHIncreased total T4, decreased TSH

But not: But not: weight loss, eye signs, pretibial myxoedemaweight loss, eye signs, pretibial myxoedema

Hyperthyroidism in pregnancy: Hyperthyroidism in pregnancy:

TreatmentTreatment PTU or carbimazole: both safePTU or carbimazole: both safe

Not teratogenicNot teratogenic

Aplasia cutis linked to Aplasia cutis linked to

CarbimazoleCarbimazole

Side effects: eg agranulocytosis, Side effects: eg agranulocytosis,

thrombocytopenia, hepatitisthrombocytopenia, hepatitis

Doses less than 150mg/day PTU & Doses less than 150mg/day PTU &

15mg/day Carbimazole will not 15mg/day Carbimazole will not

affect the fetusaffect the fetus

Breast feeding okBreast feeding ok

DO NOT BLOCK & REPLACEDO NOT BLOCK & REPLACE

Propranolol: initial treatment for Propranolol: initial treatment for

tachycardia and tremortachycardia and tremor

PTU vs CarbimazolePTU vs Carbimazole

CarbimazoleCarbimazole

Preferred in nonPreferred in non--pregnantpregnant

Longer half life and ? Better Longer half life and ? Better

compliance as once daily dosingcompliance as once daily dosing

Fewer major adverse events Fewer major adverse events

((agranulocytosisagranulocytosis))

Aplasia cutis very rareAplasia cutis very rare

PTUPTU Preferred for new treatment in Preferred for new treatment in

pregnancypregnancy

Short half life more frequent Short half life more frequent dosingdosing

More minor adverse events More minor adverse events (rashes)(rashes)

Less placental and breast transfer Less placental and breast transfer ( higher protein binding / less ( higher protein binding / less soluble)soluble)

Inhibits peripheral conversion of Inhibits peripheral conversion of T4 to T3T4 to T3

Hyperthyroidism and pregnancy: Hyperthyroidism and pregnancy:

treatmenttreatment

The place of surgeryThe place of surgery

Large goitreLarge goitre

Failed medical therapyFailed medical therapy

Side effects eg hepatitisSide effects eg hepatitis

No radioNo radio--iodine treatment in pregnancy and delay iodine treatment in pregnancy and delay pregnancy for at least 4 months afterwards pregnancy for at least 4 months afterwards

(NB diagnostic isotope scans should be avoided but if (NB diagnostic isotope scans should be avoided but if carried out risk of harm is low. If postpartum, avoid breast carried out risk of harm is low. If postpartum, avoid breast feeding for 24 hours)feeding for 24 hours)

Fetal ThyrotoxicosisFetal Thyrotoxicosis

Rare in contemporary practice especially if patient treated with Rare in contemporary practice especially if patient treated with antithyroid drugs. Beware post thyroidectomy / radioiodine ptsantithyroid drugs. Beware post thyroidectomy / radioiodine pts

DIAGNOSISDIAGNOSIS -- suspect if high maternal levels of TSIs / active suspect if high maternal levels of TSIs / active Graves’ DiseaseGraves’ Disease

Ultrasound Ultrasound -- Increased AFI / nonIncreased AFI / non--immune hydrops, FGR, fetal immune hydrops, FGR, fetal goitre, FHR > 160goitre, FHR > 160

FBS for TFTs to confirmFBS for TFTs to confirm

TREATMENTTREATMENT -- maternal carbimazole + thyroxinematernal carbimazole + thyroxine

PROGNOSISPROGNOSIS -- selfself--limiting after delivery but high mortality if limiting after delivery but high mortality if untreated in utero (50%)untreated in utero (50%)

Neonatal thyrotoxicosisNeonatal thyrotoxicosis

BMJ lesson of the week Smith et al 2000; 320: 1260BMJ lesson of the week Smith et al 2000; 320: 1260--11

Transplacental transfer of maternal auto Transplacental transfer of maternal auto antibodies possible even if mother antibodies possible even if mother previously treated with radioI / surgerypreviously treated with radioI / surgery

Take full history from women on thyroxineTake full history from women on thyroxine

Very rare 1 in 70 of 0.1Very rare 1 in 70 of 0.1--0.2%0.2%

Thyroid stimulating antibodies Thyroid stimulating antibodies

TBI index = TSH binding inhibiting IgTBI index = TSH binding inhibiting Ig

TBI > 30 predicts; >70 strongly predictsTBI > 30 predicts; >70 strongly predicts

Hyperthyroidism Summary:Hyperthyroidism Summary:

Practical ManagementPractical Management

PrepregnancyPrepregnancy

Optimize control and reassure re antithyroid drugsOptimize control and reassure re antithyroid drugs

Discuss switch to PTUDiscuss switch to PTU

AntenatallyAntenatally

Check TFTs, discuss safety of treatment and risk of uncontrolled diseaseCheck TFTs, discuss safety of treatment and risk of uncontrolled disease

Check TSI for risk of fetal hyperthyroidismCheck TSI for risk of fetal hyperthyroidism

Ultrasound for fetal assessmentUltrasound for fetal assessment

Postpartum Postpartum

Reassure re breast feeding if CBZ less than 15mg/day or PTU less than 150mg/day. Reassure re breast feeding if CBZ less than 15mg/day or PTU less than 150mg/day.

Check infant TFTs if higher doses givenCheck infant TFTs if higher doses given


Occurs in up to 10% of Occurs in up to 10% of allall pregnanciespregnancies

AntiAnti--microsomal antibodies and family history of microsomal antibodies and family history of autoimmune thyroid disease autoimmune thyroid disease (70% risk)(70% risk)

Type 1Type 1 diabetes increasediabetes increasedd riskrisk

Autoimmune thyroiditis with destruction of tissue and Autoimmune thyroiditis with destruction of tissue and release of Thyroid hormonerelease of Thyroid hormone

Lymphocytic infiltrate in the tissueLymphocytic infiltrate in the tissue

Small goitre frequentSmall goitre frequent


Presents 3Presents 3--6 months after delivery6 months after delivery

Transient hyper or hypothyroxinaemiaTransient hyper or hypothyroxinaemia

May be biphasic with hyper then hypothyroidismMay be biphasic with hyper then hypothyroidism

Diagnosis: TFTs and differentiate from Graves (no TSI, low uptake on isotope Diagnosis: TFTs and differentiate from Graves (no TSI, low uptake on isotope scan)scan)

Role of screening with post natal TFTsRole of screening with post natal TFTs

Often remits after a year but may progress to permanent hypothyroidism (30% in Often remits after a year but may progress to permanent hypothyroidism (30% in 4 years)4 years)

POSTPARTUM THYROIDITISPOSTPARTUM THYROIDITIS 2 FORMS2 FORMS

Destructive Destructive activation of previously subclinical thyroiditisactivation of previously subclinical thyroiditis

remits spontaneouslyremits spontaneously

low radioactive I uptakelow radioactive I uptake

Postpartum exacerbation of autoimmune Postpartum exacerbation of autoimmune Graves’ diseaseGraves’ disease high radioactive I uptakehigh radioactive I uptake

needs treatmentneeds treatment

POSTPARTUM THYROIDITISPOSTPARTUM THYROIDITIS

TREATMENTTREATMENT

Hyperthyroid phaseHyperthyroid phase

Beta blockers rather than antithyroid drugsBeta blockers rather than antithyroid drugs

Hypothyroid phaseHypothyroid phase

Only give thyroxine if symptomaticOnly give thyroxine if symptomatic

PROGNOSISPROGNOSIS

Tends to recur in subsequent pregnanciesTends to recur in subsequent pregnancies

25% progress to permanent hypothyroidism 25% progress to permanent hypothyroidism

within 5 yearswithin 5 years


BMJ 2000; 320:1513BMJ 2000; 320:1513

““...my vague acopia, the ebbing of my confidence, my ...my vague acopia, the ebbing of my confidence, my gradually increasing bulk, my madgradually increasing bulk, my mad--professor hair. My professor hair. My daytime naps...daytime naps...””

““...how can I repay my daughter for growing up with a ...how can I repay my daughter for growing up with a permanently exhausted mother?permanently exhausted mother?””

thyroid and pituitary disease in pregnancy · 2014-09-18 · thyroid disease in pregnancy catherine...

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