Transcript Thyroid and pregnancy - Josephine Carlos

Thyroid
Disease
in
Pregnancy
Josephine Carlos-Raboca, MD, FPCP, FPSEM
Section of Endocrinology, Diabetes and Metabolism
Makati Medical Center
Outline
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Thyroid Physiology in Pregnancy
Maternal
Fetal
Gestational Thyrotoxicosis
Grave’s Disease in Pregnancy
Hypothyroidism
Postpartum thyroiditis
H-P
Thyroid
Axis
Maternal Physiology
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Thyroid circulation
Thyroxine clearance rate
Dietary iodine requirement
hCG mediated thyroid stimulation
Thryoxine binding globulin(TBG)
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Increased serum (TBG) due to
estrogen induced sialylation of
the protein which leads to
decreased renal clearance and
longer half life ( from normal 15
minutes, increased to 3 days)
Effects of Increased TBG
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Increased total T3 and total T4
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Free hormone assay are thus
preferred
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FT4I should be done if free hormone
determination is not available
Thyroid Disposal/Clearance
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Iodinase
Type 1 – liver, kidney, thyroid
converts T4 to T3
Type 2 - pituitary, brown fat, brain
converts T4 to T3
Type 3 – placenta brain and skin
converts T4 to rT3 and T3 to T2
Increased demand for iodine
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Increased GFR
Increased iodide clearance by
the kidney
Siphoning of maternal iodide by
the fetus
WHO: RDA 200 ug/day during
pregnancy
Increased demand for thyroid
hormones
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Increased iodide clearance
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Transplacental transfer of T4
and iodine
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Placental degradation of T4
Thyroid stimulation by chorionic
gonadotropin
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Similarity of TSH and HCG
alpha subunit is common to
TSH, hCG, FSH and LH
Beta subunit is specific but
some similarity in TSH and hCG
HCG stimulates TSH receptor
has weak thyrotropic activity
1/10000 of TSH
Thyroid stimulation by hCG
Physiologic changes in pregnancy
and thyroid function test
Physiologic change
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Increased TBG
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First trimester hCG
elevation
Increased plasma
volume
Increased plasma type
3 deiodinase
Thyroid enlargement
Increased iodine
clearance
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Thyroid function test
change
 Elevation of T4 and T3
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Elevated FT4 and
suppressed TSH
Increased T4 and T3
pool size
Potential increased T4
and T3 degradation
Increased serum Tg
Reduced hormone
production in iodine
insufficient
Fetal Ontogeny and
Physiology
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T3 dependent CNS
development
Thyroid organogenesis, iodine
concentration and
hormonogeneiss
Dependence on maternal
iodothyronines
Thyroid Deficiency in the
Fetus and Neonate
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2 sources of thyroid hormones in
fetus
Fetal thyroid which begins synthesis
at 10 – 12 weeks
Maternal thyroid hormones
-current evidence shows substantial
transfer across the placenta
-placenta contains deiodinase that
converts T4 to T3
Thyroid Tests
Thyroid Hormones –
TT3,TT4, FT3, FT4
FT4I, TSH
Thyroid antibodies
TPOAb,TgAb,
TSHRAb (TSI,TBII)
Hyperthyroidism
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Etiologies
Clinical presentations
Diagnosis
Maternal and fetal
consequences
Therapeutic options
Hyperthyroidism
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Occurs in 1-2/1000 pregnancies
Causes of
hyperthyroidism in pregnancy
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Grave’s Disease
Gestational Thyrotoxicosis
Hydatidiform mole
Silent Thyroiditis
Multinodular toxic goiter
Toxic adenoma
Subacute thyroiditis
Iatrogenic hyperthyroidism\Iodine
induced hyperthyroidism
Case 1
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Leah a 25 year old G1P0 female
was confined on her 10th week
of gestation because of nausea
and vomiting several times daily
requiring parenteral fluids. She
was referred to you for
endocrine evaluation. 2 weeks
earlier she was confined for the
same problem and gastroscopy
was done which was negative.
Case 1
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She has not had any weight
gain since start of
pregnancy. She had no
history of thyroid problem.
PE showed no goiter, no
tremors nor eye signs. BP
was normal. Pulse rate was
92/minute and was afebrile.
Thyroid Function tests
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FT3 RIA 4.74 pmol/l (4.2-12)
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FT4 RIA 25 pmol/l (8.8-33)
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TSH IRMA 0.08 uIU/ml
(0.35 – 5.0)
Question
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What is your likely diagnosis?
differential diagnosis?
Conditions with suppressed
TSH
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Increased thyroid hormone
production
Grave’s Disease
Autonomous Thyroid nodule
Hyperemesis gravidarum
Molar Pregnancy
First trimester pregnancy
Conditions with Suppressed
TSH
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Normal or Low Thyroid
Production
Post therapy of
hyperthyroidism
Pituitary/hypothalamic
disease
Severe nonthyroidal illness
Gestational Thyrotoxicosis
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Spectrum of hCG-induced
hyperthyroidism which ranges
from an isolated subnormal TSH
concentration(up to 18%) to
elevation of free thyroid
hormone levels in the clinical
setting of hyperemesis
gravidarum
Question 2
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Will you treat?
Treatment is not generally
recommended.
Is vomiting related to
hyperthyroidism?
Not likely
Vomiting seen in hypothyroid,
euthyroid and hyperthyroid, probably
related to hCG induced elevation of
estradiol
Question 3
How will you follow up?
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Repeat thyroid function tests after
20th week
If persistent hyperemesis and
elevated thyroid hormones and
suppressed TSH after 20 weeks of
gestation consider antithyroid
treatment as this may be mild
Grave’s disease.
Gestational Thyrotoxicosis
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Transient
Symptoms usually resolve within 10
weeks of diagnosis
Differs from Grave’s
Non-autoimmune etiology (hCG
induced) with negative anti thyroid
and anti TSH receptor antibody
Negative goiter
Resolution in almost all patients after
20 weeks of gestation
No ophthalmopathy
Case 2
Luisa a 30 year old G2P1
female was referred to you on
her 12th week of pregnancy
because of hypertension,
palpitations and weight loss of
5 lbs since start of pregnancy.
BP was 145/95 despite bed
rest. Cardiologist gave
apresoline 10 mg tid.
Urinalysis was negative for
protein.
Case 2
Prominent eyes were noted so
endocrine referral was sought.
Further history taking revealed
hyperthyroidism 3 years ago
with ATD treatment for 1 year.
On PE, BP was 140/90 PR
110/minute, with positive lid
retraction, diffuse goiter and
bruit and fine hand tremors.
No leg edema
Thyroid tests
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FT3 RIA 15 pmol/l ( 4.2-12)
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FT4RIA 55 pmol/l (8.8 – 33)
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TSH-IRMA 0.002 uIU/L (0.355.0)
Question 1
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What is your likely diagnosis?
Chronic hypertension
Grave’s – eye signs, goiter,
bruit
Diagnosis of Grave’s
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Symptoms of hypermetabolic state
Sometimes goiter with bruit
Eye signs
Elevated free T3 and freeT4
Suppressed TSH
RAIU elevated(not done in pregnant)
Elevated TgAb and TPOAb
TSH-R Ab positive
Grave’s Hyperthyroidism
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Positive thyroid antibodies
TPOAb
TgAb
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TSHRAb (TSI)
Unusual to present for the first
time in pregnancy
Symptoms usually antedate
pregnancy for a few months
Question 2
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What are other tests are useful
to confirm your diagnosis if
available?
TPOAb
TgAb
TSHRAb/TSI – to differentiate
from silent thyroiditis
Question 3
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What is your treatment of
choice?
Which ATD is best?
PTU favored because:
 MMI has been associated with aplasia
cutis a congenital scalp defect
(Mandel 1994 Thyroid 4:129-133)
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PTU is heavily protein bound and believed
to cross placenta less
6 women without history of thyroid disease
received a single injection of either
(35S)MMI or PTU in the first half of
pregnancy prior to a therapeutic abortion
(Marchant 1977 JCEM 45:1187-1193)
Which ATD is best?
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an in vitro study showed two drugs
equally passed placental barrier
(Mortimer 1997 JCEM
82:3099)
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no prospective RCTs compared
maternal and fetal outcome;
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retrospective case series have
shown that the rate of fetal
hypothyroidism is similar with both
drugs
(Wing 1994 Am J Obstet Gynecol 170:90)
What is the dose of ATD in
pregnant?
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Initial dose may vary according
to severity of maternal
hypothyroidism
Use the lowest dose possible to
maintain maternal euthyroidism
15-10 mg MMI or 300 mg PTU
In 30% ATD may be
discontinued in last trimester
Effect of ATD overdose on
fetus
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fetal goiter which may lead to
respiratory distress
Intrauterine growth retardation
4 studies showed no defects in
either cognitive or somatic
development of children
exposed to maternal ATD in
utero but maternal thyroid
hormone levels not known
PTU vs MMI
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Duration of action
Potency
Placental passage
Breast milk
Toxicity
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Other
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short
less
about 1
less
blocks T4 to
T3
long
more
prob 1
more
aplasia
cutis
Question 4
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What are your treatment goals?
Guidelines for clinical
management of maternal
hyperthyroidism during pregnancy
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Use the lowest dose of ATDs to
maintain maternal thyroid
hormone levels in the upper 1/3
of the normal range to slightly
elevated during pregnancy.(FT4
23-25 pmol/l or 1.8-2.0 ng/dl)
Guidelines for clinical
management of maternal
hyperthyroidism during pregnancy
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Check maternal thyroid hormone
levels monthly, using free T4
levels
Measure TSI/TBII at 26-28 weeks
Consider fetal ultrasound at 26-28
weeks if the TSI/TBII levels are
elevated or if Doppler detects fetal
tachycardia
Other forms of treatment
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Beta adrenergic blockers –may be
used transiently to control adrenergic
symptoms ( small series where
propranolol was prescribed for 6-12
weeks reported higher rates of
miscarriages)
Iodides should not be used but may
be used if needed to prepare for
thyroidectomy
Surgery in latter half of second
trimester
Question 5
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What are maternal and fetal
consequences of
hyperthyroidism?
Pregnancy complications reported
in hyperthyroid women
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Maternal
 pre-ecclampsia(14% if untreated vs
6%for treated)
 Gestational hypertension
 pregnancy-induced hypertension
 placental abruption
 Congestive heart failure(63% if
untreated)
 Preterm labor(88% if untreated; 25%
partial treatment 8% if adequate
treatment)
Other potential complications of
uncontrolled hyperthyroidism
Maternal
Anemia
 Miscarriage
 Thyroid storm
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Fetal
prematurity
Pregnancy complications reported
in hyperthyroid women
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Fetal
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Small for gestation age
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Intrauterine growth retardation
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Stillbirth (50% if untreated, 16%
partial treatment)
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Fetal/neonatal hyperthyroidism
Case 3
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Marissa a 32 year old G5P2 Ab2
female was referred on her 8th
weeks of pregnancy because of
easy fatigability and
hypertension. Her weight gain
was 5 lbs in 8 weeks.
Case 3
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Patient had radioactive
treatment 3 years ago for
Grave’s disease and is on
levthyroxine replacement 75
mcg/day. Last thyroid tests
were 10 weeks ago and were
normal. PE showed BP 145/95
Pulse rate was 70/minute no
goiter, DTR were hypoactive.
Thyroid tests
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FT3RIA 3.8 pmol/L (4.2 – 12)
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FT4 RIA 8.8 pmol/l (8.8 – 33)
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TSHIRMA 25 uIU/ml (0.35 – 5.0)
Question 1
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What is your diagnosis?
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Hypothyroidism in Pregnancy
Hypertension
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Is this expected?
Diagnosis of hypothyroidism
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Nonspecific signs
fatigue
Weight gain
Constipation
Edema
TSH is first line screening test
Thyroid hormone therapy
during pregnancy
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Increased requirement during
pregnancy
By about 45% in one study (12
patients)Mandel et al NEJM
1990
By 67 ug/day in another study
Appeared early in first trimester
and throughout pregnancy
Question 2
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How will you adjust your dose?
Treatment of hypothyroidism
in pregnancy
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Initial dosage 150 mcg/day or
2 mcg/kg actual body weight
Readjustment
TSH high but <10mU/ml add
50 mcg/day
TSH>10<20 add75mcg/day
TSH>20
add 100 mcg/day
guidelines for clinical
management of maternal
hypothyroidism
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Hashimoto’s thyroiditis – 25%
increment
Subclinical hypothyroidism may not
require increment
TSH should be monitored every 8-10
weeks or if a dose adjustment is
made, should be checked 4 weeks
later. 25% of those with initial normal
serum TSH levels in the first
trimester and 37% of those with
initial normal serum TSH in second
trimester will later require dosage
increases
Hypothyroidism
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Patients should be instructed to
separate levothyroxine ingestion and
prenatal vitamin containing iron or
iron supplements by at least 6 hours
After delivery, the levothyroxine dose
should be reduced to prepregnancy
dosage and the serum TSH level
should be rechecked at 6 weeks
postpartum
Question 3
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The patient asks you on
possible consequences to baby
What will you tell her?
Complications in Pregnant
Hypothyroidism
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Maternal
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Gestational hypertension- 22% in overt,
15% in subclinical,7.6% in general
population
Pre-ecclampsia
Pregnancy induced hypertension
Postpartum hemorrhage
Anemia- 31% in overt, 0% in subclinical
Placenta abruption 18% in overt, 0% in
subclinical
Maternal consequence of
Hypothyroidism
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25756 singleton pregnancies
2.3% had subclinical hypothyroidism
Placental abruption occurred more
often (RR 3.9, 95% CI 1.1-8.2
Preterm birth (<34 weeks) more
common (RR 1.8, 95% CI 1.1 -2.9)
Casey Obstetric Gynecol 2005;105:239-245
Complications In Pregnant
Hypothyroidism
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Fetal
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Small for gestational age – 22% in
overt, 9% in subclinical, 6-8% in general
population
Stillbirth – 56% in overt, 6% in
subclinical
Transient congenital hypothyroidism due
to transplacental passage of maternal
blocking antibodies
Possible impairment in cognitive
function
Impaired somatic development
Hypothyroidism in pregnancy
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9403 singleton pregnancies
TSH >6mU/L in 2%
Fetal death OR 4.4 CI 1.9-9.5
Allan WC J Med Screening 2000;7:127
Consequence of
hypothryoidism in pregnancy
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TSH measured in 25216 pregancnt women
47 women TSH >99.7th tile
15 with TSH 98-99th tile + low T4
124 matched women with normal TSH
At 7-9 y/o had 15 test for intelligence,
attention, language, reading abililty, school
performance and visual motor performance
Haddow NEJM 1999:341;549
Haddow study
in 62 children born to women with
TSH mean 13.4 vs 1.4 in control on
17th week of gestation
FT4 0.7 vs 1 ng/dl
 Lower performance on all 15 tests,
IQ average 4 points lower
 More had IQ <85 (15% vs 5%)
 Children of 48 mothers untreated for
hypothyroidism had IQ average 7
points lower (p0.005) with 19 scoring
<85
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Haddow study
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Conclusions
Decreased intellectual and
school performance in children
exposed to mild asymptomatic
hypothyroidism
intellectual and school
performance was not affected if
hypothyroidism was treated with
thyroxine replacement even if
not adequate
Maternal thyroid peroxidase
antibodies during pregnancy: a marker
of impaired child development?
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Lower IQ in children of euthyroid
mothers with elevated TPO-ab vs
negative TPO ab titers
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Pop et al JCEM 1995
Screening
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Insufficient evidence to support
population bases screening
However aggressive case
finding is appropriate in
pregnant women
Surks JAMA 2004;291:228
Case 4
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Isabel a 40 year old G7P7 female
was referred to you 3 months after
delivery because of sluggishness
and depression. Upon further history
you elicited sore throat and neck
pain accompanied by palpitations 1
month after delivery which lasted for
2 weeks. ENT consult was done and
was given antibiotics. PE showed a
diffuse non tender goiter, no cervical
lymphadenopathy.
Thyroid tests
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FT3 3.5 pmol/l
FT4 18 pmol/l
TSH 15 uIU/ml
Question 1
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What are your considerations?
Postpartum thyroid disease
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Spectrum of autoimmune thyroid
diseases
Postpartum thyroid disease
Subacute thyroiditis
Hashimoto’s thyroiditis
Grave’s (recurrence)
Postpartum thyroiditis vs subacute
(de Quervain’s)
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PPT
painless
TPOab high
Tgab high
ESR slightly high
SAT
painful
neg or low
neg or low
very high
Risks for postpartum thyroid
disease
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High risk:
Prior episode of PPTD
History of Hashimoto’s or Grave’s
disease
Type 1 diabetes mellitus
Recurrent miscarriages
Moderate risk
Goiter
Family history of thyroid disease
Three phases of PPTD
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Transient hyperthyroidism due
to leakage of hormone low
RAIU, not pain, ESR normal or
slightly elevated lymphocytic
thyroiditis 2-3months up to 6
months post partum
Transient hypothyroidism
euthyroidism
Postpartum thyroiditis
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8-10% of women
Temporary period of hyperthyroidism
of 6 weeks to 3 months postpartum
No treatment for hyperthyroid phase
but beta blockers may be used to
relieve symptoms
6-12 months of LT4 in hypothyroid
phase; some long term
Subacute Thyroiditis
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Granulomatous type
Painful
RAIU – 0
? viral
Question 2
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What other tests will you
request?
Diagnostic tests
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RAIU - 2hrs, 5% (NV = 5-12%)
24 hrs, 15% (NV =1545%)
ESR - 23 mml/hr
TGAb - 150 IU/ml (NV = 0 - 60)
TPOAb - 1200 IU/ml
(NV = 0-100)
Question 3
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How will you manage this
patient?
Treatment for PPTD
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Levothyroxine if hypothyroidism
is symptomatic
hypothyroidism may occur up to
one year postpartum
Persistent or new
hypothyroidism occurs in about
25% after one year..
Summary Slide
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Thyroid disorders should be
considered in pregnancy in patients
at risk.
Signs and symptoms may be
misleading so there should be a high
index of suspicion.
Thyroid tests should be used and
interpreted in the light of physiologic
changes during pregnancy.
Judicious treatment is critical to
assure success in pregnancy
outcome
Thank You!