Thyroid Disease in Pregnancy

1
Thyroid DiseaseinPregnancy

• Josephine Carlos-Raboca, MD, FPCP, FPSEM
• Section of Endocrinology, Diabetes and Metabolism

Makati Medical Center
2
Outline

• Thyroid Physiology in Pregnancy
• Maternal
• Fetal
• Gestational Thyrotoxicosis
• Graves Disease in Pregnancy
• Hypothyroidism
• Postpartum thyroiditis

3
Pregnancy and Thyroid Function

• The production, circulation and
• disposal of thyroid hormones are
• all altered during pregnancy.

4
H - P Thyroid Axis
5
Thyroid Hormone production

• TRH - hypothalamus
• TSH - pituitary
• TSH receptor on thyroid cell
• Thyroglobulin (Tg) - thyroid
• Thyroid peroxidase - thyroid
• Iodine
• T4(80)
• T3 (20)

6
Maternal Physiology

• Thyroid circulation
• Thyroxine clearance rate
• Dietary iodine requirement
• hCG mediated thyroid stimulation

7
Thyroid circulation

• T4 and T3 are highly bound to proteins
• Thyroid binding globulin (TBG)( 70)
• Transthyretin (TBPA)
• Albumin
• Unbound
• Free T4(0.02)
• Free T3 (0.3)

8
Thryoxine binding globulin(TBG)

• 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)

9
Effects of Increased TBG

• Increased total T3 and total T4
• Free hormone assay are thus preferred
• FT4I should be done if free hormone determination
  is not available

10
Thyroid Disposal/Clearance

• 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

11
Increased demand for iodine

• Increased GFR
• Increased iodide clearance by the kidney
• Siphoning of maternal iodide by the fetus
• WHO RDA 200 ug/day during pregnancy

12
Increased demand for thyroid hormones

• Increased iodide clearance
• Transplacental transfer of T4 and iodine
• Placental degradation of T4

13
Thyroid stimulation by chorionic gonadotropin

• 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

14
Normal pregnancy

• TSH suppressed when hCG are highest at 8-12
  weeks of gestation
• Free T3 or T4 were significantly elevated at a
  time when hCG were maximal
• TSH suppressed
• 18 in first trimester
• 5 in second trimester
• 2 in third trimester
• Glinoer J of Clin Invest 1993

15
Thyroid stimulation by hCG
16
Physiologic changes in pregnancy and thyroid
function test

• Physiologic change
• Increased TBG
• First trimester hCG elevation
• Increased plasma volume
• Increased plasma type 3 deiodinase
• Thyroid enlargement
• Increased iodine clearance

• Thyroid function test change
• Elevation of T4 and T3
• 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

17
Fetal Ontogeny and Physiology

• T3 dependent CNS development
• Thyroid organogenesis, iodine concentration and
  hormonogeneiss
• Dependence on maternal iodothyronines

18
Thyroid Hormones and Fetal Brain Development

• Nervous system development and brain
  differentiation
• synaptogenesis
• growth of dendrites and axons
• myelination
• neuronal migration

19
Thyroid Deficiency in the Fetus and Neonate

• 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

20
Thyroid Tests
Thyroid Hormones
TT3,TT4, FT3, FT4 FT4I, TSH
Thyroid antibodies TPOAb,TgAb,
TSHRAb (TSI,TBII)
21
Hyperthyroidism

• Etiologies
• Clinical presentations
• Diagnosis
• Maternal and fetal consequences
• Therapeutic options

22
Hyperthyroidism

• Occurs in 1-2/1000 pregnancies

23
Causes of hyperthyroidism in
pregnancy

• Graves Disease
• Gestational Thyrotoxicosis
• Hydatidiform mole
• Silent Thyroiditis
• Multinodular toxic goiter
• Toxic adenoma
• Subacute thyroiditis
• Iatrogenic hyperthyroidism\Iodine induced
  hyperthyroidism

24
Case 1

• 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.

25
Case 1

• 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.

26
Thyroid Function tests

• FT3 RIA 4.74 pmol/l (4.2-12)
• FT4 RIA 25 pmol/l (8.8-33)
• TSH IRMA 0.08 uIU/ml
• (0.35 5.0)

27
Question

• What is your likely diagnosis?
• differential diagnosis?

28
Conditions with suppressed TSH

• Increased thyroid hormone production
• Graves Disease
• Autonomous Thyroid nodule
• Hyperemesis gravidarum
• Molar Pregnancy
• First trimester pregnancy

29
Conditions with Suppressed TSH

• Normal or Low Thyroid Production
• Post therapy of hyperthyroidism
• Pituitary/hypothalamic disease
• Severe nonthyroidal illness

30
Conditions with suppressed TSH

• Inflammatory
• Thyroiditis (usually subacute)
• Medications
• high dose L-T4 or T3
• dopamine
• glucocorticoids
• Acute response to somatostatin and
  analogs(octreotide)

31
Hyperemesis Gravidarum

• Severe nausea and vomiting in pregnancy resulting
  in weight loss and fluid and electrolyte
  disturbance
• 60 with suppressed TSH
• 50 with elevated FT4
• (Goodwin 1995JCEM
  751333-1337)
• Less than 15 have elevated FT3 or FT3 index
  (clinical useful test to distinguish from Graves)

32
Gestational Thyrotoxicosis

• 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

33
Question 2

• 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

34
Question 3 How will you follow up?

• 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 Graves disease.

35
Gestational Thyrotoxicosis

• Transient
• Symptoms usually resolve within 10 weeks of
  diagnosis
• Differs from Graves
• 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

36
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.

37
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

38
Thyroid tests

• FT3 RIA 15 pmol/l ( 4.2-12)
• FT4RIA 55 pmol/l (8.8 33)
• TSH-IRMA 0.002 uIU/L (0.35-5.0)

39
Question 1

• What is your likely diagnosis?
• Chronic hypertension
• Graves eye signs, goiter, bruit

40
Diagnosis of Graves

• 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

41
Graves Hyperthyroidism

• Positive thyroid antibodies
• TPOAb
• TgAb
• TSHRAb (TSI)
• Unusual to present for the first time in
  pregnancy
• Symptoms usually antedate pregnancy for a few
  months

42
Question 2

• What are other tests are useful to confirm your
  diagnosis if available?
• TPOAb
• TgAb
• TSHRAb/TSI to differentiate from silent
  thyroiditis

43
Question 3

• What is your treatment of choice?

44
Which ATD is best?

• PTU favored because
• MMI has been associated with aplasia cutis a
  congenital scalp defect
• (Mandel 1994
  Thyroid 4129-133)
• 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
  451187-1193)

45
Which ATD is best?

• an in vitro study showed two drugs equally passed
  placental barrier (Mortimer 1997 JCEM
  823099)
• no prospective RCTs compared maternal and fetal
  outcome
• retrospective case series have shown that the
  rate of fetal hypothyroidism is similar with both
  drugs
• (Wing 1994 Am J Obstet Gynecol
  17090)

46
What is the dose of ATD in pregnant?

• 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

47
Relation between maternal ATD dose and neonatal
function

• Direct correlation
• Lamberg 1981 11 preg CM
• Mortimer 1990 16 PTU or CM
• Mitsuda 1992 230 MMI or PTU
• No dose response
• Cheron 1981 11 PTU
• Gardaner 1986 6 PTU
• Momotani 1986 43 MMI or PTU
• Momotani 1997 77 MMI or PTU

48
PTU vs MMI on fetal thyroid status in maternal
GravesMomotani1997 JCEM 823633

• 77 pregnant
• 34 PTU
• 43 MMI
• 32 pregnant controls
• Conclusion
• fetal cord blood free T4 levels did not differ
  among groups
• Mean fetal cord blood TSH was similar in both ATD
  treated groups which was higher for each group vs
  control group
• Data suggest both groups can safely be used in
  pregnancy

49
Correlation of maternal PTU concentrations with
cord serum thyroid function testGardner 1986
JCEM 62217-220

• PTU given till term showed PTU concentration in
  cord higher than maternal levels
• No data comparing maternal and cord levels
  simultaneously for MMI

50
Effect of ATD overdose on fetus

• 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

51
PTU vs MMI

• Duration of action short long
• Potency less more
• Placental passage about 1 prob 1
• Breast milk less more
• Toxicity
  aplasia cutis
• Other blocks T4 to T3

52
Question 4

• What are your treatment goals?

53
Guidelines for clinical management of maternal
hyperthyroidism during pregnancy

• 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)

54
Guidelines for clinical management of maternal
hyperthyroidism during pregnancy

• 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

55
Hyperthyroidism guidelines

• If either high maintenance ATD doses are required
  (ie PTUgt600 mg/day, MMI . 40 mg/day) or if a
  patient is non-adherent or allergic to ATD
  therapy, surgery (ie subtotal thyroidectomy)
  should be considered.

56
Hyperthyroidism guidelines

• Low doses of iodides may be used transiently,
  especially pre-operatively
• frequent communication between the
  endocrinologist and obstetrician is essential so
  that ATD dose titration is performed with
  monitoring of fetal growth.

57
Antithyroid drug therapy for Graves disease
during pregnancy Momotani 1986 NEJM 31624-28

• If maternal FT4 is either elevated or in upper
  1/3 of normal, more than 90 of neonates have
  normal FT4
• If maternal FT4 is in lower 2/3 of normal, 36 of
  neonates have decrease FT4
• If maternal FT4 levels are decreased, all
  neonates have decreased FT4

58
Other forms of treatment

• 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

59
Question 5

• What are maternal and fetal consequences of
  hyperthyroidism?

60
Pregnancy complications reported in hyperthyroid
women

• Maternal
• pre-ecclampsia(14 if untreated vs 6for 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)

61
Other potential complications of uncontrolled
hyperthyroidism

• Maternal
• Anemia
• Miscarriage
• Thyroid storm
• Fetal
• prematurity

62
Pregnancy complications reported in hyperthyroid
women

• Fetal
• Small for gestation age
• Intrauterine growth retardation
• Stillbirth (50 if untreated, 16 partial
  treatment)
• Fetal/neonatal hyperthyroidism

63
ATDseffect on fetus

• Maternal factors
• Maternal ATD dosage
• TSH receptor antibody
• Maternal thyroid status

64
Course of Graves in Pregnancy Mestman 1997 Clin
Obstet Gynecol 4045-64

• occurs in 1 in 500 pregnancies
• Fluctuates during gestation
• Aggravates at 10-15 weeks
• Subsequent improvement
• In third trimester a time of immune tolerance,
  ATD can be reduced or decreased in 30
• Worsens or reactivates in postpartum period

65
Case 3

• 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.

66
Case 3

• Patient had radioactive treatment 3 years ago for
  Graves 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.

67
Thyroid tests

• FT3RIA 3.8 pmol/L (4.2 12)
• FT4 RIA 8.8 pmol/l (8.8 33)
• TSHIRMA 25 uIU/ml (0.35 5.0)

68
Question 1

• What is your diagnosis?
• Hypothyroidism in Pregnancy
• Hypertension
• Is this expected?

69
Diagnosis of hypothyroidism

• Nonspecific signs
• fatigue
• Weight gain
• Constipation
• Edema
• TSH is first line screening test

70
Thyroid hormone therapy during pregnancy

• 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

71
Question 2

• How will you adjust your dose?

72
Treatment of hypothyroidism in pregnancy

• Initial dosage 150 mcg/day or
• 2 mcg/kg actual body weight
• Readjustment
• TSH high but lt10mU/ml add 50 mcg/day
• TSHgt10lt20 add75mcg/day
• TSHgt20 add 100 mcg/day

73
Hypothyroidism

• Start with a daily dose of 2 mcg/kg per day
• If TSH is minimally elevated(ie 10 mU/L in
  pregnancy, a 0.075 - 1.0 mg of levothyroixine
  per day often is adequate

74
guidelines for clinical management of maternal
hypothyroidism

• Check serum TSH early in pregnancy
• Adjust levothyroxine dosage to maintain a normal
  serum TSH. Increment in dosage may depend on
  etiology of hypothyrodism.
• Athyreosis(Graves after I-131 therapy) 45
  increment

75
guidelines for clinical management of maternal
hypothyroidism

• Hashimotos 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

76
Hypothyroidism

• 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

77
Question 3

• The patient asks you on possible consequences to
  baby What will you tell her?

78
Complications in Pregnant Hypothyroidism

• Maternal
• 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

79
Maternal consequence of Hypothyroidism

• 25756 singleton pregnancies
• 2.3 had subclinical hypothyroidism
• Placental abruption occurred more often (RR 3.9,
  95 CI 1.1-8.2
• Preterm birth (lt34 weeks) more common (RR 1.8,
  95 CI 1.1 -2.9)
• Casey Obstetric Gynecol 2005105239-245

80
Complications In Pregnant Hypothyroidism

• Fetal
• 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

81
Implications of hypothyroidism in pregnancy

• 11 pregnancies
• T4 2.3 ug/dl
• TSH 105 mU/L
• 8 treated no complication but 1 Trisomy 21 in 41
  year old mother
• 3 untreated1 IUFD 2 normal births
• all infants normal at 3 years old
• Montoro 1981 Ann of Int Medicine

82
Hypothyroidism in pregnancy

• 9403 singleton pregnancies
• TSH gt6mU/L in 2
• Fetal death OR 4.4 CI 1.9-9.5
• Allan WC J Med Screening 20007127

83
Maternal hypothyroidism during early pregnancy
and intellectual development in progeny

• 8 children exposed to hypothyroidism in early
  pregnancy (4-10 years)
• 9 control siblings 4-15 years
• Conclusion no difference in IQ
• Liu 1994 Arch Int Medicine

84
Consequence of hypothryoidism in pregnancy

• TSH measured in 25216 pregancnt women
• 47 women TSH gt99.7th 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 1999341549

85
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 lt85 (15 vs 5)
• Children of 48 mothers untreated for
  hypothyroidism had IQ average 7 points lower
  (p0.005) with 19 scoring lt85

86
Haddow study

• 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

87
Maternal thyroid peroxidase antibodies during
pregnancy a marker of impaired child development?

• Lower IQ in children of euthyroid mothers with
  elevated TPO-ab vs negative TPO ab titers
• Pop et al JCEM 1995

88

• No congenital anomalies in most studies
• In humans, it is still still poorly understood
  why some very hypothyroid women even if untreated
  may deliver seemingly normal children
• It is unknown if there is a critical threshold of
  maternal thyroid hormone level or if in some
  cases T4 may be inactivated to a greater extent
  by placental deiodinases

89

• Euthyroidism must be reached in a timely fashion
• Surveillance needed throughout pregnancy

90
Screening

• Insufficient evidence to support population bases
  screening
• However aggressive case finding is appropriate in
  pregnant women
• Surks JAMA 2004291228

91
Case 4

• 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.

92
Thyroid tests

• FT3 3.5 pmol/l
• FT4 18 pmol/l
• TSH 15 uIU/ml

93
Question 1

• What are your considerations?

94
Postpartum thyroid disease

• Spectrum of autoimmune thyroid diseases
• Postpartum thyroid disease
• Subacute thyroiditis
• Hashimotos thyroiditis
• Graves (recurrence)

95
Postpartum thyroiditis vs subacute (de
Quervains)

• PPT SAT
• painless painful
• TPOab high neg or low
• Tgab high neg or low
• ESR slightly high very high

96
Risks for postpartum thyroid disease

• High risk
• Prior episode of PPTD
• History of Hashimotos or Graves disease
• Type 1 diabetes mellitus
• Recurrent miscarriages
• Moderate risk
• Goiter
• Family history of thyroid disease

97
Three phases of PPTD

• 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

98
Postpartum thyroiditis

• 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

99
Subacute Thyroiditis

• Granulomatous type
• Painful
• RAIU 0
• ? viral

100
Question 2

• What other tests will you request?

101
Diagnostic tests

• RAIU - 2hrs, 5 (NV 5-12) 24 hrs, 15 (NV
  15- 45)
• ESR - 23 mml/hr
• TGAb - 150 IU/ml (NV 0 - 60)
• TPOAb - 1200 IU/ml (NV 0-100)

102
Question 3

• How will you manage this patient?

103
Treatment for PPTD

• Levothyroxine if hypothyroidism is symptomatic
• hypothyroidism may occur up to one year
  postpartum
• Persistent or new hypothyroidism occurs in about
  25 after one year..

104
Summary Slide

• 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

105
Thank You!