Thyroid Disease

1
Thyroid Disease Pregnancy
2nd International Endocrine Congress Esfahan,
IranOctober 10-12, 2012

• Hossein Gharib, MD, MACP, MACEProfessor of
  Medicine, Mayo Clinic College of
  MedicinePresident-Elect, American Thyroid
  Association

2
Disclosure Thanks

• Nothing to disclose
• My sincere thanks for the invitation to be with
  you today
• This presentation is based on clinical evidence,
  recent guidelines and good clinical judgment

3
Thyroid Pregnancy

• Physiologic changes
• ? TBG
• ? I requirement
• ? urinary I excretion
• ? T4 T3 synthesis
• ? HCG
• ? immunity

4
Changes in maternalThyroid Function in Pregnancy
? goiter ? Tg ? TSH
Modified from JCEM 862349, 2001
5
Presentation of Thyroid Disease in General

• Goiter
• Symptoms of hyper- or hypothyroidism
• This is also the case in autoimmunethyroid
  diseases and also the caseduring pregnancy

6
Hypothyroidism and Pregnancy

• Hypothyroidism occurs in 0.05 of all
  pregnancies
• SCHypo occurs in 2.5-5
• Symptoms are masked and diagnosis often
  overlooked
• Most common cause worldwide is I deficiency in
  U.S. Hashimoto thyroiditis

Endo metab Clin N Am 31893, 2004
7
Screening for Thyroid Disease in Pregnancy

• A 24-year-old woman was just diagnosed withher
  first pregnancy. She enjoys good generalhealth.
  There is no h/o thyroid disease or Rx.
• Q Should she have screening TFT?

Thyroid 211081-1125, 2011
8
What are the recommendations forTSH and T4
Screening in Pregnancy

• Recommendation 72There is insufficient evidence
  to recommendfor or against universal TSH
  screening atthe 1st trimester visit
• Recommendation 73Because no studies to date have
  demonstrated a benefit to treatment ofisolated
  maternal hypothyroxinemia,universal FT4
  screening of pregnantwomen is not recommended
  
  

Thyroid 211081, 2011
9
Screening for Thyroid Disease in Pregnancy

• Screening for subclinical hypothyroidism in
  pregnancy will be a cost-effective strategy under
  a wide range of circumstances. Thung et al Am J
  Obstet Gynecol 2009
• Screening all pregnant women for autoimmune
  thyroid disease in the 1st trimester is
  cost-effective compared with not screening.
  Dosiou et al EJE, 2008
• There are few prospective RCTs to substantiate
  the benefit of screening the clinical
  epidemiological evidence does not justify
  universal screening at the present time. Lazarus
  J Thyroid Res 2011
• Routine TSH screening before pregnancy or during
  the first trimester in all pregnant women.
  Gharib et al Endocr Pract 2002

10
Screening for Thyroid Disease in Pregnancy

• Although the benefits of universal screening for
  thyroid dysfunction may not be justified at this
  time, selected screening for the following should
  be done

• Positive FHxthyroid disease
• Goiter
• TPOAb
• Symptoms
• Type 1 DM
• Miscarriage

• Other autoimmunedisease
• Infertility
• Morbid obesity
• gt30 years

Thyroid 2011
11
TSH in Pregnancy

• A 28-year-old woman who is 6 weekspregnant has a
  routine serum TSHlevel of 4.1 mIU/L FT4 1.3
  ng/dL
• Q Is this TSH normal?

12
TSH Levels in Normal Pregnanciesn343
Median and 95 TSH
4.5
3.5
2.5
TSH (mIU/L)
1.5
0.5
0.03
1st trimester
2nd trimester
3rd trimester
10
20
30
40
Weeks gestation
Panesar NS et al Ann Clin Biochem 32329, 2001
13
Guidelines for Serum TSH During Pregnancy

• Recommendation 1Trimester-specific reference
  ranges for TSH, as defined in populations with
  optimal iodine intake,should be applied
• Recommendation 2If trimester-specific reference
  ranges for TSH are not available in the
  laboratory, the following references ranges are
  recommend1st trimester, 0.1-2.5 mIU/L 2nd
  trimester,0.2-3.0 mIU/L 3rd trimester, 0.3-3.0
  mIU/L
  

14
Guidelines for Serum FT4 During Pregnancy

• Recommendation 3The optimal method to assess
  serum FT4 during pregnancyis measurement of T4
  in the dialysate or ultrafiltrate of serum
  samples employing on-line extraction/liquid
  chromatography/tandem mass spectrometry
  (LC/MS/MS)
• Recommendation 4If FT4 measurement by LC/MS/MS
  is not available, clinicians should use whichever
  measure or estimate of FT4 is available in their
  laboratory, being aware of the limitations of
  each method serum TSH is a more accurate
  indication of thyroid status in pregnancy than
  any of these alternative methods
• Recommendation 5In view of the wide variation in
  the results of FT4 assays, method-specific and
  trimester-specific reference ranges of serum FT4
  are required

15
Hypothyroidism in Pregnancy

• Thyroid hormone is crucial for fetal brain
  development
• Untreated congenital hypothyroidism is associated
  with low intelligence, impaired growth, cognitive
  and psychological disturbances (cretinism)
• Hypothyroidism later in childhood is also
  associated with impaired growth, behavioral
  problems, symptoms of ADHD

16
Thyroid and Pregnancy

• Physiologic consequences for the fetus
• Fetal development in particular that ofthe
  brain is dependent on the thyroid function of
  the mother
• The thyroid gland is not developed inthe fetus
  until 12th week
• Thyroxine (T4) passes placenta, but relatively
  poorly

17
SCH in Pregnancy

• A 26-year-old woman desires pregnancy serum TSH
  is 4.5 mIU/L and FT4 1.0 ng/dL
• Questions
• Should you order TPOAb?
• Should you Rx with T4 if TPOAbis positive?
• What if TPOAb is negative?

18
Increased Pregnancy Loss in TPOAb-Neg Women with
TSH 2.5-5.0
Negro R et al JCEM 95E44-8, 2010
19
Why is it Important to diagnose Autoimmune
Thyroid Disease in Pregnancy?

• Most thyroid diseases in young women resultingin
  thyroid dysfunction are due to autoimmunity
• Maternal thyroid dysfunction has adverse effects
  on the fetus
• Improved treatment plan for the mother is
  beneficial to the fetus

20
Effects of Hypothyroidism onPregnancy Outcomes
Maternal
Fetal
JCEM, 2007
21
Autoimmune Thyroidits

• Hyperthyroidism
• Graves disease
• Hashitoxicosis
• Euthyroidism
• Symptom-free autoimmune thyroiditis
• Hypothyroidism
• Hashimotos thyroiditis
• Atrophic thyroiditis

22
TSH Changes in TPOAb () PregnantWomen During
Gestation
TSH ?3mIU/I(in of cases)
Weeks of gestation
Glinoer D et al JCEM 79197-204, 1994
23
TPOAb and Hypothyroidism

• Women with thyroid autoimmunity (i.e. positive
  TPOAb) who are euthyroid in the early stages of
  pregnancy are at risk of developing
  hypothyroidism
• Should be monitored for elevation of TSH above
  the normal range

24
Treatment with LT4 in Pregnant Women with TAI
Effects on Obstetrical Complications
LT4 0.5 ?g/kg.d TSH lt1.0 mIU/I
0.75 ?g/kg.d TSH 1.0-2.0 mIU/I
1 ?g/kg.d for TSH gt2.0 mIU/I orTPOAb gt1,500 kIU/L
Negro R et al JCEM 912587-2591, 2006
25
Treatment with LT4 in Pregnant Women with TAI
Effects on Obstetrical Complications
Miscarriage
Preterm Delivery

Negro R et al JCEM 912587-2591, 2006
26
Study Conclusions

• Under powered study
• Neither placebo controllednor double blind
• LT4 Rx reduced miscarriageand preterm delivery

27
Autoimmune Thyroid Disease and Miscarriage

• Many studies show increased miscarriage in
  euthyroid women with thyroid antibodies
• Majority of studies demonstrate an association
  between thyroid antibodies and recurrent
  miscarriage
• A causal relationship not established
• Should we treat TPOAb women?

28
Thyroid Antibodies and Spontaneous Miscarriage
Bagis (2001)
Singh (1995)
Glafoor (2006)
Lejeune (1993)
Stagnaro-Green (1990)
Glinoer (1991)
Negro (2006)
Lijima (1997)
Netto (2004)
29
Recurrent Abortion and Thyroid Antibodies
Bassen (1997)
Dendrinos (2000)
Bassen (1995)
Esplin (1998)
Pratt (1993)
Kutteh (1999)
30
Thangaratinam S et al BMJ 342d2616, 2011
3162596-30
31
SCHypo Pregnancy

• SCH (serum TSH concentration above the upper
  limit of the reference range with a normal free
  T4) has been shown to be associated with an
  adverse outcome for both the mother and offspring

32
Perinatal Outcomes inHypothyroid Pregnancies
68 women 23 with overt hypo 45 with SCH
Overt Subclinical Control
Leung AS et al Obstet Gynecol 81349, 1993
33
Overt and Subclinical Hypothyroidism Complicating
Pregnancy
51 pregnancies
16 overt hypo
35 subclinical hypo
60 abortion Rx inadequate
0 abortion Rx adequate
71 abortion Inadequate Rx
0 abortion Adequate Rx
Adequate Rx TSH lt4 mIU/L
Abalovich m et al Thyroid 1263, 2002
34
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35
Hypothyroidism Pregnancy

• 25,216 women with TSH screen retrospectively
  reviewed
• All newborn euthyroid at birth
• IQ scores of children born to mothers with
  slight TSH elevation were lt7 points vs controls
• Undiagnosed hypothyroidism in pregnancy
  adversely affects fetuses

36
(No Transcript)
37
21,846pregnant womenat 11-14 weeks
Screen
Control
TSH gt97.5thFT4 lt2.5th
T4Rx
Follow
IQ test in all children atage 3 were similar
Lazarus et al N Engl J Med 2012366493-501
38
Guidelines Recommendations

• Recommendation 8 There is insufficient evidence
  to recommend for or against universal LT4 Rx in
  TPOAB negative women with SCHypo
• Recommendation 9 Women who are positive for
  TPOAb and have SCHypo should be treated with LT4
• 
  Thyroid, 2011

39
SCHypo and PregnancyTo Treat or Not To Treat?

• Although efficacy of LT4 Rx has not been proved,
  given that the potential benefits outweigh the
  potential risks, T4 replacementis recommended

40
Hypothyroidism Pregnancy

• A 28-year-old woman has been on T4 for
  hypothyroidism for 5 years she is now pregnant
  and taking LT4 125 mcg daily
• Q What is optimal T4 dose and TSH level?

41
Hypothyroidism Pregnancy

• Recommendation 13Treated hypothyroid women on
  LT4 who are newly pregnant should increase T4
  dose by 30
• Recommendation 15Treated hypothyroid women on
  LT4 who are planning pregnancy should have T4
  dose adjusted to TSH lt2.5 MIU/L
• Recommendation 16Maternal serum TSH should be
  monitored every 4 weeks during 1st half of
  pregnancy

Thyroid, 2011
42
Hyperthyroidism Pregnancy

• A 32-year-old woman pregnant 10 weeks presents
  with nausea, vomiting, and a 2 kg weight loss
  her first pregnancy 2 years earlier was
  uncomplicated
• On exam she is a bit dehydrated, euthyroid,
  without a goiter and has normal eyes
• TSH 0.01 (lt2.5)
• FT4 2.1 (0.8-1.8)
• FT4I 20 (5-12)
• Q Does she require antithyroid Rx?

43
Hyperthyroidism PregnancyClinical Clues in DDx
Gestational GD
Sx prepregnancy
Sx during pregnancy
N V
Goiter/GD
TRAb/TPOAb
44
Hyperthyroidism PregnancyConclusions

• Hyperemesis gravidarum is HCG-induced,
  reversible, and rarely requires ATD
• Measure TSH receptor Ab (TRAb) to distinguish
  from Graves disease

45
Hyperthyroidism Pregnancy

• Recommendation 22When serum TSH is suppressed
  (lt0.1) inthe 1st trimester, FT4 should be
  obtainedTT3 TRAb may also be helpful
• Recommendation 26ATDs are not recommended for Rx
  of gestational hyperthyroidism

46
Hyperthyroidism Pregnancy

• A 32-year-old woman is 8 weeks pregnant she
  reports palpitations, anxiety, heat intolerance
  and an 8 lb weight loss for 6 months
• On exam she is nervous, slightly hyperthyroid,
  has lid lag, and thyroid is x2 enlarged
• TSH 0.01FT4 2.8
• FT4I 16 (5-12)TRAb 75 (lt16)
• Q How do you manage?

47
TSH receptorantibodies
Stimulating
T4
TSHreceptor
T3
Blocking
Stimulation
Tg
TSH
Spencer CA 2006
3162596-47
48
Mother
Fetus
Placenta
TRH
TRH
T3
TSH
TSH
T3
T4
T4
Stimulate
TSH receptorantibodies
Block
TPOAb TgAb
Anti-thyroiddrugs
Block
Spencer CA 2006
49
Hyperthyroidism Pregnancy

• Thyroid autoantibodies (TRAb) cross placenta
• Affect fetal thyroid after week 12
• Fetus can develop intrauterinemyxedema or
  hyperthyroidism evenif mother is euthyroid
• Avoid combination T4/ATD Rx

50
Hyperthyroidism Pregnancy

• Recommendation 28PTU is preferred for Rx of
  hyperthyroidismin the 1st trimester
• Recommendation 29A combination of ATD and LT4
  (block and replace) should not be used in
  pregnancy
• Recommendation 30FT4 and TSH should be
  monitoredevery 2-6 weeks

51
How to Treat the Women with Graves
Hyperthyroidism Before Pregnancy

• Antithyroid drugs
• PTU
• MMI
• Block replace
• Radioiodine
• Total thyroidectomy

52
TSH Receptor Antibodies (TRAb) After
VariousTypes of Treatment for Graves Disease
s-TRAB ( inhibition of125-I TSH binding)
Radioiodine
Surgery
Medication
Years
Laurberg et al EJE 15869-75, 2008
53
Postpartum Thyroiditis

• A 32-year-old woman who delivered 2 months ago
  reports depression, excess fatigue and feeling
  cold
• Q Should she have TFT?
• A TSH is 37 mIU/L, FT4 0.3 ng/dL and TPOAb 580
• Q Should you treat with T4?

54
Postpartum ThyroiditisDefinition

• Autoimmune disorder characterized by lymphocytic
  infiltration of the thyroid gland and by the
  occurrence, in the postpartum period, of
  transient hyperthyroidism and/or transient
  hypothyroidism
• Most women return to the euthyroid state by 1
  year postpartum

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Prevalence of PPT
3162596-55
56
Clinical Course of Postpartum Thyroiditis
Hyper
Euthyroid
Hypo
0 3 6 9 12
Postpartum (months)
Stagnaro-Green A JCEM 874042-7, 2002
57
Pregnancy and Immune Function

• In a normal pregnancy, the maternal immune system
  undergoes a remission to allow the maintenance of
  the fetus
• Thyroid antibodies, as well as those directed
  against other tissues suppressed during
  pregnancy, often increase after delivery
• The autoimmune rebound after delivery
  characterize patients with Hashimotos and
  Graves disease, who frequently present a
  worsening of thyroid dysfunction after delivery

58
Postpartum Thyroiditis

• Women with 1 episode of PPT have a 70 chance of
  recurrence with next pregnancy
• Patients with TPOAb during pregnancy areat
  increased risk of developing PPT
• Selenium, as an antioxidant, is reportedto
  reduce risk of PPT
• When TPOAb is positive, TSH and FT4should be
  checked at 3 and 6 months PP

59
Conclusions (1)

• Profound physiologic changes of thyroid function
  occur in pregnancy
• Serum TSH is the gold standard forthyroid
  evaluation
• Targeted thyroid screening is recommended during
  pregnancy
• New trimester-specific TSH levels are now
  available and should be used
• Both overt and subclinical hypothyroidismcan
  adversely affect pregnancy

60
Conclusions (2)

• Hypothyroid patients on T4 Rx oftenrequire ?
  dose in pregnancy
• Women with SCH and positive TPOAbshould be
  treated with T4 prior to andduring pregnancy
• PTU is the drug of choice in early pregnancy
• PPT is a common and often an overlooked problem
  after delivery

61
Thank you!
62
Thank you!
63
Title/drp author BK Gharib, Hossein
Sub/drp Job BK 3162596
Subject Thyroid Disease in Pregnancy
Background Custom
Plot/brdr open/BK
Banner/brdr
232 179 68
109 131 61
102 79 18
53 40 9
Side title 43-114-149

• /colhdgs 43-114-149

PPT shooting instructions PPT File to Server(64
images)
Text BK
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Subdue Custom
Artist mls Due Date 12-21-2011
Footnotes 102-79-18
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64
Autoimmune Thyroid Disease Pregnancy
6th Annual Philippines AACE Endocrine
Congress Cebu, PHAugust 9-12, 2012

• Hossein Gharib, MD, MACP, MACEProfessor of
  Medicine, Mayo Clinic College of MedicinePast
  President, American Association of Clinical
  Endocrinologists

65
What are the Recommendations forTPOAb Screening
in Pregnancy?

• Recommendation 45There is insufficient evidence
  to recommend foror against screening for thyroid
  antibodies in the first trimester of pregnancy,
  or treating TPOAb euthyroid women with LT4 to
  prevent preterm delivery

Thyroid, 2011
66
Guidelines Recommendations

• .R 8 There is insufficient evidence to recommend
  for or against universal LT4 Rx in TPOAb negative
  women with SCHypo
• .R 9 Women who are positive for TPOAb and have
  SCHypo should be treated with LT4

Thyroid, 2011
67
Thyroid and Pregnancy

• Consequences of the physiologic changes
• High risk for false estimation of thyroid
  function tests
• Increase goiter size may becomeclinically
  significant