Current Concepts in Thyroid Disease and Pregnancy

1
Current Concepts in Thyroid Disease and Pregnancy

• John H Lazarus
• Centre for Endocrine and Diabetes Sciences
• University Hospital of Wales
• Cardiff
• Wales
• UK
• Nov 2005
• Buenos Aires

2
(No Transcript)
3
Thyroid and Pregnancy- Controlling Factors

• Estrogen E2
• Thyroxine Binding Globulin TBG
• Human chorionic gonadotrophin hCG
• Iodine I-
• Iodothyronine deiodinasesD1,D2,D3
• D1 T4 T3
• D2 T4 T3 and rT3 T2
• D3 T4 rT3 and T3 T2

4
(No Transcript)
5
TFTs in Early Pregnancy

• TSH affected by hCG
• a) Cross reaction in assay
• b) hCG a thyroid stimulator
• requirement for sensitive assay to assess
  pathological
• significance of low TSH
• Thyroid Hormone Binding Proteins
• a) Changes in TBP in gestation not a single
  linear function(especially at extremes of thyroid
  function) - therefore not always compensated by
  T3 uptake
• b) Possibly, FT4 better than FTI at this time

6
TSH and hCG during Gestation
Gestational week
7
Immunologic and Hormonal Features of Pregnancy

• Improvement in Graves, RA and other autoimmune
  diseases
• HLA-G expression
• Fas ligand expression
• Th2 response
• Th2 cytokines produced by the
  fetal/placental unit
• Progesterone increase - reduction in B cell
  activity
• Estrogen increase - fallin autoantibody levels
• Cortisol, 1,25-OH vit D and norepinephrine affect
  immune response

• Clinical
• Trophoblast
• Lymphocytes
• Hormones

8
Shift in TH1/TH2 Balance in Human Pregnancy

• Cross sectional study of normal pregnancy using
  flow cytometric analysis of TH1 and TH2 cytokines
  in PBL.
• CD4 T cells produce less TH1 cytokines
  (IFN-gamma, IL-2) and more TH2 cytokines (IL-4,
  IL10) during normal pregnancy.
• Possible role of progesterone (PIBF- progesterone
  induced blocking factor) alters TH1/TH2 balance
  to TH2 cytokines
• 
  Reinhard et al. BBRC 1998

9
The Autoimmune Aftermath of Pregnancy

• Clinical
• 1) Development of several diseases (eg.neonatal
  lupus, thyroiditis, myasthenia)
• 2) Exacerbation of several conditions (eg
  Graves disease, RA, MS)
• Immunological
• Switch from Th2 to Th1
• Fetal microchimerism
• Increase in ab titres postpartum

10
Pregnancy and Thyroid Disease - Facts and Figures

• Gestation Hyperthyroidism 0.24
• Hypothyroidism (TSH) 2-2.5
• Thyr Antibodies antiTPO 10
• Postpartum PPTD 5-9
• PP depression 30 vs 20
• PP Graves up to 40 of Graves

11
Thyroid Testing in Pregnancy

• Trimester specific reference ranges for T4,T3 and
  TSH
• Importance of TPOAb
• Monitor TSH in patients on L-T4
• Identify hypothyroidism in 1st trimester
• ? Screen with TSH
• Based on NACB Guidelines 2002

12
Thyroid Antibodies and Pregnancy Risk

• Infertility
• Pooled studies RR 1.95(1.5-2.53) p
• IVF failure
• Miscarriage
• sig increase (2-4x) in 10/13 studies in 5200
  women Ab 10.4 - 67
• Pre eclampsia
• Fetal death
• Allan 2000,Mecacci 200,Poppe and Glinoer 2003

13
TPOAb and Risk of Miscarriage
14
TPOAb-associated Reproductive -related
Complications
p
15
Hyperemesis and Thyroid FunctionGoodwin et al
TSH
SEVERE HYPEREMESIS nausea vomiting
FT4
hCG
16
Outcome of Poorly Treated Hyperthyroidism in
Pregnancy

• MATERNAL
• Miscarriage
• Placenta abruptio
• Preterm delivery
• Congestive Ht failure
• Thyroid Storm
• Pre-eclampsia

• FETAL
• Hyperthyroidism
• Neonatal hyperthyroidism
• Prematurity
• IUGR
• Fetal death /stillbirth
• Fetal abnormalities

17
Hyperthyroidism in Pregnancy
18
Management of Graves Hyperthyroidism in
Pregnancy

• Confirm diagnosis
• Start propylthiouracil or other ATD
• Render patient euthyroid - continue with low dose
  ATD up to and including labour
• Monitor thyroid function regularly throughout
  gestation (4-6wkly).Adjust ATD if necessary
• Check TSAb at 36 wks. gestation
• Discuss treatment with patient
• effect on
  patient
• effect on
  fetus
• breast
  feeding
• Inform obstetrician and paediatrician
• Review postpartum - check for exacerbation

19
TSH RECEPTOR ANTIBODY MEASUREMENTS IN PREGNANCY

• EUTHYROID previous ATD for Graves not necessary
• EUTHYROID (/-T4) - 131I/surgery for
  Graves measure early pregnancy low - no
  further action high - measure in last
  trimester check for fetal/neonatal hyperthyr
  oidism
• ON ATD FOR GRAVES measure in last
  trimester high - ? Fetal/neonatal
  hyperthyroidism

20
PTU vs Carbimazole Methimazole in Pregnancy

• PTU
• no aplasia cutis/ MMI embryopathy
• BUT frequent dosing schedule
• ANCA assoc vasculitis

21
Methimazole Embryopathy

• Since 1995 -9 cases 4 in Sweden
• Main features Choanal atresia
• oesophageal atresia 0mphalocele plus other
  abnormalities
• MMI dose - usually 20mg/ per day
• NOT seen with PTU

22
Effect of Antithyroid Drugs in Pregnancy on
Offspring

• Messer et al Acta Endoc. 1990, 123311-316S
• Studied 17 children of 13 hyperthyroid mothers
  (ATD) and 25 children of 15 euthyroid mothers
  7-11 years after birth
• No differences between groups in clinical/mental
  psychological development
• Similar to data from
• 1) McCarrol et al. Arch Dis Child 1976,
  51532-536
• 2) Burrow et al. Yale J Biol Med 1978, 51 151-156

23
Hypothyroidism and PregnancyUntreated
/Inadequately Treated

• Abortion
• Obstetric complications- placental abruption
• Fetal abnormalities eg. Preterm birth
• Impaired neurodevelopment

24
Increased L-T4 Requirements in Pregnancy

• L-T4 requirements may increase 25-40, usually in
  the first half of pregnancy
• Increased requirements may depend on cause of
  hypothyroidism (ablation vs .Hashimotos)
• 25 of those with initial normal TSH in 1st
  trimester and 37 of those with initial normal
  serum TSH in 2nd trimester will later require
  dosage increases due to
• Inc TBG concentration (2ry to E2)
• glycosylation or hepatic clearance
• Increased T4 and T3 inactivation by placental,
  fetal and uterine D3
• Increased volume of T4 distribution
• Other causes?

25
Hypothyroidism in Pregnancy
Larsen et al 2003
26
Therapy of hypothyroidism During Pregnancy

• Pre pregnancy counseling of all hypothyroid women
  , with optimization of L-T4 dose (TSH
  0.5-3.0mU/L)
• Check TSH as soon as pregnancy test is positive
• Adjust T4 dose Graves45
• Hash.25
• Monitor TSH monthly
• Reduce T4 dose to pre-pregnancy level after
  delivery

27
Thyroid Hormone and Brain Development

• Altered migration and differentiation of neurones
• Cell migration - cerebellum
• - cerebral cortex and hippocampus
• Stunted dendritic and axonal growth and
  maturation
• - Purkinje cells
• - dendritic spine number
• Delayed and poor deposition of myelin
• reduced axonal number
• Thyroid Hormone Receptors
• Presence of receptors in neural tissue at early
  developmental stage suggests fetal brain is
  target for TH even before onset of fetal gland
  function
• Bernal 2002

28
Maternal Hypothyroxinemia Psychoneurological
Deficits of Progeny Man et al
Ann Clin Lab Sci 1991 21 227-229

• Developmental deficits demonstrated as early as 8
  mo
• At age 4 and 7 yrs lower psychological scores cf
  nonhypothyroxinemic progeny
• 6 sibling sets outcome better when T4 therapy
  given
• nb possibility of socioeconomic confounding
  factors

29
TPO Antibodies in Pregnancy as a marker of Child
Development
Pop et al
JCEM 1995 80, 3561-3566

• Prospective study of 293 women
• All investigated at 32 weeks gestation
• 19 children age 4.8yrs with TPOAb (mother) had
  lower scores on McCarthy scale of children's
  abilities cf children of TPOAb -ve mothers(n200)
• TPOAb a risk factor for impaired development

30
NEURODEVELOPMENT IN IODINE SUFFICIENT AREAS

• 1967 Maternal hypothyroxinaemia related to low
  IQ of progeny (both corrected by treatment during
  pregnancy) Man et al
• 1995 Maternal antithyroid antibodies related to
  lower IQ of progeny Pop et al
• 1999 Psychomotor development correlated to 1st
  trimester FT4TPO or 3rd trimester FT4 Pop et al
• 1999 Increased risk of poor neuropsychological
  scores in progeny of women with maternal
  TSH98th percentile Haddow et
  al
• 2003 Low Maternal T4 - 3 yr prospective study
  Pop et al

31
Thyroid and IQ - Recent Studies

• Haddow et al 1999 - 19 7yr old children(mothers
  with high TSH in gestation) IQ
• Pop et al 2003 - Bayley motor and mental scores
  low in 1 2 yr olds (maternal FT4 lowest 10th
  centile)

32
Maternal thyroid failure and average child IQ
scores1

• The IQ scores of children whose mothers had
  untreated hypothyroidism during pregnancy were
  significantly lower than those of the control
  children.
• IQ scores for children whose mothers were being
  treated for hypothyroidism during pregnancy were
  similar to those of the control children.

Control
Untreated (p 0.005)
Control, n 124 Untreated hypothyroidism, n 48
1. Adapted from JE Haddow et al., N Engl J Med.
1999341529-555
33
Comparison of mean Bayley mental and motor scores
at 1 and 2 years
P0.02
P0.004
P0.02
P0.005
Cases n57
Controls n58
Year 2
Year 1
Pop et al Clin Endoc 59282-88 2003
34
Bayley mental/motor scores
Pop et al 2003 Clin Endoc 282-88
35
High TSH in Pregnancy

• Incidence 2.4 and 2.2 of 2000 Klein et al
  Clin Endoc 1991 Allan et al J Med Screen 2000
• Fetal death 3.8 in high TSH vs 0.9 in TSHgroup OR 4.4 ci 1.9-9.5
• Neurodevelomental Issues
• If T4 therapy beneficial then ve case for
  screening
• SHOULD THERE BE ROUTINE SCREENING WITH T4
  TREATMENT?

36
CATSControlled Antenatal Thyroid Screening

• Aim To ascertain if screening for thyroid
  function in early gestation is justified
• Funding Wellcome Trust
• Collaborators
• Depts Med, Med Biochem and Child Health UWCM
• Dept Preventive Medicine St Barts The London

37
Controlled Antenatal Thyroid Screening CATS
6 centres Wales 1 centre England 1 centre Italy
Sept 05 c 18,000
300 screen positive
250 control positive
38
Pregnancy FT4 concentrations in TPOAb -ve and
ve women
CATS n 936
n

204
22


105
9
115
173
6
194
98
12
7
1
sig LESS cf 11 week value
39
CATS - Urinary Iodine
WALES
24.0
24.4
20.8
No of Women
17.0
13.8
Urinary Iodine µg/L
643 women studied 11-15wks
RDA for pregnancy 41.4
40
Urinary Iodine concentrations in 100 Boston area
pregnant women1st/2nd trimester
Pearce et al Thyroid 2004 14,4, 327-8
41
Pregnancy, Neurodevelopment and Thyroid Function
2004

• Substantial evidence from both retrospective and
  prospective studies suggests that early
  gestational low maternal circulating thyroxine
  and or TSH concentrations adversely affect
  neonatal and child development at least to age
  7yrs.
• The case for routine antenatal screening of
  thyroid function with interventional thyroxine
  therapy to prevent these adverse outcomes is
  being addressed by a randomised prospective
  studyCATS

42
Patterns of Thyroid Function Post Partum
From AMINO
43

• 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).

44
Hormone Concentration
Ab Concentration
Symptomatic
asymptomatic
45
Risk Factors for Postpartum Disease

• Previous episode of PPTD
• History of AITD (eg Hashimoto)
• Diabetes Mellitus Type I
• Recurrent miscarriages
• Goitre
• Family History of AITD

46
Postpartum thyroiditis and TPO-Ab

• PPT is closely associated with the presence of
  TPO-Ab.
• If TPO-Ab are present in 1st trimester, risk for
  PPT is approx. 50.
• If TPO-Ab still present in 3rd trimester, risk of
  PPT is 80.
• Likelihood of recurrence in subsequent
  pregnancies is high (approx. 70).
• Postnatal depression is more common (2-3x) in
  woman with PPT.

• AF Muller et al. Endocrine Review 2001
  22(5)605-630.

47
Is PPT an Antenatal Disorder?
P
Kokandi et al JCEM 2003
48
Development of Postpartum Thyroid Dysfunction
Immunogenetic background eg HLA other genes
TPOAb
100
Cellular immunity
Postpartum
Thyroid reserve
? Fetal microchimerism
Pregnancy
Subclinical hypothyroidism
Overt hypothyroidism
Overt hypothyroidism
0
Time
49
Indications for Testing Thyroid Function in
Pregnancy

• On T4 prior to gestation
• History of autoimmune thyroid disease
• ve thyroid autoantibodies
• Previous postpartum thyroiditis
• Graves disease in remission
• ve FH autoimmune thyroid disease
• Type 1 DM and/ other autoimmune disease
• Previous neck irradiation/ partial thyroidectomy
  decreased thyroid reserve

50
Existing Thyroid Practice Guidelines

• Most current guidelines in thyroidology rely on
  narrative literature reviews and expert opinion
• Few are based on systematic evaluation of
  published literature
• Few guidelines recognize values such as
  protecting vulnerable persons and limiting
  expenditure
• Very few directly address the issue of
  maternal-fetal health Ladenson 2004

51
Screening for Gestational Hypothyroidism
Maternal Thyroid Disease
Screening for Hypothyroidism

• Frequency of hypothyroidism
• Effects on mother and child
• Effectiveness of screening strategies
• Effectiveness of intervention

• Relatively prevalent
• Significant health impact
• Treatment effective safe and cheap
• Early diagnosis
• superior outcome
• No PRCT as yet
• Cost implications

52
THYROID AND PREGNANCY

• Future Strategies for Health Care
• Preconception clinic
• Screening anti TPO Abs at booking
• Screening FT4 and TSH at booking
• Adequate iodine intake during gestation
• Ensure adequate maternal T4
• Postpartum thyroid assessment - 6 wks
• Long term follow up of selected patient groups

53
Acknowledgements

• Wellcome Trust
• Nick Wald LONDON
• R John, J Sibert, A Parkes CARDIFF
• Biochemists, technicians CARDIFF
• Computing staff LONDON
• Obstetricians all centres
• Midwives all centres
• Patients all centres

54
THANK YOU
55
(No Transcript)
56
(No Transcript)
57
(No Transcript)
58

• Pop et al Clin Endoc 2003 59282 Maternal
  hypothyroxinaemia and child development

59
Relation between maternal FT4 at 12 wks centile and psychological scores at 2 yrs
Pop et al Clin Endoc 2003 59 282-288
FT4
60
Fetal Mortality and Morbidity in Pregnant
Hyperthyroid Patients

• Number of reports 11(1954-1983)
• Number of pregnancies 3 - 41
• Total number of pregnancies 249
• Fetal death and stillbirth 14 (5.6)
• Fetal and neonatal abnormality 15 (5)
• NB Incidence of Hyperthyroidism in pregnancy app
  0.24

61
L-T4 Dose Increases in pregnancy

• L-T4 requirements may increase 25-40, usually in
  the first half of pregnancy
• Increased requirements may depend on cause of
  hypothyroidism (ablation vs .Hashimotos)
• 25 of those with initial normal TSH in 1st
  trimester and 37 of those with initial normal
  serum TSH in 2nd trimester will later require
  dosage increases
• Mandel et
  al New Eng J Med 1990 Kaplan Thyroid 1992

62
Childhood development in Iodine deficient areas

• Spectrum of disorders ranging from
• Cretinism to
• Mild psychomotor impairment
• Documented by Stanbury, Hetzel, DeLange plus
  many colleagues and ICCIDD

63
Maternal Hypothyroidism during pregnancy and
subsequent childhood neuropsychological
development

• Haddow et al Aug 19 1999 N Eng J Med
• 62 children 7-9 yrs. Mother hypo in gestation
  ( tested 25,216 women)
• In children from mothers receiving noT4(n48)
• mean IQ decreased 7 points cf. Controls
• 19 IQ
• ? Screen thyroid function early gestation

64
Maternal hypothyroxinaemia during early pregnancy
Pop et al Clin Endoc 2003 59, 282-288

• 3yr prospective FU study of pregnant women and
  children up to 2 yrs
• 12 wks gestation FT4 lowest 10th centile vs FT4
  50th - 90th centile
• 1yr 2yr
• mental 10 8
• motor 8 10
• Low maternal T4 an independent determinant of
  delay in neurodevelopment
• If T4 increases, development not adversely
  affected
• decrement scores all sig different from control
  group

65
Maternal Hypothyroxinaemia

• Incidence in iodine deficient areas
• Usually not associated with high TSH in I
  deficient areas
• In I sufficient areas a high TSH more likely to
  reflect nearly all women with a low T4
• Knowledge of the iodine status of the community
  is essential

66
NACB Guidelines 2002
67
METHIMAZOLE EMBRYOPATHY Choanal/Oesophageal
atresia..
Karlsson et al. JCEM 2002