Download Thyroid Disease and Pregnancy

Thyroid Screening in Pregnancy
Rhys John
Dept of Medical Biochemistry
University Hospital of Wales
Cardiff
Thyroid Economy in Normal Pregnancy
Pregnancy is assoc. with
•
Hormonal changes
•
Metabolic changes
Produces complex effects on thyroid function
Thyroid disease common in women of child bearing age
Important to know
• Changes in TFT in normal pregnancy
• How pregnancy may affect any pre-existing
disease
eg. Thyroiditis, hypothyroidism, Graves disease
TOPICS
•
•
•
•
Thyroid function in pregnancy
Hyperthyroidism
Hypothyroidism
Postpartum thyroid disease
Goitre and Physiological changes
Neurobiology of Fetal Brain
Development
• T4 delivery to fetal neurones
Maternal iodide supply
Maternal T4 synthesis
Maternal T4 placental transport
Fetal T4 T3 conversion (role of
thyroid hormone transporters)
• TH receptor development in brain
• TH effects on genes related to
neurodevelopment (eg myelin)
•
A temporal process
Thyroid and Pregnancy- Controlling Factors
•
•
•
•
•
•
Estrogen [E2]
Thyroxine Binding Globulin [TBG]
Human chorionic gonadotrophin [hCG]
Iodine [I-]
Placental iodide and thyroid hormone transport
Iodothyronine deiodinases[D1,D2,D3]
D1 T4
D2 T4
D3 T4
T3
T3 and rT3
rT3 and T3
T2
T2
Pregnancy and Thyroid Function
Gestation accompanied by:
• Reduction of T4/TBG ratio
• Reduction of free hormone levels
• More pronounced thyroid hormone
disturbance in a third of women in 2nd half of
pregnancy i.e. hypothyroxinaemia
increased T3/T4 ratio
increased (but normal) TSH
• Increase in serum Tg
• Increase in thyroid volume [> in I deficiency]
THYROID FUNCTION IN PREGNANCY
TBG
FT4
hCG
(> 50,000 IU/L)
TT4
I-
TSH
Increased
T4 demand
AITD (TPOAb)
goiter
TSH
TV
Tg
TSH
iodine
excretion
T 3 /T 4
Placental
T4 turnover
from: Smallridge & Ladenson JCEM 86:2349,2001
Autoimmune Thyroid disease and Pregnancy
Modulation of maternal immune surveillance system
Progesterone Decreases reactivity of humoral and cellular
arms of the immune system
Oestrogen exerts opposite effect
As P/Oe increases, immune system dampened
All lead to clinical improvement of autoimmune diseases
After pregnancy: Rapid reduction immune suppressor
function
Re-establishment and exacerbation of these conditions
Miscarriage in Women with +ve TPO Antibodies
15 original studies
13 (87%) +ve assoc
2 (13%) no assoc
Metaanalysis case control and longitudinal studies [Prummel and
Wiersinga 2004]
RR of 3 in women with AITD
1. ? AITD a marker only
2. ? Reduced thyroid functional reserve during pregnancy
3. ? AITD delay conception.. effect of age on pregnancy loss
Poppe & Glinoer 2003
Stagnaro-Green & Glinoer 2004
Treatment of TPOAb+ women in pregnancy
• 57 +ve TPO + T4
Miscarriage
%
3.5
Prem
%
7.3
• 58 +ve TPO no T4
13.8
22
• 869 -ve TPO
2.4
8.2
Negro et al 2006 JCEM 91: 2587-2591
Pregnancy, Thyroid Antibodies and
Outcome
• Euthyroid women with Abs tend to be older
when first pregnant
• They have reduced thyroid functional
reserve (TSH higher in Ab+ve women)
• Increased risk of obstetric complications
• T4 intervention reduces chance of
miscarriage and premature delivery
• ? Screening strategy in early pregnancy
adapted from Glinoer 2006 JCEM 91:2500-2502
Pregnancy and Thyroid Disease Facts and Figures
Gestation
Hyperthyroidism 0.2%
Hypothyroidism (TSH) 2-2.5%
Thyr Antibodies
10%
Postpartum
PPTD
5-9%
PP depression 30% [ vs 20%]
PP Graves’ up to 40% of Graves’
Pregnancy Outcome in Hyperthyroidism [%]
Hyperthyroid-90
Treated-149
Pre-eclampsia
17
11
Heart failure
8
1
Preterm delivery
32
8
Growth restriction
17
7
stillborn
18
0
thyrotoxic
2
1
hypothyroid
0
4
goitre
0
2
Causes of Low TSH in Pregnancy
Trimester
1
2
3
High hCG
Gestational Transient Thyrotoxicosis
Graves’ Hyperthyroidism
Subacute thyroiditis
Toxic adenomatous goitre
Toxic Multinodular goitre
Nodular goitre
Mutant TSH Receptor
Molar pregnancy
TSH assay error
Factitious (eg T4 addiction)
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Hyperemesis and Thyroid Function[Goodwin et al]
TSH
FT4
hCG
SEVERE
HYPEREMESIS
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
Hypothyroidism – Pregnancy
Complications [%]
Overt
Subclinical
Pre-eclampsia
31
16
Abruptio Plac
8
0
PPH
10
2
Cardiac
3
2
Wt<2000g
26
11
stillbirth
8
1
n
39
57
Hypothyroidism in Pregnancy
Larsen et al 2003
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 Graves’……45%
Hash……….25%
• Monitor TSH monthly
• Reduce T4 dose to pre-pregnancy level after
delivery
High TSH in Pregnancy
• Incidence: 2.4% of 2000 studied at 15-18
wks gestation [mostly AITD].
• 9403 women in 2nd trimester - TSH
high(>6mu/L in 2.2% [ 209])
• Fetal death = 3.8% in high TSH vs 0.9% in
TSH<6 group[odds ratio 4.4 ci 1.9-9.5]
• RR 3.0 Placental abruption & 1.8 for
preterm birth
• If T4 therapy beneficial then +ve case for
screening Klein et al Clin Endoc 1991 Allan et al J Med Screen 2000
Casey et al Obstet Gynecol 2005
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 FT4<10th percentile, not to TSH, anti TPO or 3rd
trimester FT4[ Pop et al]
•
1999 Increased risk of poor neuropsychological scores in
progeny of women with maternal TSH>98th percentile
[ Haddow et al]
•
2003 Prospective 3 yr study shows lower motor and mental
scores in infants aged 1 and 2 yrs related to Maternal FT4 at
12 wks gestation [Pop et al ]
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(n=48):
mean IQ decreased 7 points cf. Controls
19% IQ < 85 cf. 5% of controls
• ? Screen thyroid function early gestation
CATS
Controlled 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
Controlled Antenatal Thyroid
Screening [CATS]
22000 < 16 wks gestation
Test FT4 and TSH
No Test
Start T4 0.15mg/day
Test FT4 and TSH post delivery
Check FT4 after 6wks
Abnormal
Treat with T4
Check FT4 30wks
Child Developmental Testing
2 and 5 years
post delivery assessment
? requires T4
FT4 between 8 and 16 wks gestation
15.0
Mean FreeT4 (pmol/L)
14.5
14.0
13.5
13.0
12.5
12.0
8
9
10
11
12
13
Weeks Gestation
14
15
16
TSH between 8 and 16wks gestation
1.40
Median TSH (mU/L)
1.20
1.00
0.80
0.60
0.40
8
9
10
11
12
13
Weeks Gestation
14
15
16
Weeks
gestation
Number
of
subjects
Free T4 (pmol/L)
(2.5th – 97.5th centile)
TSH
(mU/L)
(2.5th – 97.5th centile)
<8
78
14.5
10.5 – 20.0
0.93
0.02 – 3.23
<9
298
14.5
11.4 – 17.9
0.98
0.02 – 2.87
<10
839
14.2
10.8 – 18.5
1.00
0.05 – 3.52
<11
1866
14.2
11.2 – 18.5
1.07
0.03 – 3.83
<12
4345
14.0
11.0 – 17.9
1.08
0.05 – 3.48
<13
3617
13.9
10.9 – 17.6
1.11
0.06 – 3.36
<14
2324
13.6
10.6 – 17.6
1.15
0.1. – 3.23
<15
1617
13.4
10.5 – 17.1
1.19
0.13 – 3.73
<16
567
13.3
10.8 – 16.6
1.27
0.15 – 3.74
Urinary Iodide Excretion in 1st
Trimester in Wales, UK2002/03
Urinary I
µg/L
30
25
0-25
26-50
51-100
101-150
151-200
201-300
>300
%20
15
10
5
0
N=164
Iodine Deficient
Iodine sufficient
Patterns of Thyroid Function Post Partum
From AMINO
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
Development of Postpartum Thyroid Dysfunction
Immunogenetic background [eg HLA + other genes]
TPOAb
100
Cellular immunity
Thyroid
reserve
%
Postpartum
Pregnancy
Subclinical hypothyroidism
Overt hypothyroidism
Overt hypothyroidism
0
Time
? Fetal microchimerism
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]
Screening for Gestational Hypothyroidism
Maternal Thyroid Disease
Screening for Hypothyroidism
• Frequency of
hypothyroidism
• Relatively prevalent
• Effects on mother and
child
• Significant health impact
• Treatment effective safe
and cheap
• Early diagnosis
superior outcome
• No PRCT as yet
• Cost implications
• Effective Treatment
• Effectiveness of
screening strategies
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
[TPOAb+ve]
•
Long term follow up of selected patient groups
THANK YOU