2. Thyroid Screening in Pregnancy Rhys John Dept of Medical Biochemistry University Hospital of Wales Cardiff

3. 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

4. TOPICS Thyroid function in pregnancy Hyperthyroidism Hypothyroidism Postpartum thyroid disease

5. 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 Goitre and Physiological changes

6. Thyroid and Pregnancy- Controlling Factors Estrogen [E 2 ] Thyroxine Binding Globulin [TBG] Human chorionic gonadotrophin [hCG] Iodine [I - ] Placental iodide and thyroid hormone transport Iodothyronine deiodinases[ D1,D2,D3] D1 T4 T3 D2 T4 T3 and rT3 T2 D3 T4 rT3 and T3 T2

7. 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]

8. from: Smallridge & Ladenson JCEM 86:2349,2001 TV THYROID FUNCTION IN PREGNANCY

9. 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

10. 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

11. Treatment of TPOAb+ women in pregnancy 57 +ve TPO + T4 58 +ve TPO no T4 869 -ve TPO Miscarriage Prem % 3.57.3 13.822 2.48.2 Negro et al 2006 JCEM 91: 2587-2591

12. 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

13. Pregnancy and Thyroid Disease - Facts and Figures Gestation Hyperthyroidism0.2% Hypothyroidism (TSH) 2-2.5% Thyr Antibodies 10% Postpartum PPTD 5-9% PP depression 30% [ vs 20%] PP Graves’ up to 40% of Graves’

14. Pregnancy Outcome in Hyperthyroidism [%] Hyperthyroid-90Treated-149 Pre-eclampsia1711 Heart failure81 Preterm delivery328 Growth restriction177 stillborn180 thyrotoxic21 hypothyroid04 goitre02

16. Hyperemesis and Thyroid Function [Goodwin et al] TSH FT4 hCG SEVERE HYPEREMESIS

17. 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

18. Hypothyroidism – Pregnancy Complications [%] OvertSubclinical Pre-eclampsia3116 Abruptio Plac80 PPH102 Cardiac32 Wt<2000g2611 stillbirth81 n 39 57

19. Hypothyroidism in Pregnancy Larsen et al 2003

20. 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

21. 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

22. NEURODEVELOPMENT IN IODINE SUFFICIENT AREAS 1967 Maternal hypothyroxinaemia related to low IQ of progeny (both corrected by treatment during pregnancy) [Man et al] 1995Maternal antithyroid antibodies related to lower IQ of progeny [Pop et al] 1999Psychomotor 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 ]

23. 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? Screen thyroid function early gestation

24. 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

25. Controlled Antenatal Thyroid Screening [CATS]

26. FT4 between 8 and 16 wks gestation

27. TSH between 8 and 16wks gestation

28. Weeks gestation Number of subjects Free T4 (pmol/L) (2.5 th – 97.5 th centile) TSH (mU/L) (2.5 th – 97.5 th centile) <87814.5 10.5 – 20.0 0.93 0.02 – 3.23 <929814.5 11.4 – 17.9 0.98 0.02 – 2.87 <1083914.2 10.8 – 18.5 1.00 0.05 – 3.52 <11186614.2 11.2 – 18.5 1.07 0.03 – 3.83 <12434514.0 11.0 – 17.9 1.08 0.05 – 3.48 <13361713.9 10.9 – 17.6 1.11 0.06 – 3.36 <14232413.6 10.6 – 17.6 1.15 0.1. – 3.23 <15161713.4 10.5 – 17.1 1.19 0.13 – 3.73 <1656713.3 10.8 – 16.6 1.27 0.15 – 3.74

29. Urinary Iodide Excretion in 1st Trimester in Wales, UK 2002/03 % Urinary I µg/L N=164 Iodine DeficientIodine sufficient

30. Patterns of Thyroid Function Post Partum From AMINO

33. 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

34. Overt hypothyroidism TPOAb Time 0 100 Thyroid reserve % Pregnancy Immunogenetic background [eg HLA + other genes] Overt hypothyroidism Subclinical hypothyroidism Postpartum Development of Postpartum Thyroid Dysfunction Cellular immunity ? Fetal microchimerism

35. 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 ]

36. Screening for Gestational Hypothyroidism Frequency of hypothyroidism Effects on mother and child Effective Treatment Effectiveness of screening strategies Relatively prevalent Significant health impact Treatment effective safe and cheap Early diagnosis superior outcome No PRCT as yet Cost implications Maternal Thyroid DiseaseScreening for Hypothyroidism

37. 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

38. THANK YOU