1. Aspects of Thyroid Disease in Pregnancy Prof John Lazarus Institute of Molecular and Experimental Medicine, Cardiff University Society of Physicians in Wales Lazarus@cf.ac.uk

2. John Lazarus has nothing to disclose

3. Acknowledgements J Bestwick S Channon C Dayan C Hales R Hall B Harris L George R John M Joomun M Ludgate A Maina B Okosieme A Parkes R Paradice K Premawardhana C Richards L Taylor P Taylor N Wald Welsh Obstetricians

4. TOPICS Physiology of thyroid in pregnancy Recent developments in hyperthyroidism and pregnancy Hypothyroidism in pregnancy Screening for thyroid function in early pregnancy

5. TV THYROID FUNCTION IN PREGNANCY Smallridge & Ladenson JCEM 86:2349,2001 Santini & Pinchera 1998

6. Chan et al Nature Clinical Practice 2009:1,45-54 T4 & T3 Passage through Placental Trophoblasts Iodide I I Thyroid Hormone Transporters MCT8 MCT10 LAT1 LAT2 OATP1A2 OATP4A1 ST,CT= Syncytio,cyto trophoblast adapted from Burns et al Thyroid 2011; 21:541-6.

7. 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 IMMUNE SYSTEM CHANGES Th1 Th2 Th17

8. Williams J Neuroendocrinol 2008; 20:784-794

9. Pregnancy and Thyroid Disease - Facts and Figures Gestation Hyperthyroidism 0.2% Hypothyroidism (TSH) 2-2.5% [Mostly subclinical ie High TSH with normal FT4] (Overt 0.5%) Isolated Hypothyroxinaemia 2.5-10% Thyr Antibodies [TPO] 10% Postpartum PPTD 5-9% PP depression 30% [ vs 20%] PP Graves’ up to 40% of Graves ’

10. Gestational Related Reference Ranges Stricker R, et al. Euro J Endocrinol 2007;157:509-514 Panesar NS et al. Ann Clin Biochem 2001,38:329-332 Upper limit non pregnant Upper limit pregnant TSH Median ‘Accurate classification of TFT in pregnant women requires the use of gestational age specific reference intervals’ % FT4

11. RECOMMENDED DAILY IODINE INTAKE [Results of WHO Technical Consultation 2005] Andersson et al Public Health Nutrition 10(12A) 1606-11, 2007 ^x X corresponds to urinary iodine 177µg/litre (approx)

12. Verbal IQ (p=0.002) Total IQ (p=0.04) Reading comprehension (p=0.04) Degree of iodine deficiency Bath et al 2013 61.6% of the women were iodine deficient (< 150 µg/gCr) [1000 women. Children 8yrs old]

13. TOPICS Physiology of thyroid in pregnancy Recent developments in hyperthyroidism and pregnancy Hypothyroidism in pregnancy Screening for thyroid function in early pregnancy

14. Management of Graves’ Hyperthyroidism in Pregnancy Confirm diagnosis PTU 1 st trimester then MMI/Carb… For discussion 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 30 wks. gestation Discuss treatment with patient effect on patient effect on fetus breast feeding Inform obstetrician and paediatrician Review postpartum - check for exacerbation

15. Antithyroid Drugs in Pregnancy PROPYLTHIOURACIL PTU related liver failure (hepatocellular inflammation) and death in children (1/100 Less in adults (1/10,000) Therefore: PTU not first line in children or adults Use PTU only during 1 st trimester [odds ratio 18 (95% CI 3-121) for choanal atresia in infants with in utero MMI exposure] Cooper and Rivkees JCEM 2009;94:1881-2 CARB/MMI PTU hepatotoxicity Carbimazole embryopathy Yoshihara et al 2012 JCEM Embryopathy % Ma lfo R ma tio n

16. Figure 1 Schematic illustration showing the time period in gestational weeks of maximal sensitivity to abnormal development in humans. Peter Laurberg, and Stine Linding Andersen Eur J Endocrinol 2014;171:R13-R20 © 2014 European Society of Endocrinology

17. 1. Restrict the use of ATDs in first trimester (weeks 6–10) of pregnancy 2. Give written instruction to fertile women treated with ATDs to: i) Perform a pregnancy test within a few days after the 1st day of a missed (or atypical week) menstrual period, if pregnancy is a possibility ii) If the pregnancy test is positive, contact physician the same day, and take no more ATDs before such contact 3. If the pregnant woman is considered in remission of Graves' disease, observe without ATDs along with weekly thyroid function testing until second trimester 4. If an ATD is necessary in early pregnancy: use PTU 5. If future pregnancy is planned: consider shift from MMI/CMZ to PTU before pregnancy 6. Consider surgical therapy in young women with severe Graves' disease Proposed measures to reduce the number and severity of antithyroid drug (ATD)-associated birth defects. Laurberg & Andersen Eur J Endoc 2014 ;171:R13-20.

18. TOPICS Physiology of thyroid in pregnancy Recent developments in hyperthyroidism and pregnancy Hypothyroidism in pregnancy Screening for thyroid function in early pregnancy

19. TPO Antibodies and Pregnancy Presence of TPOAb is a risk factor for: 1.Miscarriage [Thangaratinam et al BMJ 2011] 2.Progression of hypothyroidism [ Glinoer et al JCEM 1994] 3.Preterm delivery [Stagnaro-Green et al Thyroid 2005, He et al EJE 2012] 4. Impaired child development [Pop et al JCEM 1995] 5.Post partum thyroiditis [Premawardhana et al 2004] Treat with L-T4 if TSH> 2.5mU/L

20. Thyroid Antibodies and miscarriage Thyroid antibodies and Preterm delivery He X Eur J Endocrinol. 2012 ;167:455-64. doi: 10.1530/EJE-12-0379 Thangaratinam S et al.2011BMJ. 9;342:d2616. doi: 10.1136/bmj.d2616 META ANALYSES RR 2.07 RR 1.69

21. RCT of LT4 in euthyroid patients who were TPO-Ab+ They reported a significantly decreased rate of pregnancy loss in the treated group (3.5 % vs. 13.8%, p<.05). A limitation of the study is that the mean gestational age of starting levothyroxine was ten weeks estimated gestational age, and all but one of the losses had occurred at less than 11 weeks. (Negro 2006). Two randomized clinical trials are ongoing: TABLET trial in the UK, T4Life trial in the Netherlands RECOMMENDATION: There is insufficient evidence to recommend for or against treating with levothyroxine in euthyroid women, including those with a history of sporadic or recurrent abortion. DOES TREATMENT WITH LT4 DECREASE THE RISK FOR MISCARRIAGE IN EUTHYROID WOMEN WITH THYROID AUTOIMMUNITY?

22. Diagnosis of SCH in Pregnancy Recommendations 1.Trimester specific reference ranges (2S) 2.If not available TSH T1 2.5mU/L, T2 3mU/L, T3 3.5mU/L (2W) 3.TT4 and FT4 assays ok for pregnancy (2S) 4.If TSH elevated FT4 and TPOAb to be measured (1S) 5.Inc TSH + -ve TPOAb….measure TgAb plus thyroid US (2S) Lazarus J. et al European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children Eur Thyroid J 2014;3:76-94

23. Highest recorded TSH in 769 women on L-T4 for at least 6 months Taylor et al JCEM 2014, 99: 3895-3902

24. Adverse effects of SCH on Mother +ve Diabetes Pregnancy loss Gestational hypertension Pre-eclampsia Preterm delivery -ve High birth weight Congen malformation RDS +ve/-ve Placental abruption ↑perinatal mortality Admission to neonatal intensive care unit Low Apgar score Low birth weight

25. Subclinical hypothyroidism and neurodevelopment +ve studies Sch (before 20 wks) and impaired visual development [OR 12.14] and neurodevelopmental delay[OR10.49] (Su et al 2011). Also Li et al 2010 retrospective study but only 18 ptnts with sch. Mat TSH early preg and behavioural problems in offspring (Ghassabian et al 2011) -ve studies: Spain 1761 children (Julvez et al 2013) Netherlands 3659 children (Henrichs et al 2010) Mean IQ = in 19 children (inadequate L-T4 treatment) cf control children from euthyroid mothers (Behrooz et al 2011)

26. What is Isolated Hypothyroxinaemia? TT4 and FT4 normally distributed (unlike TSH) Variable definitions of IH (eg lowest 2.5 th -10 th centile FT4 ) TSH within gestational reference range TPOAb +ve or –ve CAUSES Iodine Deficiency Modification of T4 affinity for TBG Placental 5’ deiodinase type 3 activity Placental angiogenic factors Environmental contaminants Assoc with Fe deficiency Furnica et al 2015 JEI Korevaar et al 2015 JCEM Yu et al 2015 JCEM

27. IH in Animal Models Changes in neuronal migration, cytoarchitecture of cortex and hippocampus, Neurogenesis,, axon and dendrite formation, myelination, synaptogenesis, neurotransmission Alteration in gene expression Lavado-Autric R, J Clin Invest. 2003;111:1073–1082 Negro et al Endoc Pract 2011;17:422-429 Min et al Mol Neurobiol 2015 Dong et al Cerebral Cortex 2014; doi:10.1093/cercor/bht364

28. IH and Obstetric Outcomes No adverse outcomes in 17298 and 879 women Casey et al 2007;Hamm et al 2009 Inc breech and CS assoc with FT4<10 th Pop et al 2004 Assoc. with preterm labor and macrosomia (FT4<2.5 th ) Cleary- Goldman et al 2008 >fetal distress, sga and musculoskeletal malformations Su et al 2011 2.5 x prem delivery, 3.6 x larger fetal and infant head size Korevaar et al 2013 Studies of isolated hypothyroxinaemia in pregnancy have shown conflicting evidence with regards to adverse obstetric and neurodevelopmental outcomes and no causative relationships have been determined. Chan et al 2015

29. Maternal Hypothyroxinaemia and Cognitive Function Expressive language delay Henrichs J et al.. J Clin Endocrinol Metab 2010; 95: 4227–34 Lower mental scores in 2 yr old infants of women with < FT4 <5 th centile Julvez et al Epidemiology 2013;24:150-157 Children aged 5-6yrs poor performance in simple reaction time test Martijn JJ et al J Clin Endocrinol Metab 2013; 98: 1417–26 Children aged 8 scored 4.3 points lower IQ cf children from normothyroxinemic mothers (p = 0.001) Ghassabian et al J Clin Endocrinol Metab 2014;99:2383-2390 Preterm infants poorer cognitive performance at 5.5yrs Delahunty C,, et al, J Clin Endocrinol Metab 2010; 95: 4898–908.

30. Maternal Hypothyroxinaemia and Neuropsychiatric Function Autistic symptoms - 4x incidence of in 6yr old Roman GC, et al. Ann Neurol 2013; 733-742 Schizophrenia – Finnish nested case control study OR 1.75 (CI 1.22-2.50 p = 0.002) Gyllenberg et al Biol Psychiat 2015 ADHD symptoms in 8 year old children Modesto et al JAMA Pediatr 2015 [ see also Vermiglio et al JCEM 2004; 89:6054-6060]

31. Maternal Hypothyroxinaemia no effects No association between IH (FT4,5 th centile) and neurodevelopmental delay at 19 months (43 children) Su et al JCEM 2011;96: 3234-3241 No association between mid gestational FT4 and neurocognitive development at 2 years. Craig et al JCEM 2012;97:E22-28 No association between maternal gestational FT4 and subsequent intellectual development at 1 year (455 children) and 6-8 years (289 children) Grau et al J Trace Elem Med Biol 2015

32. CATS [Controlled Antenatal Thyroid Screening study] AIM: To evaluate the strategy of screening for thyroid function in early gestation with levothyroxine [T4] intervention therapy METHOD: A prospective randomised controlled trial of T4 treatment vs no treatment in mothers with thyroid dysfunction. PRIMARY OUTCOME: IQ of children tested between 3yr and 3 yr 6mo SECONDARY OUTCOME IQ stratification and compliance with therapy In this randomized trial, antenatal screening (at a median gestational age of 12 weeks 3 days) and treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age although there was some uncertainty. Lazarus et al New England Journal of Medicine 2012, 366: 493-501

33. Possible reasons for negative outcome Timing of screening Mild hypothyroidism in both groups Nearly 50% low T4 and normal TSH No information on IQ in normal population Specificity of cognitive impairment expressive language delay orientation decrement vision abnormalities behavioural changes TSH level at inclusion (97.5 th centile vs 99.7 th – Haddow 1999) Other

34. Odds of offspring having an IQ score in the lowest 10% by maternal perchlorate levels (in the upper 10%) in the first trimester IQ Lowest 10%Model 1Model 2Model 3 TOTAL 2.42 * 3.14 ˮ 2.74 * VERBAL2.35* 3.14 ʸ 3.19 ʸ PERFORMANCE0.841.021.01 * p = 0.02ˮ p = 0.006 ʸ p = 0.005 * p = 0.02 ʸ p = 0.005 Taylor PN et al Maternal perchlorate levels in women with borderline thyroid function in Pregnancy and the cognitive development of their offspring; Data from The Controlled Antenatal Thyroid Study J Clin Endocrinol Metab. 2014 Jul24:jc20141901.

35. Odds of IQ < 85 in Children homozygous for Thr92Ala [Type 2 Deiodinase] and with low maternal FT4 Taylor et al 2015

36. Outcomes CATS obstetric ≠ High TSH associated with miscarriage/stillbirth after 12 weeks if untreated OR = 5.46 (95%CI 1.66, 17.9) p=0.004 Isolated hypothyroxinemia (IH): a) associated with macrosomia, (OR=1.58 95%CI 1.14 to 2.17) p=0.005 b) if treated with T4 had higher birth weight of 150g (p=0.01) and 6 days longer gestation (p=0.01). ≠ Analysis of 14,336 women with TSH and FT4

37. TOPICS Physiology of thyroid in pregnancy Recent developments in hyperthyroidism and pregnancy Hypothyroidism in pregnancy Screening for thyroid function in early pregnancy

38. Justification for Screening Test Well defined disorder with known incidence/prevalence Medically important disorder Screening test simple and safe with established cut off values Effective treatment available Cost of test relative to benefit should be known Adequate logistics for the testing and follow up Patient and management acceptability YES Wald N, Law M Medical Screening in Oxford Textbook of Medicine 2010 5th Ed pp 94 – 108 1 Maternal Thyroid Disease Frequency of hypothyroidism Effects on mother and child Effectiveness of screening strategies Effectiveness of intervention

39. TSH to be obtained in early pregnancy History of thyroid dysfunction or prior thyroid surgery Age >30 years Symptoms of thyroid dysfunction or the presence of goiter TPOAb positivity Type 1 diabetes or other autoimmune disorders History of miscarriage or preterm delivery History of head or neck radiation Family history of thyroid dysfunction Morbid obesity (BMI ≥40 kg/m2) Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast Infertility Residing in an area of known moderate to severe iodine insufficiency over age 30 years ( ? Valid see Potiukova et al 2012) family history of autoimmune thyroid disease or hypothyroidism goiter thyroid antibodies, primarily thyroid peroxidase antibodies symptoms or clinical signs suggestive of thyroid hypofunction type 1 diabetes mellitus, or other autoimmune disorders infertility prior history of preterm delivery prior therapeutic head or neck irradiation or prior thyroid surgery currently receiving levothyroxine replacement Stagnaro-Green et al ATA Guidelines THYROID 2011 DeGroot et al Endo Soc Guidelines JCEM 2012 But will miss up to 65% of undiagnosed thyroid dysfunction! ATA AM ENDO SOC

40. Screening Recommendations for Thyroid Disorders during Pregnancy AACE 1999: Serum TSH in all women considering becoming pregnant ACOG 2001: Perform in symptomatic women and those with history of thyroid disease ATA 2011: TSH in early pregnancy in women at high risk of overt hypothyroidism Cochrane Collaboration 2012: Targeted thyroid function testing to those at risk of thyroid disease ENDO Soc 2012: Targeted case finding ETA 2014 : Majority recommended screening Stagnaro-Green and Pearce Nature Rev Endocrinol 2012:8;650-658 Lazarus et al Eur Thyr J 2014; 76-94

41. Current Views on Screening ATA: Not enough evidence for or against universal TSH screening [Stagnaro-Green et al Thyroid 2011[] ENDO: No agreement with regard to screening recommendations for all newly pregnant women. [ DeGroot et al JCEM 2012] Some members recommended screening of all pregnant women for serum TSH abnormalities by the 9th week or at the time of their first visit. (USPSTF Recommendation level: C, Evidence level-fair; (GRADE 2|   ) Some members recommended neither for nor against universal screening of all pregnant women for TSH abnormalities at the time of their first visit. All strongly support aggressive case finding to identify and test high- risk women for elevated TSH But will miss up to 65% of undiagnosed thyroid dysfunction

42. Conclusions Intense interest in thyroid and pregnancy Advances in thyroid physiology Developing brain and thyroid function Hypothyroxinaemia.. Is it a disease? Should we screen for thyroid dysfunction in early gestation?

43. THANK YOU

44. Recent Review 105 papers from > 6000 Thyroid hormone disorders and TPOAb associated with: Disturbed folliculogenesis Disturbed spermatogenesis Reduced fertilisation Disturbed embryogenesis Vissenberg et al Hum Reprod Update 2015

45. Maternal Thyroid Dysfunction during Gestation, Preterm Delivery, and Birthweight. The Infancia y Medio Ambiente Cohort, Spain Leon et al Paed and Perinatal Epidem 2015 :29, 113-122, HyperT4 and SGA OR1.28[1.08, 3.02]

46. Association of gestational maternal hypothyroxinemia and increased autism risk Roman et al Annals of Neurology 13 AUG 2013 DOI: 10.1002/ana.23976

47. All Mother-Children Pairs With Sufficient Maternal Serum Samples and Children's ADHD Symptom Evaluation Available (n = 5131) Child's ADHD symptomn (%) OR (95% CI) Inattention Boys749 (14.6)1.00 (0.90–1.12) Girls281 (5.5)1.18 (1.02–1.37) Hyperactivity Boys806 (15.7)1.00 (0.90–1.10) Girls289 (5.6)1.10 (0.95–1.25) Rutter B2 scores of 9 or greater Boys494 (9.6)1.02 (0.90–1.15) Girls192 (3.7) 1.23 (1.03–1.48) Combined ADHD Boys355 (6.9) 1.17 (1.00–1.36) Girls106 (2.1) 1.39 (1.07–1.80) Pakkila et alJ Clin Endocrinol Metab. 2014 Jan; 99(1): E1–E8. Pakkila et alJ Clin Endocrinol Metab. 2014 Jan; 99(1): E1–E8.. doi: 10.1210/jc.2013-294310.1210/jc.2013-2943