1. Congenital hypothyroidism: what on earth is it? A more ‘progressive’ approach. John Gregory Professor in Paediatric Endocrinology Cardiff University

2. Congenital hypothyroidism: what on earth is it? A more ‘progressive’ approach. Challenges in screening Changing incidence Consequences of ‘gland in situ’ Biochemical consequencies of TSH <20mU/L Pros & cons of changing the ‘cut-off’ Conclusions

3. Challenges in management of congenital hypothyroidism Different aetiologies of congenital hypothyroidism Guidelines for premature or low birth weight babies Biochemical: lack of agreement on cut-offs to detect congenital hypothyroidism Is there a correlation between neonatal fT4 or TSH & later neurodevelopment?

4. Changing incidence of congenital hypothyroidism? Over last 2 decades – New York 1:3378 (1978) → 1:1414 (2005) – USA 1:4098 (1987) → 1:2370 (2002) Changes in clinical evaluation & therapy Transient hypothyroidism Epidemiology – prematurity – genetic factors, sex, race & ethnicity – prenatal iodine intake –Autoimmunity Changes in lab method & screening paradigms

5. Is the incidence of congenital hypothyroidism really increasing? 1. All cases in Quebec 2. Thyroid dysgenesis 3. Goitre 5. Unknown 4. Normal gland in situ Deladoey et al, 2011 TSH cut-off decreased from 15 to 5mU/L

6. Comparison of yearly incidences of congenital hypothyroidism a = 1990-2000: TSH <15mU/L cut-off b = 2001-2009: TSH <5mU/L cut-off (all cases) c = 2001-2009: TSH <5mU/L cut-off (without additional cases) Deladoey et al, 2011

7. Congenital hypothyroidism in Wales (2003-5) Perkin Elmer autoDELFIA neonatal hTSH assay introduced –compared to ACS 180 Bayer ACS TSH method (Bayer) results approximately 50% lower –cut-off of <5mU/L therefore audited 41 infants with blood spot TSH >5mU/L –23 had TSH >20mU/L –8 had TSH 10-20mU/L 10 had TSH 5-10mU/L –9 had ↑ neonatal plasma TSH (mean TSH 20.6, range 6–30.1mU/L) –6 normalised TSH between 4 weeks and 3 months 3 infants given thyroxine –1 stopped therapy aged 2.5yrs (neonatal TSH 30.14mU/L) –2 infants remain on treatment –1 has Down syndrome (neonatal TSH 80mU/L) –1 required ↑ doses of thyroxine due to persistently raised TSH concentration (neonatal TSH 14.5mU/L)

8. Reaudit of newborn screening in Wales April ‘07 - March 2010 105,295 babies screened 49 babies had a TSH >20mU/L 364 babies had a TSH 5 – 19mU/L –37 had persistently raised TSH & referred to designated Paediatrician –6 started on thyroxine

9. Relationship of newborn bloodspot TSH and pre-therapy fT4 in 310 Scottish infants (excluding sick babies) Courtesy of Malcolm Donaldson

10. Cause of congenital hypothyroidism & initial biochemistry Dysgenesis associated with most severe hypothyroidism Majority of gland in situ cases have FT4 levels below normal Corbetta et al, 2009

11. Effect of lowering TSH cut-off on causes of congenital hypothyroidism 629,042 newborns in Italy TSH cut-off changed in 1999 (12mU/L) & 2003 (10mU/L) Using 20mU/L cut-off –misses 45% cases –misses 12/141 dysgenesis 78% of gland in situ show persistent thyroid dysfunction at 3-5yrs Corbetta et al, 2009

12. Why treat ‘subclinical’ neonatal congenital hypothyroidism? Evidence limited Persistent or worsening biochemistry Neurodevelopment Growth Lipid metabolism Heart function Pregnancy

13. Repeat testing of 67 term infants with initial TSH >6 & <10mU/L in North of England Proportion of specialists opting to treat 44.7 17/17 24.3 16/17 21.4 10/17 8.7 0/17 Korada et al, 2010 Serum TSH (mU/L)

14. TSH values at reevaluation aged 3yrs Neonatal TSH 10-20mU/L Neonatal TSH >20mU/L Prem Term Mengreli et al, 2010 311,390 infants screened in Greece 200 diagnosed CH 28% TSH 10- 20mU/L 85.1% permanent CH on reevaluation 20% structural defect

15. TSH levels through childhood in transient neonatal hyperthyrotropinaemia Group 1 normal TSH aged 2- 3yrs Group 2 TSH 4- 10.1mU/L aged 2-3yrs At 8yrs subclinical hypothyroidism persists in 31.8% 13/44 hypoplasia of one lobe Leonardi et al, 2008

16. Adverse effect of transient neonatal hyperthyrotropinaemia (1) Iranian study Iodine deficiency common No difference in TFTs or iodine status aged 9yrs No difference in growth or psychomotor performance aged 9yrs No correlation between neonatal TSH & IQ aged 9yrs ↑ neonatal TSH (n=18) Normal TSH (n=19) p value Neonatal TSH (mU/L) 23.4 +/-8.3 3.6 +/-1.0 <0.001 IQ aged 9yrs98 +/-11 106 +/-8 <0.01 Azizi et al, 2001

17. Adverse effect of transient neonatal hyperthyrotropinaemia (2) Italian study in area of endemic goitre No difference in TFTs at assessment aged 7-8yrs No difference in height or bone age aged 7-8yrs ↑ neonatal TSH (n=9) Normal TSH (n=9) p value Global IQ78.3 +/-11.1 90.9 +/-14.2 <0.05 Verbal IQ84.4 +/-15.4 96.2 +/-14.8 NS Performance IQ75.0 +/-8.5 89.2 +/-12.5 <0.01 Calaciura et al, 1995

18. Effect of compensated hyperthyrotropinaemia on metabolic rate Basal metabolic rate studies in 10 infants <2months old with normal serum T4 6 infants normal BMR (49.6+/-1.9kcal/kg/d) – TSH<6mU/L 4 infants low BMR (38.1+/-4.1kcal/kg/d) – TSH>7mU/L – thyroxine therapy normalised TSH & BMR (48.7+/- 1.0kcal/kg/d) within 3 weeks Japanese study of 16 infants with hyperthyrotropinaemia showed normal BMR Alemzadeh et al, 1992 & Miki et al, 1989

19. Implications for screening programmes of changing TSH cut-offs TSH cut-off (mU/L whole blood) Newborns recalled (n) Recall rate (%) Infants diagnosed with CH 301730.05114 203760.12144 1037841.20*200 Mengreli et al, 2010 311,390 infants screened in Greece prospective study, Jan 2000 – Dec 2002 * additional costs = 1.8% of screening budget

20. Management of a child with ‘borderline’ TSH values clinical evaluation venous fT4 & TSH & maternal TSHr Ab thyroid ultrasound +/- isotope scan thyroxine to normalise fT4 within 24hrs & TSH within 1 week trial of discontinuation aged 3yrs if TSH never elevated

21. If we don’t treat, can we subsequently diagnose untreated hypothyroidism? Neurodevelopmental delay – most will still be within the normal range Growth failure – screening programmes poor at identifying abnormal growth

22. Conclusions ↓ TSH cut-off below 20mU/L ↑ incidence of congenital hypothyroidism – mostly gland in situ & hyperthyrotropinaemia – potential risk of adverse neurodevelopment may identify iodine deficiency potential new genetic causes? therapy may prevent adverse consequencies until further trials have established benefit, cut-off should be lowered from 20mU/L