1. NEONATE BORN TO MOTHER WITH GRAVE’S DISEASE NEONATE BORN TO MOTHER WITH GRAVE’S DISEASE Baby boy born at 24 weeks gestation, weight 559G Baby boy born at 24 weeks gestation, weight 559G Mother 25year,G6 P4 Ab1 LC4. Mother 25year,G6 P4 Ab1 LC4. Known case of Grave’s disease, with uncontrolled thyrotoxicosis since 1999…non compliant on treatment (PTU/Inderal). No PNC. Known case of Grave’s disease, with uncontrolled thyrotoxicosis since 1999…non compliant on treatment (PTU/Inderal). No PNC. With pre-eclampsia, abruption- severe decelerations-Emergency C-section. With pre-eclampsia, abruption- severe decelerations-Emergency C-section.

2. NICU COURSE Maternal TSI on Sept 2003: 212% Maternal TSI on Sept 2003: 212% (Normal 0 - 129%) (Normal 0 - 129%) Resuscitated at birth Apgars 3,6 & 8.Ventilated ….given curosurf and transferred to ICN on portable ventilatorResuscitated at birth Apgars 3,6 & 8.Ventilated ….given curosurf and transferred to ICN on portable ventilator On exam, baby 24 weeks gestation AGAOn exam, baby 24 weeks gestation AGA Systemic exam WNL. No evidence of goiter/exophthalmos. Initially had heart rates in 160-170 but later normalized. Systemic exam WNL. No evidence of goiter/exophthalmos. Initially had heart rates in 160-170 but later normalized.

3. MANAGEMENT IN NICU Hypoperfusion/hypotension/metabolic acidosis needing NS bolus x 2 and inotrope support. Hypoperfusion/hypotension/metabolic acidosis needing NS bolus x 2 and inotrope support. D2-3 echo showed PDA…treated with Indomethacin D2-3 echo showed PDA…treated with Indomethacin Head sono…no IVH. Drug screen normal Head sono…no IVH. Drug screen normal

4. THYROID CHEMISTRIES Infant values Day -1 Day -7 T4,free(0.6-1.70)1.260.45 TSH(0.4-5)0.070.01 T3,total(70-204)12497

5. PRESENT CONDITION PRESENT CONDITION Presently baby on IMV, being treated for evolving lung disease…diuretics and steroid nebulization Presently baby on IMV, being treated for evolving lung disease…diuretics and steroid nebulization On TPN and NG feeds. On TPN and NG feeds.

6. OBSTETRIC HISTORY 7/96 40wks 9lbs NSVD Dallas 7/96 40wks 9lbs NSVD Dallas 9/97 40wks 7lbs NSVD Mexico 9/97 40wks 7lbs NSVD Mexico 11/01 31wks 2lbs NSVD Thomason 11/01 31wks 2lbs NSVD Thomason 9/03 36wks 3lbs NSVD Thomason 9/03 36wks 3lbs NSVD Thomason 12/00 15wks miscarriage 12/00 15wks miscarriage 7/04 24wks 1.2lbs CS Thomason 7/04 24wks 1.2lbs CS Thomason

7. BABY WITH NEONATAL THYROTOXICOSIS Baby No.3 was born at Thomason in 2001 Baby No.3 was born at Thomason in 2001 Preterm 31 wks SGA, BW:1130 G Preterm 31 wks SGA, BW:1130 G No prenatal-care. Presented 1 hour prior to delivery. No prenatal-care. Presented 1 hour prior to delivery. Had fetal bradycardia/abruptio. Had fetal bradycardia/abruptio. Ventilated Ventilated

8. CLINICAL FEATURES/COURSE IUGR. Microcephaly, Bone age noted to be advanced. IUGR. Microcephaly, Bone age noted to be advanced. Had persistent tachycardia Had persistent tachycardia Baby had fluctuating levels of T4 and T3. Baby had fluctuating levels of T4 and T3. Treated with Lugol’s iodine, Inderal and PTU Treated with Lugol’s iodine, Inderal and PTU

9. THYROID CHEMISTRY 2001 Day 1 Day 10 Day 14 T40.7>62.6 TSH < 0.1 <0.1<0.1 T326457081

10. COURSE AFTER DISCHARGE Discharged at 2 m with T4 :0.6 and T3 :69. Stopped meds prior to discharge. Discharged at 2 m with T4 :0.6 and T3 :69. Stopped meds prior to discharge. Had initially weight loss which later improved. Had initially weight loss which later improved. At 2 m age had seizures. F/Up thyroid tests were normal. At 2 m age had seizures. F/Up thyroid tests were normal. Head scan/MRI July 2004 showed non communicating hydrocephalus Head scan/MRI July 2004 showed non communicating hydrocephalus

11. THYROTOXICOSIS IN NEONATE Typically a transient hyperthyroidism Typically a transient hyperthyroidism 1 in 70 Grave’s affected pregnancies. 1 in 70 Grave’s affected pregnancies. Mortality :up to 25% Mortality :up to 25%Etiology Placental transfer : Thyroid-stimulating immunoglobulins. Maternal antibodies wane over 2-3 months Placental transfer : Thyroid-stimulating immunoglobulins. Maternal antibodies wane over 2-3 months

12. MATERNAL TBII TSH binding inhibiting immunoglobulin TSH binding inhibiting immunoglobulin Levels > 70% predictive neonatal thyrotoxicosis Levels > 70% predictive neonatal thyrotoxicosis Role of stimulatory and inhibitory immunoglobulins Role of stimulatory and inhibitory immunoglobulins Duration of disease depends on concentration, degradation rate and presence or absence of inhibitory Ab Duration of disease depends on concentration, degradation rate and presence or absence of inhibitory Ab

14. BABIES AT RISK BABIES AT RISK Raised level of TBII in pregnancy Raised level of TBII in pregnancy TBII not assessed TBII not assessed Thyotoxicosis in 3 rd trimester Thyotoxicosis in 3 rd trimester Thionamide required in 3rd trimester Thionamide required in 3rd trimester Family H/O TSH receptor mutation Family H/O TSH receptor mutation Evidence of fetal thyrotoxicosis Evidence of fetal thyrotoxicosis

15. POINTS TO CONSIDER Mother with Grave’s disease may not have thyrotoxicosis and may be euthyroid or hypothyroid. Mother with Grave’s disease may not have thyrotoxicosis and may be euthyroid or hypothyroid. Exposure to anti-thyroid drugs in-utero may delay symptoms Exposure to anti-thyroid drugs in-utero may delay symptoms Newborn Screening with T4-radioimmune assay, can detect raised levels of T4 Newborn Screening with T4-radioimmune assay, can detect raised levels of T4 Positive assay for Thyroid stimulating immunoglobulins….confirmatory Positive assay for Thyroid stimulating immunoglobulins….confirmatory Consider narcotic withdrawal Consider narcotic withdrawal

16. CLINICAL FEATURES OF NEONATAL THYROTOXICOSIS Hyperirritability Hyperirritability Tachycardia Tachycardia Goiter Goiter Exophthalmos Exophthalmos LBW and weight loss LBW and weight loss CHF CHF Craniosynostosis/ advanced bone age/microcephaly…psychomotor retardation Craniosynostosis/ advanced bone age/microcephaly…psychomotor retardation Jaundice/thrombocytopenia Jaundice/thrombocytopenia

17. APPROACH TO BABY OF MOTHER WITH GRAVES DISEASE Babies at risk Cord blood fT4,TSH,TSI + examination If high risk repeat fT4,TSH & exam Age 2-7 days In all babies repeat fT4,TSH and exam Age 10-14 days Hypothyroid. Repeat fT4/TSH Treat with thyroxine if confirmed Hyperthyroid PTU/carbimazole iodide+/- Propanolol+/- Normal.No treatment

18. TREATMENT Should biochemical abnormality in absence of symptoms be treated? Should biochemical abnormality in absence of symptoms be treated? Thionamides block hormone synthesis Thionamides block hormone synthesis PTU 5-10mg/kg/d in 3 divided doses PTU 5-10mg/kg/d in 3 divided doses Carbimazole 0.5-1.5mg/kg/d Carbimazole 0.5-1.5mg/kg/d Lugol’s iodine (8mg/drop) 1-3 drops/D Lugol’s iodine (8mg/drop) 1-3 drops/D Iopanoic acid/sodium ipodate, Propanolol, Prednisolone–in refractory cases Iopanoic acid/sodium ipodate, Propanolol, Prednisolone–in refractory cases

19. TREATMENT (CONTINUED) Exchange transfusions…to reduce TSI levels Exchange transfusions…to reduce TSI levels Baby on treatment for thyrotoxicosis is reviewed weekly until stable, then every 2 weeks and drug dose reduced. Baby on treatment for thyrotoxicosis is reviewed weekly until stable, then every 2 weeks and drug dose reduced. Usually treated for 4-8 weeks. Usually treated for 4-8 weeks. Thyrotoxicosis secondary to mutations of TSH receptor require ablative treatment with surgery. Thyrotoxicosis secondary to mutations of TSH receptor require ablative treatment with surgery.

20. SUMMARY SUMMARY Possibility of fetal thyrotoxicosis must be kept in all mothers with a history of Grave’s disease regardless of thyroid status/treatment. Possibility of fetal thyrotoxicosis must be kept in all mothers with a history of Grave’s disease regardless of thyroid status/treatment. Thyroid stimulating immunoglobulins (TSI) persist even after thyroid surgery/radioablation in mother. Thyroid stimulating immunoglobulins (TSI) persist even after thyroid surgery/radioablation in mother. Neonatal thyrotoxicosis secondary to TSIs is a transient disorder, limited by clearance of maternal antibodies Neonatal thyrotoxicosis secondary to TSIs is a transient disorder, limited by clearance of maternal antibodies

21. SUMMARY (CONTINUED) In neonates signs of thyrotoxicosis may be delayed due to effect of maternal anti- thyroid drugs or effect of blocking antibodies. Cases reported as late as 45 days. In neonates signs of thyrotoxicosis may be delayed due to effect of maternal anti- thyroid drugs or effect of blocking antibodies. Cases reported as late as 45 days. TSH binding inhibitor Ig levels from mother and from neonate correlate well with neonatal thyrotoxicosis. TSH binding inhibitor Ig levels from mother and from neonate correlate well with neonatal thyrotoxicosis.