Case presentation, Clinical features, investigations of Neonatal thyrotoxicosis(Neonatal Grave's disease). Management of thyroid Storm

1. Neonatal Thyrotoxicosis
(Neonatal Graves disease)
Sid Kaithakkoden MD
alavisaid@aol.com

2.  Baby Boy KM
 Dob-29/06/2007, born at 27 weeks by Em CS for
foetal distress
 B.Wt.-914 grams
 Apgar 4/1, 8/5
 Born blue, floppy with poor respiratory effort
 Responded well to IPPV
 Intubated and received 1 dose of surfactant
 Admitted to NNU & extubated to CPAP
22/08/2019Sid 2
Case History

3.  28 years old G4 P3, Caucasian
 Single, unemployed
 H/O substance abuse – on methadone
programme
 Urine +ve for opiates, cannabis, heroin, crack
cocaine & methadone (March 07)
 Smoking at booking- 6-14 /day
 Asthmatic on ventolin& becotide inh.
 Diagnosed Grave’s disease in 2001
 On medical therapy till 2004
 Thyroidectomy 2004 (total)
 On thyroxin
22/08/2019Sid 3
Maternal Details

4.  Needed one fluid bolus, loaded with caffeine
 UAC & long line sited
 Started on IVF, TPN & IV antibiotics
 Started on morphine infusion 10 mic
 Remained tachycardic HR >200
 MBP 55- 60 mm of Hg
 Extreme irritability & agitation
22/08/2019Sid 4
Progress of baby

5. Vitals- First 48 hours
0
20
40
60
80
100
120
140
160
180
200
4 8 12 16 20 24 28 32 36 40 44 48
Heart Rate
MBP(Invasive)
Respiratory Rate
22/08/2019 Sid 5

6.  Investigations:
 HUSS: Bilateral ventricular dilatation, B/L IVH
 Echo @ 6 hrs: (due to tachycardia & for ductal
assessment)
 Normal situs, Good LV function, FS 33%
 RV isovolemic, TR 3.2, PDA with bidirectional shunt, PFO
 Normal sugars, Ca & Mg
 SBR 111 – started on photo Rx
22/08/2019Sid 6
Progress (contd)

7. 22/08/2019Sid 7
Chest X-ray - 4 hours of life

8. 22/08/2019Sid 8
Chest X-ray -12 hours of life

9. 22/08/2019Sid 9
Chest X-ray - 24 Hours of life.

10.  Rpt Echo:
 No PDA, tachycardia, TR 3.2, FS27 %
 Rpt HUSS:
 Ventriculomegaly LVI 13, RVI 12.5
 No IVH, RI 0.78
 Day 1-
 TFT: TSH <0.05, (0.10-5.0),
 FT4 >50, (10.0-20.0) (THIS CLINCHED THE DIAGNOSIS)
 Cotisol 324
22/08/2019Sid 10
Progress (contd)

11.  Continued to be extreme irritable, agitated,
tachycardic, high MBP:
 Consultation with Paed. endocrinologist
 Started on PTU, Lugol’s Iodine & propranalol
 Not for steroid until thyroid storm
 Later reviewed by Paed. endocrinologist
 Transplacental passage of TSH receptor antibodies
 Suggested weekly TFT, antibody testing
 Continuation of drugs, to wean off propranalol, withdraw
Iodine & to continue of PTU alone, r/v after 3 months
22/08/2019Sid 11
Progress (contd)

12.  Day 7: TSH<0.05, FT4 19.9
 Conjugated Hyperbilirubinemia
 Max SBR 264,(Direct 158)
 ALP 614, ALT 100, AST 120, Alb 18
 Haematology:
 Hb 11.9 – needed red cell transfusion
 PLT 25- needed two platelet transfusion
 DCT –ve, Normal coagulation
 USS abdomen – normal liver, kidneys, distended
GB
22/08/2019Sid 12
Progress (contd)

13. Conjugated Hyperbilirubinemia
0
50
100
150
200
250
300
1 2 3 4 5 6 7
Total Bilirubin
Direct
22/08/2019 Sid 13

14. Neonatal Graves' Disease
Evaluation and management

15.  Fetal thyroid bilobed shape- by 7week
 Thyroid follicle cell & colloid formation- 10 wk
 Thyroglobulin synthesis occurs from 4wk
 Iodine trapping by 8-10 wk
 T4 and to lesser extent T3 synthesis and secretion -
from 12 week
 Hypothalamic neurons synthesise TRH by 6-8 weeks,
portal system develops by 8-10 weeks
 Maturation of the hypothalamic-pituitary-thyroid
axis -during the second half of gestation, but normal
feedback relationships are not mature until 1-2
months of PN life
22/08/2019Sid 15
Normal thyroid physiology in fetus

16. Maturation of fetal thyroid gland development & of
thyroid hormone secretion in the human infant
22/08/2019Sid 16

17. 22/08/2019Sid 17

18. Hypothalamo-pituitary-thyroid axis
22/08/2019Sid 18

19. 22/08/2019Sid 19
Thyroid physiology in fetus & newborn
Normal patterns of change for TSH, total T4, and total T3 for the fetus
(beginning at twelve weeks gestation) and continuing for the first five weeks
of life in the newborn

20. 22/08/2019Sid 20
Postnatal changes in T4 secretion in the premature infant
according to gestational age

21. 22/08/2019Sid 21
Changes in TSH and Thyroxin (T4) at term.
(Adapted from Fisher D, Klein A: Medical progress)

22. Thyroid hormone synthesis
22/08/2019Sid 22

23. 22/08/2019Sid 23

24.  Increase oxygen consumption
 Stimulate protein synthesis
 Influence growth and development.
 Affect Carbohydrate , Fat and Vitamin
Metabolism
 Cardiovascular system: Thyroid hormones
increases heart rate, cardiac contractility and
cardiac output. They also promote vasodilation
 Central nervous system: Both decreased and
increased concentrations of thyroid hormones
lead to alterations
22/08/2019Sid 24
Functions of thyroid hormones

25. 22/08/2019Sid 25
Maturation of thyroid hormone effects in the human fetus and neonate. The left
edge of the bars indicate the approximate time the effects of thyroid hormone
become manifest

26.  In the preterm baby, and fetus of similar gestation, the
thyroidaxis is immature, with reduced hypothalamic TRH
production andsecretion
 An immature response of the thyroid gland to TSH
 An inefficient capacity of the follicular cell of the thyroidto
organify iodine, and a low capacity to convert T4 into
activeT3
 The level of T4 is lowerthan that of term babies and
correlates with gestational ageand birth weight. Levels of
TSH and T3 are normal to low,free T4 concentrations are
also low
 Responses of TSH and T4 to TRH are normal, reflecting
that the site of immaturity isthe hypothalamus
22/08/2019Sid 26
Thyroid function in the preterm baby

27. 22/08/2019Sid 27
Postnatal TSH, T4, T3, and rT3 secretion in the full-term
and premature infant in the first week of life

28. Mother
 Raised thyroid binding immunoglobulin levels in pregnancy
 Thyroid binding immunoglobulin level not assessed
 Clinical thyrotoxicosis in third trimester
 Thionamide required in third trimester
 Family history of TSH receptor mutation
Baby
 Evidence of fetal thyrotoxicosis
22/08/2019Sid 28
Babies at high risk of neonatal
thyrotoxicosis

29.  Rare, account for <1% of all paediatric
hyperthyroidism
 Virtually all patients have a maternal history of
Graves disease
 Due to transplacental passage of thyrotropin
receptor stimulating antibody
 Only 1 in 70 infants of thyrotoxic mothers has
clinical symptoms
 A maternal TSI level must be very high (>5 times
normal) to produce clinical disease in the neonate
22/08/2019Sid 29
Neonatal Graves disease

30.  Onset usually begins prenatally and is present at birth
 Occasionally may be delayed to weeks
 Onset severity and course will also depend upon the TRB
Ab.
 If mother is on antithyroid medication onset may be
delayed for 3-4 days
 The frequency of neonatal Graves disease is equal in males
and females
 Fetal tachycardia and goitre can help in diagnosing
prenatally along with very high levels of TRS Ab levels in
mother
22/08/2019Sid 30
Neonatal Graves disease (contd)

31. Clinical features
22/08/2019Sid 31
 Fetal hyperthyroidism:
 Preterm delivery
(4-11% treated, 53%
untreated)
 IUGR
 Nonimmune fetal
hydrops
 Craniosynostosis
 IUD (5-7% treated, 24%
untreated)
 Goiter on USS
 Neonatal
hyperthyroidism:
 Hyperkinesis
 Diarrhea, Vomiting
 poor weight gain
 Ophthalmopathy
 cardiac failure
 Arrhythmias
 systemic and pulmonary
hypertension
 Hepatosplenomegaly
 Jaundice
 hyperviscosity syndrome
 Thrombocytopenia
 Craniosynostosis

32.  As it is caused by maternal immunoglobulin G (IgG)
antibodies, it is self-limited & resolves when the child
is aged 3-4 months
 More persistent hyperthyroidism in neonates is likely
to reflect a different pathogenesis, such as an
activating mutation of the TSH receptor
22/08/2019Sid 32
Neonatal Graves disease (contd)

33.  Mortality has been reported to be 12–20%
 Usuallyfrom heart failure, but other
complications include tracheal compression,
infections, and thrombocytopenia
 Long-term effects can include craniosynostosis
and developmental delay
 Dev’tal delay occurs even in the face of early
diagnosis and treatment, which suggests that
prenatal exposure to high levels of thyroid
hormone may have early effects that cannot be
overcome after birth
22/08/2019Sid 33
Neonatal Graves disease (contd)

34. Treatment:
22/08/2019Sid 34

35. Therapeutic regimen
22/08/2019Sid 35
Multiple medications, each of which has a
different mechanism of action:
 A beta-blocker to control the symptoms induced
by increased adrenergic tone In addition, they
inhibit deiodinationof T4 to T3.
 A thionamide, such as PTU or methimazole, to
block new hormone synthesis
 An iodine solution to block the release of thyroid
hormone
 Glucocorticoids to reduce T4-to-T3 conversion
and possibly treat the autoimmune process in
Graves' disease
 An iodinated radiocontrast agent to inhibit the
peripheral conversion of T4 to T3

36. DRUGS
22/08/2019Sid 36
Propylthiouracil.
 Dose to dose less potent.
 High Plasma protein bound
 Less transferred across
placenta and milk
 Plasma t1/2 1-2 hours
 Single dose acts for about 4-8
hours
 No active metabolite
 Multiple (2-3) daily doses
needed
 Inhibits peripheral conversion
of T4- T3
Carbimazole
 About 3 times more potent.
 Less bound
 Larger amounts transferred
across placenta
 6-10 hours
 12-24 hours
 Active metabolite-
Methimazole
 Single daily dose

37. 22/08/2019Sid 37

38.  Sedatives - in managing irritability and restlessness
 Exchange transfusion - in an attempt to reduce TSI
levels with some reduction in antibody levels but
failing to preventneonatal thyrotoxicosis
 Treatment should be reviewed approximately
weekly until stable, then every one to two weeks,
and drug doses reduced when possible
 Treatment usually required for 3-4 months
 In contrast, thyrotoxicosissecondary to activating
mutations of the TSH receptor is persistent and may
require ablative treatment usually with surgery
22/08/2019Sid 38
Treatment (contd)

39. 22/08/2019Sid 39
Copyright ©2002 BMJ Publishing Group Ltd.
Ogilvy-Stuart, A L Arch. Dis. Child. Fetal Neonatal Ed. 2002;87:165-F171
Investigation of babies with Thyrotoxicosis

40.  Rare, presents as a life-threatening
exacerbation of hyperthyroidism,
accompanied by fever, delirium, seizures,
coma, vomiting, diarrhoea, and jaundice
 Mortality rate due to cardiac failure,
arrhythmia, or hyperthermia is ~30%, even
with treatment
 Thyrotoxic crisis is usually precipitated by
acute illness (e.g., stroke, infection, trauma,
diabetic ketoacidosis), surgery especially on
the thyroid
22/08/2019Sid 40
Thyroid storm

41. 22/08/2019Sid 41
Diagnostic criteria for thyroid storm*
* A score of 45 or more is highly suggestive of thyroid storm;
a score of 25 to 44 supports the diagnosis; and a score
below 25 makes thyroid storm unlikely.
Adapted from Burch, HB, Wartofsky, L, Endocrinol Metab Clin North Am
1993; 22:263
Thermoregulatory dysfunction
Temperature
99-99.9 5
100-100.9 10
101-101.9 15
102-102.9 20
103-103.9 25
104.0 30
Central nervous system effects
Mild
10
Agitation
Moderate
20
Delirium
Psychosis
Extreme lethargy
Severe
30Seizure
Coma
Gastrointestinal-hepatic dysfunction
Moderate
10
Diarrhea
Nausea/vomiting
Abdominal pain
Severe 20
Unexplained jaundice
Cardiovascular dysfunction
Tachycardia
99-109 5
110-119 10
120-129 15
130-139 20
140 25
Congestive heart failure
Mild
5
Pedal edema
Moderate 10
Bibasilar rales
Severe
15
Pulmonary edema
Atrial fibrillation 10
Precipitant history
Negative 0
Positive 10

42.  Intensive monitoring and supportive care,
identification and treatment of the precipitating
cause, and measures that reduce thyroid hormone
synthesis
 Large doses of propylthiouracil (PO/PR (inhibitory action on
T4 ® T3 conversion makes it the agent of choice)
 One hour after the first dose of PTU, stable iodide is given to
block thyroid hormone synthesis via the Wolff-Chaikoff
effect (the delay allows the antithyroid drug to prevent the
excess iodine from being incorporated into new hormone)
 high doses of propranolol have been documented to
decrease T4 - T3 conversion
 glucocorticoids , antibiotics if infection is present, cooling,
and intravenous fluids
22/08/2019Sid 42
Thyroid storm -treatment

43. Thank you