Thyroid disorders in neonate radha

THYROID DISORDERS IN
NEWBORN
Dr. RADHA REDDY S
DrNB NEONATOLOGY
MODERATOR : Dr ARNAB SENGUPTA

INTRODUCTION
• Thyroid hormone is critical for linear growth and maturation of
thyroid dependent tissues like brain.
• Thyroid gland – synthesize , store & release c(20%) & T4.
• T4 acts as prohormone for T3
• Most of the physiologic effect of thyroid hormone is by T3
-Fanaroff & Martin’s textbook

PHYSIOLOGICAL ACTIONS THYROID
HORMONE :
• Pre & Post natal maturation of brain, retina, cochlea – thyroid
hormone dependent.
• Also essential for neuronal migration ,myelination and other
structural changes in fetal brain.
• BMR – TH stimulates BMR by increased ATP production and by
maintaining ion gradient
• key driver of thermogenesis
• Growth – req for production & action of GH & IGF

• CVS - sensitivity to chatecholamines & no. & affinity of β1
receptors in heart.
• C.O SBP DBP PP
• Enhance gluconeogenesis & glycosis.
• proteins - rate of formation
• Lipids - oxidation of FA
CHOLESTEROL ,PL & TG
Stimulates formation of LDL receptors.

uptodate : laboratory assessment of thyroid function

• Both T4 and T3 are inactivated by inner ring deiodination to reverse T3
(rT3) and 3,3’-diiodothyronine respectively.
• Three iodothyronines are involved in this process.
• Type I deiodinase (D1) has both inner and outer ring deiodination
activity , located in the liver, kidney, and the thyroid and is important for
T3 production.
• Type II deiodinase (D2) catalyses only outer ring deiodination and is
found in the brain, pituitary, and brown adipose tissue. It is important
for local T3 production within these tissues.
• Type III deiodinase (D3) has only inner ring activity and is present in
brain, skin, and intestine.
• T3 and T4 are also inactivated to sulphated analogues by
sulphotransferase in fetal liver

THYROID PHYSIOLOGY IN PREGNANCY
Changes in maternal thyroid physiology during normal
pregnancy :
- Increased renal blood flow and glomerular filtration lead to
increased clearance of iodine from maternal plasma.
- The high circulating level of hCG in the first trimester leads to
transient increase in free T4 and decline in TSH levels , that
resolve by 14th week of gestation.
-cloherty manual of neonatal care

• Increased thyroxine-binding globulin (TBG) levels occur early in
pregnancy from diminished hepatic clearance , which increases total
triiodothyronine (T3) and T4 levels in early pregnancy and decline by
2 and 3 trimesters.
• The negative feedback control mechanisms of the hypothalamic–
pituitary– thyroid (HPT) axis remain intact throughout pregnancy.

• Iodine and thyrotropin-releasing hormone (TRH), antithyroid drugs,
TSH receptor–stimulating and –blocking immunoglobulin G (IgG)
antibodies freely cross the placenta but it is impermeable to TSH
• T4 ,T3 crosses the placenta in limited amounts due to inactivation by
the placental enzyme type 3 deiodinase (D3).
• In the setting of fetal hypothyroxinemia, maternal–fetal transfer of T4
is increased, particularly in the second and third trimesters, which
helps protect the developing fetus from the effects of fetal
hypothyroidism.

NORMAL THYROID PHYSIOLOGY IN FETUS
• The normal bilobed thyroid shape is evident by 7 weeks
• Thyroid follicles containing colloid by 10 weeks.
THYROID FUNCTION :
• Thyroglobulin synthesis by 4 weeks
• Iodine trapping by 8 – 10 weeks
• T4 and some T3 synthesis & secretion at 12 weeks.
• Hypothalamic neurons contain TRH at 6-8 wks
• Pituitary portal vascular system 8-10wks
uptodate : thyroid physiology and screening in preterms

• Thyrotropin(TSH) secretion 12 wks
• Maturation of HTP axis occurs in 2nd half of gestation
• Normal feedback @ 1-2m postnatal life.
• The fetus is dependent upon maternal iodine intake and iodine is
transferred across the placenta for fetal thyroid hormone production.
• To meet the iodine needs of the fetus , the recommended iodine
intake of fetus is higher during pregnancy (250-300mcg) daily.
uptodate : thyroid physiology and screening in preterms

POSTNATAL THYROID FUNCTION
TERMS :
• With the fall in ambient temperature, there is a surge in TSH to 80
mU/ml within about 30 minutes.
• This stimulates the thyroid gland to release T4 and T3, which rise to
well above normal levels.
• In term babies, the total and free T4 levels fall over the next 4-6
weeks.
• T3 levels gradually reach infancy levels between 2 and 12 weeks of
age.
• TSH value reaches adult levels by 2 years of age.
•Archives of Disease in Childhood - Fetal and Neonatal Edition 87(3):F165-71Dec
2002

PRETERM
• >30 wks - T4 and free T4 levels increase over the next 6-8 weeks to
levels comparable to those of babies born at term.
• <30 wks(<1500 g) - TSH and T4 surges are limited
- fall in T4 in the first 1- 2 wks after birth, and
- transient hypothyroxinaemia is common.
2002

• multifactorial,
• loss of the maternal T4 contribution,
• immaturity of the hypothalamic-pituitary axis,
• the responsiveness of the thyroid gland to TSH, and
• immaturity of peripheral tissue deiodination.
• Non thyroidal illness – Medications and Morbidities
- dopamine and steroids decrease TSH
Exogenous iodine suppresses thyroid hormone synthesis, a property known as the Wolff–Chaikoff effect.
However, the ability of the thyroid gland to escape from the suppressive effect of an iodine load does not mature
until 36 to 40 weeks’ gestation. Thus, premature infants are more susceptible than term infants to iodine-induced
hypothyroidism.
2002

DOES THIS HYPOTHYROXINAEMIA MATTER?
 It is associated with increase in perinatal mortality and morbidity, with
prolonged oxygen supplementation, mechanical ventilation, and
hospital stay,
 Increased incidence of intraventricular haemorrhage, and
 Risk of echolucencies in cerebral white matter on ultrasonography.
 Long term - increased risk of neurodevelopmental problems, reduced
intelligence quotient (IQ), and disabling cerebral palsy
2002

SHOULD PRETERM BABIES BE SUPPLEMENTED WITH
THYROID HORMONES?
• Although the degree of hypothyroxinaemia is associated with morbidity and
mortality, it is unclear whether this is the cause or simply a reflection of illness
severity.
• Supplementation with thyroid hormones is unlikely to influence tissue levels of
T3, which are determined by specific deiodinase enzymes, and may even be
detrimental.
• Current evidence does not indicate benefit from therapy of hypothyroxinemia of
prematurity in the absence of raised TSH
Cochrane review
2002

MATERNAL HYPOTHYROIDISM
• Unrecognized or untreated hypothyroidism - spontaneous abortion ,
preterm birth, intrauterine growth restriction, congenital anomalies,
fetal distress in labor, and fetal and perinatal death.
• Affected fetuses may experience neurodevelopmental impairments,
particularly if both the fetus and the mother are hypothyroid during
gestation
• Women with preexisting hypothyroidism who are treated
appropriately typically deliver healthy infants.

• Immediatletely after conception usual l-thyroxine dose should be
increased by 25% to 30% .
• Thyroid function tests should be measured as pregnancy is confirmed,
- every 4 weeks during the first half of pregnancy,
- at least once between 26 and 32 weeks’ gestation,
- 4 weeks after any l-thyroxine dose change.
• The TSH level should be 0.1 to 2.5 milliunits/L in the I trimester,
0.2 to 3 milliunits/L in the second trimester,
0.3 to 3 milliunits/L in the third trimester.
• Achieving this goal often requires an l-thyroxine dose of 20% to 50% higher
than in the nonpregnant state.

CONGENITAL HYPOTHYROIDISM
• CH is one of the most common preventable causes of intellectual
disability.
• CH is more common among Hispanic (1/1,600) and Asian Indian infants
• CH is also more common in infants with trisomy 21, congenital heart
disease, and other congenital malformations including cleft palate and
renal, skeletal, or gastrointestinal anomalies.
• CH may be permanent or transient.

Etiology and Pathogenesis
1. Primary hypothyroidism
a. Defective embryogenesis of thyroid : (70%)
i. Agenesis (athyreosis)
ii. Dysgenesis – hypoplasia or ectopia
b. Inborn error of hormone synthesis or metabolism (30%)
(familial dyshormonogenesis)
i. Iodide-trapping defect
ii. Iodide organification (oxidation) defect
(a) Without deafness
(b) With deafness (Pendred syndrome)

iii. Deiodination defect
(a) Generalized
(b) Limited to thyroid gland
(c) Limited to peripheral tissues
iv. Thyroglobulin synthetic defect
v . Peripheral tissue resistance to thyroid hormone

Central hypothyroidism
a. Genetic mutation or deletion (see Table 88.1)
i. Isolated deficiency of TSH alpha-subunit
ii. Abnormality of hypothalamic-pituitary development, with multiple
pituitary hormone deficiencies
b . Midline congenital defect (septo-optic dysplasia, holoprosencephaly,
cleft lip, single central incisor)
c .Acquired birth injury (usually hypothalamic TRH deficiency; birth
injury, hemorrhage, hydrocephalus, meningitis, trauma, nonaccidental
injury)

THYROID DYSGENESIS:
• Thyroid dysgenesis includes agenesis, hypoplasia, and ectopy (failure
to descend normally into the neck).
• Rarely, it is associated with a mutation in one of the transcription
factors necessary for thyroid gland development (PAX8, FOXE1,
NKX2.1, NKX2.5).
• BAMFORTH – LAZAROUS SYNDROME : FOXE1 mutations , curly spiky
hair ,cleft palate , choanal atresia and bifid epihlottis
• Sporadic with no increased risk to subsequent siblings.

• No goiter, low total and free T4 levels, elevated TSH, and normal TBG.
• The serum concentration of thyroglobulin (Tg) reflects the amount of
thyroid tissue present and is low in cases of thyroid agenesis or
hypoplasia.
• Ultrasound confirms the presence or absence of a normally located
thyroid gland.
• Scintigraphy with RAI or pertechnetate (99mTc) can locate a normally
placed or ectopic gland that is able to concentrate iodine.

THYROID DYSHORMONOGENESIS
• The most common defect is abnormal TPO activity, which results in
impaired organification of iodine.
• Additional defects affect other key steps in thyroid hormone synthesis
such as Tg synthesis, iodine trapping, hydrogen peroxide generation,
and iodotyrosine deiodination.
• Pendred’s syndrome is an important cause of sensorineural deafness
associated with goiter due to a mild organification defect

• In thyroid dyshormonogenesis, goiter may be present.
• Total and free T4 levels are low, TSH is elevated, and TBG is normal.
• Defects in Tg synthesis can be distinguished from other abnormalities
in thyroid hormone formation by measurement of serum Tg, which is
low in Tg synthetic defects and high in other forms of
dyshormonogenesis.
• Unlike in thyroid dysgenesis, thyroid imaging typically reveals a
normally placed thyroid gland that may be normal or large in size.

TSH RESISTANCE
• It is usually caused by mutations in the TSH receptor.
• Rarely, it is due to a loss-of-function mutation in the stimulatory Gsα
subunit that links TSH binding to TSH receptor action (Albright
hereditary osteodystrophy).
• In TSH resistance, the thyroid gland is small.
• T4 is normal or low, and TSH is elevated with the severity of
hypothyroidism depending on the degree of TSH resistance.

Central (hypothalamic–pituitary)
hypothyroidism
• Less common cause .
• usually associated with other pituitary dysfunction as hypoglycemia
,microphallus and midfacial abnormalities.
• Septo-optic dysplasia is an important cause of central hypothyroidism.
• Goiter is not present.
• Total and free T4 are low, TSH is low or inappropriately normal, and TBG is
normal.
• If central hypothyroidism is suspected, cortisol and growth hormone levels
should be measured and magnetic resonance imaging performed to
visualize the hypothalamus and pituitary.

TRANSIENT CH
• Antithyroid drugs: intrauterine exposure to MMI or PTU can cause
transient hypothyroidism that typically resolves within 1 week and
does not require treatment.
• Iodine excess / Iodine deficiency
• TSH receptor–blocking antibodies
• Transient hypothyroxinemia of prematurity (THOP) is the most com-
mon pattern of thyroid dysfunction seen in preterm infants.
• Large liver hemangiomas

SICK EUTHYROID SYNDROME
• Ill neonates- T3 is decreased
• T4- low/ normal
• fT4 ~normal
• TSH normal
• RDS can lead to Euthyroid sick syndrome in preterms
• During recovery- TSH transiently elevated –upto 15
• Treatment not indicated unless TSH increase with decease in fT4 or
TSH remains elevated for a month or longer

CLINICAL FEATURES
•Asymptomatic at birth- 95%
• B.Wt , length are normal , but head size is slightly increase .
• Puffy eyelids, large tongue, thick, dry, cold skin, long abundant coarse hair,
lethargy, inactivity, hypotonia,
• prolonged Jaundice – (Indirect in primary, both in central)
• feeding difficulty - choking spells
• poor or hoarse crying, constipation
• respiratory difficulties
• bradycardia, hypotension with narrow pulse pressure, anemia
• abdominal distention, umbilical hernia and hyporeflexia

DIAGNOSIS
-Indian Society for Pediatric and Adolescent Endocrinology (ISPAE) –

NEONATAL SCREENING
• Newborn screening for hypothyroidism was first performed and
consequently established in 1972 in Quebec, Canada.
• Three major strategies are used for newborn screening:
 Initial thyroxine (T4) assay, with reflex thyrotropin [TSH] assay
 Initial TSH assay
 Simultaneous T4 and TSH assay

• Blood obtained by heel prick b/w 2-5 days of life, placed on a filter
paper is sent for screening
• Most screening tests measure TSH which detects only primary
hypothyroidism , but not the rarer – central hypothyroidism & CH
with delayed TSH elevation.
• Preterm and LBW infants are more prone for delayed TSH elevation ,
hence repeat testing is req at 2-6 weeks of life.
• Preterm infants are prone to both false-positive and false-negative
results of initial newborn screening

• S.Tg levels are - LOW in thyroid agenesis
,defects in TSH receptor.
- HIGH in thyroid ectopic
• Radiographic findings – delay of osseous
development
- distal femur & prox tibial epiphysis
absent .
- beaking of T12 , L1,L2
- XRAY skull – wide open sutures and
wormian bones
- delayed eruption of teeth

TREATMENT AND MONITORING
• LEVOTHYROXINE (T4) - Orally with initial dose 10-15mcg/kg/day
(37.5-50mcg/day)
• Newborns with T4 <5mcg/dL or thy aplasia – high doses r preferred
• Rapid normalization of thyroid function(2wks) is imp. for optimal ND
outcomes.

• LT4 tablets should be crushed and mixed with 1-2 mL milk and should
not be mixed with soy protein formulas ,conc .iron , Ca – as they inh
absorption
• Excessive thyroid hormone therapy must be avoided, can result in
rapid epiphyseal closure and craniosynostosis.

MATERNAL HYPERTHYROIDISM
• Poorly controlled maternal hyperthyroidism - spontaneous abortion,
preterm delivery, intrauterine growth restriction, fetal demise,
preeclampsia, placental abruption, thyroid storm, and congestive
heart failure.
• In the first trimester, propylthiouracil (PTU) rather than methimazole
(MMI) is recommended due to possible teratogenic effects of MMI,
- aplasia cutis congenita, tracheoesophageal fistula, and choanal
atresia.
2002

• As PTU can cause severe maternal liver dysfunction, in the second
trimester, PTU should be switched to MMI.
• Both MMI and PTU cross the placenta, and the fetus is more sensitive than
the mother to the effects of antithyroid drugs,
• So fetal hypothyroidism and goiter can occur even with doses in the
therapeutic range for the mother.
• Propranolol helps in controlling hypermetabolic symptoms.
• Long-term use can cause hypotension, bradycardia, and impaired response
to hypoglycaemia in neonate.
2002

• Iodine is generally contraindicated because prolonged administration
can cause fetal hypothyroidism and goiter
• Surgical thyroidectomy if required should be performed during 2nd
trimester
• Radioactive iodine (RAI) is contraindicated during pregnancy.
2002

• BREAST FEEDING
• Both propylthiouracil (PTU) and methimazole (from carbimazole) are
detected in breast milk but appear not to affect neonatal thyroid
function if the mother’s dose of carbimazole is < 15mg/day and
PTU < 150mg/day.
• PTU would be preferable, but carbimazole is not contraindicated.

NEONATAL THYROTOXICOSIS
• Rare, but associated with a high mortality
• Etiology: - transplacental passage of thyroid stimulating
immunoglobulins (TSIs) from mothers with Graves’ disease.
- rarely, Hashimoto’s thyroiditis.
2002

• Neonatal thyrotoxicosis secondary to TSIs is a transient disorder
• Persistent hyperthyroidism, which is dominantly inherited, can occur
in the absence of maternal autoimmunity because of activating
mutations in the TSH receptor and stimulatory G protein as in
McCune- Albright syndrome.
• Fetal outcome is related to the control of maternal thyrotoxicosis
• S/S are more if mother is hyperthyroid in the second half of
pregnancy.
2002

• CLINICAL FEATURES :
• Hyperthyroid fetus is often growth retarded
• Tachycardia is common and often used to diagnose fetal
thyrotoxicosis
• Non-immune hydrops , secondary to cardiac failure.
• Goitre may be apparent on ultrasound scanning.
• IUD , preterm deliveries
2002

• Neonate – at birth or later 10-45 days
• Infants often have a goitre.
• CNS signs - irritability, jitteriness, and restlessness.
• Eye signs - periorbital oedema, lid retraction, and exophthalmos may
be present even in the absence of maternal eye signs.
• CVS signs - include tachycardia and arrhythmias, but may progress to
cardiac failure. Systemic and pulmonary hypertension may be present
• Hypermetabolism signs - voracious appetite, weight loss, diarrhoea,
sweating, and flushing
2002

• Other signs - persisting acrocyanosis, hepatosplenomegaly,
lymphadenopathy, thymic enlargement, bruising and petechiae
secondary to thrombocytopenia, and hyperviscosity.
• Advanced bone age, craniosynostosis, and microcephaly may be
evident in both the fetus and newborn.
2002

• Antithyroid drugs
• Care should be exercised not to induce hypothyroidism with excessive
medication
• Iodine (Lugol solution) and an antithyroid drug, methimazole (MTZ), are
typically used
• Iodine should be given at least 1 hour after methimazole to avoid
exacerbating hyperthyroidism acutely
• Thionamides (PTU and carbimazole) act by blocking the organification of
iodine and the coupling of iodothyronine residues—that is, blocking
thyroid hormone synthesis

• Saturated KI (48 mg iodine per drop)- one drop /day or Lugol solution
(8 mg iodine/drop ) - one drop three times daily.
• Methimazole is given in doses of 0.2-1 mg/kg/day in 1-3 divided
doses.
• Propylthiouracil (PTU) is no longer recommended for use in children
because of associa- tion with liver failure
• Most symptoms of hyperthyroidism are closely related to increased
adrenergic response.

• Propranolol may be used in a dose of 0.5-2 mg/kg/day 8 hourly.
• S/E - serious hypoglycaemia, bradycardia, and hypotension, so babies
require close monitoring.
• Severely thyrotoxic babies may be treated with prednisolone, which
impairs peripheral conversion of T4 to T3, and compensates for
hypercatabolism of endogenous glucocorticoids induced by T3 and T4.
• Circulating T4 has a half-life of 3-4 days in neonates ,hence little or no
clinical response to antithyroid drugs can be expected during the first few
days of therapy.

• It is recommended that thyroid function be measured weekly until FT4
concentrations are stable and then every 2 weeks
• MTZ should be decreased and eventually discontinued when FT4
concentrations have normalized.
• Neonatal Graves disease typically resolves by 6 months of age; treatment
duration usually lasts about 1-2 months.
• Sedatives may also be helpful in managing irritability and restlessne
• Exchange transfusion has been used in an attempt to reduce TSI levels

Familial Abnormalities of Thyroxine-Binding
Proteins
• Thyroxine-Binding Globulin (TBG) Defects -X-linked pattern
- TBG excess and deficiency are usually diagnosed incidentally with lab
work, demonstrat- ing abnormal T4 with normal free T4
• Increased Transthyretin (TTR) : - Gene mutations , Serum T4 is
elevated, but FT4 is normal.
• Familial Dysalbuminemic Hyperthyroxinemia - gain-of-function
mutations in the human serum albumin , resulting in enhanced
binding of T4 .

KEY POINTS
• Maintenance of normal thyroid hormone levels is important for
metabolism, linear growth, and brain development during infancy and
childhood.
• The hypothalamic-pituitary axis along with iodine metabolism exert
primary control over thyroid hormone production.
• Women with pre-existing hypothyroidism who are treated appropriately
deliver healthy infants.
• Congenital hypothyroidism is one of the most preventable cause of ID.
• Early detection of congenital hypothyroidism by newborn screening has
dramatically improved outcomes
• Neonatal hyperthyroidism is uncommon (1%) and is almost always
transient.

Thyroid disorders in neonate radha

Thyroid disorders in neonate radha

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