Thyroid Function: Fetal, Maternal Relationship

1. Thyroid Function: Fetal, Maternal Relationship • Thyroid Function in Pregnant Women • Thyroid gland increase in size by 10-20%. • Through monodeiodination the placenta provides iodine to the fetus. • Estrogen stimulates an increase in Thyroid Binding Globulin (TBG). • Hypothyroid mother have increased T4 requirements during pregnancy due to placental degradation of T4 to rT3, transfer of T4 to the fetus and increased maternal clearance of T4. • Placental Human Chorionic Gonadotropin (HCG) increases maternal T4.

4. Thyroid Function: Fetal, Maternal Relationship • Stages of Neurological Development and Thyroid Hormone: • Phase I : • 17 days in rat, 10-12 weeks in humans. • Probable role in brainstem and cerebral neurogenesis. • Thyroid hormones are from mother. • Phase II: • Fetal thyroid synthesizes and secretes thyroid hormone. • Brain is exposed to both fetal and maternal hormones. • Phase III: • After birth. Brain depends on neonatal thyroid hormone. • Some in milk. • Cerebellar neuronal proliferation, migration and differentiation. Myelination and gliogenesis.

5. Thyroid Function: Fetal, Maternal Relationship • Key is maternal thyroid status during the first trimester – during fetal brain development. • Hypothyroid or iodine (recommend 200 µg/day) deficient mother result in affected fetus. Hypothyroid fetus may be minimally effected. • Antibody transfer – Thyroid serum immunoglobulin (TSI - hyperthyroidism) and TSH-receptor antibody – TBII (hypothyroidism)

6. Thyroid Function: Fetal, Maternal Relationship • T4, T3, FT4, and TSH – ALL in amniotic fluid. Less than maternal and fetal serum levels. • Cordocentesis – more accurate levels. • Can treat in utero with T4 or T3. • T4 detectable in fetal serum by 12 weeks. • FT4 in cord blood is equal to or greater than maternal blood. • Fetal T4 is mostly metabolized to rT3. Gradually decreases after birth. rT3 has little metabolic activity. • Cord blood T3 and FT3 are 30 to 50% of maternal concentrations at term.

10. Thyroid Function: Fetal, Maternal Relationship • TSH present at 12 weeks. • Higher in fetus • Surge at term/delivery. • T4 binding proteins – pre-albumin, albumin and TBG. Most bound to TBG. Estrogen causes increased production of TBG. • At birth – TSH surges during the first 30 minutes. Peak persists for 6 – 24 hours. • In response to TSH there is a peak in T4, FT4, and T3. Peaks at 24 hours. Hyperthyroid state. • Gradual reduction in T4, T3, rT3 over 4 to 6 weeks. Gradually goes to adult levels by puberty.

11. Thyroid Function: Fetal, Maternal Relationship • Preterm infants: • Surge in TSH and TH occurs but is less than seen in term infants. • TSH returns to normal at 3 to 10 days. • The concentration of T3 and rT3 in breast milk is not sufficient to prevent hypothyroidism.

12. Thyroid Function: Fetal, Maternal Relationship Congenital Hypothyroidism: • Neonatal screening first done in 1972 in Quebec, Canada. • Primary Hypothyroidism • Defective embryogenesis – agenesis, dysgenesis. • Inborn errors • Iodide trapping defect • Iodide organification (oxidation) defect. Pendred’s Syndrome. • Coupling Defect • Deoiodination defect – deiodinases I, II, III. • TG synthetic defects • Goiter with calcifications • Peripheral tissue resistance to thyroid hormone • Unresponsiveness of thyroid to TSH.

13. Thyroid Function: Fetal, Maternal Relationship • Goitrous cretinism caused by maternal goitrogens • Iodide deficiency

14. Thyroid Function: Fetal, Maternal Relationship • Central hypothyroidism • Genetic mutation or deletion • Isolated deficiency of TSH ß-subunit. • Abnormal hypothalamus-pituitary development. • Midline defect • Cleft lip, holoprosencephaly, seto-optic dysplasia. • Acquired birth injury • Hemorrhage, meningitis, trauma.

15. Thyroid Function: Fetal, Maternal Relationship • Female: male ratio 2:1. for CH. • Maternal ingestion of goitrogens iodides, thiocarbamides, potassium pechlorate. Expectorants with iodide, amiodarone (contains Iodine) • Iodide Deficiency – goiter. Result is low T4 level in developing brain. • Recommend Infant supplementation of 40 µg per day iodide.

16. Thyroid Function: Fetal, Maternal Relationship • Central hypothyroidism • Secondary – pituitary – TSH. Normal or elevated TRH, low TSH, low T4. • Tertiary – hypothalamic – TRH. Low TRH, low or normal T4, low or normal TSH. Respond to TRH treatment.

17. Thyroid Function: Fetal, Maternal Relationship • Neonatal Screening • Filter paper spot. Obtained at 24 hours to 5 days. • Measure TSH, screen for primary hypothyroidism. Detects most cases of primary hypothyroidism. • Incidence 1:3500-4000. • Secondary and Tertiary CH is 1:80-100,000.

18. Thyroid Function: Fetal, Maternal Relationship • Clinical manifestations • Appear gradually – lethargy, hypotonia, periorbital edema, mottled skin, feeding intolerance, hoarse cry, constipation, hypothermia.. • Clinical features - large tongue, umbilical hernia, thick skin, dry skin, hyporeflexia, umbilical hernia, coarse hair. • Lingual thyroid – base of tongue. • Goiters – large or small cervical mass.

19. Thyroid Function: Fetal, Maternal Relationship • Laboratory • Elevated TSH most sensitive for primary hypothyroidism. • TSH surge at birth. Level gradually go down after birth. Maybe higher than 10 mU/l at 24 hours. Samples taken before 24 hours maybe high in normal infant. • Primary hypothyroidism – high TSH and low or low-normal T4 and FT4.

20. Thyroid Function: Fetal, Maternal Relationship • Central hypothyroidism • Low FT4, low-normal T4, and normal TSH. • Nonthyroidial illnesses – Respiratory Distress – low or normal T4, normal FT4, and normal TSH. • In severe myxedema get cardiomegaly, and slowing of EEG pattern (brain).

21. Thyroid Function: Fetal, Maternal Relationship • Transient Primary Neonatal Hypothyroidism • Marked by persistent elevation of TSH. • Higher in areas with iodine deficiency • Low T4, low FT4, and high TSH. • May confuse with transient hypothyroxinemia. • Can be caused by transplacental antithyroid drugs, excessive iodine. • Placental transfer of TRAb – TSH receptor antibody. Persist for 2 to 3 months.

22. Thyroid Function: Fetal, Maternal Relationship • Transient Hyperthyrotropinemia • Elevated TSH, normal T4 and FT4. • May represent mild transient or permanent hypothyroidism. • Cause is unknown. • Best outcomes if treated by 4 to 6 weeks. Treat for 2-3 years.

23. Thyroid Function: Fetal, Maternal Relationship • Transient Hypothyroxinemia • Preterm infants • Immature hypothalamic-pituitary axis. Maybe normal for GA. • Low T4 and FT4 compared to term. Normal TSH. • TBG – slightly low. • Prevalence 1:6,000. • Shows response to TRH – increase T4 and TSH (tertiary) • T4 normalizes by 4- 6 months. • Developmentally normal at 1 year. • No effect of T4 administration on developmental outcome.

24. Thyroid Function: Fetal, Maternal Relationship • Transient Hypothyroxinemia • Screen preterm infants at 5 days. Repeat at 2, 4, 6 weeks. • Supplementation at less than 28 weeks showed improved mental outcome, less morbidity. Infants greater than 28 weeks showed greater morbidity. • T4 supplementation Currently not recommended.

25. Thyroid Function: Fetal, Maternal Relationship • Euthyroid Sick Syndrome • Alterations in TH occur as an adaptive response to decreased metabolic rates in ill patients. Non thyroidal illness. • Low T3, high rT3, normal TSH, low normal T4 and normal FT4. • Slowly normalizes. • Supplementation not indicated.

26. Thyroid Function: Fetal, Maternal Relationship • Treatment • Treat as quickly as possible following initial screening. A delay of 8 days results in lower IQ scores. • Half life for T4 is 3-4 days in neonate but in adults it is 6 days. • In cases that are not clear cut – TREAT – 2-3 years. • L-thyroxine – 12-15µg/kg/day. Began as soon as possible – optimally by 2 weeks. Pills. • Cerebral cortex get most of its T3 from deiodination of T4. • Goiters – if TSH is elevated and T4 low treat with L-thyroxine. Can be caused by antithyroid medications and excessive iodide

27. Thyroid Function: Fetal, Maternal Relationship • Breast Milk • Small amounts of PTU in milk. • Good concentration of iodides in BM. • Should NOT give methamizole to nursing mothers.

28. Thyroid Function: Fetal, Maternal Relationship • Amniotic fluid - Measurement of iodothyronines not good • Cord blood – measure TSH and Iodotyroinines. Much better. • TRH to mother causes increase TSH and T3 and does not reduce postnatal surge of TSH.

29. Thyroid Function: Fetal, Maternal Relationship • Prognosis: • Clinically improves quickly • Reduce goiter if present. • Improved growth rate – skeletal. • Normal neurological development is dependent on early diagnosis and supplementation • 80% supplemented before 3 months had IQ score greater than 85 but 77% showed some problems with speech, math ability and fine motor function. • BEST OUTCOMES IF STARTED BY ONE WEEK OF AGE. Minor difference in school achievements and test scores. • First trimester T4 is derived from the mother – swallowing, transdermal. Protects the fetal brain. • Overall good.

33. Thyroid Function: Fetal, Maternal Relationship • Thyrotoxicosis • Occurs in infants born to mother with active Graves disease (before or during pregnancy), Hashimoto disease, or treated Graves disease (surgical or ablation). • Due to placental transfer of TSH-receptor immunoglobulin (TRAb) and TSI. • Infants born to mother with Graves can be normal – depends on amount of antibody.

34. Thyroid Function: Fetal, Maternal Relationship • Thyrotoxicosis – clinically. • Irritability, tremors, sweating, weight loss, enlarged spleen and liver, exophthalmia, hyperthermia, arrhythmias. • TSI level decrease over 3 weeks to 6 months. • Maternal antithyroid medications may render the neonate euthyroid or hypothyroid until the antithyroid medications disappear. Late thyrotoxicosis.

35. Thyroid Function: Fetal, Maternal Relationship • Thyrotoxicosis • TRAb – a polyclonal antibody that initially blocks the TSH receptor. A second population of TRAb then stimulates the receptor to cause thyrotoxicosis. • Low TSH, high T4. • Palpable thyroid gland.

36. Thyroid Function: Fetal, Maternal Relationship • Thyrotoxicosis – treatment • Lugol solution (Iodine) and PTU or MTZ. • May need supplement withT4. • ß-adrenergic drugs reduce symptoms. • Digoxin for failure. • Steroids in some cases. • Mortality rate – less than 15%. • Prenatal therapy with PTU.

37. Summary: Thyroid Function - Fetal, Maternal Relationship • Hypothyroid mothers have increased T4 requirements during pregnancy. • Key is maternal thyroid status during the first trimester – during fetal brain development. • Cord blood – measure TSH and Iodotyroinines. Much better than amniotic fluid. • Thyroid hormones are from mother - deficient mother result in affected fetus. • Antibody transfer – Thyroid serum immunoglobulin (TSI - hyperthyroidism) and TSH-receptor antibody – TBII (hypothyroidism). • T4 & TSH detectable in fetal serum by 12 weeks.

38. Summary: Thyroid Function - Fetal, Maternal Relationship • At birth – TSH surges during the first 30 minutes. Hyperthyroid state.T4, T3, rT3 drop over 4 to 6 weeks. • Neonatal Screening - Filter paper spot. Obtained at 24 hours to 5 days. • Measure TSH, and screen for primary hypothyroidism. • Screen preterm infants at 5 days. Repeat at 2, 4, 6 weeks. • Transient Primary Neonatal Hypothyroidism • antithyroid drugs, excessive iodine, or TRAb – TSH receptor antibody.

39. Summary: Thyroid Function - Fetal, Maternal Relationship • Transient Hypothyroxinemia • Treat as quickly as possible following initial screening. A delay of 8 days results in lower IQ scores. • L-thyroxine – 12-15µg/kg/day. Began as soon as possible – optimally by 2 weeks. Pills. • Thyrotoxicosis • Occurs in infants born to mother with active Graves disease (before or during pregnancy), Hashimoto disease, or treated Graves disease (surgical or ablation).