Thyroid and Pregnancy, Review of Physiology
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Thyroid and Pregnancy Facts and Messages A series of changes in thyroid hormone economy take place in normal pregnancy. As a result of these changes, thyroid hormone levels in pregnancy differ from those in the non-pregnant state.
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Thyroid and Pregnancy, Review of Physiology
- 1. Thyroid and Pregnancy Facts and Messages Usama Ragab Youssif, MD Zagazig University 4th Annual ENDO-ESMA Mercure Ismailia – Egypt Friday, 16 SEP 2022 Email: usamaragab@medicine.zu.edu.eg Slideshare: https://www.slideshare.net/dr4spring/ Mobile: 00201000035863
- 3. Intro A series of changes in thyroid hormone economy take place in normal pregnancy. As a result of these changes, thyroid hormone levels in pregnancy differ from those in the non-pregnant state.
- 6. Human Chorionic Gonadotropin (hCG) • During pregnancy large amounts of hCG is produced (pregnancy test) High hCG Turn-on Thyroid Low TSH
- 7. Excess hCG ↑ hCG ↑gland size Goiter ↑Iodine requirement ↑ Thyroid hormone ↓TSH
- 8. Thyroid Size ↑ by 10–20% due to hCG stimulation; exacerbated by relative iodine deficiency. BUT may be a sign of low thyroid function so merits TFT
- 9. Another issue • High hCG = excess T4 = thyrotoxic sx • Blunting of the pituitary–thyroid axis • GTT may coexist with hyperemesis gravidarum. • The more hCG the more the Sx e.g. multiple pregnancies
- 10. Other explanations A variant of hCG = high concentrations of circulating asialoagalcto-hCG with high thyrotrophic bioactivity have been demonstrated in women with GTT and HEG (pathogenic hCG isoforms that are undetectable in routine assays). A variant of receptor= a mutant TSH receptor that is hypersensitive to hCG has also been reported in a family with gestational hyperthyroidism.
- 11. GTT Message… • GTT is transient • Not treated • Treat Sx GTT GD Common; occurs in 2%–3% of pregnancies Less common: occurs in 0.2– 0.4% of pregnancies Occurs in early pregnancy May occur at any stage of pregnancy Transient Persistent Symptoms are mild Symptoms may be severe No goitre Diffuse goitre may be present No proptosis May have proptosis Patient is negative for antithyroid antibodies Patient is positive for antithyroid antibodies Does not require anti-thyroid drugs Usually requires anti-thyroid drug treatments No association with adverse pregnancy outcomes Associated with adverse pregnancy outcomes
- 13. Iodine Stores ↓ • Increased renal iodide clearance • Losses through the feto-placental unit. • Increase in thyroid hormone
- 15. Messages • BUT, iodine crosses the placenta, so excessive quantities can suppress the fetal thyroid, causing hypothyroidism and goiter.
- 17. TSH Facts often ↓ initially due to thyroid stimulation by hCG; thereafter returns towards normal. Being maximal at about 10–12 weeks gestation
- 18. Thyroid physiology during pregnancy hCG Free T4 TSH Modified from: Korevaar, T. I. M. et al. (2017) Thyroid disease in pregnancy: new insights in diagnosis and clinical management Nat. Rev. Endocrinol.
- 19. ATA Message • Upper limit ~0.5IU/L lower than non-pregnant TSH. • We may use trimester- specific reference ranges for TSH • If local ranges not available, 4mU/L should be used as upper limit for TSH reference range.
- 21. Total vs free hormone TBG – TBA – TBPA Almost Bound to T3 and T4 Inactive Affected by TBG Very small amount unboud “free” Biologically Active
- 23. Thyroid physiology during pregnancy Free T4 Estrogen TBG Total T4 Modified from: Korevaar, T. I. M. et al. (2017) Thyroid disease in pregnancy: new insights in diagnosis and clinical management Nat. Rev. Endocrinol.
- 24. Message Total thyroid hormone concentrations may be misleading; rely on free thyroid hormone concentrations
- 25. Bottom-line for TF in pregnancy… hCG Free T4 TSH Estrogen TBG Total T4 Modified from: Korevaar, T. I. M. et al. (2017) Thyroid disease in pregnancy: new insights in diagnosis and clinical management Nat. Rev. Endocrinol.
- 27. The Fetal thyroid • TRH, TSH, and T4 are first detectable at 8–10 weeks’ gestation. • The fetal hypothalamic–pituitary–thyroid axis is not functionally mature until 18–20 weeks’ gestation, so the fetus is dependent on placental transfer of maternal T4 to protect from hypothyroidism • Maternal T4 is transferred to the fetus throughout the entire pregnancy and is important for normal fetal brain development, especially before the fetal thyroid gland begins functioning • So, mother is important
- 28. Message Thyroid dysfunction in childbearing period is a problem if strict follow-up is not done Once the hypothyroid women got pregnant: increase the T4 dose by 30% and follow TFT more frequently (every 4 weeks)
- 30. Thyroid-related substances and crossing of the placental barrier Nature Reviews Endocrinology. volume 13, pages 610–22 (2017). Essential for replacement When low = affect fetal development It may cross placenta even after – ectomy or Iodine ablation Iodine replacement is essential = 250 mcg Avoid under or over-replacement Avoid conception for 6 months To be discussed… To be discussed…
- 31. Thyroid Function For All???
- 32. Indications for thyroid screening in pregnancy • Women with a history of thyroid disease (including hyperthyroidism, hypothyroidism, and post-partum thyroiditis) or thyroid surgery • Women with a goitre • Women with symptoms or signs suggestive of hypothyroidism or hyperthyroidism • Women with a family history of thyroid disease • Women known to be positive for thyroid antibodies • Women with type 1 diabetes or other autoimmune disorders • Women with a history of infertility, miscarriage, or preterm delivery • Women with a history of head or neck irradiation
- 33. Final Bottomline Physiological change Effect on thyroid function test Key point for clinicians ↑ Thyroxine-binding globulin ↑ Serum total T3 and T4 Total thyroid hormone concentrations may be misleading; rely on free T4 Secretion of hCG Negative feedback action of raised T4 ↑ fT4 and ↓ TSH Trimester Specific ranges High hCG levels may result in GTT ↑ Iodine clearance ↑ placental iodide losses ↓ Hormone production in iodine-deficient areas Need to be mindful of iodine deficiency and ensure optimal intake ideally from before conception Increased type 3 5-deiodinase (inner ring deiodination) activity from the placental ↑ T3 and T4 degradation Increasing thyroid demand in pregnancy (by 30%) Thyroid enlargement (in some women) Increased thyroglobulin Be aware that a small goitre is common in pregnancy, but may be a sign of low thyroid function so merits thyroid function testing The placental barrier TSH, I, autoantibodies, drugs…
- 34. Thank You
Editor's Notes
- Glycoprotein hormones (GPHs) are the most complex molecules with hormonal activity. They include three pituitary hormones, the gonadotropins follicle-stimulating hormone (FSH; follitropin) and luteinizing hormone (LH; lutropin) as well as thyroid-stimulating hormone (TSH; thyrotropin) -------- It is closely related to TSH Common alpha subunit (Common in LH, FSH and TSH) Can weakly bind to the TSH receptors present on the thyroid gland. When the concentrations of hCG are very high (i.e. >200,000), as can be seen in the first trimester of pregnancy, it may turn on the thyroid gland and cause it to make extra thyroid hormone which, in turn, may turn off the production of TSH from the pituitary.
- ↑ by 10–20% due to hCG stimulation; exacerbated by relative iodine deficiency. Be aware that a small goitre is common in pregnancy but may be a sign of low thyroid function so merits TFT.
- GTT Free thyroid hormones are elevated, with ensuing blunting of the pituitary–thyroid axis and suppressed TSH levels. hCG secretion begins in early pregnancy and peaks by about 8–10 weeks gestation. Serial measurements of TSH and hCG levels in early pregnancy show an inverse relationship with peak hCG levels, corresponding to suppressed TSH concentrations. High hCG = excess T4 = thyrotoxic sx Blunting of the pituitary–thyroid axis causes suppression of TSH GTT may coexist with hyperemesis gravidarum. Hydatidiform moles can cause particularly severe gestational thyrotoxicosis.
- High concentrations of circulating asialo-hCG with high thyrotrophic bioactivity have been demonstrated in women with both conditions (pathogenic hCG isoforms that are undetectable in routine assays). A mutant TSH receptor that is hypersensitive to hCG has also been reported in a family with gestational hyperthyroidism.
- GTT is typically transient and does not require specific treatment with anti-thyroid drugs. It should be distinguished from hyperthyroidism, which usually necessitates anti-thyroid therapy
- Iodine deficiency may therefore be precipitated during pregnancy, especially in women with borderline iodine nutrition status. --------------- Pregnancy is accompanied by a state of relative iodine deficiency. This results from increased renal iodide clearance as well as losses through the feto-placental unit. Furthermore, the increase in thyroid hormone production requires an increased iodide supply, and the thyroid gland responds to these changes with moderate enlargement and increased thyroglobulin secretion. Iodine deficiency may therefore be precipitated during pregnancy, especially in women with borderline iodine nutrition status. A daily iodine intake of 250 μ is recommended in pregnancy but this is not realized in many parts of the world, including in industrialized countries. Daily antenatal multivitamin preparations containing 150 μg of iodine in the form of potassium iodide are recommended in some countries but policies on iodine supplementation in pregnancy are generally lacking
- Median UICs can be used to assess the iodine status of populations, but single spot or 24-hour UICs are not a valid marker for the iodine nutritional status of individual patients. The WHO recommends 200 micrograms of iodine/day supplementation in pregnancy. Daily antenatal multivitamin preparations containing 150 μg of iodine in the form of potassium iodide are recommended in some countries but policies on iodine supplementation in pregnancy are generally lacking A daily iodine intake of 250 μ is recommended in pregnancy but this is not realized in many parts of the world, including in industrialized countries. Sustained iodine intake from diet and dietary supplements exceeding 500 lg daily should be avoided during pregnancy due to concerns about the potential for fetal thyroid dysfunction. ------------- All pregnant women should ingest approximately 250 mcg iodine daily. To achieve a total of 250 mcg iodine ingestion daily, strategies may need to be varied based on country of origin. In most regions, including the United States, women who are planning pregnancy or currently pregnant, should supplement their diet with a daily oral supplement that contains 150 mcg of iodine in the form of potassium iodide. This is optimally started 3 months in advance of planned pregnancy. Iodine crosses the placenta, so excessive quantities can suppress the fetal thyroid, causing hypothyroidism and goitre.
- A rise in total thyroid hormone (T4 and T3) levels is seen from as early as 6 weeks gestation due to estrogen-mediated increases in TBG concentrations, as well as the thyroid-stimulating actions of hCG. FT4 levels fall in the second half of pregnancy but remain within the non-pregnant reference range.
- Based on studies in healthy pregnant women, the upper limit of normal TSH is estimated at approximately 2.5 mU/L in early pregnancy, and 3.0 mU/L in latter pregnancy, although these thresholds vary more widely, according to the population studied, as well as the assay method employed. The lower limit of normal TSH in pregnancy is also less than the non-pregnant reference range. Thus, the non-pregnant TSH reference range will underestimate hypothyroidism in early pregnancy whilst over-diagnosing hyperthyroidism. It is now recommended that each laboratory derive its own population-based, trimester-specific pregnancy normative data.
- ↑ concentration due to ↓ hepatic clearance plus ↑ oestrogen-mediated synthesis.
- Levels may increase in 1st trimester due to hCG stimulation but fall as TBG ↑. In 2nd and 3rd trimesters, levels may be below the limit of the non-pregnant reference range, in part as placental deiodinase degrades maternal thyroid hormone. Small quantities nevertheless do cross the placenta and are essential in early fetal neurological development.
- The figure shows the most important changes that occur in thyroid physiology during pregnancy. An increase in thyroxine-binding globulin (TBG), an increase in thyroxine consumption by the fetus and and an increase in placental type 3 deiodinase expression require an upregulation of thyroid hormone production to maintain adequate thyroid hormone availability. This upregulations is largely mediated via increased thyroidal stimulation by human chorionic gonadotropin (hCG), which ultimately leads to a net increase in free T4 concentration and a subsequent decrease in TSH concentration.
- TRH, TSH, and T4 are first detectable at 8–10 weeks’ gestation. The fetal hypothalamic–pituitary–thyroid axis is not functionally mature until 18–20 weeks’ gestation, so the fetus is dependent on placental transfer of maternal T4 to protect from hypothyroidism Maternal T4 is transferred to the fetus throughout the entire pregnancy and is important for normal fetal brain development, especially before the fetal thyroid gland begins functioning So, mother is important
- The figure graphically depicts thyroid-related drugs and substances capable of affecting the function of the fetal thyroid gland as well as other tissues crossing the placenta. Of note, the fetus cannot escape the Wolff–Chaikow effect, that is, a phenomenon in which low iodine concentrations lead to decreased thyroid hormone production and high thyroid hormone concentrations lead to increased thyroid hormone production, until after roughly the 36th week of pregnancy, at which time high iodine concentrations are likely to cause low thyroid hormone production. TSHR-Ab, TSH receptor antibody; PTU, propylthiouracil.
- Personal or family history of thyroid disease Autoimmune disorders (e.g., type 1 diabetes, coeliac disease, Addison’s disease) History of head and neck irradiation History of infertility History of adverse pregnancy outcomes (e.g., preterm delivery, stillbirths, low birthweight) Suggestive symptoms and signs of thyroid disease Other suggestive features of thyroid disease (e.g., anemia, dyslipidemia, hyponatremia) Goiter Being positive for anti-thyroid antibodies