THYROID DISEASE

IN PREGNANCY

Grand Rounds

December 5, 2018

Maria Kolojeski, DO (PGY3)https://www.wddty.com/magazine/2016/june/depression-its-not-your-brain-its-your-thyroid.html

REVIEW OF THYROID HORMONES

Hypothalmus

Thyroid Releasing Hormone (TRH)

Anterior Pituitary

Thyroid-Stimulating Hormone (TSH)

Thyroid

Triiodothyronine (T3)

Thyroxine (T4)

Iodine

THYROID CHANGES IN PREGNANCY

Thyroid Volume: 30% larger in 3rd vs 1st trimester

Increased thyroid binding globulin

Increased in total T3 & T4 levels

Free T3 & T4 typically remain stable

Weak stimulation of TSH receptors by hCG (first 12 weeks)

Increases serum free T4

Thyrotropin (AKA: Thyroid Stimulating Hormone [TSH])

Decreases in early pregnancy

Transient subclinical hyperthyroidism, Gestational transient hyperthyroidism

Returns to baseline in second trimester

Increased in third trimester due to placental deiodinase

THYROID

LABORATORY WORKUP

➢ First Trimester

➢ 0.1 - 2.5 mIU/L

➢ Second Trimester

➢ 0.2 - 3.0 mIU/L

➢ Third Trimester

➢ 0.3 - 3.0 mIU/L

➢ If TSH abnormal order free T4

➢ Rarely T3 toxicosis is the cause

➢ Consider antibody testing if

euthyroid but clinical signs presentWilliams Obstetrics 24ed. Ch. 58 – Fig.1.

❖ Universal screening not recommended

THYROID HORMONES & THE FETUS

Maternal T4 crosses the placenta

Fetal brain development

Provides thyroid hormone

before 12 weeks

Fetal thyroid begins to produce own

thyroid hormone & concentrate

iodine

30% of T4 at term is estimated

to be of maternal production

IODINE REQUREMENTS

Iodine deficiency in Pregnancy

Causes

Increased thyroid hormone production

Increased renal iodine loss

Fetal iodine requirement

Mild mental impairment to cretinism

Iodine Intake in Pregnancy

Reproductive age: 150mcg daily

Pregnant: 220mcg daily

Lactating: 290mcg daily

About 50% of PNV don’t contain iodine

Not to excess 500mcg daily

http://www.faqs.org/nutrition/images/nwaz_01_img0114.jpg

HYPERTHYROIDISM

Prevalence: 0.2 - 0.4% pregnancies (US); studies in UK (0.7 - 1.7%), China (1%)

Causes: Graves disease (95%), trophoblastic disease, toxic multinodular goiter, toxic adenoma, thyroiditis, exogenous thyroid hormone

Diagnosis: low TSH and high free T4

Symptoms: fatigue, nervousness, frequent stools, sweating, tachycardia, tremors, weight loss, heat intolerance, insomnia, palpitations, HTN, insomnia, +/- goiter

Additional symptoms associated with Grave’s Disease: ophthalmopathy, dermopathy

Complications: SAB, preeclampsia, heart failure, preterm birth, low birth weight, fetal thyroid disease, infection, anemia, hearing loss

SUBCLINICAL HYPERTHYROIDISM

Prevalence in pregnancy: 1.7%

No associations with adverse pregnancy outcomes

Antithyroid medications have can have adverse effects on the fetus

THYROID STIMULATING ANTIBODIES

Risk of immune-mediated fetal hypothyroidism and hyperthyroidism

Thyroid stimulating immunoglobulins (TSI) stimulate fetal thyroid

1-5% of neonates have hyperthyroidism or neonatal Grave’s disease

TSH-binding inhibitory immunoglobulins inhibit fetal thyroid

Decreased occurrence with maternal treatment during pregnancy

However – increased risk if previous maternal treatment via surgery or radioiodine ablation

Consider fetal thyrotoxicosis in all women with a history of Grave’s

American Thyroid Association and American Associate of Clinical Endocrinologists recommend antibody testing between 22-26wga in women with a history of Grave’s disease.

ACOG does not, due to no change in management.

HYPERTHYROIDISM MANAGEMENT

Thioamides – decrease production of T3 & T4; cross the placenta

Proplthiouracil (PTU) – first trimester

Inhibits iodination of tyrosine and conversion of T4 to T3 in peripheral tissues

Hepatotoxicity (0.1-0.2%), ANCA (20%; rare for serious vasculitis)

Methimazole (MMI) – second & third trimesters

Inhibits iodination of tyrosine

Associated with esophageal and choanal atresia, fascial dysmorphism, aplasia cutis, omphalocele

Side effects: transient leukopenia (10%), agranulocytosis (0.3 - 0.4%)

Dosage: PTU 50-150mg PO TID; MMI 10-40mg PO divided into BID or TID dosing

Surveillance: measure T4 level q2-4 weeks

Beta blockers

Used for management of tachycardia and tremors

Avoid longer than 2-6 weeks due to increased risk of IUGR, bradycardia & hypoglycemia

Dosing

Metoprolol 25-50mg daily

Propranolol 20mg q6-8hr

HYPERTHYROIDISM MANAGEMENT

Thyroidectomy – rarely performed during pregnancy

Reserved for individuals with allergy to thioamides or agranulocytosis

Pretreatment with a beta-blocker and potassium iodine

Fetal Monitoring

Fetal heart rate monitoring, growth ultrasounds;

Consider fetal thyroid ultrasound if mother with Grave’s or TRAb 2-3x normal

Postpartum

Methimazole preferred due to PTU side effects

If dose >20mg daily, then infants should have thyroid function testing at 1 and 3 months of age

TSH and free T4 at 6 weeks

Not recommended

Routine thyroid antibody testing

Some recommend if require treatment with thioamides to test initially, at 18-22 and 30-34 wga

Routine fetal thyroid evaluation: fetal US, cord blood sampling

Consider in cases of IUGR, fetal tachycardia, fetal hydrops, goiter

HYPERTHYROID EMERGENCIES

Thyroid StormThyrotoxic Heart Failure & Pulmonary Hypertension

Incidence: 1-2% of pregnant patients with hyperthyroidism

High risk of maternal heart failure

Abrupt onset

Diagnosis: fever, tachycardia, cardiac dysrhythmia, CNS dysfunction

If suspect, order TSH & free T4, CBC, LFTs, Ca2+

Treat underlying cause

Avoid delivery

Incidence: 8% pregnant patients with uncontrolled hyperthyroidism

Excess T4 -> high-output cardiomyopathy that can develop into dilated cardiomyopathy

Precipitating conditions: preeclampsia, anemia, sepsis

Frequently these conditions are reversible

Inhibit release of T3 & T4

• PTU 1,000mg PO load, then 200mg PO q6hr

• Iodine (1-2hr after PTU)

• Sodium iodine 500-1,000mg IV q8hr OR

• Potassium iodide, 5 drops PO q8hr OR

• Lugol solution, 10 drops PO q8hr OR

• Lithium carbonate, 300mg PO q6hr (iodine allergy)

Block peripheral T4 -> T3

• Dexamethasone, 2mg IV q6hr x 4 OR

• Hydrocortisone, 100mg IV q8hr x 3

Consider beta-blocker

for tachycardia

• Caution in those with heart failure

• Propranolol, 10-40mg PO q4-6hr; (labetalol, esmolol)

MANAGEMENT of THYROID STORM or

THYROTOXIC HEART FAILURE in PREGNANCY

Don’t forget supportive care!

O2, IVF, telemetry, NG tube, cooling measure, avoid salicylates

HYPOTHYROIDISM

Complicates 2 – 10 per1,000 pregnancies

Causes: Iodine deficiency, chronic autoimmune thyroiditis (Hashimoto’s),

prior radioiodine ablation/surgery, pituitary/hypothalamic disorders

Diagnosis: high TSH and low free T4

Consider measurement of TPO antibodies if TSH≥2.5

Symptoms: fatigue, constipation, cold intolerance, muscle cramps, dry skin,

hair loss, prolonged relaxation of DTRs, weight gain, edema, +/- goiter

Paresthesias: early symptom present in 75% of hypothyroid patients

Other: large tongue, myxedema, hoarse voice

Complications: SAB, preeclampsia, preterm birth, low birth weigh, impaired

neuropsychologic development, placental abruption, fetal death

HYPOTHYROIDISM

SUBCLINICAL HYPOTHYROIDISM

Prevalence in pregnancy: 2-5%

Approximately 1/3 have TPO antibodies

Possible increased risk of NICU admission, RDS, abruption, preterm birth, GDM

No evidence that treatment improves outcomes

ISOLATED MATERNAL HYPOTHYROXINEMIA

Prevalence in pregnancy: 1.3%

No increased rates of TPO antibodies

Inconsistent data on adverse pregnancy outcomes (neurodevelopment, macrosomia)

No evidence that treatment improves outcomes

ANTITHYROID ANTIBODIES

Hashimoto’s thyroiditis

glandular destruction via thyroid peroxidase (TPO) Ab & antithyroglobulin Ab (TG)

Euthyroid Autoimmune Thyroid Disease

TPO & TG antibodies are present in 6-20% of reproductive-aged women

Women with these antibodies are at an increased risk for

Early pregnancy loss (2-5 fold)

Placental abruption (3 fold)

Postpartum thyroid complications

Permanent thyroid failure

1 in 180,000 neonates will experience fetal hypothyroidism as a result of maternal TPO antibodies attacking the fetal thyroid

HYPOTHYROIDISM MANAGEMENT

T4 replacement recommended

Levothyroxine 1-2mcg/kg daily

Surveillance: measure TSH levels q4-6 weeks

If preexisting hypothyroidism, need for T4 increase in 1/3 of patients

Increased T4 needs can occur as early as week 5 of gestation

Anticipatory increase in dose by 25% at pregnancy confirmation (in those with no reserve)

Adjust dosages in 25-50mcg increments

Postpartum

Return to prepregnancy dose if preexisting condition

Measure TSH at 4-6 weeks after delivery

Safe to use in breastfeeding; can improve milk production

Not recommended

Routine thyroid antibody testing

MYXEDEMA COMA

Extreme/severe hypothyroidism

Mortality rate: 20%

Rare in pregnancy

Diagnosis: “think low”

Hypoventilation, hypothermia, hypotension, hyponatremia, and bradycardia

Treatment

Levothyroxine (IV/NG) 300-500mcg bolus IV, 75-100mcg IV daily

NG doses 30-50% higher than IV; PO 50-200mcg daily once stable

Liothyronine (T3 replacement) 10mcg q8hr

Hydroxycortison 100mg q8hr until cortisol level known, then titrate

Supportive: IVF, electrolyte replacement, telemetry, intubation, warming

Cardiac enzymes and cultures to further evaluate

FETAL & NEONATAL EFFECTS Goitrous Thyrotoxicosis

Transfer of TSI across the placenta; increased risk if 3x normal limit

Nonimmune hydrops, heart failure, accelerated bone maturation, tachycardia, IUGR

Treatment: increase thioamide (regardless of maternal levels)

May need antithyroid drug during neonatal period

Fetal Thyrotoxicosis

Placental transfer of TSI s/p ablation or thyroidectomy

Goitrous Hypothyroidism

Due to maternal intake of thioamides

Delayed bone maturation, hydramnios, hyperextension

Treatment: decrease maternal thioamide dosage

Possible intramniotic thyroxine injection

Nongoitrous Hypothyroidism

Transfer of TSH receptor blocking antibodies

Williams Obstetrics 24ed. Ch. 58 – Fig.3.

FETAL & NEONATAL MANAGEMENT

Method of diagnosis: amniotic fluid or fetal cord blood sampling

Goiter complications

Compression of trachea and/or esophagus hydramnios and/or airway compromise

Fetal neck hyperextension labor dystocia

Fetal Thyrotoxicosis

Maternal thioamides; treat mother with levothyroxine supplementation if needed

Fetal Hypothyroidism

Discontinuation of maternal thioamide (if applicable and able)

Intraamniotic levothyroxine injections

50 - 800mg q1-4 weeks (no established protocol)

CONGENITAL HYPOTHYROIDISM

Prevalence: 1 in 2000 - 4000 births; female:male = 2:1

Causes

Iodine deficiency – most common

Developmental disorders – agenesis and hypoplasia

Hereditary defects in thyroid hormone production (dyshormonogenesis)

Failure of stimulation from pituitary

Complications: mental deficiencies/cognitive defects, limb length

Most treatable cause of mental deficiency

One study found that 8% of 1420 infants had other major congenital malformations

Universal newborn screening: TSH & free T4; required in US

Management: Thyroxine replacement (early & aggressive)

THYROID NODULES

Present in 1-2% of reproductive aged women

15% of Chinese women at nodules >2mm – 50% multiple; mostly nodular hyperplasia

Some studies have shown 40% malignancy rate of solitary nodules

Workup

TSH

Neck ultrasound (adequate for detecting nodules >0.5cm)

Malignant characteristics: irregular margins, microcalcifications, hypoechogenic pattern

FNA

Surgery: second trimester is optimal timing

Reserved for fast going masses, compression symptoms (recurrent laryngeal nerve)

Radioiodine scanning – contraindicated in pregnancy

Recommend waiting 6 months after ablation

Recommend waiting 3 months after delivery to undergo ablation due to storage of iodide in the breast tissue

THYROID CANCER

Requires multidisciplinary approach

Typically well differentiated and slow growing

Monitor with ultrasound every trimester

If discovered in 1st - 2nd trimesters, possible thyroidectomy in 3rd

trimester – otherwise delay surgery until after delivery.

Injury or inadvertent removal of parathyroid glands

Injury to recurrent laryngeal nerve

Persistent disease s/p radioiodine treatment

Pregnancy has does not lead to recurrence, however progression can occur

Follow with US and thyroglobulin levels

Continue levothyroxine

POSTPARTUM THYROIDITIS

➢ Thyroid dysfunction within 12 months of delivery

➢ Transient autoimmune thyroiditis account for 5-10% of cases

➢ Approximately 50% of women with TPO antibodies in first trimester developed

postpartum thyroiditis

➢ Most cases will resolve spontaneously➢ One third develop overt hypothyroidism

Thyrotoxicosis

Release of excess thyroid hormone

Abrupt onset

Small, painless goiter

Lasts a few months

Fatigue, irritability, weight loss,

palpitations, heat intolerance

Thioamides ineffective

Consider beta-blocker if severe

Hypothyroidism

Thyromegaly more common

Typically 4-8 months postpartum

Fatigue, cold intolerance, weight

gain, constipation, depression

T4 replacement for 6-12 months

REFERENCES1. American College of Obstetrics and Gynecology. “Practice Bulletin No. 148: Thyroid Disease in Pregnancy.” Obstetrics and

Gynecology. 2015;125:996-1005.

2. Cunningham, F. Gary,, et al. Williams Obstetrics. 24th edition. New York: McGraw-Hill Education, 2014.

3. Foley, F. Michael,, et al. Obstetric Intensive Care Manual. 5th edition. New York: McGraw-Hill Education, 2018.

4. Lafranchi, Stephen and Maynika Rastogi. “Familial Thyroid Dyshormonogenesis.” Orphanet Encyclopedia, August, 2010,https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=95716. Accessed 2 December 2018.

5. National Library of Medicine (US). Genetics Reference [Internet]. Bethesda, MD: The Library; 27 November 2018. Congenital Hypothyroidism; [reviewed 2015 September]. Available from: https://ghr.nlm.nih.gov/condition/congenital-hypothyroidism#inheritance. Accessed 2 December 2018.

6. Newborn screening for congenital hypothyroidism. Journal of Clinical Research in Pediatrtic Endocrinology vol. 5 Suppl 1,Suppl 1 (2013):8-12.

7. Ross, S. Douglas. (2018). Hyperthyroidism during pregnancy: treatment. In J. E. Mulder (Ed.), UpToDate. https://www-uptodate-com.proxy.kumc.edu/contents/hyperthyroidism-during-pregnancy-treatment?search=hyperthyroidism%20in%20pregnancy&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H17 . Accessed 4 December 2018.

8. Ross, S. Douglas. (2018). Hypothyroidism during pregnancy: clinical manifestation, diagnosis, and treatment. In J. E. Mulder (Ed.), UpToDate. https://www-uptodate-com.proxy.kumc.edu/contents/hypothyroidism-during-pregnancy-clinical-manifestations-diagnosis-and-treatment?search=hypothyroid%20in%20pregnancy&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed 4 December. 2018.

9. Ross, S. Douglas. (2018). Overview of Thyroid Disease in Pregnancy. In J. E. Mulder (Ed.), UpToDate. https://www-uptodate-com.proxy.kumc.edu/contents/overview-of-thyroid-disease-in-pregnancy?search=thyroid%20diseases%20and%20pregnancy&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed 11 November 2018.

QUESTIONS?

THYROID DISEASE IN PREGNANCY