MFM Clinical Guideline

Thyroid Disease in

Thyroid disease is the 2nd most common endocrinopathy in pregnancy after diabetes. In pregnancy: thyroid volume ↑ 30%, total/bound T3 and T4 levels ↑, but free/unbound T3 and T4 levels are stable due to ↑ thyroid binding globulin. In the 1st trimester, TSH levels ↓ due to high levels of hCG,which directly stimulates the TSH receptor, but return to baseline in the 2nd trimester. TSH does not cross the placenta. Maternal T4 is transferred to the and is important for fetal brain development, especially before the fetal thyroid gland begins to synthesize thyroid hormone at 12-14 weeks.

Screening for Thyroid Disease in Pregnancy

Table 1: Screening. Table 2: Pregnancy reference ranges. Who to Screen Trimester TSH FT4* Age > 30 1st 0.1 - 2.5 0.8 - 1.2 BMI > 40 mIU/L ng/dL Current signs/symptoms of thyroid dysfunction 2nd 0.2 - 3 mIU/L 0.6 - 1 ng/dL Known positive thyroid 3rd 0.3 - 3 mIU/L 0.5 - 0.8 Goiter ng.dL *Due to inaccuracy of thyroid testing in pregnancy, Hx head/neck irradiation or thyroid surgery FT4 goal FHx thyroid disease should be the upper half of the reference range Pregestational diabetes Table 3: Interpreting the results. Autoimmune disorders TSH FT4 Hx of pregnancy loss, PTD, infertility Use of amiodarone or lithium, recent administration of Overt ↓ ↑ iodinated radiologic contrast Subclinical ↓ NL Hyperthyroidism Residing in an area of known Gestational 1st trim: ↓ UL How to Screen Hyperthyroidism 2nd trim: NL/ Step 1: TSH, FT4 NL slight ↑ Step 2 (TSH ↑): TPO antibodies Step 2 (TSH ↓): FT3, thyroid stimulating immunoglobulin Overt ↑ ↓ (TSI)* Subclinical Hypothyroidism ↑ NL *TSI is a type of thyrotropin receptor (TRaB) Isolated Hypothyroxinemia NL ↓

Hypothyroidism in Pregnancy

Thyroid peroxidase (TPO) antibodies - ↑ in 90% cases of Hashimoto's, can be seen in low concentration in euthyroidism and Graves; 2-17% of all pregnant women will be positive for either TPO or Tg antibodies; TPO antibodies are able to cross the placenta, however, they are not associated w/ fetal thyroid dysfunction  Associations: ↑ risk of spontaneous pregnancy loss  Unclear associations: recurrent pregnancy loss, PTD, perinatal death, , , neonatal RDS  Management: o TPO+, euthyroid: TSH q trimester . May be at risk of hypothyroidism due to the stress of pregnancy as the ability of the thyroid to augment hormone production is compromised

MFM Clinical Guideline

o TPO+, euthyroid, RPL 2 ongoing RCTs are attempting to address if treatment to newly pregnant euthyroid women w/ TPO decreases loss; ATA guidelines state that treatment w/ (25-50 mcg) may be considered given its potential benefits; if treating or if REI has started treatment, discontinue treatment in the 2nd trimester and check TSH in 4-6 wks, again in the 3rd trimester, and again approx 3 months postpartum w/ a PCP/endocrinologist

Overt Hypothyroidism  Incidence: 2 - 10 / 1,000 o Associated w/ T1 DM (20-30%), Addison’s disease, pernicious anemia, myasthenia gravis  Signs & symptoms: fatigue, constipation, cold intolerance, muscle cramps, weight gain, , dry skin, hair loss, prolonged relaxation phase of DTR, goiter, vision changes, mood imbalances  Diagnosis: ↑ TSH, ↓ FT4  Hashimoto (chronic ) is the most common cause in areas w/o iodine deficiency and is characterized by glandular destruction by autoantibodies (esp. TPO)  Adverse pregnancy outcomes (poor control): /IUFD, PTD, preeclampsia, abruption  Adverse fetal/neonatal outcomes (poor control): LBW, impaired neuropsychological development, rarely hypothyroidism (1/180,000 offspring in women w/ Hashimoto's)  Preconception management: o Maintain TSH < 2.5 for those planning pregnancy  Pregnancy Management: o Initiating treatment: levothyroxine (Synthroid, Levoxyl, Thyroxine, Levothyroid, Tirosint (gel capsule, can be helpful w/ hx bariatric surgery or malabsorptive diseases )) contains only T4, initiate at 1-2 mcg/kg/day (approx ~ 100 mcg), take on an empty stomach w/ no food or meds for 30 - 60 min afterwards (see table below) o Ongoing treatment: as soon as patient finds out she is pregnant, increase weekly dose by 2 additional pills (9 pills/wk) or ↑ daily dose by 20-30% (compensates for the 20-30% ↑ requirement of most pregnant women) and order initial labs, make subsequent adjustments as needed o Other preparations: should ideally not be started in pregnancy, but may be continued in those well controlled before pregnancy . Cytomel, Triostat, Liothyronine - contain only T3, may be required for symptomatic relief in those w/ T4 replacement and ↓ T3 . Natural/dessicated thyroid (Armour Thyroid) - contain both T3/T4, derived from porcine thyroid glands . Supplements: some patients may be on additional supplements to optimize conversion of T4 → T3 and are safe to continue  Zinc - 30 - 60 mg QD in divided doses, don’t take w/ thyroid meds  Selenium - 200 - 400 mg QD in divided doses, don’t take w/ thyroid meds o Dose adjustments: repeat TSH q 4 - 6 weeks and adjust dosing in 20-30% increments (typically 25 - 50 mcg) to keep TSH w/in trimester specific ranges o Fetal surveillance: none is needed in women who are euthyroid w/ treatment; consider surveillance starting at 34 wks for those who are poorly controlled  Postpartum management: o Those being treated before pregnancy: if euthyroid on a stable dose before pregnancy, restart levothyroxine at prepregnancy dose and check TSH at the postpartum visit or if excessive weight gain ↓ dose by 20-30% and check TSH at the postpartum visit o Those initiating treatment in pregnancy: ↓ dose by 20-30% and check TSH at the postpartum visit or if on a very low dose, may consider d/c at delivery and check TSH at the postpartum visit

MFM Clinical Guideline

Subclinical Hypothyroidism  Incidence: 2-5% of pregnancies  Diagnosis: ↑ TSH, NL FT4  Adverse pregnancy outcomes: studies are conflicting and there is no evidence that treatment improves pregnancy outcomes  Adverse fetal/neonatal outcomes: 2 cohort studies in 1999 suggested that untreated subclinical hypothyroidism may lead to adverse neurodevelopmental outcomes in offspring  2012 Controlled Antenatal Thyroid Screening (CATS) Study and 2017 MFMU study (RCTs) showed no difference in neurodevelopment in offspring in treated vs. untreated women at 3 year and 5 year follow up o Advocates who support the 2017 ATA guidelines, criticise that levothyroxine wasn’t started until an average of 13 (CATS) to 17 weeks (MFMU), MFMU subgroup analysis for < 14 wks was not powered for this outcome, and that earlier treatment may lead to improved outcomes  Management: o 1st trimester diagnosis: consider treatment w/ 50 mcg levothyroxine and following the above management of overt hypothyroidism; counsel that it is not yet known if treatment in the 1st trimester improves neurologic outcomes in offspring o 2nd/3rd trimester diagnosis: treatment is not recommended as it has not been shown to improve outcomes in the above RCTs

Euthyroid Women s/p Thyroidectomy or Ablation:  Management: TSH every 4-6 weeks initially, may space out to 6-8 weeks when stable

Isolated Hypothyroxinemia  Diagnosis: NL TSH, ↓ FT4  Management: treatment is not recommended, no follow up is required

Hyperthyroidism in Pregnancy

Thyroid stimulating immunoglobulin (TSI) - a type of Thyrotropin/TSH receptor antibodies (TRAb) - ↑ in 95% of active Graves Disease (GD) and may remain high following ablation or surgery  Can cross the placenta and cause either fetal hyperthyroidism or hypothyroidism o 1-5% will develop neonatal GD caused by transplacental passage of TSI, especially in those who aren’t adequately treated or have had a thyroidectomy  Generally ↓ as pregnancy progresses  Check w/ initial labs and again at 28-32 weeks on all hyperthyroid patients and those w/ a hx of GD treated w/ surgery/ablation

Gestational/transient Hyperthyroidism  Incidence: 1-3% of pregnancies, hCG typically peaks at 7-11 weeks and should return to normal by 14-18 weeks  Diagnosis: ↓ TSH, FT4 that normalizes in the 2nd half of pregnancy  Associated with: , multiple gestations, and  Gestational or true hyperthyroidism?: no hx of thyroid disease and no clinical signs of hyperthyroidism suggests gestational o TSH should normalize in the 2nd trimester o TSI can help if unclear (should be + in Graves)

MFM Clinical Guideline

 Management: treatment w/ thioamides is not recommended, treat w/ beta blockers for symptomatic relief PRN, if there are palpable thyroid nodules, needs an u/s and FT3 to check for T3 toxicosis  Follow up: repeat labs in the 2nd trimester

Overt Hyperthyroidism  Incidence: 0.2% of pregnancies o 95%: Grave’s disease o 5%: toxic multinodular goiter, toxic adenoma, factitious thyrotoxicosis (meds) o Rare: struma ovarii (teratoma containing thyroid tissue)  Diagnosis: ↓ TSH, ↑ FT4 (rarely ↑ FT3 in T3 toxicosis from multinodular goiter)  Signs & symptoms: nervousness, tremors, tachycardia, frequent stools, sweating, heat intolerance, weight loss, goiter, dysphagia, insomnia, palpitation, acute/labile hypertension o Graves: ophthalmopathy localized or pretibial  Adverse pregnancy outcomes: preeclampsia, maternal heart failure  Adverse fetal/neonatal outcomes: ↑ medically indicated PTD, LBW, fetal loss, hydrops, IUGR, goiter, tachycardia o Neonates are usually euthyroid o Antibodies can cross the placenta and causing immune mediated hypo or hyperthyroidism in the neonate  Preconception Management: should be euthyroid by either drugs, surgery, or ablation before attempting pregnancy o Pregnancy should be delayed for 6 months after radioiodine ablation o Discuss possible adverse effects of drugs  Pregnancy Management: o Goal: maintain FT4 at the upper limits of normal w/ the lowest dosage of medication possible and attempt to wean off medication by the time of delivery (goal: by 36 weeks) o GD euthyroid on low dose of methimazole (<5-10 mg) or PTU (< 100-200 mg): consider d/c meds due to potential teratogenic effects; take into account the disease history, goiter size, duration of therapy, results of recent thyroid tests, TSI status, and risk of . High risk of relapse if d/c: meds for a short time (< 6 months), suppressed TSH on meds, large doses of meds, orbitopathy, large goiter, high levels of TSI . Following cessation: TSH and FT4 every 1-2 weeks, if she remains euthyroid continue to check TSH and FT4 every 2-4, then every 4-6 weeks during the 2nd and 3rd trimesters if euthyroid o Slightly increased FT4, TSI negative - consider expectant management and rechecking TSH, FT4 in 4 wks  Those requiring medication: o Thioamides (block the synthesis of thyroid hormones) . Baseline CBC: 10% will have transient leukopenia (continue therapy), 1% develop agranulocytosis (d/c therapy) . serial leukocyte counts aren’t helpful, look for fever or sore throat → CBC . Measure FT4 every 4 weeks to be on the lowest possible dose that maintains FT4 in the high normal range o Propylthiouracil (PTU) - start 50 - 150 mg po TID (if changing from methimazole, use 1:20 dose ratio; ex. 5 mg Methimazole → 100 mg PTU) . Additionally, partially inhibits the conversion of T4 → T3 and crosses the placenta less readily than Methimazole . Use in the 1st trimester, but may continue to use if the patient has an allergy to methimazole . Associated w/ fulminant hepatotoxicity (0.1-0.2%): CMP baseline and repeat if symptomatic

MFM Clinical Guideline

o Methimazole - start at total daily dose of 10 - 40 mg daily . Avoid in 1st trimester, treatment of choice in 2nd + 3rd trimesters  Associated w/ an embryopathy (esophageal or choanal atresia) and cutis aplasia (congenital skin defects) o Beta Blockers - may be needed for symptomatic relief (tachycardia, tremors, shakes) and will ↓ T4 conversion to more biologically active T3 . Propranolol 40 mg tab BID or 60-80 mg ER cap until euthyroid, then wean off  Fetal Testing: o Assess for fetal goiter on morphology scan and again at 28-30 weeks o Patients who have elevated TSI at any time, who require medications, or if fetal goiter is noted on u/s, should have surveillance in the 3rd trimester w/ 2x weekly testing and serial growth scans  Postpartum: Check TSH, FT4 w/in 7 - 14 days postpartum and again at postpartum visit o Breast feeding: both meds are excreted in breast milk and safe at most doses (Methimazole < 20 mg and PTU < 450 mg), check w/ pediatric team before d/c

Subclinical Hyperthyroidism  Incidence: 1.7% of pregnancies  Diagnosis: ↓ TSH, NL FT3/FT4  Adverse pregnancy outcomes: none  Adverse fetal/neonatal outcomes: none  Management: treatment is not recommended  Follow up: repeat labs only if patient develops signs of overt hyperthyroidism, if TSI + then repeat TSH in 2nd and 3rd trimesters

Thyroid Nodules  Management: TSH, FT4, thyroid u/s and endocrinology consult

Postpartum Thyroiditis

 Incidence: 5% of women o Consider in women presenting with postpartum depression  Diagnosis: thyroid dysfunction w/in 12 months of delivery o Typical course: hyperthyroidism w/in 6 months → spontaneous remission → hypothyroidism → resolution by 12 months o If etiology is unclear send TSI . Typically positive in GD and negative in postpartum thyroiditis  Management: o In most women, the condition will resolve spontaneously, check for goiter o Refer to an endocrinologist, symptomatic treatment with propranolol as needed (start 10- 20 mg QID)

Thyroid Storm & Thyrotoxic Heart Failure in Pregnancy

Thyroid Storm  Hypermetabolic state caused by excess thyroid hormone  Incidence: 1-2% of pregnant patients w/ hyperthyroid

MFM Clinical Guideline

: fever tachycardia, cardiac dysrhythmia, CNS dysfunction  High risk of maternal heart failure, acute onset pre-e

Thyrotoxic Heart Failure  Incidence: 8% of pregnant women w/ uncontrolled hyperthyroidism  Heart failure and pulmonary hypertension from cardiomyopathy caused by the myocardial effects of excess T4  Usually precipitated by preeclampsia, anemia, sepsis

Table 1: Medications that can interfere w/ thyroid medications Table 2: Management of thyroid storm/HF

REFERENCES 1. ACOG Practice Bulletin #148: Thyroid disease in pregnancy. April 2015. 2. Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum. 2017. 3. Ross DS. Overview of thyroid disease in pregnancy. Up To Date. Accessed 8/28/16. 4. Casey B, de Veciana M. Thyroid screening in pregnancy. AJOG. Oct 2014, (211):4;351 - 353. 5. Reference Values During Pregnancy. Perinatology.com.