Appendix

APPENDIX: PREGNANCY AND POSTPARTUM THYROID DISEASE MANAGEMENT GUIDELINES OF THE AMERICAN THYROID ASSOCIATION—SUMMARY OF RECOMMENDATIONS

Thyroid Function Tests in Pregnancy

Recommendation 1

Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake, should be applied. Level B-USPSTF

Recommendation 2

If trimester-specific reference ranges for TSH are not available in the laboratory, the following reference ranges are recommended: first trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L. Level I-USPSTF

Recommendation 3

The optimal method to assess serum FT4 during pregnancy is measurement of T4 in the dialysate or ultrafiltrate of serum samples employing on-line extraction/liquid chromatography/tandem mass spectrometry (LC/MS/MS). Level A-USPSTF

Recommendation 4

If FT4 measurement by LC/MS/MS is not available, clinicians should use whichever measure or estimate of FT4 is available in their laboratory, being aware of the limitations of each method. Serum TSH is a more accurate indication of thyroid status in pregnancy than any of these alternative methods. Level A-USPSTF

Recommendation 5

In view of the wide variation in the results of FT4 assays, method-specific and trimester-specific reference ranges of serum FT4 are required. Level

B-USPSTF

Hypothyroidism in Pregnancy

Recommendation 6

OH should be treated in pregnancy. This includes women with a TSH concentration above the trimester-specific reference interval with a decreased FT4, and all women with a TSH concentration above 10.0 mIU/L irrespective of the level of FT4. Level A-USPSTF

Recommendation 7

Isolated hypothyroxinemia should not be treated in pregnancy. Level

C-USPSTF

Recommendation 8

SCH has been associated with adverse maternal and fetal outcomes. However, due to the lack of randomized controlled trials there is insufficient evidence to recommend for or against universal LT4 treatment in TAb– pregnant women with SCH. Level I-USPSTF

Recommendation 9

Women who are positive for TPOAb and have SCH should be treated with LT4. Level B-USPSTF*

Recommendation 10

The recommended treatment of maternal hypothyroidism is with administration of oral LT4. It is strongly recommended not to use other thyroid preparations such as T3 or desiccated thyroid. Level A-USPSTF

Recommendation 11

The goal of LT4 treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range (first trimester, 0.1–2.5 mIU/L, second trimester, 0.2–3.0 mIU/L, third trimester, 0.3–3.0 mIU/L). Level A-USPSTF

Recommendation 12

Women with SCH in pregnancy who are not initially treated should be monitored for progression to OH with a serum TSH and FT4 approximately every 4 weeks until 16—20 weeks gestation and at least once between 26 and 32 weeks gestation. This approach has not been prospectively studied. Level I-USPSTF

Recommendation 13

Treated hypothyroid patients (receiving LT4), who are newly pregnant should independently increase their dose of LT4 by ~25%–30% upon a missed menstrual cycle or positive home pregnancy test and notify their caregiver promptly. One means of accomplishing this adjustment is to increase LT4 from once daily dosing to a total of nine doses per week (29% increase). Level B-USPSTF

Recommendation 14

There exists great interindividual variability regarding the increased amount of T4 (or LT4) necessary to maintain a normal TSH throughout pregnancy, with some women requiring only 10%–20% increased dosing, while others may require as much as an 80% increase. The etiology of maternal hypothyroidism, as well as the preconception level of TSH, may provide insight into the magnitude of necessary LT4 increase. Clinicians should seek this information upon assessment of the patient after pregnancy is confirmed. Level A-USPSTF

Recommendation 15

Treated hypothyroid patients (receiving LT4) who are planning pregnancy should have their dose adjusted by their provider in order to optimize serum TSH values to < 2.5 mIU/L preconception. Lower preconception TSH values (within the nonpregnant reference range) reduce the risk of TSH elevation during the first trimester. Level B-USPSTF

Recommendation 16

In pregnant patients with treated hypothyroidism, maternal serum TSH should be monitored approximately every 4 weeks during the first half of pregnancy because further LT4 dose adjustments are often required. Level B-USPSTF

Recommendation 17

In pregnant patients with treated hypothyroidism, maternal TSH should be checked at least once between 26 and 32 weeks gestation. Level I-USPSTF

Recommendation 18

Following delivery, LT4 should be reduced to the patient’s preconception dose. Additional TSH testing should be performed at approximately 6 weeks postpartum. Level B-USPSTF

Recommendation 19

In the care of women with adequately treated Hashimoto’s thyroiditis, no other maternal or fetal thyroid testing is recommended beyond measurement of maternal thyroid function (such as serial fetal ultrasounds, antenatal testing, and/or umbilical blood sampling) unless for other pregnancy circumstances. Level A-USPSTF

Recommendation 20

Euthyroid women (not receiving LT4) who are TAb+ require monitoring for hypothyroidism during pregnancy. Serum TSH should be evaluated every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation. Level B-USPSTF

Recommendation 21

A single RCT has demonstrated a reduction in postpartum thyroiditis from selenium therapy. No subsequent trials have confirmed or refuted these findings. At present, selenium supplementation is not recommended for TPOAb+ women during pregnancy. Level C-USPSTF

Thyrotoxicosis in Pregnancy

Recommendation 22

In the presence of a suppressed serum TSH in the first trimester (TSH < 0.1 mIU/L), a history and physical examination are indicated. FT4 measurements should be obtained in all patients. Measurement of TT3 and TRAb may be helpful in establishing a diagnosis of hyperthyroidism. Level B-USPSTF

Recommendation 23

There is not enough evidence to recommend for or against the use of thyroid ultrasound in differentiating the cause of hyperthyroidism in pregnancy. Level I-USPSTF

Recommendation 24

Radioactive iodine (RAI) scanning or radioiodine uptake determination should not be performed in pregnancy. Level D-USPSTF

Recommendation 25

The appropriate management of women with gestational hyperthyroidism and hyperemesis gravidarum includes supportive therapy, management of dehydration, and hospitalization if needed. Level A-USPSTF

Recommendation 26

ATDs are not recommended for the management of gestational hyperthyroidism. Level D-USPSTF

Recommendation 27

Thyrotoxic women should be rendered euthyroid before attempting pregnancy. Level A-USPSTF

Recommendation 28

PTU is preferred for the treatment of hyperthyroidism in the first trimester. Patients on MMI should be switched to PTU if pregnancy is confirmed in the first trimester. Following the first trimester, consideration should be given to switching to MMI. Level I-USPSTF

Recommendation 29

A combination regimen of LT4 and an ATD should not be used in pregnancy, except in the rare situation of fetal hyperthyroidism. Level D-USPSTF

Recommendation 30

In women being treated with ATDs in pregnancy, FT4 and TSH should be monitored approximately every 2–6 weeks. The primary goal is a serum FT4 at or moderately above the normal reference range. Level B-USPSTF

Recommendation 31

Thyroidectomy in pregnancy is rarely indicated. If required, the optimal time for thyroidectomy is in the second trimester. Level A-USPSTF

Recommendation 32

If the patient has a past or present history of Graves’ disease, a maternal serum determination of TRAb should be obtained at 20–24 weeks gestation. Level B-USPSTF

Recommendation 33

Fetal surveillance with serial ultrasounds should be performed in women who have uncontrolled hyperthyroidism and/or women with high TRAb levels (greater than three times the upper limit of normal). A consultation with an experienced obstetrician or maternal–fetal medicine specialist is optimal. Such monitoring may include ultrasound for heart rate, growth, amniotic fluid volume and fetal goiter. Level I-USPSTF

Recommendation 34

Cordocentesis should be used in extremely rare circumstances and performed in an appropriate setting. It may occasionally be of use when fetal goiter is detected in women taking ATDs to help determine whether the fetus is hyperthyroid or hypothyroid. Level I-USPSTF

Recommendation 35

MMI in doses up to 20–30mg/d is safe for lactating mothers and their infants. PTU at doses up to 300mg/d is a second-line agent due to concerns about severe hepatotoxicity. ATDs should be administered following a feeding and in divided doses. Level A-USPSTF

Clinical Guidelines for Iodine Nutrition

Recommendation 36

All pregnant and lactating women should ingest a minimum of 250μg iodine daily. Level A-USPSTF

Recommendation 37

To achieve a total of 250μg of iodine ingestion daily in North America all women who are planning to be pregnant or are pregnant or breastfeeding should supplement their diet with a daily oral supplement that contains 150μg of iodine. This is optimally delivered in the form of potassium iodide because kelp and other forms of seaweed do not provide a consistent delivery of daily iodide. Level B-USPSTF

Recommendation 38

In areas of the world outside of North America, strategies for ensuring adequate iodine intake during preconception, pregnancy, and lactation should vary according to regional dietary patterns and availability of iodized salt. Level A-USPSTF

Recommendation 39

Pharmacologic doses of iodine exposure during pregnancy should be avoided, except in preparation for thyroid surgery for Graves’ disease. Clinicians should carefully weigh the risks and benefits when ordering medications or diagnostic tests that will result in high iodine exposure. Level C-USPSTF

Recommendation 40

Sustained iodine intake from diet and dietary supplements exceeding 500–1100μg daily should be avoided due to concerns about the potential for fetal hypothyroidism. Level C-USPSTF

Spontaneous Pregnancy Loss, Preterm Delivery, and Thyroid Antibodies

Recommendation 41

There is insufficient evidence to recommend for or against screening all women for anti-thyroid antibodies in the first trimester of pregnancy. Level I-USPSTF

Recommendation 42

There is insufficient evidence to recommend for or against screening for thyroid antibodies, or treating in the first trimester of pregnancy with LT4 or IVIG, in euthyroid women with sporadic or recurrent abortion, or in women undergoing in vitro fertilization (IVF). Level I-USPSTF

Recommendation 43

There is insufficient evidence to recommend for or against LT4 therapy in TAb+ euthyroid women during pregnancy. Level I-USPSTF

Recommendation 44

There is insufficient evidence to recommend for or against LT4 therapy in euthyroid TAb+ women undergoing assisted reproduction technologies. Level I-USPSTF

Recommendation 45

There is insufficient evidence to recommend for or against screening for anti-thyroid antibodies in the first trimester of pregnancy, or treating TAb+ euthyroid women with LT4, to prevent preterm delivery. Level I-USPSTF

Thyroid Nodules and Thyroid Cancer

Recommendation 46

The optimal diagnostic strategy for thyroid nodules detected during pregnancy is based on risk stratification. All women should have the following: a complete history and clinical examination, serum TSH testing, and ultrasound of the neck. Level A-USPSTF

Recommendation 47

The utility of measuring calcitonin in pregnant women with thyroid nodules is unknown. Level I-USPSTF

Recommendation 48

Thyroid or lymph node FNA confers no additional risks to a pregnancy. Level A-USPSTF

Recommendation 49

Thyroid nodules discovered during pregnancy that have suspicious ultrasound features, as delineated by the 2009 ATA guidelines, should be considered for FNA. In instances in which nodules are likely benign, FNA may be deferred until after delivery based on patients’ preference. Level I-USPSTF

Recommendation 50

The use of radioiodine imaging and/or uptake determination or therapeutic dosing is contraindicated during pregnancy. Inadvertent use of radioiodine prior to 12 weeks of gestation does not appear to damage the fetal thyroid. Level A-USPSTF

Recommendation 51

Because the prognosis of women with well-differentiated thyroid cancer identified but not treated during pregnancy is similar to that of nonpregnant patients, surgery may be generally deferred until postpartum. Level

B-USPSTF

Recommendation 52

The impact of pregnancy on women with medullary carcinoma is unknown. Surgery is recommended during pregnancy in the presence of a large primary tumor or extensive lymph node metastases. Level I-USPSTF

Recommendation 53

Surgery for thyroid carcinoma during the second trimester of pregnancy has not been demonstrated to be associated with increased maternal or fetal risk. Level B-USPSTF

Recommendation 54

Pregnant women with thyroid nodules that are read as benign on FNA cytology do not require surgery during pregnancy except in cases of rapid nodule growth and/or if severe compressive symptoms develop. Postpartum, nodules should be managed according to the 2009 ATA guidelines. Level B-USPSTF

Recommendation 55

When a decision has been made to defer surgery for well-differentiated thyroid carcinoma until after delivery, neck ultrasounds should be performed during each trimester to assess for rapid tumor growth, which may indicate the need for surgery. Level I-USPSTF

Recommendation 56

Surgery in women with well-differentiated thyroid carcinoma may be deferred until postpartum without adversely affecting the patient’s prognosis. However, if substantial growth of the well-differentiated thyroid carcinoma occurs or the emergence of lymph node metastases prior to midgestation occurs, then surgery is recommended. Level B-USPSTF

Recommendation 57

Thyroid hormone therapy may be considered in pregnant women who have deferred surgery for well-differentiated thyroid carcinoma until postpartum. The goal of LT4 therapy is a serum TSH level of 0.1–1.5 mIU/L. Level I-USPSTF

Recommendation 58

Pregnant patients with an FNA sample that is suspicious for thyroid cancer do not require surgery while pregnant except in cases of rapid nodular growth and/or the appearance of lymph node metastases. Thyroid hormone therapy is not recommended. Level I-USPSTF

Recommendation 59

The preconception TSH goal in women with DTC, which is determined by risk stratification, should be maintained during pregnancy. TSH should be monitored approximately every 4 weeks until 16–20 weeks of gestation and once between 26 and 32 weeks of gestation. Level B-USPSTF

Recommendation 60

There is no evidence that previous exposure to radioiodine affects the outcomes of subsequent pregnancies and offspring. Pregnancy should be deferred for 6 months following RAI treatment. LT4 dosing should be stabilized following RAI treatment before pregnancy is attempted. Level

B-USPSTF

Recommendation 61

Ultrasound and Tg monitoring during pregnancy in patients with a history of previously treated DTC is not required for low-risk patients with no Tg or structural evidence of disease prior to pregnancy. Level B-USPSTF

Recommendation 62

Ultrasound monitoring should be performed each trimester during pregnancy in patients with previously treated DTC and who have high levels of Tg or evidence of persistent structural disease prior to pregnancy. Level B-USPSTF

Postpartum Thyroiditis

Recommendation 63

Women with postpartum depression should have TSH, FT4, and TPOAb tests performed. Level B-USPSTF

Recommendation 64

During the thyrotoxic phase of PPT, symptomatic women may be treated with beta blockers. Propranolol at the lowest possible dose to alleviate symptoms is the treatment of choice. Therapy is typically required for a few months. Level B-USPSTF

Recommendation 65

ATDs are not recommended for the treatment of the thyrotoxic phase of PPT. Level D-USPSTF

Recommendation 66

Following the resolution of the thyrotoxic phase of PPT, TSH should be tested every 2 months (or if symptoms are present) until 1 year postpartum to screen for the hypothyroid phase. Level B-USPSTF

Recommendation 67

Women who are symptomatic with hypothyroidism in PPT should either have their TSH level retested in 4–8 weeks or be started on LT4 (if symptoms are severe, if conception is being attempted, or if the patient desires therapy). Women who are asymptomatic with hypothyroidism in PPT should have their TSH level retested in 4–8 weeks. Level B-USPSTF

Recommendation 68

Women who are hypothyroid with PPT and attempting pregnancy should be treated with LT4. Level A-USPSTF

Recommendation 69

If LT4 is initiated for PPT, future discontinuation of therapy should be attempted. Tapering of treatment can be begun 6–12 months after the initiation of treatment. Tapering of LT4 should be avoided when a woman is actively attempting pregnancy, is breastfeeding, or is pregnant. Level C-USPSTF

Recommendation 70

Women with a prior history of PPT should have an annual TSH test performed to evaluate for permanent hypothyroidism. Level A-USPSTF

Recommendation 71

Treatment of TAb+ euthyroid pregnant woman with either LT4 or iodine to prevent PPT is ineffective and is not recommended. Level D-USPSTF

Thyroid Function Screening in Pregnancy

Recommendation 72

There is insufficient evidence to recommend for or against universal TSH screening at the first trimester visit. Level I-USPSTF

Recommendation 73

Because no studies to date have demonstrated a benefit to treatment of isolated maternal hypothyroximenia, universal FT4 screening of pregnant women is not recommended. Level D-USPSTF

Recommendation 74

There is insufficient evidence to recommend for or against TSH testing preconception in women at high risk for hypothyroidism. Level I-USPSTF

Recommendation 75

All pregnant women should be verbally screened at the initial prenatal visit for any history of thyroid dysfunction and/or use of thyroid hormone (LT4) or anti-thyroid medications (MMI, carbimazole, or PTU). Level B-USPSTF

Recommendation 76

Serum TSH values should be obtained early in pregnancy in the following women at high risk for overt hypothyroidism:

History of thyroid dysfunction or prior thyroid surgery

Age > 30 years

Symptoms of thyroid dysfunction or the presence of goiter

TPOAb positivity

Type 1 diabetes or other autoimmune disorders

History of miscarriage or preterm delivery

History of head or neck radiation

Family history of thyroid dysfunction

Morbid obesity (BMI ³40 kg/m2)

Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast

Infertility

Residing in an area of known moderate to severe iodine sufficiency

Level B-USPSTF

*Dissent from one committee member: There is no consistent prospective evidence demonstrating that women who are TPOAb+, but who have SCH only, achieve maternal or perinatal benefit from LT4 treatment. Correspondingly, there is no indication to treat women who are TPOAb+ and have SCH with LT4.

†Dissent from one committee member: There is no good evidence that improved maternal or perinatal outcomes will be obtained if the criteria for thyroid function screening were different for a pregnant than a nonpregnant population. Correspondingly, criteria for screening pregnant women should not differ from the nonpregnant population.