Thyroid Function Tests in Pregnancy
Question 1: How do thyroid function tests change during pregnancy?
Question 2: What is the normal range for TSH in each trimester?
There is strong evidence in the literature that the reference range for TSH is lower throughout pregnancy; i.e., both the lower normal limit and the upper normal limit of serum TSH are decreased by about 0.1–0.2 mIU/L and 1.0 mIU/L, respectively, compared with the customary TSH reference interval of 0.4–4.0 mIU/L of nonpregnant women. The largest decrease in serum TSH is observed during the first trimester and is transient, apparently related to hCG levels, which are highest early in gestation (Table 2). The median TSH values in the three trimesters in Table 2 are quite consistent, except for the study by Marwaha et al. (18) which, for unexplained reasons, reports higher TSH values throughout pregnancy. Serum TSH and its reference range gradually rise in the second and third trimesters, but it is noteworthy that the TSH reference interval remains lower than in nonpregnant women (13,15). Since hCG concentrations are higher in multiple pregnancies than in singleton pregnancies, the downward shift in the TSH reference interval is greater in twin pregnancies than in singleton pregnancies (19). In a study of 63 women with hCG concentrations >200,000 IU/L, TSH was suppressed (≤0.2 mIU/L) in 67% of women, and in 100% of women if hCG concentrations were >400,000 IU/L (20).
In a small percentage of women, TSH can be very suppressed (<0.01 mIU/L) and yet still represent a normal pregnancy. There are slight but significant ethnic differences in serum TSH concentrations. Black and Asian women have TSH values that are on average 0.4 mIU/L lower than in white women; these differences persist during pregnancy (21,22). Pregnant women of Moroccan, Turkish, or Surinamese descent residing in The Netherlands, have TSH values 0.2–0.3 mIU/L lower than Dutch women throughout pregnancy (23). TSH ranges vary slightly depending on differences between methods of analysis (24). Subclinical hyperthyroidism is not associated with adverse pregnancy outcomes; therefore, a TSH value that is within detection is unlikely to be clinically significant (25).
Table 2. Sample Trimester-Specific Reference Intervals for Serum TSH
Haddow et al. (13)
Stricker et al. (14)
Panesar et al. (15)
Soldin et al. (16)
Bocos-Terraz et al. (17)
Marwaha et al. (18)
■ 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
Question 3: What is the optimal method to assess FT4 during pregnancy?
■ 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
Question 4: What are the definitions of OH and SCH in pregnancy?
Question 5: How is isolated hypothyroxinemia defined in pregnancy?
Question 6: What adverse outcomes are associated with OH in pregnancy?
Question 7: What adverse outcomes are associated with SCH in pregnancy?
Question 8: What adverse outcomes are associated with isolated hypothyroxinemia in pregnancy?
Question 9: Should OH be treated in pregnancy?
Question 10: Should isolated hypothyroxinemia be treated in pregnancy?
Isolated hypothyroxinemia should not be treated in pregnancy. Level C-USPSTF
Question 11: Should SCH be treated in pregnancy?
■ 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
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.
Question 12: When provided, what is the optimal treatment of OH or SCH?
■ 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-USPST
Question 13: When provided, what is the goal of OH or SCH treatment?
■ 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
Question 14: If pregnant women with SCH are not initially treated, how should they be monitored through gestation?
Question 15: How do treated hypothyroid women (receiving LT4) differ from other patients during pregnancy? What changes can be anticipated in such patients during gestation?
Question 16: What proportion of treated hypothyroid women (receiving LT4) require changes in their LT4 dose during pregnancy?
Question 17: In treated hypothyroid women (receiving LT4) who are planning pregnancy, how should the LT4 dose be adjusted?
■ 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
Question 18: In treated hypothyroid women (receiving LT4) who are newly pregnant, what factors influence thyroid status and LT4 requirements during gestation?
■ 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
Question 19: In hypothyroid women (receiving LT4) who are newly pregnant, how often should maternal thyroid function be monitored during gestation?
■ 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
Question 20: How should the LT4 dose be adjusted postpartum?
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
Question 21: What is the outcome and long-term prognosis when SCH and/or OH are effectively treated through gestation?
Question 22: Except for measurement of maternal thyroid function, should additional maternal or fetal testing occur in treated, hypothyroid women during pregnancy?
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
Question 23: In euthyroid women who are TAb+ prior to conception, what is the risk of hypothyroidism once they become pregnant?
In 1994, Glinoer et al. (60) performed a prospective study on 87 thyroid autoantibody positive (TAb+) euthyroid women evaluated before and during early pregnancy. Twenty percent of women in the study developed a TSH level of > 4 mIU/L during gestation despite normal TSH and no requirement for LT4 prenatally. This occurred despite the expected decrease in TAb titers during pregnancy. Twelve years later, in a prospective and randomized study, Negro et al. demonstrated similar results (28). The authors found that in TAb+ euthyroid women, TSH levels increased progressively as gestation progressed, from a mean of 1.7 mIU/L (12th week ) to 3.5 mIU/L (term), with 19% of women having a supranormal TSH value at delivery. These findings confirm that an increased requirement for thyroid hormone occurs during gestation. In women who are TAb+, both OH and SCH may occur during the stress of pregnancy as the ability of the thyroid to augment production is compromised and increasing demand outstrips supply. When this happens, an elevated TSH occurs. In summary, patients who are TAb+ have an increased propensity for hypothyroidism to occur later in gestation because some residual thyroid function may still remain and provide a buffer during the first trimester.
Question 24: How should TAb+ euthyroid women be monitored and treated during pregnancy?
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
Question 25: Should TAb+ euthyroid women be monitored or treated for complications other than the risk of hypothyroidism during pregnancy?
■ 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
Question 26: What are the causes of thyrotoxicosis in pregnancy?
Question 27: What is the appropriate initial evaluation of a suppressed serum TSH concentration during the first trimester of pregnancy?
Question 28: How can gestational hyperthyroidism be differentiated from Graves’ hyperthyroidism 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
Question 29: What is the appropriate management of gestational hyperthyroidism?
■ 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
Question 30: How should women with Graves’ disease be counseled before pregnancy?
■ RECOMMENDATION 27
Thyrotoxic women should be rendered euthyroid before attempting pregnancy. Level A-USPSTF
Question 31: What is the management of patients with Graves’ hyperthyroidism in pregnancy?
■ 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
The combination of LT4 and ATDs has not been shown to decrease the recurrence rate of Graves' disease postpartum, results in a larger dose of ATDs in order to maintain the FT4 within the target range, and may lead to fetal hypothyroidism (95). The only indication for the combination of ATDs and LT4 is in the treatment of fetal hyperthyroidism.
■ 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
Question 32: What tests should be performed in women treated with ATDs during pregnancy? What is the target value of FT4?
■ 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
Question 33: What are the indications and timing for thyroidectomy in the management of Graves’ disease during pregnancy?
■ RECOMMENDATION 31
Thyroidectomy in pregnancy is rarely indicated. If required, the optimal time for thyroidectomy is in the second trimester. Level A-USPSTF
Question 34: What is the value of TRAb measurement in the evaluation of a pregnant woman with Graves’ hyperthyroidism?
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
Question 35: Under what circumstances should additional fetal ultrasound monitoring for growth, heart rate, and goiter be performed in women with Graves’ hyperthyroidism in pregnancy?
■ 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
Question 36: When should umbilical blood sampling be considered in women with Graves’ disease in pregnancy?
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
Question 37: What are the etiologies of thyrotoxicosis in the postpartum period?
Question 38: How should the etiology of new thyrotoxicosis be determined in the postpartum period?
Question 39: How should Graves’ hyperthyroidism be treated in lactating women?
■ RECOMMENDATION 35
MMI in doses up to 20–30 mg/d is safe for lactating mothers and their infants. PTU at doses up to 300 mg/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
Question 40: Why is increased iodine intake required in pregnancy and lactation, and how is iodine intake assessed?
Because of increased thyroid hormone production, increased renal iodine excretion, and fetal iodine requirements, dietary iodine requirements are higher in pregnancy than they are for nonpregnant adults (125). Women with adequate iodine intake before and during pregnancy have adequate intrathyroidal iodine stores and have no difficulty adapting to the increased demand for thyroid hormone during gestation. In these women, total body iodine levels remain stable throughout pregnancy (126). However, in areas of even mild to moderate iodine deficiency, total body iodine stores, as reflected by urinary iodine values, decline gradually from the first to the third trimester of pregnancy (127). Iodine, required for infant nutrition, is secreted into breast milk. Therefore, lactating women also have increased dietary iodine requirements (128,129).
Spot urinary iodine values are used most frequently for determination of iodine status in general populations. A limitation of urinary iodine testing is that identifying particular individuals at risk for iodine deficiency is problematic because there is substantial diurnal and day-to-day variation in urinary iodine excretion (129).
Question 41: What is the impact of severe iodine deficiency on the mother, fetus, and child?
Question 42: What is the impact of mild to moderate iodine deficiency on the mother, fetus, and child?
Groups of pregnant women whose median urinary iodine concentrations are 50–150 μg/L are defined as mildly to moderately iodine deficient. Women with mild to moderate iodine deficiency during pregnancy are at increased risk for the development of goiter (130). In addition, decreased thyroid hormone associated with even mild to moderate iodine deficiency may have adverse effects on the cognitive function of the offspring (132–134). Mild to moderate maternal iodine deficiency has also been associated with attention deficit and hyperactivity disorders (137).
Question 43: What is the iodine status of pregnant and breastfeeding women in the United States?
Surveillance of urinary iodine values of the U.S. population has been carried out at intervals since 1971. Following a precipitous drop in urinary iodine values between 1971 and 1994, U.S. dietary iodine intake has stabilized (138–142). The U.S. population overall remains iodine sufficient. However, U.S. women of reproductive age are the most likely group to have low urinary iodine values.
According to the World Health Organization (WHO) guidelines, median urinary iodine values for pregnant women between 149 and 249 μg/L are consistent with optimal iodine intake (132). In the 2001–2006 National Health and Nutrition Examination Survey (NHANES) surveys, the median urinary iodine concentration among 326 pregnant women was marginal at 153 μg/L and 17% of pregnant women had urinary iodine concentrations < 50 μg/L (143). It is not clear whether these women were truly iodine deficient or whether their low values just represented random fluctuation. Current data regarding iodine sufficiency among lactating U.S. women are very limited. It is possible that a subset of pregnant and lactating U.S. women may have mildly to moderately inadequate dietary iodine intake resulting in insufficient amounts of iodine in the breast milk to meet infants’ dietary requirements (144,145).
Question 44: What is the iodine status of pregnant and breastfeeding women worldwide?
Since 1990, the number of households worldwide using iodized salt has risen from less than 20% to more than 70% (146). Despite these advances, however, iodine deficiency affects over 2.2 billion individuals globally, especially in South Asian, East Asia Pacific, and East and South African regions, and remains the leading cause of preventable intellectual deficits (134).
Question 45: Does iodine supplementation in pregnancy and lactation improve outcomes in severe iodine deficiency?
In areas of severe iodine deficiency, iodine supplementation of mothers prior to conception or in early pregnancy results in children with improved cognitive performance relative to those given a placebo (147–149). The prevalence of cretinisim and other severe neurological abnormalities is significantly reduced (150). Maternal iodine supplementation in severely iodine-deficient areas also decreases rates of stillbirth and neonatal and infant mortality (151,152).
Question 46: Does iodine supplementation in pregnancy and lactation improve outcomes in mildly to moderately iodine-deficient women?
Eight controlled trials of iodine supplementation in mildly to moderately iodine-deficient pregnant European women have been published (153–160), although doses and timing of iodine supplementation varied and only two trials examined effects on offspring development. Iodine supplementation of moderately deficient pregnant women appears to consistently decrease maternal and neonatal thyroid volumes and Tg levels. Effects on maternal thyroid function have been mixed, with significant maternal TSH decreases with supplementation described in four (149,151,152,154) of the eight published trials, and increases in maternal T4 or FT4 noted in just two (151,154).
In both studies where assessed, neurodevelopmental outcomes were improved in children from mildly to moderately iodine-deficient areas whose mothers received iodine supplementation early in pregnancy (148,154). The timing of supplementation is likely to be critical because the beneficial effects of iodine on offspring development appeared to be lost if supplementation is started after 10–20 weeks gestation.
No trials to date have specifically examined the effects of iodine supplementation in lactation.
Question 47: What is the recommended daily iodine intake in women planning pregnancy, women who are pregnant, and women who are breastfeeding?
Iodine is an essential nutrient required for thyroid hormone production and is primarily derived from the diet and from vitamin/mineral preparations. The Institute of Medicine recommended dietary allowances to be used as goals for individual total daily iodine intake (dietary and supplement) are 150 μg/d for women planning a pregnancy, 220 μg/d for pregnant women, and 290 μg/d for women who are breastfeeding (161). WHO recommends 250 μg/d for pregnant women and for lactating women (130).
Dietary iodine sources vary regionally. Sources of iodine in the U.S. diet have been difficult to identify, in part because there are a wide variety of potential sources and food iodine content is not listed on packaging. Iodized salt remains the mainstay of iodine deficiency disorder eradication efforts worldwide. However, salt iodization has never been mandated in the United States and only approximately 70% of salt sold for household use in the United States is iodized (162). In the U.S. dairy foods are another important source of dietary iodine due to the use of iodophor disinfectants by the dairy industry (163–165). Commercially baked breads have been another major source of iodine in the United States due to the use of iodate bread conditioners (165). However, the use of iodate bread conditioners has decreased over the past several decades. Other sources of iodine in the U.S. diet are seafood, eggs, meat, and poultry (166). Foods of marine origin have higher concentrations of iodine because marine animals concentrate iodine from seawater (155–157).
In the United States, the dietary iodine intake of individuals cannot be reliably ascertained either by patient history or by any laboratory measure. Due to concerns that a subset of pregnant U.S. women may be mildly to moderately iodine deficient and an inability to identify individual women who may be at risk, the ATA has previously recommended 150 μg daily as iodine supplementation for all North American women who are pregnant or breastfeeding (167). The goal is supplementation of, rather than replacement for, dietary iodine intake.
Recommendations regarding iodine supplementation in North America have not been widely adopted. In the NHANES 2001–2006 dataset, only 20% of pregnant women and 15% of lactating women reported ingesting iodine-containing supplements (168). Of the 223 types of prenatal multivitamins available in the United States, only 51% contain any iodine (169). Iodine in U.S. prenatal multivitamins is typically derived either from potassium iodide (KI) or from kelp. The iodine content in prenatal multivitamin brands containing kelp may be inconsistent due to variability in kelp iodine content (162).
Question 48: What is the safe upper limit for iodine consumption in pregnant and breastfeeding women?
Most people are tolerant of chronic excess dietary iodine intake due to a homeostatic mechanism known as the Wolff–Chaikoff effect (170,171). In response to a large iodine load, there is a transient inhibition of thyroid hormone synthesis. Following several days of continued exposure to high iodine levels, escape from the acute Wolff–Chaikoff effect is mediated by a decrease in the active transport of iodine into the thyroid gland, and thyroid hormone production resumes at normal levels (172).
Some individuals do not appropriately escape from the acute Wolff–Chaikoff effect, making them susceptible to hypothyroidism in the setting of high iodine intake. The fetus may be particularly susceptible, since the ability to escape from the acute Wolff–Chaikoff effect does not fully mature until about week 36 of gestation (173,174).
Tolerable upper intake levels for iodine have been established to determine the highest level of daily nutrient intake that is likely to be tolerated biologically and to pose no risk of adverse health effects for almost all individuals in the general population. The upper intake levels are based on total intake of a nutrient from food, water, and supplements and apply to chronic daily use. The U.S. Institute of Medicine has defined the tolerable upper limit for daily iodine intake as 1100 μg/d in all adults, including pregnant women (1.1mg/d) (155) and WHO has stated that daily iodine intake > 500 μg may be excessive in pregnancy, but these maximal values are based on limited data.
Medications may be a source of excessive iodine intake for some individuals. Amiodarone, an antiarrythmic agent (175), contains 75mg iodine per 200mg tablet. Iodinated intravenous radiographic contrast agents contain up to 380mg of iodine per milliliter. Some topical antiseptics contain iodine, although systemic absorption is generally not clinically significant in adults except in patients with severe burns (176). Iodine-containing anti-asthmatic medications and expectorants are occasionally used. In addition, some dietary supplements may contain large amounts of iodine.
Spontaneous Pregnancy Loss, Preterm Delivery, and Thyroid Antibodies
Question 49: Is there an association between thyroid antibody positivity and sporadic spontaneous abortion in euthyroid women?
Question 50: Should women be screened for TPO antibodies before or during pregnancy with the goal of treating TPOAb+ euthyroid women with LT4 to decrease the rate of spontaneous miscarriage?
Question 51: Is there an association between thyroid antibodies and recurrent spontaneous abortion in euthyroid women?
Question 52: Should women with recurrent abortion be screened for thyroid antibodies before or during pregnancy with the goal of treating TAb+ euthyroid women with LT4 or intravenous immunoglobulin therapy (IVIG) to decrease the rate of recurrent spontaneous abortion?
■ 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
Question 53: Should euthyroid women who are known to be positive for thyroid antibodies either before or during pregnancy be treated with LT4 in order to decrease the chance of sporadic or recurrent miscarriage?
■ RECOMMENDATION 43
There is insufficient evidence to recommend for or against LT4 therapy in TAb+ euthyroid women during pregnancy. Level I-USPSTF
Question 54: Is there an association between thyroid antibody positivity and pregnancy loss in euthyroid women undergoing IVF?
Several authors have reported an increased risk of pregnancy loss after assisted reproductive procedures in women who are positive for thyroid antibodies (202–204). Other authors have found no association (205,206). A meta-analysis of four trials of patients undergoing IVF found an increased risk of pregnancy loss with the presence of thyroid antibodies (RR 1.99, 95% CI 1.42–2.79) (207).
Question 55: Should women undergoing IVF be screened for TPO antibodies before or during pregnancy?
Negro et al. (208) performed a prospective placebo- controlled intervention trial of LT4 in TPOAb+ women undergoing assisted reproduction technologies. Though underpowered for its proposed endpoint, no difference in pregnancy loss was observed. Patients undergoing assisted reproductive procedures for infertility may have a number of reasons for infertility or subfertility, and this may explain the conflicting data.
■ RECOMMENDATION 44
There is insufficient evidence to recommend for or against LT4 therapy in euthyroid TAb+ women undergoing assisted reproduction technologies. Level I-USPSTF
Question 56: Is there an association between thyroid antibodies and preterm delivery in euthyroid women?
Preterm delivery, or birth prior to 37 weeks, affects 12.3% of pregnancies in the United States (209). It remains one of the most prevalent and morbid perinatal complications. It is the leading cause of neonatal death and the second leading cause of infant death (210). The cost of preterm delivery to the health care system is enormous (211). Preterm birth has remained difficult to predict, prevent, and treat primarily because there are multiple potential causes and pathways that end in premature labor (212). Examples include infection, trauma, cervical insufficiency, premature rupture of membranes, and maternal medical conditions.
Medical conditions such as hypertension and diabetes have been associated with a risk of preterm delivery, either due to the spontaneous onset of labor or from complications prompting medically indicated delivery. Patients with uncontrolled hyperthyroidism also have higher rates of preterm delivery, most commonly due to medical intervention (80,213). The most severe example of uncontrolled hyperthyroidism, thyroid storm, results in high rates of preterm labor and delivery (214).
The relationship of thyroid antibodies and preterm delivery has also been investigated. Glinoer et al. (183) reported in a prospective cohort that women who were positive for either TPOAb or TgAb had a significantly increased prevalence of preterm birth (16% vs. 8%, p< 0.005). Ghafoor et al. (215) evaluated 1500 euthyroid women and found an increase in preterm delivery in TPOAb+ women as compared with women who were TPOAb– (26.8% vs. 8.0%, p< 0.01). In contrast, Iijima et al. (182) did not find an increased risk for preterm birth in women positive for seven different auto- antibodies and thyroid antibodies. This study had an unusually low rate of preterm birth in both study and control groups (3% vs. 3.1 %). Interestingly, Haddow et al. (216) reported a significant increase in preterm premature rupture of the membranes in TAb+ women but not in preterm birth among women who were positive for TPOAb and TgAb in the first trimester. Their data revealed a positive association between very preterm delivery (< 32 weeks) and thyroid antibody positivity (OR 1.73, 95% CI 1.00–2.97). However, the adjusted odds ratio for very preterm delivery and thyroid antibody positivity failed to reach statistical significance (adjusted OR 1.70, 95% CI 0.98–2.94).
Question 57: Should women be screened for thyroid antibodies before or during pregnancy with the goal of treating TAb+ euthyroid women with LT4 to decrease the rate of preterm delivery?
Negro et al. (28) reported an increased risk of preterm delivery among euthyroid TPOAb+ women compared with euthyroid TPOAb– women in the only published prospective interventional trial to date (22.4% vs. 8.2%, p< .01). The TPOAb+ subjects were then randomized to either treatment with LT4 or no treatment, with the dose based on TSH level. The treated group had a significantly lower rate of preterm delivery than did the untreated group (7% vs. 22.4%, p< .05).
■ RECOMMENDATION 45
There is insufficient evidence to recommend for or against screening for 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
Question 58: What is the frequency of thyroid nodules during pregnancy?
Question 59: What is the frequency of thyroid cancer in women with thyroid nodules discovered during pregnancy?
Question 60: What is the optimal diagnostic strategy for thyroid nodules detected during pregnancy?
■ 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
As with the general population, the routine measurement of calcitonin remains controversial (232). Calcitonin measurement should be performed in pregnant women with a family history of medullary thyroid carcinoma or MEN 2. However, the utility of measuring calcitonin in all pregnant women with thyroid nodules has not been evaluated in the literature. The pentagastrin stimulation test is contraindicated in pregnancy (233)
.■ RECOMMENDATION 47
The utility of measuring calcitonin in pregnant women with thyroid nodules is unknown. Level I-USPSTF
Fine-needle aspiration FNA is a safe diagnostic tool in pregnancy and may be performed in any trimester (229,234–242). Two retrospective case series of FNAs performed during pregnancy, involving a total of 94 patients, have been published. In the cases in which surgery was performed, pathological examination of the specimens confirmed the diagnosis of all FNAs classified by cytology as either benign or malignant. Six of the 16 (37.5%) cases reported by cytology as suspicious for malignancy were found to be malignant at pathological examination (219,220). Pregnancy does not appear to increase the difficulty of making a cytological diagnosis of thyroid tissue obtained by FNA. There have been no prospective studies which have evaluated the reliability of FNA in pregnancy.
■ 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
The use of radionuclide scanning is contraindicated during pregnancy (243–245). Inadvertent scanning performed prior to 12 weeks gestation does not appear to damage the fetal thyroid
.■ 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
Question 61: Does pregnancy impact the prognosis of thyroid carcinoma?
■ 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
Question 62: What are the perioperative risks to mother and fetus of surgery for thyroid cancer during pregnancy?
■ 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
Question 63: How should benign thyroid nodules be managed during pregnancy?
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
Question 64: How should DTC be managed during pregnancy?
■ 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
Question 65: How should suspicious thyroid nodules be managed during pregnancy?
■ 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
Question 66: What are the TSH goals during pregnancy for women with previously treated thyroid cancer and who are on LT4 therapy?
■ 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
Question 67: What is the effect of RAI treatment for DTC on subsequent pregnancies?
■ 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
Question 68: Does pregnancy increase the risk of DTC recurrence?
Question 69: What type of monitoring should be performed during pregnancy in a patient who has already been treated for DTC prior to pregnancy?
■ 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
Question 70: What is the definition of PPT and what are its clinical implications?
Question 71: What is the etiology of PPT?
Question 72: Are there predictors of PPT?
Question 73: What is the prevalence of PPT?
Question 74: What symptoms are associated with PPT?
Question 75: Is PPT associated with depression?
■ RECOMMENDATION 63
Women with postpartum depression should have TSH, FT4, and TPOAb tests performed. Level B-USPSTF
Question 76: What is the treatment for the thyrotoxic phase of PPT?
■ 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
Question 77: Once the thyrotoxic phase of PPT resolves, how often should TSH be measured to screen for the hypothyroid phase?
■ 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
Question 78: What is the treatment for the hypothyroid phase of PPT?
■ 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
Question 79: How long should LT4 be continued in women with PPT?
■ 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
Question 80: How often should screening be performed after the hypothyroid phase of PPT resolves?
■ RECOMMENDATION 70
Women with a prior history of PPT should have an annual TSH test performed to evaluate for permanent hypothyroidism. Level A-USPSTF
Figure 2 presents an algorithm for the treatment and monitoring of PPT.
Question 81: Does treatment of TAb+ euthyroid women with LT4 or iodine during pregnancy prevent PPT?
■ 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
Question 82: Does treatment of TAb+ euthyroid women with selenium during pregnancy prevent PPT?
Thyroid Function Screening in Pregnancy
Question 83: Should all pregnant women be screened for serum TSH level in the first trimester of 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
Question 84: Should serum TSH testing be carried out in a targeted population of pregnant women?
- Women with a history of thyroid dysfunction and/or thyroid surgery. The prevalence of hypothyroidism following thyroid lobectomy has been reported as high as 33% (307).
- Women with a family history of thyroid disease.
- Women with a goiter.
- Women with thyroid antibodies. Based on NHANES data, the odds ratio for OH is approximately 40 in individuals with TPOAb compared with women who are TPOAb– (308).
- Women with symptoms or clinical signs suggestive of hypothyroidism. It is important to note that women with OH are not invariably symptomatic. In a case–control study, although OH patients were more likely than euthyroid controls to report hypothyroid symptoms, only 30% of patients were symptomatic and 17% of the controls complained of hypothyroid symptoms (309).
- Women with type I diabetes, in whom the rate of development of new onset hypothyroidism in pregnancy was 16% in one series (310).
- Women with a history of either miscarriage or preterm delivery.
- Women with other autoimmune disorders that are frequently associated with autoimmune thyroid dysfunction, including vitiligo, adrenal insufficiency, hypoparathyroidism, atrophic gastritis, pernicious anemia, systemic sclerosis, systemic lupus erythematosus, and Sjögren’s syndrome (311).
- Women with infertility should have screening with TSH as part of their infertility work-up. In one study 2% of women presenting for infertility treatment were found to have hyperthyroidism (312). The prevalence of hypothyroidism (overt and subclinical) among infertile women ranged from 1% to 43% in different studies (69).
- Women with prior therapeutic head or neck irradiation. The 8-year prevalence of hypothyroidism has been calculated to be up to 67% following external radiation to the head and neck (313).
- Women with morbid obesity. A body mass index ³ 40 kg/m2 has been associated with an increased prevalence of hypothyroidism: in two recent studies cohorts of morbidly obese women had an overall prevalence of SCH and OH of 13.7% (314) and 19.5% (315), respectively.
- Women age 30 or older. The prevalence of hypothyroidism increases with age. The prevalence of an elevated serum TSH (> 5 mIU/L) increases from about 4% in women age 18–24 years to almost 7% in women aged 35–44 years (308,316).
- Women treated with amiodarone. The prevalence of thyroid dysfunction in individuals taking amiodarone varies depending whether regions are iodine deficient of sufficient, but overall 14%–18% of patients taking amiodarone will develop overt hyperthyroidism or overt hypothyroidism (317).
- Women treated with lithium. Recent estimates of the prevalence of hypothyroidism in patients using lithium have been variable, ranging between 6% and 52% (318).
- Women with a recent (in the past 6 weeks) exposure to iodinated radiological contrast agents. The prevalence of iodine-induced thyroid dysfunction may be as high as 20%, depending on the dietary iodine status of the exposed individuals (319).
■ 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
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 ≥40 kg/m2)
Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast
Residing in an area of known moderate to severe iodine insufficiency
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.
Figure 3 is an algorithm for the interpretation and management of the results of first trimester screening.
FIG. 3. An algorithm for the interpretation and management of the results of first trimester screening. TFT, thyroid function tests