American Thyroid Association 2026 Guidelines for Thyroid Disease in Preconception,Pregnancy,and Postpartum

Thyroid physiology before, during, and after pregnancy

Thyroid parameters are not meaningfully impacted during a normal menstrual cycle. During ovarian stimulation for fertility treatment, the increase in estrogens causes an increase in type 3 deiodinase activity and thyroxine (T4)-binding globulin (TBG) concentrations which necessitates increased thyroid hormone production and causes a slight rise in thyrotropin (TSH) concentrations (Fig. 1A).^8–11 Pregnancy itself is also associated with changes in thyroid physiology that make the interpretation of thyroid function tests different in pregnant compared with nonpregnant individuals (Fig. 1B). For example, TBG increases from week 7 of gestation to reach a peak by approximately week 16 and stabilizes thereafter, ¹² and logically, total thyroid hormone concentrations (T4 and triiodothyronine [T3]) follow this same pattern. As pregnancy progresses, there is an increase in the transfer of maternal T4 to the fetal compartment, an increase in T4 degradation by type 3 deiodinase expressed in the placenta, and an increase in renal iodine excretion. Furthermore, through its affinity for the TSH receptor, human chorionic gonadotropin (hCG) stimulates thyroid hormone production with peak stimulatory effects around the end of the first trimester. ¹⁰ The healthy thyroid system adapts to these alterations through changes in thyroid hormone production, iodine uptake, and regulation of the hypothalamic–pituitary–thyroid axis.^8–10 The net effect of all physiological changes is a slight transient increase in fT4 and a decrease in TSH that is most pronounced at the end of the first trimester. Thus, in normal physiology, a TSH below 0.4 mU/L occurs frequently.^13,14 Furthermore, the immune tolerance of pregnancy, necessary to tolerate the allogeneic fetus, is associated with a decrease in thyroid antibody concentrations as gestation progresses. This explains why Graves’ disease can become quiescent during pregnancy and why thyroperoxidase antibody (TPOAb) positivity is less common in the third trimester than preconception. ¹⁵ Nevertheless, from 28 weeks onward, there is a considerable increase in active transplacental IgG transport, and cord blood concentrations can ultimately increase to those of the mother.^16–18 The subsequent immune system rebound that occurs postpartum is a precipitating factor for postpartum thyroiditis (PPT) and de novo or relapsed Graves’ disease. ¹⁵

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FIG. 1.

(A) Thyroid physiology during ovarian stimulation. Physiological alterations of serum TSH, fT4, and TBG concentrations are expected from the rise of estrogen during ovarian stimulation. Thyroxine requirements are extracted from studies of women with hypothyroidism taking fixed levothyroxine doses. (B) Thyroid physiology during pregnancy. Physiological alterations of serum TSH, TT3, TT4, fT4, and thyroid antibody concentrations are expected from the effects of hCG, estrogen, and other factors during pregnancy. TT3, total triiodothyronine; TT4, total thyroxine; TBG, thyroxine-binding globulin; hCG, human chorionic gonadotropin; TSH, thyrotropin; fT4, free thyroxine; TBG, thyroxine-binding globulin.

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FIG. 2.

Transplacental passage of thyroid parameters and drugs. Maternal TSHR-Ab, iodine, radioactive iodine, the antithyroid drugs (propylthiouracil and methimazole), propanolol, and the thyroid hormones [(lio)thyronine and (levo)thyroxine] all traverse the placenta and have the potential to induce direct effects to the fetus. Maternal TPOAb and TgAb can also traverse the placenta but do not affect the fetus. Maternal TSH does not cross the placenta. TPOAb, thyroperoxidase antibody; TgAb, thyroglobulin antibody; TSHR-Ab, thyrotropin receptor antibody.

In specific subgroups, physiological processes may have a different effect on clinical parameters. For example, in women with hypothyroidism using levothyroxine (LT4) and who are undergoing ovarian stimulation, the increase in TBG caused by high estrogen concentrations can cause a clinically relevant increase in TSH (mean: +1.50 mU/L) that persists into pregnancy and may necessitate an earlier or larger LT4 dose increase as compared with women with hypothyroidism who conceive naturally. ¹⁹ Another example is twin pregnancies, in which there is a higher hCG concentration as compared with singleton pregnancies, causing a greater stimulation of thyroid hormone production, resulting in lower TSH and higher fT4 concentrations.^20,21 Yet, for a twin pregnancy in a hypothyroid woman using LT4 (in which no or very little thyroidal response to hCG stimulation can be anticipated), LT4 consumptive factors have a larger impact on thyroid physiology (i.e., larger volume expansion, larger fetal T4 transfer, higher type 3 deiodinase activity due to higher estradiol and a larger placenta) which could necessitate a larger LT4 dose increase as compared with a singleton pregnancy. A final example is TPOAb-positive women, who are known to have a slightly higher mean TSH and a higher risk of overt hypothyroidism, partly because of an impaired thyroidal response to hCG stimulation during early pregnancy.^22–25

Knowledge regarding placental transfer of thyroidal factors is key to understanding normal physiology and pathophysiology, as well as the risks and benefits of various treatment modalities. As shown in Figure 2, thyroid hormones, thyroid antibodies, iodine, and antithyroid drugs (ATDs) all traverse the placental barrier.

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FIG. 3.

Iodine availability during pregnancy. Examples of supplements and foods with high and low iodine content are shown. Iodine is taken up by the NIS at the basolateral membrane of the thyroid follicular cell in both the mother and fetus, as needed for thyroid hormone production, for which requirements are higher during pregnancy. NIS, sodium/iodide symporter.

Analytical considerations

Pregnancy-specific physiology can also affect thyroid function assay performance, a basic understanding of which is beneficial to health care practitioners. In addition to the aforementioned physiological changes, other changes, such as an increase in free fatty acids and a decrease in albumin concentrations,^26–28 may influence the performance of fT4 immunoassays. It is known that these could result in falsely lower serum fT4 concentrations in a method-specific manner, especially during the second half of pregnancy.^13,29–31 Recent data have renewed the favorability of the use of fT4 measurements analyzed via analog immunological methods early in pregnancy as compared with alternative options. Most notably, fT4 measured via analog methodology better correlates with TSH in the first trimester than total T4, ³² and fT4 has also been associated with maternal and child outcomes, a finding which has not been demonstrated for other test methodologies.^32–35 These findings suggest fT4 analog measurement is an appropriate marker of thyroid function in the first half of pregnancy. ³⁶ The use of a laboratory and trimester-specific fT4 reference interval would likely eliminate any pregnancy-specific analytical changes ³⁷ and is thus the preferred method for fT4 interpretation during pregnancy. However, such reference intervals cannot be effectively transferred amongst differing manufacturers or testing platforms and may not be widely available.

When pregnancy and trimester-specific reference intervals for fT4 are unavailable, alternative strategies for interpreting or assessing thyroid hormone availability during pregnancy can be considered, taking into account the advantages and disadvantages of each strategy. One option would be to use nonpregnancy reference intervals for fT4, taking into account that this will likely lead to small differences in diagnosis, including more diagnoses of overt hypothyroidism and isolated hypothyroxinemia, especially after the first trimester. ³⁸ Another option is to use direct methods for measurement of fT4, such as equilibrium dialysis or ultrafiltration combined with liquid chromatography/tandem mass spectrometry. However, direct methods are not free from technical problems and are significantly more laborious, time-consuming, expensive, and less widely available. Comparisons of direct methods with commonly used immunoassays have yielded heterogeneous results.^30,37,39,40 Another option is to use the fT4 index, which is defined as the total T4 adjusted for protein binding using the thyroid hormone binding ratio. ⁴¹ This formula assesses whether the amount of total T4 present in serum can be accounted for by the amount of binding protein present. The fT4 index has limited availability, and gestational reference intervals are typically not established. Furthermore, the calculations may be insensitive to the dynamic changes of gestational thyroid function. ⁴¹ Another option that could be considered is to use the total T4, adjusting for the increase expected by the TBG rise. Considering the changes of serum total T4 through pregnancy, the reference interval for total T4 can be adjusted by increasing the nonpregnant reference limits by 5% per week, beginning with week 7, and plateauing at a 50% increase from week 16 of pregnancy onward. ¹²

Importantly, maternal TSH remains the best marker of maternal thyroid status during pregnancy. TSH measurement by third generation immunoassays is not affected by the pregnancy-associated binding protein changes. However, different immunoassays may give different TSH results as is well-established in nonpregnant populations. ⁴² Therefore, when there is concern over the correct interpretation of fT4 concentrations, the TSH result should be prioritized during evaluation. The general principle that the intraindividual thyroid function test variation is smaller than that between individuals also applies in pregnancy.^43,44 Therefore, it is optimal to use the same TSH and/or fT4 assay, or an alternative described above, for follow-up over the course of pregnancy.

Except for the characterization of hyperthyroidism, the relevance of measuring serum free or total T3 in pregnancy is generally low, as there is no clear association between these biochemical markers and adverse pregnancy or child outcomes other than gestational diabetes mellitus.^45–47 In addition, maternal free or total T3 concentrations may not reflect T3 status in the fetal brain. ⁴⁸ When T3 estimates are needed, it is reasonable to apply the same considerations as described above for free and total T4 estimates for interpretation. Considerations for free and total T3 measurements in hyperthyroidism during pregnancy are discussed in Box 5.

Definition of (ab)normal thyroid function tests

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For women planning pregnancy or those who are postpartum, thyroid dysfunction is defined according to local reference intervals for TSH and fT4 used for the general population. During pregnancy, physiological and analytical alterations can be accounted for through the use of laboratory and trimester-specific TSH and fT4 reference intervals. Recommendations on the definition of an abnormal TSH and fT4 in pregnancy (Box 1) should be used to guide clinical practice and cannot replace clinical evaluation, risk assessment, and patient involvement through shared decision-making. Gestational TSH and (f)T4 measurements should be interpreted with the understanding of the limitations inherent to each reference interval. There remain considerable intra-assay and intralaboratory differences in TSH and, especially, fT4 measurements, despite (local) standardization efforts. ⁴⁹ Laboratory and trimester-specific reference intervals are a statistical estimation of normal variation within a population. These do not incorporate the risk of adverse outcomes but remain the preferred method until risk-based intervals become available. The committee acknowledges, however, the fact that trimester- and laboratory-specific reference intervals are currently unavailable in the majority of hospitals worldwide. In such cases, clinicians can be guided by the knowledge of the physiological changes that occur in healthy pregnant women with a decrease in TSH, especially in the first trimester. The 2017 ATA guidelines, after reviewing the significant geographic and ethnic diversity of TSH concentrations in pregnancy, recommended the following TSH cutoffs in the absence of laboratory and trimester-specific TSH reference intervals: reduction of the lower reference range by 0.4 mU/L and the upper reference range by 0.5 mU/L in the first trimester, followed by a gradual return to the nonpregnant range in the subsequent trimesters. Based on expert opinion and an extrapolation of average values from reference interval studies, this committee agrees that this is acceptable and would correspond, for the typical patient, to a first-trimester reference interval of 0.1–4.0 mU/L.^38,50 An upper limit of 4.0 mU/L is about 0.5 mU/L lower than the nonpregnancy upper TSH limit for most assays. It would be reasonable for centers where the nonpregnancy upper limit is well above 4.5 mU/L to deduct 0.5 mU/L from the upper TSH limit instead.^38,50 Owing to the large interassay differences in absolute fT4 concentrations, recommendations for absolute fT4 reference intervals are not feasible, but considerations for different alternatives are discussed above.

The abovementioned alternative strategies (e.g., a fixed TSH upper limit of 4.0 mU/L or deducting 0.5 mU/L from the nonpregnancy upper limit) were proposed with the aim to approximate laboratory- and trimester-specific TSH reference intervals in pregnancy. ¹ However, recent studies have shown that these alternatives tend to misclassify a substantial number of patients. For example, for overt hypothyroidism in the first trimester, use of a fixed TSH upper limit of 4.0 mU/L would identify 46.1% of all women with overt hypothyroidism but identify the remainder as either euthyroid (11.9%), subclinically hypothyroid (36.8%), or with isolated hypothyroxinemia (5.2%), as compared with a laboratory with trimester-specific reference intervals. ³⁸ However, it is still uncertain if this misclassification will cause clinical harm. These numbers are similar when the subtraction approach is used (46.1%, 13.5%, 35.2% and 5.2%, respectively). ³⁸ Furthermore, recent data on the natural course of thyroid function test abnormalities during pregnancy suggest that mild cases (slightly increased TSH) of overt and subclinical hypothyroidism may be transient in approximately half of all cases.^51,52 This may suggest that future disease definitions and/or treatment indications could be improved by accounting for the persistent of disease upon remeasurement.

Thyroid function testing indications

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Thyroid function tests are some of the most frequently ordered laboratory tests. In women without known thyroid disease, infertility, or recurrent miscarriage, the indications for thyroid function testing for those planning pregnancy or those who are postpartum are similar as for the general population. During pregnancy, defining a thyroid function testing indication is complicated by the concept that thyroid disease symptoms overlap with those related to a normal pregnancy and also because mild forms of thyroid disease can present without symptoms. Because thyroid hormone demands are increased in pregnancy, risk factors for maternal thyroid dysfunction can be specific to gestation. Furthermore, the risk of thyroid disease according to general (nonpregnancy) risk factors may be larger during pregnancy as compared with a nonpregnant state. Therefore, we recommend that risk factors for thyroid disease during pregnancy (Table 1) are used to determine the indication for thyroid function testing during pregnancy.

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Table 1.

Risk Factors for Thyroid Dysfunction During Pregnancy

Various studies have shown that risk factors recommended in the previous version of these guidelines would lead to screening of 55–78% of all pregnant women, while detection rates varied between 75% and 85% for overt hypothyroidism and between 54% and 60% for subclinical hypothyroidism.^53–56 In an effort to optimize these numbers, we commissioned two studies to validate previous risk factors ⁵⁷ and to identify new risk factors for thyroid function test abnormalities and TPOAb positivity. ⁵⁸ For the risk factors we recommend, the selection of some was supported by good volume and high-quality data (thyroid antibody positivity), while the selection of other risk factors was based on reasonable extrapolation of data from nonpregnant populations (e.g., medication use, Down/Turner syndrome, prior radiation/thyroid surgery, history of autoimmune disease, iodine deficiency, family history of autoimmune thyroid disease) or expert opinion (remainder). For women with a history of infertility or recurrent miscarriages, we recommend thyroid function testing if this has not already been performed preconception, unless there are other risk factors present, recognizing that women with such history are frequently tested before conceiving. Three specific risk factors were considered but not added as a thyroid function testing indication. A past medical history of a single miscarriage is common and often attributable to nonthyroidal risk factors, and current data are insufficient to consider it as a risk factor for thyroid disease during pregnancy. While BMI and age were recognized as risk factors for thyroid disease during pregnancy (for overt hypothyroidism/isolated hypothyroxinemia and subclinical hypothyroidism, respectively), the absolute risk differences were small and identification of an objective dichotomous cutoff for these variables remains difficult. ⁵⁷

It is important to note that the risk factors that are considered an indication for thyroid function testing during pregnancy are not exhaustive. Furthermore, the use of this set of risk factors will not enable the identification of all women with thyroid dysfunction, specifically overt hypothyroidism. Therefore, these risk factors should be used to supplement general clinical reasoning. Similar to the US Preventive Services Task Force recommendations for the general population, ⁵⁹ there is insufficient evidence to recommend routine thyroid function testing (universal screening) in women planning pregnancy, in pregnant women, or in women during the postpartum period. Detailed overviews of the pros and cons of routine thyroid function testing are described elsewhere.^60,61

Epidemiology and physiology

In 2023, there were 18 countries with insufficient dietary iodine intake out of 127 countries worldwide with available nationally representative data, corresponding to approximately one-third of the world’s population^64,65; the most current global iodine status data are available from the Iodine Global Network. ⁶⁵ In the United States, data from the National Health and Nutrition Examination surveys show that a substantial portion of pregnant women are iodine insufficient, with median UICs as a population biomarker for iodine status declining since the early 2000s.^66–69 There is strong evidence that severe maternal iodine deficiency in pregnancy and its effect on thyroid status are associated with adverse obstetrical outcomes, as well as increased risks of maternal and neonatal hypothyroidism, perinatal and infant mortality, low child intelligence quotient (IQ), and child neurocognitive impairment.^70–74 Data on the adverse effects of mild-to-moderate iodine deficiency in pregnant women are less clear. Mild-to-moderate iodine deficiency has not been associated with adverse obstetric outcomes.^73,75,76 Observational data show associations between mild/moderate iodine deficiency and impaired fetal brain development.^77,78 Children of pregnant women with mild-to-moderate iodine deficiency before 14 weeks’ gestation had lower IQ scores in a dose-dependent manner. ⁷⁹ Adequately powered randomized controlled trials examining child neurodevelopment have not been performed in mild-to-moderate iodine-deficient pregnant women,^80,81 but it is biologically plausible that neurodevelopmental effects observed in milder forms of iodine deficiency can be extrapolated from the literature on severe iodine deficiency. However, in small randomized controlled trials, use of iodine supplementation for women with mild-to-moderate iodine deficiency has not resulted in clinically relevant alterations in maternal and neonatal thyroid function.^80–85 The sodium/iodide symporter (NIS) plays a crucial role in mediating iodide uptake required not only for thyroid hormone synthesis in both the maternal and fetal thyroid gland but also for the placental transfer of iodide. As such, some of the nutritional effects associated with maternal iodine deficiency could also result in fetal iodine deficiency (Fig. 3).

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FIG. 4.

Thyroid hormone and iodine content in breastmilk. Although the World Health Organization suggests a median UIC threshold of >100 mcg/L to indicate adequate iodine nutrition in lactating women, UIC alone may not fully reflect the iodine status of this group, as UIC tends to be lower in lactating women compared with nonlactating women, since iodine is excreted both in urine and breast milk. NIS and Pendrin are expressed in lactating mammary cells and facilitate the uptake of iodine from maternal circulation into breastmilk. Iodide transport across the apical epithelial membrane also occurs through transporters that include ANO1 and CFTR. Limited data suggest that iodine occurs in various forms in breastmilk, mostly iodide (∼77%) and other organic materials like iodinated milk proteins (∼11%). It also occurs in thyroid hormones, predominantly T1 (∼7–25%) but very little T4 or T3 (∼1%; no data on T2). ³⁵⁴ The maximum methimazole/carbimazole content of breast milk is 0.1–0.2% of the maternal dose, and for PTU, this is <0.1%.^342,343 AP, apical; ANO1, anoctamin-1; BL, basolateral; CFTR, cystic fibrosis transmembrane conductance regulator; PTU, propylthiouracil; T3, triiodothyronine; T4, thyroxine; UIC, urinary iodine concentration.

Clinical presentation and evaluation

The clinical presentation of iodine deficiency would be reflected as hypothyroidism and its sequelae. It is important to note that there are no validated biomarkers to assess chronic iodine intake on the individual level. Instead, iodine status is measured across populations and is usually assessed by median spot or 24-hour UICs; median UIC values between 100 and 199 mcg/L indicate population iodine sufficiency among nonlactating, nonpregnant women, while median UICs between 150 and 249 mcg/L indicate optimal iodine nutrition in pregnant populations.

Other available measures for assessing population iodine status include serum or whole-blood thyroglobulin concentrations and neonatal TSH concentrations. ⁸⁶ Serum or whole-blood thyroglobulin values have been proposed for assessing iodine status of populations of pregnant women, ⁸⁷ but there is currently no consensus on their threshold values, and poor harmonization between assays further limit their utility.^86,88 Neonatal TSH concentrations may be available in regions where these measurements are used to screen for congenital hypothyroidism and may be higher in iodine-deficient regions. The prevalence of neonatal TSH concentrations greater than 5.0 mU/L should be <3% in iodine-sufficient regions. ⁸⁹ However, the timing of assessing neonatal TSH relative to the neonatal TSH surge, as well as the use of iodophor cleansers at the time of delivery, may limit the utility of neonatal TSH as a marker for population iodine nutrition. Finally, there is a substantial degree of intraindividual variation in the ability of the thyroid gland to adapt to insufficient iodine availability, even in those living in severely iodine-deficient regions. Therefore, serum thyroid function tests are not considered sensitive indicators of population iodine status in most groups, including pregnant and postpartum women. ⁹⁰

Although the World Health Organization suggests a median UIC threshold of >100 mcg/L to indicate adequate iodine nutrition in lactating women, UIC alone may not fully reflect the iodine status of this group, as UIC tends to be lower in lactating women compared with nonlactating women, since iodine is excreted both in urine and breast milk (Fig. 4). ⁹¹ Thus, spot breast milk iodine concentrations have also been considered as a biomarker of iodine status in lactation. Breast milk iodine content (BMIC) reflects recent iodine intake, but there is intraindividual variability. Cross-sectional studies have suggested that a median BMIC range of 100–200 mcg/L is considered adequate in lactating women ⁹² ; however, no formal minimal threshold has been established. As such, the optimal metric for assessing the iodine status in populations of lactating women is currently unclear. ⁹²

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FIG. 5.

Strategy for ATD discontinuation upon pregnancy confirmation. Factors important for considering when maternal ATD may be successfully discontinued in pregnancy include the duration and dose of ATD use, maternal TSH concentration, signs of Graves’ disease burden (i.e., thyroid eye disease, goiter), and the maternal TRAb and/or TSI concentration. The 1-year risk of Graves’ disease relapse typically ranges between 30% and 70% following ATD discontinuation based on these risk factors.

Treatment and management

Pregnant and lactating women are recommended to receive a total of 250 mcg iodine daily as provided by iodine supplements and/or dietary iodine intake. ⁹¹ Ensuring adequate iodine status as a public health measure is best achieved when iodine supplementation is advised for women in general during these life stages, not just those residing in at-risk areas. However, strategies for optimal iodine intake vary by geographic region. Iodine supplementation of 150 mcg/day should be advised in all women preconception, in pregnancy, and lactation (unless there is high iodine intake evident due to traditional dietary habits) and ideally beginning at least 3 months before conception. Women may need higher amounts of supplementation if at increased risk for iodine deficiency based on information about population iodine status in the region or dietary patterns in the woman (Fig. 3; e.g., not using iodized salt, not ingesting dairy foods, following a vegan diet). ⁹³ The supplemental iodine doses reported in the literature to assess their effects on obstetric and offspring outcomes have ranged from 50 to 300 mcg/day, in line with the range of region-specific background dietary iodine intakes of the various populations studied.^72,80,81 In low-resource countries and regions where neither salt iodization nor daily iodine supplements are feasible, the most vulnerable populations for iodine deficiency can be protected by providing an annual dose of 400 mg iodized oil to pregnant women and women of childbearing age.^91,94 It should be noted that this should not be used as a long-term strategy or in regions where other options for adequate iodine nutrition are available.

Finally, excess iodine exposure during pregnancy should also be avoided, except in preparation for the surgical treatment of Graves’ disease (when saturated solution of potassium iodide may be used) and when potassium iodide is used as an alternative treatment for Graves’ disease during pregnancy (in which potassium iodide of up to 50 mg/day has been described).^95,96 Clinicians should carefully weigh the risks and benefits when ordering medications or diagnostic tests that will result in high iodine exposure (e.g., amiodarone or iodinated contrast media) during pregnancy. Amiodarone is currently classified by the US Food and Drug Administration to pose possible human fetal risk, although it is recognized that its potential benefits may warrant use of the drug in pregnant women. In particular, sustained excessive dietary iodine intake and dietary supplements use exceeding 500 mcg daily should be avoided during pregnancy, due to concerns for fetal and maternal thyroid dysfunction. ⁹⁷

Thyroid function testing and monitoring in infertility

It is important to emphasize that the definition of thyroid dysfunction in women with infertility or those undergoing fertility treatment is the same as that of the general population and thus should be defined according to local reference intervals that are used for the general population. There are two main arguments that support thyroid function testing in women with infertility or history of recurrent miscarriage. First, overt and subclinical hypothyroidism are part of their differential diagnosis (for infertility mainly, in a woman presenting with irregular menses). Second, it has been proposed that overt and subclinical hypothyroidism could be an indication for LT4 treatment in this specific subgroup, as fertility outcomes may be improved and progression from subclinical to overt hypothyroidism can be avoided.

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There is value in determining TPOAb status in women with infertility or history of recurrent miscarriage. Approximately 7–9% of euthyroid TPOAb-positive women develop overt or subclinical hypothyroidism during follow-up, mostly in the one year before conception but also during gestation.^98–100 Even though LT4 treatment is not indicated for euthyroid TPOAb positivity, TPOAb measurement as part of thyroid function testing is valuable for identifying those more likely to develop hypothyroidism and, therefore, more likely to require LT4 treatment in the near future. The TPOAb status also has some prognostic value for the risk of miscarriage, preterm birth, and PPT. The cost for implementation and a lack of a proven benefit of intervention are the primary arguments against routine TPOAb testing. In view of this, an individualized approach to TPOAb testing may be warranted, where women with a higher likelihood of having antibodies can be considered for testing. This may include women with high-normal TSH concentrations, history of recurrent miscarriages, other autoimmune diseases, or a first-degree relative with thyroid autoimmunity.^24,101,102 Robust cost-effectiveness analyses are needed to determine the true cost implications of preconception routine thyroid antibody testing.

For any woman taking LT4 and planning pregnancy, a TSH between 0.5 and 2.5 mU/L is a reasonable treatment target. This strategy creates a margin of safety for maintaining a euthyroid state in anticipation of the increased thyroid hormone demand and LT4 dose adjustments that occur during ovarian stimulation and pregnancy. It is important to note that variations of preconception TSH concentrations within the reference interval do not affect fertility or pregnancy outcomes or the effectiveness of LT4 treatment to a clinically relevant extent.^{100,103–106}

Overt hypothyroidism in infertility

Epidemiology and physiology

The prevalence of undiagnosed overt hypothyroidism in women with a history of infertility or recurrent miscarriages is approximately 0.2%, which is similar to that in women of childbearing age in the general population.^101,107 The main risk factor for overt hypothyroidism is thyroid autoimmunity; around 70% of all women with overt hypothyroidism detected in the setting of the work-up for infertility or recurrent miscarriages are TPOAb positive. ¹⁰¹ Furthermore, hypothyroidism is more common in women with other autoimmune diseases. This is particularly relevant for autoimmune diseases that are part of multiple autoimmune endocrinopathies,^38,108,109 and it can be beneficial to further investigate any sign of such abnormalities in anticipation of pregnancy. Greater age is also associated with a higher risk of overt hypothyroidism, and there are considerable regional and interpopulation (ethnicity-based) differences in the prevalence of hypothyroidism.^{38,107,109,110}

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Subclinical hypothyroidism in infertility

Epidemiology and physiology

The prevalence of undiagnosed subclinical hypothyroidism in women with infertility or recurrent miscarriages is approximately 2.4%, which is similar to that of women of childbearing age in the general population.^{101,120–123} The main risk factor for subclinical hypothyroidism is thyroid autoimmunity; about 40% of all women with subclinical hypothyroidism, detected in the setting of the diagnostic work-up for infertility or history of recurrent miscarriages, are TPOAb positive, and this rises to 80% for those with a TSH >10 mU/L.^101,108 Other risk factors include obesity, and considerable regional and interpopulation differences in the prevalence of subclinical hypothyroidism occur.^101,107

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Thyroid autoimmunity in infertility

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This section focuses on TPOAb positivity in women with infertility (considerations related to TgAb positivity in women with infertility can be found in Box 4). TPOAb positivity has a better diagnostic accuracy for hypothyroidism than TgAb positivity and is associated with adverse fertility and pregnancy outcomes, unlike TgAb positivity. Therefore, a TPOAb measurement remains the preferred test to establish or risk stratify for autoimmune hypothyroidism. Assessing TgAb positivity is at the discretion of the physician but can be considered in certain cases (e.g., a euthyroid TPOAb-negative woman with a high-normal TSH and a high risk of thyroid autoimmunity based on previous thyroiditis, concomitant autoimmune disease, or having a first-degree relative with thyroid autoimmunity). Although it is reasonable to also apply recommendations in this subsection to TgAb positive women, this group was not specifically defined during the design of the methodology supporting this guideline.

Subclinical and overt hyperthyroidism in infertility

The epidemiology, physiology, clinical presentation, evaluation, and management of preconception subclinical and overt hyperthyroidism are discussed in Section G. For this subsection, we briefly highlight two considerations specifically for women with subclinical or overt hyperthyroidism who are planning pregnancy in the setting of infertility and/or recurrent miscarriages. First, it is relevant to assess the schedule and timing of fertility treatments since (age-dependent) time constraints may warrant a faster diagnostic and/or therapeutic route than usual care. This concept applies to any woman with thyroid disease who is planning pregnancy but can be more relevant for those with subclinical and overt hyperthyroidism owing to the required diagnostics and longer time to reach euthyroidism. Second, for sporadic cases in which the TSH remains persistently suppressed to <0.1 mU/L and both fT4 and T3 are normal, yet no clear underlying cause can be identified after a regular work-up, intensified follow-up during preconception and pregnancy can be considered to identify the possible progression of hyperthyroidism at an early phase. Alternatively, it may be reasonable to consider low-dose propylthiouracil (PTU) preconception. The goal of this approach would be to normalize the TSH concentration prior to pregnancy. This is based on expert opinion and supported by a large observational study showing that a suppressed TSH is associated with a delayed time to pregnancy in untreated women. ¹⁰⁴ PTU can be stopped upon a positive pregnancy test to reduce the risk of fetal birth defects associated with PTU exposure, and the patient should be instructed to do so immediately or seek contact upon a positive pregnancy test. If only cryopreservation of oocytes or embryos is planned without the anticipation of an embryo transfer in the immediate future, ATDs can be continued before and during the fertility preservation treatment.

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Overt hypothyroidism in preconception and pregnancy

In women known to have hypothyroidism prior to pregnancy, the basis of disease management during the preconception, gestational, and postpartum periods is similar to the general recommendations for nonpregnant patients. Some additional considerations specific to these periods, based on established clinical practice rather than high-quality evidence, are outlined in Box 3. Longstanding overall agreement to treat overt hypothyroidism during pregnancy with LT4 has limited the synthesis of evidence on the risks of untreated hypothyroidism and the benefits of treatment. Most available data on overt hypothyroidism during pregnancy are from studies published 20–30 years ago and therefore include more severe cases than those typically detected in current clinical practice. Nonetheless, LT4 treatment benefits are still considered to outweigh any risks. In general, women with hypothyroidism who remain euthyroid with LT4 treatment have similar fertility, pregnancy, and postpartum outcomes as women without hypothyroidism.

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Preconception treatment and management

The management of hypothyroidism outside of the perinatal period is summarized in detail elsewhere, ¹¹¹ and preconception recommendations specifically for women with infertility can be found in Section E. The guidance for the management of overt and subclinical hypothyroidism in women planning pregnancy is summarized in Flowchart 1 and for pregnant women in Flowchart 2. Following an established diagnosis, a logical LT4 treatment target for a woman wishing to conceive is a TSH in the reference interval but below 2.5 mU/L, in order to create a margin of safety for remaining euthyroid in anticipation of a state of increased thyroid hormone demand during pregnancy. The fetal central nervous system is relatively impermeable to T3 and the majority of fetal T3 present in the central nervous system during pregnancy is derived locally from maternal T4 actively transported into the intervillous space. ⁴⁸ Treatment with liothyronine or desiccated thyroid leads to a relative excess of T3 and relatively low concentrations of T4, which could lower fetal central nervous system T4 and T3 availability.^48,153,154 Therefore, women using liothyronine or desiccated thyroid preparations should be recommended to switch to LT4 monotherapy to avoid insufficient thyroid hormone availability for the fetal brain. For switching from combination T3 and T4 therapy to LT4 monotherapy, every 5 mcg of liothyronine may be considered equivalent to 20 mcg LT4. For switching from desiccated thyroid extract to LT4 monotherapy, every 60 mg grain of desiccated thyroid may be considered equivalent to 88 mcg LT4. ¹⁵⁵

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Flowchart 1.

Approach to increased TSH levels in preconception. Green boxes indicate a diagnosis, yellow boxes indicate an action, and orange boxes indicate recommended follow-up. ^aWomen with a high TSH have a higher risk of TPOAb positivity. TPOAb positivity is associated with a 7–9% risk of developing subclinical hypothyroidism preconception or during pregnancy. TPOAb status can guide screening in a future pregnancy and aid in counseling for postpartum thyroiditis risk. Euthyroid TPOAb positivity is not an indication for levothyroxine (refer to Recommendations Table 7). ^bOr alternatives as described in the thyroid function testing subsection of this guideline. ^cFor example, when fertility is already planned or when the chance of a successful pregnancy due to age or comorbidities would be further limited by postponing treatment. ^dBased on expert opinion, this could be defined, for example, as a TSH concentration >6 mU/L or in case of subclinical hypothyroidism with concomitant TPOAb positivity.

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Flowchart 2.

Approach to increased TSH levels in pregnancy. Green boxes indicate a diagnosis, yellow boxes indicate an action, and orange boxes indicate recommended follow-up. ^aWomen with a high TSH have a higher risk of TPOAb positivity. TPOAb positivity can be used for counseling on postpartum thyroiditis and guide screening in future pregnancies. ^bOr alternatives as described in the thyroid function testing subsection of this guideline. ^cFor mild forms of overt hypothyroidism, the risk profile and chance of TSH normalization are similar to those of subclinical hypothyroidism. Therefore, confirmatory testing can be considered using a shared decision-making approach. ^dThe distinction between the first and second trimester remains arbitrary, and management can be altered if the gestational age is within reasonable proximity on a case-by-case approach.

Subclinical hypothyroidism in preconception and pregnancy

In women known to have subclinical hypothyroidism prior to pregnancy, there is a lower threshold to start LT4 treatment during preconception or early gestation as compared with subclinical hypothyroidism in nonpregnant populations. A carefully balanced diagnostic, counseling, and treatment strategy is required to optimize potential LT4 benefits while preventing potential harms related to overtreatment and patient anxiety. For this topic, there is abundant low-to-moderate quality evidence but only sparse high-quality evidence to support recommendations. The main foundations of the available evidence are three randomized trials that investigated LT4 for subclinical hypothyroidism during pregnancy. The task force has assessed subanalyses and between-study comparisons from the randomized trials, often supported by observational studies, to form recommendations for this subsection.

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Thyroid autoimmunity in preconception and pregnancy

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This section focuses on TPOAb positivity; considerations on TgAb positivity can be found in Box 4. Autoimmune hyperthyroidism is discussed below in Section G. The interpretation of TPOAb positivity in the perinatal period is similar to that outside of pregnancy, in the sense that euthyroid TPOAb positivity should be considered a risk factor for thyroid disease rather than a disease entity in itself. However, increased thyroid hormone demand makes pregnancy a window of increased risk of new onset, or progression of, hypothyroidism in women with thyroid autoimmunity, thus warranting active screening and follow-up. Recommendations in this subsection are based on a large body of prospective cohort studies and multiple randomized trials.

Isolated hypothyroxinemia in preconception and pregnancy

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Isolated hypothyroxinemia is predominantly a pregnancy-specific thyroid function test abnormality with an unclear etiology. Recommendations in this subsection are based on a large body of prospective cohort studies and two randomized trials.

Epidemiology and physiology

A suppressed serum TSH concentration is frequently encountered in early gestation, when the hCG concentration rapidly increases through placental production. Gestational transient thyrotoxicosis (GTT) is the physiological condition resulting from the weak thyroid-stimulating effect of hCG on TSH receptors, typically manifesting as a suppressed TSH and mildly increased fT4 concentrations. Upon the presentation of biochemical hyperthyroidism in pregnancy, GTT should be distinguished from other less common hyperthyroidism etiologies, including (new onset or recurrent) Graves’ disease. Other etiologies of thyrotoxicosis in pregnant women are exceedingly rare and include toxic multinodular goiter and toxic adenoma, the thyrotoxic phases of subacute painful or painless thyroiditis, TSH-secreting pituitary adenoma, struma ovarii, functional thyroid cancer metastases, and germline TSH receptor mutations that are hypersensitive to hCG. ¹⁹¹ Thyrotoxicosis can also result from overtreatment with thyroid hormone replacement or the intentional or unintentional intake of thyroid hormone. ¹⁹²

The prevalence of GTT varies widely, due to the heterogeneity in the definition of GTT, overlap with other reasons for a suppressed TSH in pregnancy, and the inclusion of women with hyperemesis gravidarum in some studies.^8,193,194 It is estimated that the general prevalence of GTT ranges from <1% to 11% during pregnancy, ¹⁹⁵ depending on the geographic region. GTT occurs in up to 66% of women with hyperemesis gravidarum. ¹⁹⁶ Data on mild hyperthyroidism (usually due to GTT) during pregnancy are reassuring, as it is not associated with higher risks of adverse pregnancy or birth outcomes, such as preeclampsia, gestational hypertension, preterm birth, and small for gestational age.^{34,160,197,198}

Graves’ disease is the most common cause of nonphysiological, pathological thyrotoxicosis in women of childbearing age, occurring in approximately 0.4% of women during preconception and 0.2% during pregnancy. ¹⁹⁹ Autonomous thyroid nodules (ATNs), including multinodular goiter, have an estimated yearly incidence of 1–18 per 100,000 among nonpregnant women aged 20–39 years,^200,201 while the prevalence of coexisting ATNs and Graves’ disease (termed the Marine–Lenhart syndrome) in nonpregnant individuals was 0.26% in a study from Japan, an overall iodine-sufficient region. ²⁰²

Clinical presentation and evaluation

Women may come to attention during preconception and pregnancy for abnormal thyroid function tests checked in response to hyperthyroid symptoms or during routine prenatal care. Guidance for the evaluation of a decreased TSH in women planning pregnancy is summarized in Flowchart 3. Hyperthyroidism found during preconception should generally be evaluated and treated in the same way as in individuals not planning pregnancy, ²⁰³ with the added consideration of fertility treatment if applicable.

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Flowchart 3.

Approach to decreased TSH levels in preconception. Green boxes indicate a diagnosis, yellow boxes indicate an action, and orange boxes indicate recommended follow-up. ^aIdeally, the treatment for the etiology of hyperthyroidism should be completed and euthyroidism restored (confirmed by two TSH concentrations in the reference range at least six weeks apart) before fertility treatment begins. ^bFor example, if the TSH has been persistently <0.1 mU/L. ^cRefer to “Subclinical and Overt Hyperthyroidism in Infertility” in Section E.

The evaluation of hyperthyroidism in a pregnant woman presents distinct challenges. It is important to distinguish Graves’ disease in pregnancy from other causes (Table 2). GTT is more common in states associated with high hCG concentrations, such as early pregnancy, hyperemesis gravidarum, ¹⁹⁶ and multiple gestation pregnancies. ¹⁹⁸ In contrast, women with untreated Graves’ disease during pregnancy would be expected to have persistently low TSH concentrations, persistently increased fT4 concentrations after the first trimester, ²⁰⁴ and hyperthyroid symptoms that have often times been present before pregnancy. Positive serum TRAb and/or TSI titers, the presence of thyroid eye disease, and a family history of Graves’ disease and/or personal or other family history of autoimmunity also support the diagnosis of Graves’ disease. It should be noted that serum TRAb and TSI concentrations are used interchangeably in this text, as there are no data to show superiority or differences in the upper limit of normal clinical decision cutoffs between the two. In women with hyperemesis gravidarum and no other clinical signs of hyperthyroidism, the relatively frequent occurrence of GTT, as well as the likely absent need for symptom treatment, supports the general lack of benefit of routinely checking serum thyroid function.

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Table 2.

Distinguishing Between Gestational Transient Thyrotoxicosis (GTT) and Graves’ Disease

Guidance for the evaluation of a decreased TSH in pregnant women without known thyroid disease is summarized in Flowchart 4. Pregnant women with suppressed TSH concentrations should initially have a fT4 concentration measured, followed by serum TRAb or TSI levels if the fT4 concentration is elevated. A (f)T3 measurement can be considered if the fT4 is normal and distinguishing subclinical hyperthyroidism from overt hyperthyroidism would change management, or to help distinguish the etiology of hyperthyroidism (Box 5 and Table 2). A typical approach to a pregnant woman with a decreased TSH concentration and a concurrently normal fT4 and (f)T3 concentration (i.e., subclinical hyperthyroidism) is to repeat serum thyroid function every two to four weeks until the TSH normalizes (as most cases of GTT will). If subclinical hyperthyroidism persists into the third trimester or evolves into overt hyperthyroidism, additional follow-up and/or reconsideration of the hyperthyroidism diagnosis should be considered. Those with persistent overt hyperthyroidism, particularly after 20 weeks’ gestation, should undergo TRAb and/or TSI testing, followed by treatment or ongoing monitoring as indicated. There is no role of thyroid ultrasonography as a method to distinguish GTT from Graves’ disease in pregnant women owing to their similar thyroidal mechanism of action.

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Flowchart 4.

Approach to decreased TSH levels in pregnancy. Green boxes indicate a diagnosis, yellow boxes indicate an action, and orange boxes indicate recommended follow-up. (f)T3 = serum free and/or total T3 (see Box 5 in these guidelines). ^aFor women with a clear presentation of hCG-induced hyperthyroidism/gestational transient thyrotoxicosis (e.g., with a nonfully suppressed TSH, twin pregnancy, or hyperemesis gravidarum without extrathyroidal signs of Graves’ disease), it is reasonable to follow up with a TSH and fT4 in two to four weeks before checking TRAb and/or TSI. ^bAssess for a palpable thyroid nodule. If present, then follow biochemical progression and consider ATDs depending on the severity of hyperthyroidism. For example, repeat TRAb and/or TSI, (f)T3 measurement, thyroid ultrasound, and postpartum diagnostic imaging. TSI, thyroid-stimulating immunoglobulin.

For women with preexisting ATNs who become pregnant, there is a lack of rigorous data regarding the patterns of thyroid function changes during gestation, but the physiologically greater thyroid hormone needs during pregnancy may result in gradual improvement of the hyperthyroidism, even potentially resulting in normal thyroid function tests as pregnancy progresses. Thyroid hormone production in individuals with ATNs depends on iodine availability, emphasizing the need to be cautious with excess iodine intake and exposure during pregnancy. It is not possible to confirm an ATN as the etiology of hyperthyroidism in pregnancy, given the inability to perform nuclear medicine uptake and scanning during this period. For the evaluation of hyperthyroidism in lactation, guidance regarding radiopharmaceutical use is found in Section I.

Preconception management of hyperthyroidism (Graves’ disease)

Women of childbearing age with newly diagnosed hyperthyroidism should be assessed for their desire to conceive in the near future. About 20% of women with hyperthyroidism present with menstrual disturbances and hyperthyroidism is associated with reduced fertility, although thyrotoxic women remain ovulatory. ⁹ In a hyperthyroid woman desiring pregnancy, regardless of the underlying cause, the biochemical goal is to restore and maintain euthyroidism (confirmed by at least two sets of normal thyroid function tests obtained at least six weeks apart) before attempting conception.

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Small studies show that correction of hyperthyroidism improves fertility, although this may be related to the restoration of menstrual cycle regularity. There are no high-quality studies comparing the relative impact of specific treatment modalities for Graves’ disease on fertility; one small prospective study describes the improvement of menstrual irregularity in hyperthyroid women upon ATD initiation. ²⁰⁸ Our understanding of the risks and benefits of thyroid surgery and ¹³¹I treatment in Graves’ disease on fertility is primarily derived from their use in women with a history of differentiated thyroid cancer (DTC) (also see Section H), with mostly reassuring findings for effects on ovarian reserve, transient amenorrhea, and pregnancy rates following these therapies.^209–212 Although supporting data are limited, it is reasonable to expect that once euthyroid, fertility and fecundity for women with a history of treated Graves’ disease are similar to those without a history of Graves’ disease.

The management of hyperthyroidism due to Graves’ disease during preconception presents unique considerations (Table 3). Options for treatment with ATDs, ¹³¹I therapy, or total thyroidectomy should be discussed through a shared decision-making process. The choice and timing of these management decisions should weigh the pros and cons of the treatment options on fertility, the health of a future pregnancy and the fetus, and general maternal health. Women who are already taking methimazole (MMI) should be advised to switch to PTU (if available) once they are actively trying to conceive. If PTU is not available, the lowest effective dose of MMI can be used for the shortest duration possible. The relative risks of MMI and PTU during preconception and pregnancy are discussed below (subsection on ATDs).^213–215 While being treated with an ATD, women should be instructed to contact their clinician immediately should they become pregnant.

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Table 3.

Advantages and Disadvantages of Treatments for Preconception Graves’ Disease

Women with Graves’ disease who are considering radioactive iodine (RAI) treatment before conception should be counseled that serum TRAb and/or TSI concentrations will likely increase after RAI administration, which is associated with an increased risk of fetal and neonatal hyperthyroidism. ²¹³ In pregnancy, however, the risk of fetal and neonatal hyperthyroidism is negligible if the serum TRAb and/or TSI concentrations are <3-fold the upper limit of normal.^213,216 Attempting pregnancy could be considered if preconception serum TRAb and/or TSI concentrations are <3× the upper limit of normal or slightly above this threshold as TRAb and/or concentrations are expected to further decline during pregnancy as a result of increased immune tolerance. However, no guidance can be provided on a specific, safe preconception TRAb, and/or TSI concentration cutoff, as the expected decrease of individual TRAb and/or TSI concentrations in pregnancy is difficult to predict. Women who receive preconception ¹³¹I treatment for Graves’ disease should be advised to defer pregnancy for at least six months to minimize the potential adverse effects of radiation (as extrapolated from data on ¹³¹I treatment for DTC). ²¹⁷

Finally, some women may elect to undergo total thyroidectomy for the definitive treatment of Graves’ disease before pursuing pregnancy. Postoperative hypothyroidism should be managed with LT4 to ensure stable euthyroidism (confirmed by two consecutive normal thyroid function tests six weeks apart), along with attaining a TRAb and/or TSI concentration that minimizes the risk of fetal/neonatal hyperthyroidism before attempting to conceive.

Gestational management of GTT and Graves’ disease

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Subclinical hyperthyroidism in pregnant women generally does not require treatment, as the majority of such cases are attributable to GTT. Observational studies have not shown an association between untreated subclinical hyperthyroidism in pregnancy and adverse obstetric outcomes.^{33,34,160,187,218,219} GTT is typically self-limited and can be managed supportively with adequate hydration, control of hyperemesis if present, and alleviation of thyrotoxic symptoms with propranolol in the same routine doses as those used outside of pregnancy. ATD therapy should generally not be used for the treatment of subclinical hyperthyroidism. If GTT is particularly severe, low-dose PTU could be considered through shared decision-making and counseling about the harms and benefits of its use in pregnancy (see subsection below on ATD use in pregnancy).

For Graves’ disease during pregnancy, the risks of obstetric and medical complications are related to the control of maternal hyperthyroidism and the duration of euthyroidism throughout gestation.^222,223 Poor control of thyrotoxicosis caused by Graves’ disease has been associated with pregnancy loss, pregnancy-induced hypertension, intrauterine growth restriction, stillbirth, seizure disorder among offspring,^{34,204,223–225} and thyroid storm and congestive heart failure in the mother during gestation. ²²⁶ In women without Graves’ disease, the association of hyperthyroidism in the first half of pregnancy with adverse pregnancy outcomes is not consistent, and absolute risk differences are small.^{33,160,204,224,225,227–229} An important difference is that for Graves’ disease, hyperthyroidism is likely more severe and lasts longer. Accordingly, women with Graves’ disease who have overt hyperthyroidism at initial presentation or develop overt hyperthyroidism during pregnancy should be promptly treated, with the main goal to minimize the severity and duration of thyrotoxicosis.

Management options for Graves’ disease in pregnancy (Table 4) include observation alone, ATD therapy, and total thyroidectomy in cases of uncontrollable hyperthyroidism or thyroid storm (Box 6). Limited data suggest that long-term use of saturated solution of potassium iodide (SSKI) may be an alternative option for the management of Graves’ disease in iodine-sufficient populations, particularly if there is a higher risk or contraindications (i.e., allergies) to the usual therapies.^{96,213,230–232} Fetal thyroid ultrasound, fetal heart rate monitoring, and regular communication with the obstetrician or maternal-fetal medicine subspecialist are key for optimal risk assessment. The combination of persistently positive serum TRAb and/or TSI concentrations without a functioning maternal thyroid gland (such as after thyroidectomy and possibly after RAI therapy if it was administered preconception) can be particularly challenging and may require combined therapy with ATDs (to treat the fetus) and LT4 (to maintain maternal euthyroidism).

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Table 4.

Risks and Guidance for Treating Graves’ Disease During Pregnancy

ATD treatment of Graves’ disease in preconception and pregnancy

Women receiving ATD therapy for Graves’ disease should confirm pregnancy promptly if suspected and contact their physician, at which time discontinuation of ATD should be considered (Fig. 5). Upon ATD discontinuation, the risk of Graves’ hyperthyroidism relapse is 30–70%, depending on the duration of treatment and severity of the disease at diagnosis. However, as the average time to Graves’ hyperthyroidism relapse is about three months, there is a good possibility that the teratogenic window has passed when it is necessary to restart ATDs. Small studies have suggested that low-dose ATD use, stable thyroid function for >6 months before pregnancy ²³³ (preferably with serum TSH >0.35), and negative serum TRAb and/or TSI concentration ²³⁴ confer the highest chance of remission after ATD withdrawal. After discontinuing ATDs in pregnancy, serum TSH, fT4, and clinical examination may be monitored every one to two weeks in the first trimester, then every two to four weeks in the second and third trimesters. The choice of which ATD may be the safest to continue should be considered, based on data of ATD risks during pregnancy as discussed below.

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FIG. 6.

Risks of antithyroid drugs during pregnancy. The relative and absolute risks, as well as examples of affected organ systems and severity of congenital malformations, associated with maternal antithyroid drug use during pregnancy are summarized from data reported in two large epidemiological studies. CMZ, carbimazole; MMI, methimazole.

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During pregnancy, if the woman is not a candidate for discontinuation of ATDs, she should receive close monitoring with attempts to decrease the dose or even discontinue ATDs in the second half of pregnancy or, in certain cases, be considered for thyroidectomy. Associated risks of continuing ATD use in pregnancy are important to consider, with congenital malformations being the most relevant (Fig. 6). Three large cohort studies from Denmark and South Korea have shown that both carbimazole (CMZ)/MMI and PTU use in pregnancy are associated with a higher risk of embryopathies, compared with women without Graves’ disease.^214,215,235 In the South Korean cohort, the absolute risks for the prevalence of congenital malformations per 1000 live births increased by 8.8 cases (CI, 3.92–13.70 cases) in the women who took PTU alone, 17.1 cases (CI, 1.94–32.15 cases) for those who took MMI alone, and 16.5 cases (CI, 4.73–28.32 cases) for those who took both PTU and MMI, compared with pregnant women who were not prescribed an ATD. ²¹⁵ In addition, the types of abnormalities appear to be milder in those who receive only PTU (i.e., face/neck and urinary tract deformities) compared with those seen with MMI (i.e., deformities spanning seven organ systems; see Fig. 6). ²³⁶ Therefore, if PTU is locally available, it is preferred over MMI as ATD therapy in the first trimester.

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FIG. 7.

Trajectories of postpartum thyroiditis subtypes. The typical trends of serum thyroid hormone concentrations seen in various subtypes of postpartum thyroiditis are summarized. During the thyrotoxic phases of the destructive subtypes, antithyroid drugs are not indicated, as the underlying etiology is not increased thyroid hormone production (as compared with the postpartum recurrence or exacerbation of Graves’ disease, shown in the gray dotted line). During the hypothyroid phase of thyroiditis, a short course of thyroid hormone replacement may be considered in women with profound symptoms of hypothyroidism, with the plan to taper or stop the dose after 6–12 months.

These studies also showed that the risk of congenital malformations did not differ for pregnancies where MMI was switched to PTU in the first trimester versus those where MMI use was continued throughout the first trimester, suggesting that switching from MMI to PTU may not meaningfully impact the congenital malformation risk.^214,215,235 In these studies, the switch to PTU in most women happened well into the first trimester (median time, 44 days from pregnancy start in the Danish study ²³⁵ but unknown in the Korean study, as the switch between prepregnancy and first trimester was based on prescription data alone ²¹⁵ ) after the typical time in which the most sensitive aspects of organogenesis have already been completed. It is therefore possible that MMI exposure in early pregnancy was the driving factor underlying these results. In the Korean study, the cumulative MMI dose of >495 mg and longer duration of its use were associated with increased risk of malformations, whereas there were no such associations for PTU. ²¹⁵ These data suggest that for those women who continue to require ATD therapy in pregnancy who were not switched to PTU before conceiving, switching from MMI to PTU may lower the risk of congenital abnormalities, especially when switched early in the first trimester or when using a high MMI dose. When switching from MMI to PTU, a dose ratio of approximately 1:20 can be used (e.g., MMI 5 mg/day is equal to PTU 50 mg twice daily). If ATD therapy continues to be required after 16 weeks’ gestation (the time of skin closure), it remains unclear whether PTU should be continued or switched to MMI. As both medications are associated with potential adverse effects and switching between the two may potentially result in a period of suboptimal control, we are unable to make a recommendation regarding the choice of a preferred ATD after 16 weeks’ gestation.

Women who require continued ATD treatment in pregnancy should be closely monitored with thyroid function testing (serum TSH and fT4 as soon as pregnancy is confirmed and every two to four weeks thereafter) and serum TRAb and/or TSI testing in the first trimester. At each assessment, the decision to continue conservative management of Graves’ disease (i.e., holding the ATD and observing) should be guided both by clinical signs/symptoms and thyroid function tests.

Finally, there are limited data on ATD treatment and risks of adverse obstetric outcomes. Both MMI and PTU treatment of Graves’ disease lower the risk of miscarriage, preterm delivery, and low birth weight compared with no use of ATDs or uncontrolled hyperthyroidism despite ATD use. ²²⁴ The available data regarding ATD risks in women of childbearing age relate mostly to hepatotoxicity and pancreatitis; although there have been sparse case reports of fulminant hepatic failure associated with PTU use but not MMI in pregnancy, there seem to be no overall differences in hepatotoxicity between women treated with PTU in pregnancy compared with those not exposed to an ATD. ²³⁷ There are no data regarding the risks of agranulocytosis and pancreatitis in pregnancy, but they are likely to be similar to those of nonpregnant populations.^238–240 Baseline liver function tests and a white blood cell count should be obtained whenever an ATD is started, similar to the recommendations for ATD use in nonpregnant individuals. ²⁰³

Thyroid surgery for Graves’ disease in pregnancy

The decision to recommend total thyroidectomy for Graves’ disease in pregnancy should be reserved only for exceptional circumstances. ²²² Indications include a severe intolerance to ATDs or the inability to control hyperthyroidism with maximum doses of ATDs, which could result in life-threatening hyperthyroidism to the mother and/or hyperthyroidism or hypothyroidism in the fetus (e.g., the latter is more likely if high-dose ATDs are needed to control maternal hyperthyroidism, as in cases of thyroid storm in pregnancy). If thyroid surgery is required imminently, β1-selective blockers should be used to the extent needed to control maternal hyperadrenergic symptoms of hyperthyroidism, and other therapeutic options (such as potassium iodide, glucocorticoids, cholestyramine, plasmapheresis) should be considered on a case-by-case approach in a multidisciplinary setting, also taking into account general drug preferences during pregnancy (e.g., using hydrocortisone instead of dexamethasone). Women should be counseled that there are increased risks of surgical complications with thyroid surgery during pregnancy, compared with the nonpregnant state; better surgical outcomes of thyroidectomy during pregnancy are associated with operations performed by high-volume surgeons, compared with low-volume surgeons. ²⁴¹

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Risk of Graves’ disease relapse in pregnancy

Limited data suggest that euthyroid women in pregnancy with a history of remitted Graves’ disease have generally similar risks of adverse pregnancy and offspring outcomes to those without a Graves’ disease history, with the exception of increased fetal and neonatal hyperthyroidism risks^213,242 in women who have persistently increased serum TRAb and/or TSI concentrations (which may occur after a total thyroidectomy or previous preconception ¹³¹I treatment).^224,225

For women with a history of Graves’ disease that is in remission following previous treatment, disease recurrence is rare due to pregnancy-specific immune tolerance, especially if serum TRAb and/or TSI titers are less than threefold the upper limit of normal.^213,216 Although women with a history of Graves’ disease that is now in remission (including those who have received a course of ATD) have a low risk of Graves’ disease relapse in pregnancy, they should have continued monitoring of thyroid function each trimester and postpartum after three to six months or when developing new thyrotoxicosis symptoms.

Risks of fetal and neonatal hyperthyroidism associated with maternal Graves’ disease

The risks of fetal and neonatal hyperthyroidism are related to maternal TRAbs that cross the placental barrier (Fig. 2) through the neonatal fragment crystallizable receptor (FcRn) and stimulate the fetal thyroid gland. Monitoring for fetal and neonatal hyperthyroidism should be performed if the TRAb and/or TSI concentrations are above three times the upper limit of normal. This also includes, for example, euthyroid pregnant women with a history of past Graves’ disease who were definitively treated with a total thyroidectomy or ¹³¹I. In particular, risks of fetal and neonatal hyperthyroidism are higher in cases when the woman received ¹³¹I therapy within two years of conception, as the maternal TRAb concentrations are likely to still be elevated. ²⁴³ The indications for monitoring of fetal and neonatal hyperthyroidism in pregnant women with Graves’ disease are summarized in Table 5.

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Table 5.

Monitoring Fetal and Neonatal Hyperthyroidism in Pregnant Women with Active or Past History of Graves’ Disease

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Signs of fetal and neonatal hyper- and hypothyroidism are summarized in Tables 6A and 6B. If fetal goiter is found by ultrasound but the diagnosis remains unclear, amniotic fluid or umbilical cord sampling may be considered at 20–24 weeks’ gestation. Although umbilical blood sampling better reflects fetal thyroid status than amniotic fluid sampling,^244–246 it is associated with a 1–2% risk of fetal death, ²⁴⁷ and its benefits must be weighed against this risk. Meanwhile, amniotic fluid sampling is associated with a 0.1% risk of rupture of membranes, and normal fetal thyroid function tests obtained through this route do not completely exclude fetal thyroid dysfunction. ²⁴⁸ All cases of fetal and neonatal hyperthyroidism are considered high-risk pregnancies and should be managed by a multidisciplinary team.

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Table 6.

Signs and Symptoms of Fetal and Neonatal Hyperthyroidism (A) and Hypothyroidism (B)

For confirmed cases of fetal hyperthyroidism, treatment largely consists of maternal ATDs. In women already receiving LT4 replacement for iatrogenic hypothyroidism from past ¹³¹I treatment or thyroidectomy, maternal ATDs should be given in addition to LT4, as ATDs cross the placenta to impact the fetal thyroid gland (Fig. 2).

Infants born to women with Graves’ disease who have maternal serum TRAb concentrations >3× upper limit of normal should be closely followed and monitored for neonatal thyroid dysfunction.^216,243 If the mother is receiving ATDs, their infants may be initially euthyroid at birth but can become thyrotoxic when the effect of the ATDs dissipates, due to the relatively longer half-life of TRAb and/or TSI compared with that of ATDs. Risk assessment and follow-up strategies should be made in a multidisciplinary setting involving the endocrinologist, obstetrician, maternal fetal medicine subspecialist, and pediatrician. Neonatal Graves’ hyperthyroidism may require ATD treatment and may present with fluctuating hypothyroidism or hyperthyroidism in case of combined stimulating and blocking TRAb. However, treatment is likely to be short-term, as remission of neonatal Graves’ disease is common by 20 weeks of life, ²⁴⁹ and remission by 48 weeks after birth is nearly always observed. ²⁵⁰ Neonates born to a mother with poorly controlled Graves’ disease may also develop primary or central hypothyroidism that would require LT4 replacement at birth or upon withdrawal of maternal ATD use.^251–253

Postpartum management of Graves’ disease

In the postpartum period, there is a swift normalization of the immune system after the period of prolonged immune tolerance in pregnancy. While serum TRAb and TSI concentrations in women with Graves’ disease decline gradually during pregnancy, they are anticipated to increase in the postpartum period, thereby conferring a 25–55% estimated risk of Graves’ disease relapse after delivery. ²⁵⁴ In addition, some data, though not all, report an increased prevalence of new-onset Graves’ disease in the postpartum period.^255–258 Guidance on the evaluation and management of hyperthyroidism during lactation can be found in Section I.

Autonomous thyroid nodules

Epidemiology and physiology

Overt hyperthyroidism may arise from the presence of an ATN during pregnancy, although this is exceedingly rare. There are no robust data on the risks of adverse pregnancy outcomes in women with ATNs. It is relevant to note that in women with an ATN (either with or without ATD treatment), the maternal thyroid function is not a marker of fetal thyroid status (which is opposite to women with Graves’ disease, because in hyperthyroidism due to an ATN, there are no TRAb/TSI that stimulate fetal thyroid hormone production).

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Epidemiology and physiology

Observational studies drawn from both iodine-deficient and -sufficient regions report a similar prevalence of thyroid nodules between pregnant and nonpregnant women,^260,261 with estimates ranging from 9% to 33% upon screening, but of which only a minority (∼6%) are clinically significant. ²⁶² Greater age, ²⁶³ and associated with this, higher parity, ²⁶⁴ are the most relevant risk factors for the detection of a thyroid nodule during pregnancy. For thyroid nodules detected during pregnancy, their size, total number, and frequency of suspicious sonographic features are similar to those of nonpregnant women. ²⁶¹ Limited data suggest that the prevalence of nonautonomous thyroid nodules increases with each trimester of pregnancy. ²⁶³ There are no rigorous data regarding the prevalence of ATNs in pregnant women, but it is understood that they are generally more likely to be present in those living in iodine-deficient regions. ²⁶⁵ ATNs (including multinodular goiter) have an estimated yearly incidence of 1–18 per 100,000 among nonpregnant women aged 20–39 years.^200,201

In women with a known history of or new diagnosis of thyroid cancer prior to pregnancy, most of the literature supports that pregnancy itself does not adversely affect overall thyroid cancer outcomes. The size of a thyroid tumor may increase slightly during pregnancy, but the increase is usually not clinically significant.^266,267 Diagnosis during pregnancy does not appear to be associated with the presenting stage of thyroid cancer, ²⁶⁸ and for most patients diagnosed with DTC during pregnancy, delaying treatment until postpartum does not appear to impact achieving an excellent response to therapy. ²⁶⁹ Furthermore, the physiology of pregnancy does not appear to be associated with thyroid cancer progression or recurrence in pregnant women with DTC who have previously received initial treatment (i.e., surgery with or without RAI therapy). The risks of recurrence, clinically significant progression of DTC, and progression-free and overall survival are generally similar between nonpregnant patients and pregnant patients who have a history of or are diagnosed with DTC during pregnancy.^270–273 Progression of DTC during pregnancy is predicted by the presence of a structurally or biochemically incomplete response to therapy at the time of conception, ²⁷⁴ similar to the considerations of DTC risk used for the nonpregnant patient. Women at high risk for disease progression or immediate complications during pregnancy include those with distant metastatic disease and/or grossly invasive DTC on neck ultrasound or other imaging.

Clinical presentation and evaluation

Thyroid ultrasonography remains the most accurate and sensitive tool for the detection or confirmation of a palpated thyroid nodule in women during preconception or pregnancy. Upon discovery of a thyroid nodule, serum TSH should be measured to rule out possible hyperthyroidism arising from an autonomously functioning thyroid nodule. The definitive diagnosis of an autonomously functioning thyroid nodule cannot be made during pregnancy, given the contraindication to any radioisotope use, including scintigraphy and the common occurrence of physiological (subclinical) hyperthyroidism (Section C).

For nonfunctioning thyroid nodules detected during preconception and pregnancy, evaluation for malignant risk is generally similar to that of nonpregnant individuals. Obtaining a history of risk factors for thyroid cancer, as well as assessment for any relevant syndromic or familial risks, should be performed. There is a possible positive association between higher parity and the risk of thyroid cancer, but this is likely not clinically significant, and studies are complicated by residual confounding factors (age, breastfeeding, thyroiditis, obesity, other factors).^275,276 If indicated by sonographic risk criteria, fine-needle aspiration (FNA) biopsy to evaluate the malignant potential of a thyroid nodule should be completed prior to pregnancy. The patient may be counseled to maintain contraception until the planned evaluation and/or treatment are complete, although the clinical suspicion for advanced disease and possible decreased reproductive potential of the patient should be weighed in this consideration. If the patient is pregnant when a nodule is identified, FNA biopsy may be performed after shared decision-making, taking into account subsequent management options of its results.

The anticipated slight enlargement of the thyroid gland during pregnancy (especially during the first trimester)^261,263,277 should be considered when evaluating the malignant risk of a thyroid nodule. For nontoxic thyroid nodules, the sonographic risk of malignancy (estimated by tools such as the ATA thyroid nodule risk stratification system ²⁷⁸ and American College of Radiology Thyroid Imaging Reporting and Data System criteria) ²⁷⁹ is not different between pregnant and nonpregnant individuals. However, since overall survival appears not to differ if surgery is performed during or after delivery in pregnant women with thyroid cancer, patient preference for the timing of FNA biopsy (i.e., during pregnancy or postpartum), as well as sonographic features, should be taken into account. For pregnant women who undergo FNA biopsy and are found to have a cytologically indeterminate thyroid nodule, pregnancy is neither associated with a higher rate of malignancy nor the initial stage of thyroid cancer.^268,271,280 As molecular marker tests of cytologically indeterminate thyroid nodules have not been validated for use in pregnancy, their diagnostic performance is unknown in this setting.

Management of benign thyroid nodules

Recommendations for the management of ATNs during preconception and pregnancy are discussed in Section F. Appropriate evaluation and treatment (thyroid surgery and/or thermal ablative therapies) of benign, nonfunctional thyroid nodules should ideally be completed prior to pregnancy (refer to the ATA 2026 thyroid nodule guidelines). While thyroid surgery does not change the outcome of a future pregnancy, untreated or incompletely treated postoperative hypothyroidism and hypocalcemia secondary to permanent maternal hypoparathyroidism would increase the obstetrical and offspring risks of pregnancy (see Section F). For pregnant women with nonfunctional thyroid nodules that become symptomatic during pregnancy (e.g., associated compressive symptoms to the anterior neck or rapid nodule growth), shared decision-making should weigh the risks and benefits of these therapies during pregnancy.

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Management of DTC preconception and in pregnancy

Women of childbearing age with a new diagnosis of DTC who desire pregnancy should be counseled on the potential effects of thyroid cancer treatment (e.g., the extent and risks of thyroid surgery, possible postoperative ¹³¹I treatment, and extent of TSH suppression) on fertility and future pregnancy (Tables 7 and 8). Data regarding the efficacy and safety of ablative and targeted systemic therapies in this population are extremely limited.

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Table 7.

Guidance for the Management of DTC Preconception

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Table 8.

Guidance for the Management of DTC in Pregnancy

In women undergoing IVF/ICSI, limited data suggest that prior treatment of papillary thyroid cancer (PTC) is associated with a reduction in the number of retrieved oocytes per cycle and a lower number of high-grade embryos compared with women who have not received treatment for PTC, in analyses adjusted for age, BMI, concomitant fertility factors, and ART protocols. ²⁸¹ One small study has reported that women undergoing IVF/ICSI were more likely to have a clinical pregnancy or live birth following hemithyroidectomy, compared with those who had a total thyroidectomy. ²⁸² Otherwise, there appear to be no independent risks from postoperative RAI treatment or TSH suppression on ART outcomes. No data are available regarding the potential risks of advanced DTC therapies (i.e., targeted systemic therapies) in women undergoing ART.

Management of thyroid cancer in lactation

Although there are fewer direct risks of maternal DTC treatment options to the breastfed infant compared with the fetus during pregnancy, several considerations are pertinent to consider. Thyroid surgery performed during lactation is considered generally safe, as only clinically insignificant amounts of anesthetic drugs are transferred into breastmilk and are not thought to pose a danger to the breastfeeding infant. Current guidelines from the United States and United Kingdom advise that lactating women who undergo surgery can begin breastfeeding as soon as they are awake enough to hold the baby, ²⁸⁵ which is different from prior recommendations advising the disposal of breastmilk for 24 hours after receiving anesthesia. Considerations regarding postoperative ¹³¹I ablation and the treatment of maternal postoperative (± postablative) hypothyroidism in breastfeeding women are discussed in Section I.

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Finally, there are no data on the use and safety of RFA for the treatment of thyroid cancer during lactation. The concentrations of targeted systemic therapies in human breastmilk, or if there may be adverse effects of maternal targeted therapy use on breastmilk production or the health outcomes of the breastfed child, also remain unknown. Serious adverse reactions of maternal use of these therapies to the breastfed infant remain an undetermined possibility.

Medullary and advanced thyroid cancers

The relatively rare scenario of a newly diagnosed medullary or advanced thyroid cancer in a pregnant woman requires careful consideration, balancing the risks and benefits of treatment options during this critical life stage. All decisions should be made in the context of a multidisciplinary team, including a maternal fetal medicine subspecialist if available, on a case-by-case basis, weighing the risks and benefits to the mother and the fetus.

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Postpartum thyroiditis

PPT is defined as a characteristic pattern of (transient) autoimmune thyroid dysfunction occurring within 12 months after delivery, although it may also occur after a pregnancy loss (Fig. 7). The classic triphasic pattern of PPT, similar to other forms of thyroiditis, comprises an initial period of destructive thyrotoxicosis arising from painless release of preformed thyroid hormone from the inflamed thyroid gland, usually appearing between one and six months postpartum. This is followed by a hypothyroid phase that usually occurs between four and eight months postpartum, in which typical symptoms of hypothyroidism may occur in some individuals, and is followed by the last phase when there is gradual restoration of euthyroidism over another two to three months.

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Clinical presentation and evaluation

It is important to distinguish between the thyrotoxic phase of PPT and Graves’ disease, given the differences in their natural history and recommended management.^326,327 The timing of the presentation following birth, biochemical differences, and other clues in the diagnostic evaluation are helpful in differentiating the two entities (Table 9). Serum TRAb and/or TSI positivity, highly specific and sensitive biomarkers of Graves’ disease, and a total-triiodothyronine:total-thyroxine ratio of >20 ³²⁸ are confirmatory for Graves’ disease in most cases. In contrast, the onset of thyrotoxicosis in the first six months, shorter duration, and milder signs and symptoms of thyrotoxicosis are more suggestive of PPT. If these factors are not able to determine the etiology, conservative follow-up should be considered, and in severe cases, a thyroid nuclear uptake scan can be considered, although the potential consequences related to breastfeeding (including a decrease in specificity and need to temporarily discard breastmilk during the scan) need to be taken into account.

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Table 9.

Distinguishing Between the Thyrotoxic Phase of Postpartum Thyroiditis (PPT) and Graves’ Disease

Although the time course of the phases and the clinical presentation of PPT vary, women may be symptomatic and come to attention during only the thyrotoxic or hypothyroid phase or both. A recommended algorithm for the evaluation and management of postpartum thyroid dysfunction is shown in Flowchart 5. Finally, it should be noted that postpartum depression may arise following PPT in some women, which has been studied in various observational cohorts.^329–331 Although there is substantial heterogeneity in the available literature and there are overlapping symptoms between the conditions, there appears to be no association between PPT, thyroid autoimmunity, and risk of postpartum depression.^332–334 If a woman develops depression in the postpartum period, thyroid function testing should be obtained in accordance with general population screening recommendations.

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Flowchart 5.

Approach to abnormal TSH levels in postpartum. Green boxes indicate a diagnosis, yellow boxes indicate an action, and orange boxes indicate recommended follow-up.

Other postpartum thyroid dysfunction

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The role of thyroid function in breastmilk production and the potential of thyroid dysfunction to affect milk production, duration of lactation, or frequency of lactation are unclear, but clinically relevant adverse effects are unlikely. Some animal studies have reported impaired lactation following the use of PTU, but human data are sparse. There are small studies of deficient lactation in women with hypothyroidism, but these studies either included women already treated with levothyroxine ³³⁵ or who had the onset of lactation failure preceding the diagnosis of hypothyroidism. ³³⁶ Given the uncertainties around the available evidence, we are unable to recommend for or against screening for thyroid dysfunction in women having difficulty with lactation. Evaluation for Sheehan’s syndrome may be considered in case of a lack of breastmilk production after hypotension. Similarly, we are unable to recommend for or against the treatment of hypo- and hyperthyroidism for the strict purpose of improving milk production; in this scenario, lactating women with overt thyroid dysfunction should be treated in accordance with the usual care of nonlactating patients.