Due to the increasing occurrence of thyroid disorders during pregnancy and postpartum, the impact on pregnancy and the postpartum period is receiving more and more attention, and the understanding of thyroid disorders during pregnancy and the postpartum period is gradually improving, especially in recent years when many prospective randomized controlled studies have provided new insights into the effects of various thyroid disorders and their treatment on maternal, fetal, and future pediatric IQ. It is against this backdrop that the American Thyroid Association has brought together international experts in thyroid disease and pregnancy from the American Thyroid Association, the Asian and Oceanic Thyroid Association, the Latin American Thyroid Society, the American College of Obstetricians and Gynecologists, and the Midwives Alliance of North America to develop guidelines for the diagnosis and treatment of thyroid disorders during pregnancy and the postpartum period. The guidelines consist of nine main sections, each consisting of a series of relevant questions, a discussion of the issues, and finally concluding recommendations. It should be reminded that although most of the recommendations were unanimously agreed by the committee experts, consensus could not be reached on recommendations 9 and 76. 1. Thyroid Function Tests in Pregnancy The thyroid gland in women during pregnancy can adapt to the progressively increasing metabolic demands of pregnancy through changes in thyroid hormones and regulation of the hypothalamic-pituitary-thyroid axis. Therefore, thyroid function tests in healthy women during pregnancy differ from those in non-pregnant healthy women. In general, TSH values are lower throughout pregnancy than in non-pregnant women (reference value of 0.4C4.0 mIU/L), with a lower normal limit of approximately 0.1-0.2 mIU/L and an upper normal limit of approximately 1.0 mIU/L. In addition, there are ethnic differences in serum TSH concentrations during pregnancy. Finally, different assays also result in different normal TSH reference values. The guideline recommendations for thyroid function tests in pregnancy include: 1) a trimester-specific range of TSH reference values should be established in the normal pregnancy population based on optimal iodine intake; 2) if the laboratory fails to establish a trimester-specific range of normal TSH values, the following reference values are recommended: 0.1-2.5 mIU/L in the first trimester; 0.2-3.0 mIU/L in the middle trimester -3) The best way to assess serum FT4 levels during pregnancy is to use solid phase extraction-liquid chromatography-tandem mass spectrometry (LC/MS/MS) with dialysate or ultrafiltrate from a serum sample. 4) If the laboratory is not able to use solid phase extraction-liquid chromatography-tandem mass spectrometry to determine FT4, it can also (5) Considering the high variability of FT4 test results, specific FT4 assays and a range of serum FT4 reference values specific for every 3 months should be established. 2. Hypothyroidism in pregnancy Excluding rare etiologies such as pituitary TSH tumors and thyroid hormone resistance syndrome, primary hypothyroidism in pregnancy refers to elevated serum TSH concentrations during pregnancy. In the presence of elevated maternal TSH levels, FT4 must be tested to distinguish between subclinical hypothyroidism and clinical hypothyroidism. Clinical hypothyroidism is defined as an elevated TSH level >2.5 mIU/L with a reduced FT4 concentration. If the TSH level is 10.0 mIU/L or higher, clinical hypothyroidism should be considered regardless of whether the FT4 level is lower than normal. Subclinical hypothyroidism is defined as serum TSH between 2.5-10 mIU/L but normal FT4 concentrations. Another more common type is maternal isolated hypo-T4emia, which is defined as a normal maternal TSH level but an FT4 concentration below the 5th or 10th percentile of the normal reference value for pregnancy. The guideline recommendations for the diagnosis and management of hypothyroidism in pregnancy include (in the order of thyroid function tests in pregnancy, as follows):6) All clinical hypothyroidism in pregnancy should be treated, including TSH levels above the reference range specified for each trimester accompanied by a decrease in FT4, and if the pregnant woman’s TSH is above 10 mIU/L, then treatment is required regardless of the FT4 concentration.7) Maternal isolated hypo-T4emia in pregnancy (8) Although subclinical hypothyroidism may have adverse effects on the pregnant woman and the fetus, there is a lack of sufficient evidence on whether LT4 therapy is needed for subclinical hypothyroid pregnant women with negative thyroid antibodies due to the lack of randomized controlled studies (author’s note: considering the adverse effects of subclinical hypothyroidism and weighing the pros and cons, the author recommends LT4 therapy for subclinical hypothyroidism, and the American 9) Pregnant women with subclinical hypothyroidism who are positive for TPOAb should be treated with LT4 (author’s note: there is no consensus among experts on this point, but the author recommends clinical treatment with LT4 for the same reasons as above). 10) LT4 is recommended for the treatment of hypothyroidism in pregnancy, and other thyroid agents such as T3 or thyroid tablets are not recommended. 11) LT4 The goal of treatment is to normalize maternal serum TSH values (0.1-2.5 mIU/L at 1-3 months; 0.2-3.0 mIU/L at 4-6 months; 0.3-3.0 mIU/L at 7-9 months).12) Pregnant women with subclinical hypothyroidism who start without treatment should have their serum TSH and FT4 tested every 4 weeks until 16-20 weeks of gestation to be alert for However, this strategy has not been prospectively studied.13) Patients with hypothyroidism who are receiving LT4 therapy need to be further clarified for pregnancy in the event of menopause or a positive home pregnancy test, and the LT4 dose should be increased by 25-30% in women with definite pregnancy. It is easier to change from taking LT4 once a day before pregnancy to 9 times a week, which will increase the LT4 dose by approximately 29%.14) The increase in LT4 dose during pregnancy is highly variable, with some pregnant women needing only a 10%-20% increase, while others may need an 80% increase, so it needs to be individualized, but it is important to maintain the TSH within the normal range during pregnancy. 15) For women with hypothyroidism who are planning to become pregnant, the LT4 dose should be adjusted before pregnancy to keep TSH below 2.5 mIU/L before pregnancy. Lower levels of TSH before pregnancy (within the normal reference range for non-pregnant women) may reduce the likelihood of increased TSH in the first trimester. 16) For pregnant women on LT4 therapy, the TSH should be monitored every 4 weeks during the first half of pregnancy TSH should be monitored every 4 weeks during the first half of pregnancy, as the dose of LT4 often needs to be adjusted according to the value of TSH.17) For pregnant women on LT4 therapy, TSH must be tested at least once during the 26th and 32nd weeks of pregnancy.18) For postpartum hypothyroid patients, the dose of LT4 is restored to the pre-pregnancy dose and TSH should be tested once at 6 weeks postpartum.19) For adequately treated Hashimoto (19) In patients with adequately treated Hashimoto’s thyroiditis, other than the need to test the mother’s thyroid function, other tests such as other thyroid tests for pregnant women, fetal ultrasound, and cord blood samples are not recommended unless pregnancy abnormalities occur.20) In pregnant women who are thyroid antibody positive but have normal thyroid function and are not receiving LT4 therapy, the possibility of hypothyroidism needs to be monitored during pregnancy and should be monitored every 4 weeks during the TSH should be monitored every 4 weeks during the first half of pregnancy and must be tested at least once during the 26th and 32nd weeks of pregnancy.21) Although a randomized controlled study has confirmed that selenium treatment during pregnancy reduces the incidence of postpartum thyroiditis, there are no follow-up studies to confirm or refute this conclusion, so selenium supplementation is not currently recommended for TPOAb-positive pregnant women. 3, thyrotoxicosis during pregnancy Thyrotoxicosis is a clinical syndrome manifested by increased excitability and hypermetabolism of the body due to increased serum FT4 and/or FT3 concentrations. The most common cause of thyrotoxicosis in pregnancy is hyperthyroidism in pregnancy syndrome, which is a transient hyperthyroidism that occurs in the first half of pregnancy and is characterized by elevated FT4 or TT4 with undetectable TSH receptors and no serum markers of thyroid autoimmunity, and occurs due to elevated hCG during pregnancy, possibly associated with severe pregnancy vomiting. Graves’ disease, on the other hand, is the most common cause of autoimmune thyrotoxicosis. Less common non-autoimmune causes of thyrotoxicosis include toxic multinodular goiter, toxic adenoma, and artificially caused thyrotoxicosis. Due to the effects of hCG, TSH levels during pregnancy can be as low as 0.03 mIU/mL or even undetectable. Therefore, the diagnosis of hyperthyroidism in pregnancy must be made in conjunction with FT4 levels, and a diagnosis of clinical hyperthyroidism can be established with undetectable TSH receptors or elevated FT4. For a pregnant woman diagnosed with gestational thyrotoxicosis, it is crucial to distinguish gestational hyperthyroid syndrome from Graves’ disease hyperthyroidism. The absence of previous history of thyroid disease and clinical manifestations such as goiter and ophthalmopathy often suggest the diagnosis of gestational hyperthyroid syndrome. Guidelines for the diagnosis and management of thyrotoxicosis in pregnancy include:22) For pregnant women with TSH suppression (TSH <0.1 mIU/L) in the first trimester, further history and physical examination are required, and FT4 testing is mandatory for all patients, and TT3 and TRAb testing may be useful for definitive diagnosis of hyperthyroidism.23) There is insufficient evidence to support or (24) Radioiodine scans or iodine aspiration tests should not be performed during pregnancy.25) Treatment for hyperthyroidism in pregnancy and severe vomiting in pregnancy includes supportive therapy, management of dehydration, and consideration of hospitalization if the condition is severe.26) Antithyroid medications are not recommended for hyperthyroidism in pregnancy (author's note: hyperthyroidism in pregnancy actually refers to hCG-associated hyperthyroidism). 27) Women with hyperthyroidism should normalize their thyroid function before pregnancy. 28) Propylthiouracil is recommended for the treatment of hyperthyroidism in the first trimester of pregnancy, and if methimazole is used, it should be switched to propylthiouracil in the first trimester of pregnancy and methimazole after the first trimester. The main reason for using propylthiouracil is that the use of methimazole during the first trimester may lead to congenital malformations such as skin dysplasia, whereas no teratogenicity has been reported with propylthiouracil, while switching to methimazole after the third trimester is because propylthiouracil may cause serious liver toxicity. The author recommends using propylthiouracil during pregnancy without switching to methimazole because if hepatotoxicity does not occur with propylthiouracil at 3 months, it is not very likely that hepatotoxicity will occur later, but regular liver function tests must be performed).29) Combination of LT4 and antithyroid drugs is not recommended unless fetal hyperthyroidism occurs (author's note: because LT4 rarely passes through the placenta, the combination of LT4 and antithyroid drugs is not recommended. (Author's note: Because LT4 passes through the placenta rarely, combined use of LT4 and antithyroid drugs will inevitably result in higher doses of antithyroid drugs, which is detrimental to the fetus).30) During antithyroid drug therapy, pregnant women's FT4 and TSH should be monitored every 2-6 weeks, and the target value for serum FT4 is to maintain it at the upper limit of the moderate normal reference value (author's note: A simpler approach is to maintain FT4 at the upper 1 /3 of the normal reference value).31) /31) Thyroidectomy is rarely used to treat hyperthyroidism in pregnancy, and if needed, the best time to perform the procedure is in the fourth to sixth month of pregnancy. 32) If a pregnant woman has a history of Graves' disease or is newly diagnosed with Graves' disease, she should have a TRAb test in the 20th to 24th week of pregnancy. (33) Pregnant women with uncontrolled hyperthyroidism or with high levels of TRAb (3 times greater than the upper limit of normal reference value) should undergo fetal ultrasound, which includes heart rate, fetal growth, amniotic fluid volume and fetal thyroid. This should be discussed with an experienced obstetrician.34) Umbilical cord puncture should be performed only in certain rare cases, and the timing should be appropriate. In pregnant women taking antithyroid medications, cordocentesis is sometimes useful to determine whether the fetus is hyperthyroid or hypothyroid if fetal goiter is detected.35) Methimazole at doses up to 20-30 mg daily is also safe for nursing mothers and infants. Propylthiouracil is generally used as a second-line drug of choice at doses up to 300 mg/day because of the potential for severe hepatotoxicity. Antithyroid drugs should be taken immediately after breastfeeding and should be given in divided doses. 4. Clinical recommendations for iodine nutrition during pregnancy The need for iodine in pregnant women increases compared to non-pregnancy due to increased production of thyroid hormones, increased urinary iodine excretion, and the fetal demand for iodine during pregnancy. In addition, the infant's iodine needs are primarily taken up through breast milk, so maternal iodine needs are also increased. The guidelines recommend the following iodine nutrition for pregnant and postpartum women during pregnancy:36) All pregnant and lactating women should receive at least 250ug of iodine per day.37) In North America, in order to ensure a daily intake of 250ug of iodine, it is recommended that oral iodine-containing dietary supplements containing 150ug of iodine be given to women who are planning, already pregnant and lactating, and supplementation in the form of potassium iodide is recommended, mainly Considering that other forms of iodine do not provide a more stable iodine intake (author's note: the other 100ug of iodine is provided by food because the diet also contains iodine).38) For regions outside of North America, the strategy to ensure adequate iodine intake can be appropriately adapted to the local dietary structure and iodized salt.39) Unless due to Graves' 's disease requires a pharmacologic dose of iodine during preoperative preparation, otherwise pregnant women should not be exposed to pharmacologic doses of iodine. Clinicians should always weigh the pros and cons when deciding to prescribe medications or perform diagnostic tests that will expose pregnant women to high levels of iodine.40) Given the potential risk of fetal hypothyroidism from excessive iodine intake, pregnant women should not consume more than 500-1100 ug of iodine per day from diet and iodine-containing dietary supplements (author's note. Too much or too little iodine intake can lead to an increased incidence of thyroid disease, so iodine intake should be moderate, not the more the better). 5. Spontaneous abortion, preterm birth and thyroid antibodies Spontaneous abortion is defined as a miscarriage that occurs before the 20th week of pregnancy. Although there is a relatively clear correlation between positive thyroid antibodies and spontaneous miscarriage, a causal relationship between positive thyroid antibodies and spontaneous miscarriage cannot be demonstrated at this time. Preterm birth is also one of the most common perinatal complications, and it is the leading cause of neonatal death and the second leading cause of infant mortality. Although the relationship between thyroid antibodies and preterm birth has been studied, different studies have reached inconsistent conclusions. Given the inconsistency of the findings, the guidelines do not provide a clear answer to the recommendation on the relationship between spontaneous abortion, preterm birth, and thyroid antibodies, including the following:41) There is insufficient evidence to support or oppose the need to screen all pregnant women for thyroid antibodies in the first trimester of pregnancy.42) There is insufficient evidence to support the need to screen or treat for thyroid antibodies in the following three conditions (42) There is insufficient evidence to support or oppose the need for screening or treatment for thyroid antibodies in women who have taken LT4 or intravenous immunoglobulin during pregnancy in the first trimester, in women with normal thyroid function who have had a single or multiple miscarriages, or in women who have undergone in vitro fertilization.43) There is insufficient evidence to support or oppose the need for LT4 treatment in women who are positive for thyroid antibodies during pregnancy but have normal thyroid function.44) There is insufficient evidence to support or oppose the need for screening for thyroid antibodies in all pregnant women. (44) There is insufficient evidence to support or oppose the need for LT4 treatment in women with normal thyroid function but positive thyroid antibodies during pregnancy who have undergone assisted reproductive technology.45) There is insufficient evidence to support or oppose the need for screening for thyroid antibodies in the first trimester of pregnancy or the need for LT4 treatment in women with positive thyroid antibodies and normal thyroid function to prevent preterm delivery. There is insufficient evidence to support or oppose this. The key to the management of thyroid nodules and thyroid cancer in pregnancy is to find a good balance between definitive diagnosis and clinical management while avoiding possible adverse effects on the mother, the fetus, and the pregnancy itself. Careful palpation of the thyroid and cervical lymph nodes is important in the diagnosis of thyroid nodules and thyroid cancer. Among the ancillary tests, thyroid ultrasound is the most accurate, as it can clarify the presence of thyroid nodules, understand their characteristics, monitor changes in nodule size, and assess the condition of the cervical lymph nodes. Signs of a malignant nodule suggested by thyroid ultrasound include hypoechoic nodules, irregular margins, disorganized blood vessels within the nodule, nodules that are taller than they are wide, and microcalcifications. Fine needle aspiration of the thyroid is a safe diagnostic modality and can be performed at any time during pregnancy. Thyroid fine needle aspiration is generally not indicated for thyroid nodules smaller than 10 mm unless malignant nodules are suspected clinically or on ultrasound. All pregnant women with thyroid nodules should have TSH and FT4 testing to assess thyroid function, but the results are usually normal. Guidelines for the diagnosis and management of thyroid nodules and thyroid cancer in pregnancy recommend the following:46) The optimal diagnostic strategy for the screening of thyroid nodules in pregnancy is based on risk stratification, and all women should undergo a complete history taking, detailed physical examination, serum TSH testing and neck ultrasound.47) Whether calcitonin testing in pregnant women with thyroid nodules is (48) Thyroid nodules or lymph node puncture do not increase the risk of pregnancy per se.49) Thyroid nodules found during pregnancy with ultrasound suggestive of malignancy should be examined by thyroid needle aspiration. For thyroid nodules that may be benign, thyroid fine needle aspiration can be postponed until after delivery, depending on the wishes of the pregnant woman.50) Isotope iodine imaging, test doses or therapeutic doses of isotope iodine intake are contraindicated during pregnancy. It appears that inadvertent maternal isotopic iodine ingestion during the first 12 weeks of pregnancy does not damage fetal thyroid tissue (author's note: because the fetal thyroid gland is not capable of iodine uptake during the first 12 weeks of pregnancy, isotopic iodine does not concentrate in the fetal thyroid gland, thus avoiding fetal thyroid damage from isotopic iodine, but for safety reasons, maternal isotopic iodine ingestion during the first 12 weeks of pregnancy should still be avoided). (51) The prognosis of well-differentiated thyroid cancer found during pregnancy is similar to that of non-pregnant patients if left untreated, so surgery can usually be postponed until after delivery.52) The effect of pregnancy on medullary thyroid carcinoma is unclear, and surgery is recommended for larger primary thyroid malignancies found during pregnancy or when lymph node metastases are present.53) Surgery for thyroid cancer performed in the second trimester of pregnancy has not been found to be associated with a significant reduction in the risk of thyroid cancer. (54) Thyroid nodules in pregnant women with benign nodules suggested by fine needle aspiration usually do not require surgery unless the nodule is rapidly enlarging or there is severe pressure on the thyroid gland. The principles of management of thyroid nodules found in the postpartum period can be found in the 2009 American Thyroid Association guidelines.55) If the decision is made to postpone surgery for well-differentiated thyroid cancer, the maternal neck ultrasound should be performed every 3 months to assess the growth of the tumor, which will help determine whether surgery is needed immediately.56) Postponing surgery for well-differentiated thyroid cancer to the postpartum period will not adversely affect the patient's prognosis It will not adversely affect the patient's prognosis, but surgery is recommended if significant tumor growth or lymph node metastasis is detected before mid-pregnancy.57) Pregnant women with well-differentiated thyroid cancer who delay surgery until postpartum may consider thyroid hormone therapy, with the goal of LT4 therapy being to control serum TSH levels to 0.1C1.5 mIU/L.58) Unless the following conditions occur namely (59) Women with differentiated thyroid cancer (as determined by risk stratification) should have their pre-pregnancy TSH target maintained during pregnancy, and serum TSH should be monitored every 4 weeks until weeks 16-20 of pregnancy, unless there is rapid growth of thyroid nodules and/or lymph node metastasis. (60) There is no evidence that previous exposure to radioiodine affects future pregnancies and the resulting offspring. Pregnancy should not be considered until 6 months after radioiodine treatment, and if pregnancy is planned after radioiodine treatment, a stable dose of LT4 should be achieved prior to pregnancy.61) In patients with low-risk thyroid cancer who do not have elevated thyroglobulin levels or organic disease prior to pregnancy, ultrasound and thyroid monitoring during pregnancy is not required if there is a history of treatment for differentiated thyroid cancer prior to pregnancy. 62) In pregnant women with high levels of thyroglobulin before pregnancy or with persistent organic disease, ultrasound should be performed every 3 months during pregnancy if previously treated for differentiated thyroid cancer. 7. Postpartum thyroiditis Postpartum thyroiditis is a thyroid dysfunction that occurs within one year after delivery in women who had normal thyroid function before pregnancy. Its typical clinical presentation is a transient thyrotoxicosis at the beginning, followed by a transient hypothyroidism, and finally a return to normal thyroid function. All hyperthyroidism caused by postpartum thyroiditis can be recovered, but some hypothyroidism can become lifelong hypothyroidism. Most women with postpartum thyroiditis tend to have no hyperthyroid symptoms such as palpitations or fatigue during the hyperthyroid phase, but often have hypothyroid symptoms such as chills and dry skin during the hypothyroid phase. The guideline recommendations for the diagnosis and management of postpartum thyroiditis include:63) Women with postpartum depression should be tested for TSH, FT4, and TPOAb.64) During the thyrotoxic phase of postpartum thyroiditis, beta-blockers can be given to symptomatic women, and propranolol (Takayasu) at the lowest dose but with symptomatic relief is a better option, and treatment may (65) Anti-thyroid medication is not recommended during the thyrotoxic phase of postpartum thyroiditis.66) After the thyrotoxic phase of postpartum thyroiditis has resolved, TSH should be tested every 2 months (or when symptoms of hypothyroidism appear) for 1 year after delivery to detect the onset of the hypothyroid phase of postpartum thyroiditis.67) When symptoms of hypothyroidism appear in postpartum thyroiditis, TSH should be retested after 4-8 weeks or immediately. The TSH should be retested after 4-8 weeks or LT4 treatment should be started immediately (LT4 treatment may be given if the hypothyroidism is severe or if pregnancy is planned or if the patient wishes to be treated). In postpartum thyroiditis without symptoms of hypothyroidism, TSH can be retested after 4-8 weeks.68) Women with postpartum thyroiditis with hypothyroidism should be given LT4 if they are planning to become pregnant.69) When LT4 therapy is started for postpartum thyroiditis, future discontinuation should be considered and dose reduction can be started 6-12 months after starting therapy, but not if the patient is planning to become pregnant, is breastfeeding or is pregnant. (70) Women with a history of postpartum thyroiditis should have their TSH checked annually to assess for possible permanent hypothyroidism.71) The use of LT4 or iodine to prevent the development of postpartum thyroiditis in pregnant women with positive thyroid antibodies but normal thyroid function is not effective and is therefore not recommended. Screening for thyroid function during pregnancy There is still a great deal of debate about the need to screen all pregnant women for thyroid function in order to identify and treat thyroid dysfunction during pregnancy. Guidelines for thyroid screening in pregnancy recommend the following:72) There is insufficient evidence to support or oppose routine TSH screening of pregnant women in the first trimester of pregnancy.73) To date, no studies have confirmed the benefit of treating isolated maternal low T4emia, and therefore routine FT4 screening of pregnant women is not recommended.74) There is insufficient evidence to support or oppose routine TSH screening of women at high risk for hypothyroidism. (75) All pregnant women should be asked verbally at the first prenatal visit about any previous history of thyroid dysfunction, or if they have taken LT4, or if they have taken antithyroid medication.76) Serum TSH values should be obtained early in pregnancy in women at high risk for hypothyroidism for the presence of hypothyroidism: previous history of thyroid dysfunction or history of thyroid surgery; age >30 years; screening for thyroid dysfunction or goiter; positive TPOAb antibodies; type 1 diabetes or other autoimmune disease; history of miscarriage or preterm delivery; history of head and neck radiation; family history of thyroid dysfunction; morbid obesity (BMI ≥40 kg/m2); use of amiodarone, lithium, or recent use of iodine contrast; infertility; residence in Moderate to severe iodine deficiency (author’s note: this point did not reach consensus among experts. In view of the risks of hypothyroidism, the author recommends screening for thyroid function in pregnant women at high risk of hypothyroidism to detect possible hypothyroidism as early as possible and intervene early to avoid adverse effects on the pregnant woman, the fetus and the pregnancy itself). 9. Conclusion and future research directions It should be noted that many of the recommendations in the guidelines for the diagnosis and management of thyroid disease during pregnancy and postpartum still lack high quality evidence-based medical evidence because of the lack of high-quality double-blind placebo-controlled trials in the field of thyroid and pregnancy research. There is an urgent need for high-quality randomized controlled studies, such as whether LT4 treatment in thyroid-positive pregnant women with normal thyroid function can prevent spontaneous abortion and preterm delivery, and whether iodine supplementation during lactation has an effect on infant thyroid function and cognition.