Question 4: What are the diagnostic criteria for clinical hypothyroidism in pregnancy? The diagnostic criteria for clinical hypothyroidism in pregnancy are: TSH > upper reference value in pregnancy and FT4 < lower reference value in pregnancy. 2011 ATA guideline also suggests that women with TSH > 10 mIU/L in T1 pregnancy can be diagnosed with clinical hypothyroidism, regardless of whether there is a decrease in FT4 or not. However, the academic community has not yet reached a consensus on the criterion of TSH >10 mIU/L. Recommendation 2-1: The diagnostic criteria for clinical hypothyroidism in pregnancy are: serum TSH > upper limit of the reference value for pregnancy (97.5th) and serum FT4 < lower limit of the reference value for pregnancy (2.5th). (Recommendation Level A) Recommendation 2-2: If serum TSH > 10 mIU/L, treat as clinical hypothyroidism regardless of whether FT4 is decreased. (Recommendation Level B) Question 5: What are the risks of clinical hypothyroidism in pregnancy for pregnancy outcomes? The prevalence of clinical hypothyroidism in pregnancy in the United States is 0.3% to 0.5%; the prevalence reported domestically is 1.0% [11]. Most foreign studies have shown that clinical hypothyroidism in pregnancy increases the risk of adverse pregnancy outcomes and may also have adverse effects on fetal neurointellectual development [12]. Adverse pregnancy outcomes include preterm labor, low birth weight, and miscarriage, etc. Abalovich et al. showed that clinical hypothyroidism in pregnancy has a 60% increased risk of miscarriage; Leung et al. reported a 22% increased risk of gestational hypertension; and Allen et al. found that pregnant women with clinical hypothyroidism have an increased risk of stillbirth. The most common cause of clinical hypothyroidism is autoimmune thyroiditis, which accounts for about 80% of cases. Other causes include thyroid surgery and 131 iodine therapy. Question 6: What are the risks of clinical hypothyroidism in pregnancy on fetal development? When clinical hypothyroidism in pregnancy is effectively treated, there is no evidence of adverse pregnancy outcomes and harm to fetal mental development. Therefore, the fetus does not require any additional monitoring measures. However, there is a lack of well-defined studies on the effects of untreated clinical hypothyroidism on fetal mental development. Recommendation 2-3: The evidence that clinical hypothyroidism during pregnancy impairs the neurointellectual development of the offspring and increases the risk of preterm labor, miscarriage, low-birth-weight babies, stillbirth, and gestational hypertension is certain and treatment must be given. (Recommendation level A) Question 7: What are the goals of treatment for clinical hypothyroidism in pregnancy? It is proposed that the TSH goals for levothyroxine (L-T4) in the treatment of clinical hypothyroidism in pregnancy are 0.1-2.5 mIU/L in T1, 0.2-3.0 mIU/L in T2, and 0.3-3.0 mIU/L in T3. Question 8: Drugs and dosages for the treatment of clinical hypothyroidism in pregnancy? L-T4 therapy is preferred for clinical hypothyroidism in pregnancy. Treatment with triiodothyronine (T3) and dry thyroid tablets is not recommended. The complete replacement dose for non-pregnant clinical hypothyroidism is 1.6 to 1.8 μg/kg body weight/day, and for pregnant clinical hypothyroidism it can be as high as 2.0 to 2.4 μg/kg body weight/day. The starting dose of L-T4 is 50 to 100 μg/day, which is increased as soon as possible according to the patient’s tolerance level. Slow dose increases are required for those with comorbid heart disease. In patients with severe clinical hypothyroidism, give twice the replacement dose within a few days of starting therapy to normalize the extra-thyroidal T4 pool as soon as possible. Recommendation 2-4: Serum TSH treatment goals for clinical hypothyroidism in pregnancy are 0.1-2.5 mIU/L at T1, 0.2-3.0 mIU/L at T2, and 0.3-3.0 mIU/L at T3. As soon as clinical hypothyroidism is identified, begin treatment to achieve these treatment goals as early as possible. (Recommendation level A) Recommendation 2-5: Choose levothyroxine (L-T4) therapy for clinical hypothyroidism in pregnancy. Do not give triiodothyronine (T3) or dry thyroid tablets. (Recommendation Level A) Question 9: Why is it necessary to increase the supplemental dose of L-T4 in a pregnancy complicated by hypothyroidism? Maternal and fetal demand for thyroid hormones increases during pregnancy. Healthy pregnant women can increase endogenous thyroid hormone production and secretion through self-regulation of the hypothalamic-pituitary-thyroid axis [4]. The increase in maternal thyroid hormone requirement occurs at 4-6 weeks of gestation [13] and then gradually rises until it reaches a steady state at 20 weeks of gestation, where it continues to be maintained until delivery. Therefore, women with hypothyroidism who are under treatment need to increase the dose of L-T4 by approximately 30-50% after pregnancy. Clinical hypothyroidism due to thyroidectomy and 131 iodine ablation may require a larger dose [14]. Question 10: How to increase the dose of L-T4 as soon as possible after clinical hypothyroidism is combined with pregnancy An RCT in Boston, USA, suggests that in patients with clinical hypothyroidism who are being treated with L-T4, the dose of L-T4 should be increased as soon as pregnancy is detected. The simplest way to do this is to immediately increase the dose by an additional 2 days per week (i.e., a 29% increase from pre-pregnancy) [15]. This approach prevents the development of hypothyroxinemia in T1 as quickly and effectively as possible. Recommendations 2-7: The L-T4 replacement dose needs to be increased by approximately 30-50% after pregnancy in women with clinical hypothyroidism. Timely dose adjustments are made based on the serum TSH treatment goals described above. (Recommendation Level A) Question 11: Under what conditions can a woman with clinical hypothyroidism become pregnant? Women with clinical hypothyroidism who plan to become pregnant need to have their thyroid hormone levels restored to normal by L-T4 replacement therapy. Specific treatments are aimed at serum and, more ideally, at reach. Although there is no difference in pregnancy outcome between these two control levels, the risk of mild hypothyroidism in early pregnancy is further reduced in the latter. One study confirmed that only 17% of pregnant women required increased doses of L-T4 during pregnancy when TSH was <1.2 mIU/L [16]. RECOMMENDATION 2-6: Pregnancies planned in women with established clinical hypothyroidism require serum TSH to be brought to level before pregnancy can occur. (Recommendation level A) Question 12: How often should clinical hypothyroidism be monitored during pregnancy? When a patient with clinical hypothyroidism becomes pregnant, thyroid function, including serum TSH, should be monitored every 4 weeks during the first half of pregnancy, and the L-T4 dose should be adjusted according to control goals. Testing thyroid function every 4 weeks detects 92% of abnormal values. If thyroid function is tested every 6 weeks, only 73% abnormal values are detected [15]. Serum thyroid function should be measured at 26 to 32 weeks of gestation. Recommendation 2-8: The frequency of thyroid function monitoring in pregnant women with clinical hypothyroidism during the first half of pregnancy (1-20 weeks) is every 4 weeks. Serum thyroid function markers should be tested once at 26 to 32 weeks of gestation. (Recommendation Level A) Question 13: How is the L-T4 dose adjusted after delivery for clinical hypothyroidism in pregnancy? The increased demand for thyroid hormones in clinical hypothyroidism during pregnancy is due to the pregnancy itself. Therefore, the postpartum L-T4 dose should be reduced accordingly and the maternal serum TSH level should be rechecked at 6 weeks postpartum. Recommendations 2-9: The postpartum L-T4 dose in pregnant women with clinical hypothyroidism should be reduced to the pre-pregnancy level and requires review of the serum TSH level at 6 weeks postpartum to adjust the L-T4 dose. (Recommendation level A)