Q14: How is subclinical hypothyroidism in pregnancy diagnosed? Subclinical Hypothyroidism (SCH) in pregnancy is defined as a pregnant woman with a serum TSH level above the upper limit of the pregnancy-specific reference value and an FT4 level within the pregnancy-specific reference value range. Recommendation 3-1: The diagnostic criteria for subclinical hypothyroidism in pregnancy are: serum TSH > upper limit of the pregnancy-specific reference value (97.5th) and serum FT4 within the reference value range (2.5th ~97.5th). (Recommendation level A) Question 15: What are the risks of subclinical hypothyroidism on pregnancy outcomes? Subclinical hypothyroidism during pregnancy increases the risk of adverse pregnancy outcomes.Casey retrospective study reported that untreated pregnant women with subclinical hypothyroidism had a 2-3 times elevated risk of adverse pregnancy outcomes.A case-control study conducted by Benhadi et al. analyzed the causes of miscarriage in 2497 Dutch pregnant women and found that high TSH levels increased the risk of miscarriage [17].Negro et al. conducted an RCT study screened 4000 pregnant women in early pregnancy and gave L-T4 intervention to those who were TPOAb positive and had TSH >2.5mIU/L. The results confirmed that L-T4 intervention reduces the risk of adverse pregnancy outcomes [18].Cleary-Goldman conducted a study of 10,990 pregnant women and found that TPOAb-negative pregnancies were associated with a higher risk of miscarriage than those with TSH <2.5 mIU/L had a significantly higher risk of miscarriage compared to those with TSH <2.5 mIU/L [19].Ashoor et al. recently reported that 202 pregnant women who had terminated their pregnancies due to miscarriage or stillbirth had significantly higher proportions of serum TSH levels higher than the 97.5th percentile point, and FT4 levels The proportion of serum TSH levels above the 97.5 percentile point and FT4 levels below the 2.5 percentile point were also significantly higher. In China, Wang Sen et al. observed pregnancy complications in 756 women with <12 weeks of gestation and found that the incidence of miscarriage in the TSH>2.5 mIU/L group was 15.48%, which was significantly higher than that in the normal pregnant women group [20]. However, Mannisto et al. analyzed the results of thyroid function tests in 5805 pregnant women at 12 weeks of gestation and found no effect on perinatal mortality [21]. A recent meta-analysis showed that 28 of 31 similar studies supported that subclinical hypothyroidism can increase the risk of adverse pregnancy outcomes [128]. Question 16: What are the risks of subclinical hypothyroidism on fetal neurointellectual development? The effect of subclinical hypothyroidism in pregnancy on fetal neurointellectual development is unclear. The results of a large-scale case-control study showed that the offspring of untreated pregnant women with subclinical hypothyroidism had a 7-point reduction in IQ scores and delayed motor, language, and attentional development in children between the ages of 7 and 9 years, compared with pregnant women with normal A-function [12]. Yu et al. gave L-T4 prospective intervention to 23 pregnant women with pure subclinical hypothyroidism (TPOAb negative, normal FT4) at <7 weeks of gestation, and the control group was 53 unintervened subclinical hypothyroid and 54 normal pregnant women. The results showed that maternal subclinical hypothyroidism alone could lead to a reduction of 5.94 and 6.09 points in the motor development score and the intellectual development score (PDI) of the children born, respectively; the L-T4 intervention could protect the MDI and PDI of children born to mothers with subclinical hypothyroidism to the level of the offspring of normal pregnant women. Another retrospective study by this group obtained the same conclusion: screening sera from 1268 pregnant women at 16-20 weeks, 18 cases of pure subclinical hypothyroidism (normal FT4, TPOAb) and 140 cases of normal pregnant women were obtained, and their offspring were followed up at 25-30 months postnatal, and the MDI and PDI were reduced by 9.98 and 9.23 points compared with those of the normal control group, and the differences were statistically significant [22]. was statistically significant [22]. They further analyzed the relationship between the degree of elevated TSH in pregnant women and children's intellectual development and found that the MDI and PDI of the offspring of pregnant women with TSH ≥3.93 mIU/L were significantly lower, while the above scores of the offspring of pregnant women with TSH <3.93 mIU/L were not significantly different from those of normal controls, suggesting that the degree of elevated TSH in pregnant women is related to the impairment of intellectual development of their offspring. They suggested that the cut-off value for abnormal TSH in pregnant women should be the upper limit of the pregnancy-specific reference range (3.93 mIU/L) and not 2.5 mIU/L [23]. The results of the recently published CATS study showed that in 390 pregnant women with subclinical hypothyroidism or hypo-T4emia, who initiated an L-T4 (150 μg/day) intervention at an average of 13 weeks, IQ at 3 years of age of their birth offspring was measured and did not differ significantly compared with the non-intervention group (N=404) [129]. The negative results may be related to 3 reasons: first, the intervention was initiated too late at 13 weeks of gestation; second, the degree of subclinical hypothyroidism in the pregnant women was mild, with a median TSH of 3.8 mIU/L on average; and third, the IQ was too coarsely tested, and more detailed neurocognitive indicators should have been tested. Question 17: Should subclinical hypothyroidism in pregnancy be treated? Subclinical hypothyroidism with TPOAb positivity in pregnancy should be treated with L-T4. One RCT showed that L-T4 intervention in 63 women with subclinical hypothyroidism with TPOAb positivity at 9 weeks' gestation reduced adverse pregnancy outcomes [24]. Another RCT study showed that in 36 pregnant women with normal thyroid function (defined as TSH <4.2 mIU/L) and TPOAb positivity, intervention with L-T4 at T1 gestation resulted in fewer preterm deliveries and fewer miscarriages. However, in subclinical hypothyroidism, TPOAb negative individuals can be left untreated [130]. The therapeutic agents, therapeutic goals, and monitoring frequency for subclinical hypothyroidism are the same as those for clinical hypothyroidism.The starting dose of L-T4 can be chosen according to the degree of TSH elevation.For TSH > upper pregnancy-specific reference value, the starting dose of L-T4 is 50 μg/day; for TSH > 8.0 mIU/L, the starting dose of L-T4 is 75 μg/day; for TSH > 10 mIU/L, the starting dose of L-T4 is 100 μg/day. dose of 100 μg/day. Adjust the dose of L-T4 according to the therapeutic target for TSH. Recommendation 3-2: Subclinical hypothyroidism in pregnant women increases the risk of adverse pregnancy outcomes and neurointellectual developmental impairment in the offspring. However, due to insufficient evidence from evidence-based medicine, this guideline neither opposes nor recommends the administration of L-T4 therapy to pregnant women with subclinical hypothyroidism who are TPOAb negative. (Grade E) Recommendation 3-3: L-T4 therapy is recommended for TPOAb-positive women with subclinical hypothyroidism. (Grade B) Recommendation 3-4: Treatment of subclinical hypothyroidism in pregnancy, treatment goals, and frequency of monitoring are the same as for clinical hypothyroidism.The therapeutic dose of L-T4 may be less than for clinical hypothyroidism. Different doses of L-T4 may be given depending on the degree of TSH elevation. (Recommendation level B)