1. Clinical epidemiology and etiology. Epidemiologic data show that the incidence of hypothyroidism during pregnancy and pregnancy is as follows: overt hypothyroidism (OH) 0.3C0.5%, subclinical hypothyroidism (SCH) .2C3%. Thyroid autoantibodies were found in 5C15% of women of childbearing age, and chronic autoimmune thyroiditis was the main cause of hypothyroidism during pregnancy.In 2000, a prospective study in the United States tested serum TSH levels in 9,471 pregnant women during the third trimester of pregnancy, and the results showed that hypothyroidism was diagnosed in 2.2% of the total population, and subclinical hypothyroidism was present in 55% of patients. autoimmune thyroiditis, and more than 80% of patients with OH (serum TSH level of 11C200 mU/L) had autoimmune thyroiditis. The study also suggested a four-fold increase in fetal mortality in hypothyroid pregnant women, leading to the conclusion that the major adverse obstetric outcome associated with increased TSH in the pregnant population before the third trimester of pregnancy is increased fetal mortality. Other causes of hypothyroidism are treatment for hyperthyroidism (use of radioactive iodine or surgical removal) or surgery for thyroid tumors. Hypothalamic pituitary hypothyroidism is rare and may include lymphocytic pituitary inflammation occurring during pregnancy or postpartum. However, worldwide, iodine deficiency (ID), known to affect more than 1.2 billion people, is the most important cause of hypothyroidism. 2.Clinical features. Symptoms and signs may increase the clinical suspicion of hypothyroidism in pregnancy (weight gain, chills, dry skin, etc.), but symptoms such as malaise, lethargy, and constipation may go unnoticed. Since some pregnant women may be asymptomatic, the obstetrician should pay special attention to this aspect when the first prenatal diagnostic examination is performed in order to facilitate the diagnosis and to assess the functional status of the thyroid gland in a more systematic way. Only thyroid function tests can make a definitive diagnosis. 3. Diagnostic features. Increased serum TSH suggests primary hypothyroidism, and serum FT4 levels further identify SCH and OH: a normal FT4 is SCH, and a level significantly lower than that of a normal person of childbearing age is OH. Thyroid autoantibody concentrations are measured – thyroid peroxidase (TPO) and thyroglobulin (TG) antibodies (TPO-Ab and TG-Ab), and thyroid autoantibody concentrations (TPO-Ab and TG-Ab). Ab and TG-Ab), can clarify the autoimmune origin of thyroid dysfunction. Normal serum TT4 levels are altered during pregnancy under the influence of rapidly increasing levels of T4-binding globulin (TBG). As a result, total T4 levels in the middle and last trimesters of a normal pregnancy can reach levels up to 1.5 times the normal range of non-pregnant values (5C12 μg/dl or 50C150 nmol/L). The normal reference range provided by most FT4 test manufacturers is established from non-pregnant normal serum. Therefore, this reference range should not be used in pregnancy due to the fact that FT4 analysis is affected by alterations in serum contents (primarily TBG and serum albumin). Recently, it has been suggested that reference value ranges for FT4 in pregnancy be established for specific laboratories or for early to mid-late pregnancy, but there is no consensus on this issue. Therefore, the Guidelines recommend that attention be paid to the interpretation of serum FT4 levels during pregnancy and that each laboratory establish specific reference ranges for the three trimesters of pregnancy (first, middle, and last trimester). The thyrotropic activity of increased circulating blood concentrations of human chorionic gonadotropin can affect the level of serum TSH values, especially (but not exclusively) near the end of the first trimester. Thus, using the traditional normal reference range for serum TSH (0.4 mIU/L-4.0 mIU/ L), one possibility is to misdiagnose pregnant women with pre-existing mildly elevated TSH as normal, and conversely, there is a risk of suspecting a normal pregnant woman with a mildly lowered serum TSH value of hyperthyroidism.In 2005, Dashe et al. published a columnar line graph of changes in serum TSH during pregnancy, evaluating Serum TSH reference ranges in 13,599 singleton and 132 twin pregnancies, with a significant decrease in serum TSH levels during the first trimester, and even a greater decrease in twin pregnancies compared to singleton pregnancies (0.4 mIU/L), The chart showed that 342 singleton pregnancies with serum TSH values higher than 2 standard deviations above the mean had 28% of their patients using non-pregnant serum TSH reference value (0.4C4.0 mIU/L) would not be recognized. Other researchers have suggested the use of “trimester-specific” reference ranges for determining serum TSH levels during pregnancy. For example, it has been suggested that the low limit of normal for serum TSH in the first and middle trimesters is 0.03 mIU/L, which decreases to 0.13 mIU/L by the end of the trimester, whereas serum TSH levels above 2.3 mIU/L in the first trimester and 3.1C3.5 mIU/L in the middle and last trimesters suggest that subclinical hypothyroidism may be occurring. 4, the results of pregnancy hypothyroidism: maternal aspects. Although hypothyroidism does not exclude the possibility of pregnancy, it has been proved that there is a certain relationship between hypothyroidism and reduced fertility.Abalovich et al.’s study of 150 pregnant women (114 cases of primary hypothyroidism) showed that 34% of the untreated female hypothyroidism patients due to pregnancy, 11% of the OH, 89% of the SCH, 99 cases of thyroxine treatment after normal thyroid function when the Spontaneous abortion occurred in 60% of patients with OH and 70% of patients with SCH when thyroxine treatment was inadequate. In addition, preterm labor was observed in 20% of OH patients and 90% of SCH patients. In contrast, when thyroxine treatment was adequate and thyroid function was maintained normal, 100% of OH and 91% of SCH pregnancies were delivered at term with no abortions. The study concluded that pregnancy outcome was not determined by whether the hypothyroidism was initially OH or SCH, but rather by the appropriate initial thyroxine therapy. When hypothyroid patients become pregnant and remain pregnant, they are at increased risk for early and late obstetric complications such as increased rates of miscarriage, anemia, gestational hypertension, placental abruption, and postpartum hemorrhage, which are more common in OH than in SCH, and most importantly, adequate thyroxine therapy significantly reduces the risk of adverse obstetric outcomes. 5, Outcomes of hypothyroidism in pregnancy: fetal aspects. Untreated maternal OH is associated with the development of adverse neonatal outcomes that include preterm labor, low birth weight, and neonatal respiratory disease. Although increased fetal and perinatal mortality has not been confirmed by all findings, studies have been reported. Adverse obstetric effects such as gestational hypertension may also contribute to the overall increased neonatal risk. Although the occurrence of these complications is less common in SCH mothers than in OH mothers, some have been reported in neonates of SCH mothers. Multiple studies have confirmed that an exponential (1-3 fold) increase in the rate of preterm labor (before 32 weeks) occurs in SCH pregnancies. A new prospective randomized intervention trial study found that thyroid antibody-positive pregnant women who were treated with thyroxine had a significantly lower rate of preterm delivery compared to thyroid antibody-positive pregnant women who were not treated with thyroxine and those whose thyroid function during pregnancy showed progressive development of SCH. In a perinatal study of hypothyroid patients, the occurrence of gestational hypertension (i.e., eclamptic convulsions, preeclampsia, and pregnancy-induced hypertension) was significantly more common in OH (22%) and SCH (15%) compared with the control population (8%). In addition, 36% of OH and 25% of SCH patients who remained hypothyroid until delivery developed gestational hypertension, and the study also observed a prevalence of low birth weight due to gestational hypertension in pregnant women with OH and SCH that was second only to the incidence of preterm labor. Another study in a population of pregnant women with a prevalence of SCH of 2.3% showed that pregnant women with SCH were more than three times more likely to experience placental abruption compared with controls (relative risk 3; 95% confidence interval 1.1C8.2), and the incidence of preterm births (delivered at or before 34 weeks’ gestation) in pregnant women was almost twice as high as that in the control group (relative risk 1.8, 95% confidence period 1.1 C2.9). 6, Maternal thyroid hormones and fetal brain development. A large body of evidence strongly suggests that thyroid hormones play an important role in promoting normal fetal brain development. Since the fetus does not have the ability to produce thyroid hormones until mid-pregnancy, the presence of thyroid hormones in the fetus during early pregnancy can only be interpreted as being of maternal origin. Thyroid hormones and specific nuclear receptors are found in the fetal brain at 8 weeks after conception. Physiologic amounts of FT4 were found in the body cavity fluid and amniotic fluid of developing first trimester fetuses.Studies in different brain regions of human fetuses suggest the presence of increased concentrations of T4 and T3 from 11-18 weeks after pregnancy. Individual developmental types of thyroid hormone concentrations and iodinated thyrotropine deiodinase activity show a complex interaction between the two changes in pregnancy-specific D2 and D3 deiodinase activities. The dual-enzyme system suggests that the pathway to adjust T3 to appropriate levels requires the involvement of normal brain development while avoiding T3 overload. 7. Clinical studies on the role of maternal hypothyroidism on the neuropsychological outcome of pregnancy. Because of the heterogeneity of “hypothyroidism” in pregnancy, which is often referred to, it is important to consider the different clinical states. There is a great deal of variability in the time of onset of thyroid insufficiency (first trimester vs. last trimester), the severity of the disease (SCH vs. OH), the gradual worsening of the disease over the course of the pregnancy (etiologically dependent), and the adequacy of treatment. It is difficult to achieve a global consensus that these variable clinical conditions factor into the impact of maternal hypothyroidism on offspring. However, there is general agreement that studies have shown that the offspring of mothers with hypothyroidism are at significantly higher risk for neuropsychological developmental indicators, IQ scores, and school learning abilities. A series of articles published thirty years ago by Evelyn Man and colleagues suggested that children of mothers with inappropriately treated hypothyroidism had significantly lower IQ. However, a large prospective study of outcomes in children born to mothers with hypothyroidism during pregnancy was first reported by Haddow and colleagues in 1999. In that study, the severity of hypothyroidism among the mothers of school-age children surveyed ranged from OH to probable SCH. The primary outcome of extensive psychological testing was that the mean IQ (out of 7) of children born to untreated hypothyroid mothers was lower than the mean IQ of children born to healthy and thyroxine-treated mothers.In addition, three times as many children born to untreated mothers with hypothyroidism had IQs that were lower than the mean IQs of the control group.The study demonstrated that unexposed or untreated hypothyroidism (or probable SCH) during pregnancy was associated with the occurrence of adverse pregnancy outcomes and a three-fold increase in the incidence of learning capacity. associated with a 3-fold increased risk of incidence of loss. Interestingly, one striking finding was the duality of the researchers’ investigation of children born to mothers who were treated for hypothyroidism during pregnancy but who had inadequate thyroxine dosage (mean TSH values of 5-7 mIU/L), and the use of very advanced technical tests to follow these children to the age of 5 years, with the result that intellectual factors were affected in some and not in others. There was a mild reduction in intelligence in the study cases of preschoolers by and large, with an inverse correlation with maternal TSH levels at the end of the third trimester. Otherwise, language, visuospatial fine-motor completion, or pre-school abilities were not negatively affected. It is concluded that children born to mothers with unsatisfactory treatment for hypothyroidism may be at risk for covert and selective clinical problems associated with cognitive dysfunction, depending on the extent of the condition and the duration of maternal under-treatment with thyroxine. Developmental indices in children of approximately ten months of age were found to correlate with early maternal FT4 levels, and toddlers born to mothers with early low T4 who naturally normalized their FT4 levels by late gestation were found to have normal development, suggesting that persistent low T4 status will affect fetal neurological development. Neurologic development in iodine deficiency (ID): Because ID can cause maternal and fetal hypothyroidism, the consequences of maternal hypothyroidism must be considered individually. A meta-analysis of cases, almost all of which had severe ID, confirmed that ID resulted in an average reduction of 13.5 IQ points in neuromotor and cognitive function in infants. A new study of children born to mothers with gestational ID showed that these children had a mean reduction in IQ of 10 points more than the overall value, and in addition, the study pointed attention to the hypo- and hyperfunctionality found in 69% of children born to mothers who had experienced gestational hypothyroxinemia. 8, treatment Because, the rapid increase in TBG levels after pregnancy leads to a physiologic increase in estrogen levels, an increase in the volume of thyroid hormone distribution (blood vessels, liver, placenta), and finally an increase in placental transport and metabolism of maternal T4. Therefore, levothyroxine is given for the treatment of hypothyroid mothers if iodine nutrition is adequate. Pregnant women with hypothyroidism require larger replacement doses of thyroxine than nonpregnant patients, and the daily dosage usually needs to be increased by an average of 30-50% or more of the original dosage in pregnant women who were already taking thyroxine before pregnancy. The initial therapeutic dose of thyroxine should be 100C150 μg /day or determined by body weight (bw). The dose of complete thyroxine replacement therapy for non-pregnant women is 1.7C2.0 μg/kg bw, which should be increased to 2.0C2.4 μg/kg bw in pregnancy due to increased requirements. In the early stages of severe hypothyroidism, the dose of thyroxine given from the earliest days may be equivalent to twice the final daily replacement dose to allow rapid normalization of the extra-thyroidal pool of thyroxine. Pregnant women who have been treated with thyroxine prior to pregnancy need to have their preemptive daily thyroxine dose adjusted to an appropriate thyroxine replacement level as early as 4C6 weeks of gestation to ensure maintenance of normal maternal thyroid function early in pregnancy. Some thyroidologists recommend that thyroxine doses be increased prior to pregnancy or as soon as pregnancy is confirmed, before the expected increase in serum TSH levels. It is important to note that 25% of pregnant women with hypothyroidism maintain normal serum TSH levels during the first trimester, and of these, 35% maintain normal serum TSH levels through the middle trimester without increasing the daily replacement dose, but will need to increase the amount of thyroxine replacement during subsequent pregnancies to maintain a normal state of thyroid function, which is very important. The magnitude of the increase in thyroxine volume during pregnancy is determined primarily by the etiology of the hypothyroidism, i.e., by the presence or absence of residual functional thyroid tissue. Pregnant women with no functional thyroid tissue remaining (after radioactive iodine treatment, total thyroidectomy, or as a result of congenital underdevelopment of the gland) require a larger increase in thyroxine than Hashimoto’s patients, who usually have some functional thyroid tissue remaining. As a simple rule of thumb, the thyroxine dose can be increased according to the degree of initial TSH elevation: for serum TSH between 5C10 mIU/L, the thyroxine dose averages 25C50 μg per day; for 10-20 mIU/L, it averages 50C75 μg per day; and for those with >20 mIU/L, it averages 75C100 μg per day. Serum FT4 and TSH levels should be tested within one month of initial treatment. The overall goal is to maintain normal FT4 and TSH levels throughout pregnancy to ensure a normal pregnancy. The ideal goal of thyroxine therapy is to achieve a serum TSH value of 2.5 mIU/L or less. Since it is sometimes difficult to correctly interpret detected FT4 and TSH results in the context of pregnancy, it is useful to optimize therapeutic monitoring during pregnancy by establishing pregnancy-specific laboratory reference ranges for FT4 and trimester-specific reference ranges for serum TSH. Once the thyroid function test results have normalized with treatment, these pregnant women should be tested every 6C8 weeks. If the thyroid function test results are still abnormal, the thyroxine dose should be adjusted and retested after 30 days, etc., until the thyroid function test results are normal. Approximately four weeks or more after delivery, most patients will need to reduce the amount of thyroxine taken during pregnancy. It should be kept in mind that pregnant women with evidence of thyroid autoimmunity are at risk of developing postpartum thyroiditis (PPT), so it is important to continue monitoring thyroid function for at least six months after delivery. Among pregnant women whose hypothyroidism is not diagnosed until after the first trimester, there are indications that the children born to them may suffer from impaired intelligence and cognitive abilities. The current consensus is that maternal thyroid function is rapidly normalized by the administration of thyroxine to maintain the course of the pregnancy. Despite this, prospective parents are unlikely to be fully reassured and remain concerned about potential brain damage in their child, which may have occurred if severe intrauterine hypothyroidism persists for a prolonged period of time. Conclusion Because hypothyroidism can potentially impair fetal neurodevelopment and increase the incidence of miscarriage and preterm birth, prevention of maternal (and fetal) hypothyroidism is of paramount importance. 10. Recommendations of the Guidelines (1) It is well known that both maternal and fetal hypothyroidism can have serious effects on the fetus. Therefore maternal hypothyroidism should be avoided (for OH, the USPSTF recommendation level is A; moderate evidence. GRADE: 1 ). It is recommended to look for target cases at the first prenatal follow-up visit (USPSTF recommended level is B; moderate evidence. GRADE: level 2 ). (2). If hypothyroidism has been diagnosed prior to pregnancy, it is recommended that the dose of thyroxine previously taken be adjusted to achieve a pre-pregnancy TSH of less than 2.5 mIU/L (USPSTF recommended level is I; poor evidence. GRADE: Level 2 ). (3). Increased thyroxine doses are often required at 4-6 weeks of gestation and may need to be increased by 30-50% (USPSTF recommended level is A; good evidence. GRADE: 1 ) (4). If OH has been diagnosed during pregnancy, thyroid function testing should be normalized as soon as possible. Thyroxine dosing should be achieved as early as possible to normalize thyroglobulin, and thereafter serum TSH levels should be maintained at less than 2.5 mI/L in the first trimester (or less than 3 mI/L in the middle and last trimesters) or less than the TSH trimester-specific normal reference range. AF should be tested once every 30-40 days (USPSTF recommended level is A with good evidence. GRADE: 1 ). (5). Patients with autoimmune thyroid disease (TAI) who have normal thyroid function in the early stages of pregnancy are at risk for developing hypothyroidism and should be monitored for TSH levels above the upper limit of the normal range (USPSTF Recommended Level: A, Good Evidence. GRADE: Level 1 ). (6). It has been shown that SCH (serum TSH concentrations above the upper limit of normal, normal FT4) is strongly associated with poor maternal and offspring outcomes. Findings have shown that thyroxine therapy improves obstetric outcomes, but long-term neurodevelopmental changes in the offspring have not been demonstrated. That said, the potential benefits gained from thyroxine therapy outweigh the potential risks, and the panel therefore recommends thyroxine replacement therapy for pregnant women with SCH. (For obstetric outcomes, the USPSTF recommendation level is B, moderate evidence. GRADE: Grade 1 ; for neurodevelopmental outcomes, the USPSTF recommendation level is I, poor evidence. GRADE: very low ). (7). After delivery, most pregnant women with hypothyroidism will need to reduce the dose of thyroxine taken during pregnancy (USPSTF recommendation level is A, good evidence. GRADE: Level 1 ).