1. Establishment of reference ranges for specific thyroid-related indicators in pregnancy
The normal range of thyroid-related indicators in pregnancy is different from that of non-pregnant population because pregnancy itself can lead to changes in thyroid function. In early pregnancy, the sudden rise in estrogen levels leads to an increase in thyroxine-binding globulin and a gradual increase in total serum thyroid hormone levels to 150% of the pre-pregnancy level, which plateaus by 16-20 weeks of gestation until delivery. Thyrotropin (TSH) levels are often mildly reduced in early pregnancy because of a significant increase in circulating human chorionic gonadotropin, which shares an alpha subunit with TSH and stimulates TSH receptors to increase thyroid hormone synthesis and mild hyperthyroidism (hyperthyroidism) symptoms. At the same time, iodine degradation in the placenta is accelerated and clearance through the kidneys is increased, T4 is deiodinated in the placenta to form anti-T3, and peripheral metabolism of thyroid hormones increases as a result. Combining the above factors, the normal range of thyroid-related indicators during pregnancy should be different from that of non-pregnant population.
2. Effects of hyperthyroidism in pregnancy on pregnancy
Poorly controlled hyperthyroidism during pregnancy can lead to preterm delivery, intrauterine growth retardation, low birth weight, preeclampsia, congestive heart failure, and intrauterine fetal death. However, if over-treated, fetal hypothyroidism can result.
Since thyroid hormone receptor antibodies (TRAb) can pass through the placenta and high titers of TRAb between 22 and 26 weeks of gestation are a risk factor for fetal and neonatal hyperthyroidism, pregnant women with current Graves’ disease or those treated with isotope iodine for Graves’ disease before pregnancy should be tested for thyroid autoantibodies before 22 weeks of gestation. The risk of fetal hyperthyroidism is significantly higher and may manifest as intrauterine growth retardation, fetal tachycardia, fetal goiter, accelerated bone age, excess amniotic fluid, preterm delivery and intrauterine death.
When TT4 is 1.5 times higher than the upper limit of the pregnancy-specific reference range, TSH < 0.1 mIU/L and TRAb positive, anti-thyroid treatment needs to be considered.
3.The effect of hypothyroidism in pregnancy on the development of offspring
Pregnant women with hypothyroidism are more likely to suffer from miscarriage, anemia, hypertension, placental abruption, postpartum hemorrhage and other obstetric complications. Untreated hypothyroidism in pregnancy can lead to increased incidence of preterm birth, low birth weight, neonatal whistle distress syndrome, and increased risk of embryonic and perinatal mortality.
Many animal studies have shown that the offspring of hypothyroid mothers have poorer physical development, mental development, and responsiveness to external stimuli than the offspring of normal mothers. For example, there is poor skin development, thinning of the epithelium, decreased number of hair follicles, and reduced hair. In Saudi Arabia, we observed the development of the offspring of medically hypothyroid female rats and found that the offspring of hypothyroid female rats had significantly less parietal-rump length and epiphyseal growth plate thickness than the control group. Brazilian scholars observed that the offspring of hypothyroid female rats had reduced response threshold to thermal stimulation, i.e., increased responsiveness to thermal stimulation, but no significant change in the threshold of mechanical stimulation. Another scholar conducted a test on changes in leucine metabolism in the brains of hypothyroid female rat offspring treated with propylthiouracil and found a significant increase in leucine oxidation and a decrease in the conversion of mannitol to glycolipids and glycoproteins in the brains of hypothyroid female rat offspring, suggesting abnormal brain cell metabolism, which could be corrected in adult offspring treated with triiodothyronine (T3).
Risk factors for hypothyroidism in pregnancy include maternal age over 30 years, comorbid other autoimmune diseases, previous neck radiation therapy, use of medications that affect thyroid function (e.g., amiodarone, lithium carbonate, etc.), use of iodine-containing contrast media, persistent TPOAb positivity, family history or past history of thyroid disease, and presence of goiter or hypothyroid symptoms.
4. Increasing attention to subclinical hypothyroidism in pregnancy
The diagnosis of subclinical hypothyroidism also relies on laboratory tests, with serum TSH exceeding the upper limit of the pregnancy-specific reference value and serum FT4 within the normal range being diagnostic. Current guidelines recommend L-T4 treatment in pregnant women with subclinical hypothyroidism in pregnancy with a positive TOPAb to reduce adverse pregnancy outcomes. However, L-T4 therapy is neither opposed nor recommended for pregnant women with TPOAb-negative subclinical hypothyroidism due to insufficient evidence-based medical evidence. Our scholars found that normal TSH levels could be maintained throughout pregnancy in TPOAb-negative subclinical hypothyroid pregnant women after treatment with L-T4.
5. The effect of hypo-T4emia on pregnancy
Hypo-T4emia is very common in pregnant women and is defined as normal serum TSH levels with FT4 levels below the 5th or 10th percentile of the reference range, when the pregnant woman can only provide enough thyroid hormone to maintain her own metabolism, but not enough thyroid hormone to ensure normal fetal development. To avoid interference with postnatal feeding factors, a 3-week postnatal assessment of neonatal behavior showed that mothers of low-scoring neonates had low T4emia at 12 weeks of gestation, but there was no significant correlation with T4 levels at 24 and 32 weeks of gestation. This indirectly demonstrates that early pregnancy is a critical period for fetal neurological development and it is important to ensure the supply of fetal thyroid hormones during this period. Similarly, scholars in China have observed that the intelligence and motor scores of the offspring of pregnant women with low T4 in the early and middle stages of pregnancy were lower than those of the control group at 20-30 months of age.
6. Simple positive thyroid autoantibodies
Habitual abortion occurs in 1% to 2% of couples and is caused by a variety of factors, including chromosomal abnormalities, abnormal pelvic anatomy, positive anticardiolipin antibodies, and endocrine diseases (such as uncontrolled diabetes mellitus, hyperprolactinemia, and thyroid disease). Patients with thyroid autoimmune status with normal thyroid function have spontaneous abortion rates two to five times higher than those of the normal population. In China, the positive rates of TPOAb and TgAb in women of childbearing age in iodine-appropriate areas are 9.8% and 9.0%, respectively. About 10%-20% of pregnant women in early pregnancy are positive for TPOAb or TgAb alone and have normal thyroid function.
7. The effect of iodine nutrition status on thyroid disease during pregnancy
Iodine is an important raw material for the synthesis of thyroid hormones and is essential for neuronal migration and myelin formation in fetal brain tissue. Pregnant women and lactating mothers require 250 μg of iodine daily to ensure fetal development and infant feeding. Severe iodine deficiency can lead not only to maternal and fetal goiter, increased miscarriage, stillbirth and neonatal mortality, but also to irreversible neurological damage in the offspring, such as cretinism.
As mentioned above, thyroid disorders are very common during pregnancy. Among all thyroid disorders in pregnancy, hypothyroidism and subclinical thyroid abnormalities (including subclinical hypothyroidism, positive autoantibodies to the thyroid gland alone, and low T4emia) can increase the incidence of adverse pregnancy outcomes and affect the physical and intellectual development of the offspring. Adequate iodine nutrition in early pregnancy is also important for the mental development of the offspring, and ensuring adequate iodine intake in pregnant women is a global public health issue.
The selection of a pregnancy-specific reference range for the diagnosis of thyroid disease in pregnancy is useful to avoid the underdiagnosis of pregnant women with mildly elevated TSH and mildly decreased FT4 in subclinical thyroid function. Prompt L-T4 treatment of pregnant women with hypothyroidism, subclinical hypothyroidism and subclinical hypothyroidism with positive TOPAb during pregnancy reduces adverse pregnancy outcomes and reverses impaired intelligence in the offspring. Whether there is a clear benefit of L-T4 treatment in pregnant women with simple hypo-T4emia and simple TPOAb positivity needs to be confirmed in more large interventional randomized controlled trials, although current guidelines do not recommend nor oppose L-T4 interventional therapy, arguing that, with fewer adverse effects and good treatment compliance, interventional therapy may have potential clinical benefits if done with informed patient consent.