Combined thyroid diseases in pregnancy, including hypothyroidism (hypothyroidism), hyperthyroidism (hyperthyroidism), postpartum thyroiditis, combined thyroid nodules in pregnancy and thyroid cancer, etc.
In 2012, the Endocrinology Branch of the Chinese Medical Association and the Perinatal Medicine Branch of the Chinese Medical Association jointly formulated the Guidelines for the Diagnosis and Treatment of Thyroid Diseases in Pregnancy and the Postpartum Period by referring to relevant foreign guidelines and combining some clinical data from China. However, due to the differences in laboratory quality control standards, etc., the establishment of standardized diagnosis and treatment methods for these diseases and the exploration of the diagnostic and treatment characteristics of our population is still an important aspect in the field of obstetrics in China at present, which deserves high attention and active response from every obstetrician.
I. Clinical management of hypothyroidism in pregnancy
For units and individuals who have the conditions, it is recommended to perform thyroid function screening during planned pregnancy or as early as possible after pregnancy is confirmed, in order to detect thyroid function abnormalities as early as possible, intervene to correct them as early as possible, and reduce the impact on pregnancy. Combined hypothyroidism in pregnancy is associated with iodine deficiency, autoimmune thyroiditis, and radiological or surgical thyroid depletion.
Hypothyroidism is generally defined as a higher-than-normal thyroid stimulating hormone (TSH) level accompanied by a decrease in free thyroxine (FT4) level, while subclinical hypothyroidism in pregnancy is defined as a higher-than-normal TSH level with normal FT4 level. Clinically, the combination of clinical hypothyroidism in pregnancy is rare, generally accounting for 0.3% to 0.5% of pregnancies; while the combination of subclinical hypothyroidism in pregnancy is more common, generally accounting for 2% to 3% of pregnancies.
Clinical manifestations of hypothyroidism
Generally include fatigue, cold sensitivity, dry skin, etc., often not obvious, especially during pregnancy, and often confused with non-specific symptoms of pregnancy. Serum thyroid function tests are the basis for confirming the diagnosis and should often be accompanied by testing for relevant antibodies, such as thyroid peroxidase antibodies (TPO-Ab) or thyroglobulin antibodies (TG-Ab), to explore their etiologic origin as well as to plan follow-up protocols (including postpartum).
Pregnancy combined with clinical hypothyroidism or subclinical hypothyroidism may increase the probability of miscarriage, anemia, hypertensive disorders of pregnancy, placental abruption, and postpartum hemorrhage, and may increase the probability of preterm birth, low birth mass infants, and neonatal respiratory distress syndrome.
It is now believed that thyroid hormones are essential for embryonic brain development, and studies have shown that offspring born to untreated pregnant women with combined hypothyroidism have a lower intelligence quotient (IQ) than children of the same age.
L-thyroxine is the main drug for hypothyroidism and should be started immediately after diagnosis to achieve the treatment standard as quickly as possible (TSH levels of 0.1 to 2.5 mU/L before and during early pregnancy, 0.2 to 3.0 mU/L during middle pregnancy, and 0.3 to 3.0 mU/L during late pregnancy), and serum thyroid function indicators should be tested every 2 to 4 weeks during dose adjustment and every 4 to 6 weeks after stabilization. After stabilization, serum thyroid function indexes should be tested every 4-6 weeks.
For patients who were already taking thyroxine before pregnancy, an increase in dose of 30% to 50% is usually required during the 4th to 6th week of pregnancy, especially for those with complete loss of thyroid tissue (e.g., patients treated with radiation or surgically removed). After delivery, the amount of thyroxine taken is generally reduced to pre-pregnancy levels. For patients with normal thyroid function but positive thyroid-related antibodies, it is recommended that serum thyroid function indicators be tested once every 4-6 weeks during pregnancy for early detection of possible thyroid function abnormalities.
Pregnancy-associated hyperthyroidism
Combined hyperthyroidism in pregnancy is defined as TSH levels below the lower limit of normal and FT4 levels above the upper limit of normal. Graves’ disease is an autoimmune disease associated with the autoimmune antibody – thyroid stimulating hormone receptor antibody (TR-Ab), which mimics TR-Ab mimics TSH function and stimulates thyroid hormone secretion, leading to hyperthyroidism.
The clinical manifestations of hyperthyroidism include fear of heat, sweating, hyperphagia, panic and anxiety, which are difficult to distinguish from non-specific symptoms during pregnancy; specific goiter and thyroid ophthalmopathy are of clinical significance for a clear diagnosis. The differential diagnosis needs to be distinguished from transient hyperthyroidism in pregnancy, which often occurs in early pregnancy, is associated with hCG stimulation, is mostly transient, and mostly improves naturally after mid-pregnancy, may be accompanied by severe pregnancy vomiting, is negative for TR-Ab test, and generally does not require anti-hyperthyroid medication.
The secretion of hCG in early pregnancy tends to aggravate hyperthyroidism, while it will gradually decrease in late pregnancy. However, childbirth, cesarean section, and infection may trigger hyperthyroidism crisis and need attention.
Combined hyperthyroidism in pregnancy may increase the risk of miscarriage, preterm delivery, hypertensive disorders in pregnancy, fetal growth restriction (FGR), and low birth weight babies. Because TR-Ab can stimulate fetal thyroid hormone secretion through the placenta and antihyperthyroid drugs can also inhibit fetal thyroid hormone secretion through the placenta, attention needs to be paid to abnormal fetal thyroid function.
The occurrence of hyperthyroidism in the fetus can lead to serious consequences such as FGR, fetal heart failure, intrauterine death, rapid bone maturation, premature closure of the cranial suture with impaired intelligence in the newborn, and neonatal hyperthyroidism. Similarly, hypothyroidism in the fetus can lead to severe consequences such as delayed fetal skeletal development and neurological developmental disorders.
Propylthiouracil and tapazole are the main drugs used in the treatment of hyperthyroidism, and beta-blockers can be used to control the clinical symptoms of hyperthyroidism. Since antihyperthyroid drugs can enter the fetus through the placenta, the lowest effective dose should be used in principle to keep FT4 levels normal or slightly above the upper limit of normal.
In view of the possible teratogenic effect of tapazole on the fetus and the possible hepatic damaging effect of propylthiouracil on pregnant women, currently, propylthiouracil is recommended for early pregnancy in general, while tapazole is recommended for middle and late pregnancy. Serum thyroid function indicators need to be tested every 2 weeks during the drug adjustment phase, and every 2-4 weeks after the indicators are stabilized, and liver function needs to be tested every 3-4 weeks for propylthiouracil.
Partial thyroidectomy may be considered during midtrimester for those with severe adverse reactions to antihyperthyroid drugs or those requiring excessive doses of antihyperthyroid drugs (more than 30 mg/d of tabazol or more than 450 mg/d of propylthiouracil).
It is now believed that antihyperthyroid drugs can also be used during lactation, and higher doses (30 mg/d of tabazol or 300 mg/d of propylthioxypyrimethamine) generally have no effect on thyroid function in nursing infants. 131I should not be used for the treatment of combined hyperthyroidism in pregnancy.
Postpartum thyroiditis
Postpartum thyroiditis refers to thyroid disease that occurs within 1 year after delivery when the thyroid gland function is normal before pregnancy. It is not uncommon in clinical practice, with a prevalence of about 7% of mothers. Postpartum thyroiditis is an autoimmune disease in which an autoantibody-mediated immune response leads to the release of thyroid hormones or the destruction of thyroid tissue. Depending on the degree of thyroid hormone release and thyroid tissue destruction, typical cases go through hyperthyroidism, hypothyroidism and recovery, while atypical cases present with hyperthyroidism or hypothyroidism.
Patients with positive thyroid-related antibodies (e.g., TPO-Ab or TG-Ab), unlike Graves’ disease, show negative TR-Ab. TPO-Ab positivity, type 1 diabetes mellitus, subclinical hypothyroidism in pregnancy, Graves’ disease in remission, chronic viral hepatitis, and autoimmune diseases are high-risk factors for postpartum thyroiditis. Postpartum thyroiditis can occur in 40% to 60% of TPO-Ab positive pregnant women in early pregnancy, 18% to 25% of type 1 diabetic patients, and 25% of patients with subclinical hypothyroidism in pregnancy. Therefore, it is necessary to check thyroid function at 6 to 12 weeks postpartum and 6 months postpartum in these patients.
Most patients with postpartum thyroiditis present with hyperthyroidism followed by hypothyroidism. The hyperthyroid phase mostly occurs 1 to 6 months after delivery, most commonly 3 months after delivery, and usually lasts only 1 to 2 months. Compared with Graves’ disease, hyperthyroidism has mild symptoms, negative TR-Ab and decreased iodine uptake, whereas 95% of patients with Graves’ disease have positive TR-Ab and increased iodine uptake, although, of course, iodine uptake testing should be contraindicated during pregnancy and lactation. The hypothyroid phase mostly occurs after hyperthyroidism and usually occurs 3 to 8 months after delivery, most commonly 6 months after delivery, and usually lasts 4 to 6 months. Patients with postpartum depression should exclude the possibility of combined postpartum thyroiditis.
Treatment of postpartum hyperthyroidism is generally available with beta-blockers, which can be used to control symptoms, unless the condition is severe and usually does not require anti-hyperthyroidism medication, and the condition mostly resolves on its own. The treatment of postpartum hypothyroidism should be decided according to the TSH level and the patient’s reproductive needs. For those with TSH >10 mU/L, or those with the requirement to continue reproduction, or those with symptoms, levothyroxine is usually taken for treatment. Those with TSH level 4-10 mU/L, no requirement to continue reproduction, and no symptoms can be observed and followed up, and thyroid function will be rechecked every 4-8 weeks, and most of them will remit naturally.
Long-term follow-up after remission of postpartum thyroiditis is recommended, with serum thyroid function indicators checked at least once a year, as long-term follow-up reveals persistent hypothyroidism in 20% to 64% of patients with postpartum thyroiditis. For long-term thyroxine supplementation, care should be taken not to overdose, as this may increase the risk of atrial fibrillation and osteoporosis.
IV. Combined thyroid nodules and thyroid cancer in pregnancy
Theoretically, the high level of hCG and high estrogen status of pregnancy may stimulate thyroid nodule hyperplasia, but there is no evidence that pregnancy has adverse effects on thyroid cancer.
For solid thyroid nodules with a diameter of 1 cm or more and a volume of 0.5 to 1.0 cm3 with ultrasound suggesting high risk suspicion, aspiration cytology is recommended. For those with cytology suggesting malignancy or highly suspicious malignancy, surgery is recommended in mid pregnancy. For those found in late pregnancy, if the tumor is of low malignancy and slow development, surgery can be appropriately postponed until after termination of pregnancy.
Thyroxine tablets are recommended to be given after surgery for malignant tumors to suppress TSH levels at the lower limit of normal and FT4 at the upper limit of normal. Radioactive iodine therapy should not be applied during pregnancy and breastfeeding. Radioactive iodine therapy can be considered after stopping breastfeeding for at least 4 weeks. After radioactive iodine therapy is observed for at least 1 year, the next pregnancy can be considered after tumor control is stable and thyroid function is stabilized. It is currently believed that radioactive iodine treatment has no significant effect on the next pregnancy.
There are concerns that the TSH level values recommended by the American Thyroid Association (ATA) are too strict. A study from China found that in 4800 pregnant women with thyroid function indicators in early pregnancy, 27.8% were diagnosed with subclinical hypothyroidism if the American criteria for combined subclinical hypothyroidism in pregnancy (TSH level 0.1-2.5 mU/L) were used, and only 20%-30% of them had TSH levels >3 mU/L during mid- to late-pregnancy with natural follow-up; whereas, using the investigators’ own unit’s Only 4% of pregnant women were diagnosed with subclinical hypothyroidism using the investigator’s own laboratory diagnostic criteria (TSH level 0.1-4.9 mU/L). Another domestic study showed that the prevalence of late pregnancy hypothyroidism was 6.8% using TSH levels >4.8 mU/L as the criterion.
Therefore, we need to figure out our own laboratory diagnostic criteria, and of course, this work involves many issues such as geographical collaboration, laboratory standardization, international recognition, ethicality, and comparison of target endpoints. It is suggested that the Obstetrics and Gynecology Section of the Chinese Medical Association or the Perinatal Medicine Branch should organize national efforts to conduct research in this area in the future, and start with epidemiological surveys in different regions of the country with large multicenter samples according to the requirements of evidence-based medicine, so as to finally obtain clinical laboratory diagnostic criteria suitable for China. This is a clinically important work and has positive social significance for improving the quality of birth population in China.
(I) The timing of termination of pregnancy for patients with severe hypothyroidism not detected before pregnancy and detected during pregnancy
At present, this condition is not an indication for mandatory termination of pregnancy, but a decision needs to be made after adequate communication with the patient about the possible risks of continuing the pregnancy, such as impaired fetal mental development.
(ii) Thyroxine supplementation in pregnant women with normal TSH levels but low free triiodothyronine (FT3) or FT4 levels
Because of the lack of strong evidence that supplementation improves pregnancy outcome and the long-term prognosis of the fetus, it is controversial whether to administer medication, but De Groot et al. suggest that thyroxine supplementation can be appropriate and thyroid function should be actively monitored.
(C) The choice of medication in combined hyperthyroidism in pregnancy
Previous studies in the United States found that the application of tabazol in early pregnancy may lead to fetal malformation, so propylthiouracil was mostly used in the United States; while studies in Europe found that there was no significant difference in the teratogenicity of the two, and propylthiouracil had a greater impact on the liver function of pregnant women, so tabazol was mostly used. A large sample of anti-hyperthyroid drug studies from Taiwan reported that 25% of 2,830 patients with combined hyperthyroidism in pregnancy received anti-hyperthyroid drugs, and there was no significant difference in the teratogenicity of the two drugs. Published guidelines tend to favor the use of propylthiouracil in early pregnancy and switching to tapazole after midtrimester, with a reference value of 10 mg of tapazole equivalent to 100-150 mg of propylthiouracil for the dose interchange of the two drugs.