Question 34: What are the causes of thyrotoxicosis in pregnancy?
The prevalence of thyrotoxicosis in pregnancy is 1%, with clinical hyperthyroidism accounting for 0.4% and subclinical hyperthyroidism for 0.6%. Graves’ disease accounts for 85% of cases, including pre-pregnancy and new onset Graves’ disease; Syndromeof Gestational Hyperthyroidism (SGH), also known as transienthyperthyroidism, accounts for 10%; hyperthyroidism , nodular goiter, and staphyloma account for only 5% of cases [53, 54].
Recommendation 7-1: Serum TSH <0.1 mIU/L at T1 suggests the possibility of thyrotoxicosis. Further determination of FT4, TT3 and TRAb, TPOAb should be done. but 131 iodine uptake rate and radionuclide scan examination are contraindicated. More so, 131 iodine therapy should not be done. (Recommendation level A)
Question 35: What is the diagnosis of hyperthyroidism syndrome of pregnancy (SGH)?
It occurs in the first half of pregnancy, is transient, and is associated with increased production of hCG and overstimulation of thyroid hormone production [54]. It is characterized clinically by onset at 8-10 weeks, hypermetabolic symptoms such as palpitations, anxiety, excessive sweating, elevated serum FT4 and TT4, reduced or undetectable serum TSH, and negative thyroid autoantibodies. The disease is associated with Hyperemesis Gravidarum, and SGH occurs in 30-60% of those with hyperemesis gravidarum.The clinical manifestations of hyperemesis gravidarum are severe nausea and vomiting in early pregnancy, weight loss of 5% or more, associated with dehydration and ketosis, and elevated serum hCG levels, with an incidence of 0.5-10/1000 [55].Tan et al. reported 39 cases of pregnancy SGH needs to be differentiated from hyperthyroidism in Graves’ disease, which is often associated with ocular signs and positive thyroid autoantibodies such as TRAb and TPOAb.
Recommendation 7-2 The diagnosis of hyperthyroidism can be established after serum TSH <0.1mIU/L and FT4 > upper limit of pregnancy-specific reference value and exclusion of hyperthyroid syndrome of pregnancy (SGH). (Recommendation level A)
Question 36: What is the management of hyperthyroidism syndrome in pregnancy?
Symptomatic treatment is the mainstay. Vomiting needs to be controlled, dehydration corrected and water-electrolyte balance maintained in severe pregnancy vomiting. The administration of ATD therapy is not advocated [56] because serum thyroid hormones can generally return to normal by 14 to 18 weeks of gestation. ATD (e.g., PTU) can be used for a short period of time when identification of SGH from Graves’ hyperthyroidism is difficult. hyperthyroidism in Graves’ disease does not resolve easily and requires further treatment with ATD.
Recommendation 7-3: Hyperthyroidism syndrome of pregnancy (SGH) is associated with excessive placental secretion of hCG. Treatment is based on supportive therapy to correct dehydration and electrolyte disturbances. The administration of ATD therapy is not advocated. (Recommendation level A)
Question 37: What is the choice of treatment for women with Graves’ disease before pregnancy?
If a patient with Graves’ disease chooses surgical thyroidectomy or 131 iodine therapy, the following recommendations are made: (1) If the patient has a high titer of TRAb and plans to become pregnant within two years, surgical thyroidectomy should be chosen. This is because the quality of the fetus is affected by maintaining high TRAb titers for several months after the application of 131 iodine treatment [57]; (2) 48 hours before 131 iodine nail ablation treatment, a pregnancy test is required to verify pregnancy to avoid the radiation effects of 131 iodine on the fetus; and (3) pregnancy should not occur until 6 months after thyroid surgery or 131 iodine nail ablation treatment. This phase is treated with L-T4 replacement therapy to maintain serum TSH at 0.3 to 2.5 mIU/L levels.
If ATD therapy is chosen for patients with Graves’ disease, the following recommendations are important: (1) methimazole (MMI) and propylthiouracil (PTU) are risky for both mother and fetus; (2) MMI has a risk of fetal malformation, so it is recommended to stop MMI and switch to PTU before planning pregnancy. MMI to avoid the occurrence of hepatotoxicity of PTU.
Thyroid functional status during pregnancy is directly related to pregnancy outcome [58,59]. Poorly controlled thyrotoxicity is associated with miscarriage, gestational hypertension, preterm delivery, low birth weight, intrauterine growth restriction, stillbirth (fetal death at delivery), thyroid crisis, and maternal congestive heart failure [60].
Recommendation 7-4: Women with established hyperthyroidism should preferably become pregnant after thyroid function has been controlled to normal to reduce adverse pregnancy outcomes. (Recommendation level A)
Question 38: How are medications chosen to control hyperthyroidism that occurs during pregnancy?
Two types of antithyroid drugs (ATDs) are commonly used: MMI and PTU. Fetal developmental malformations have been reported with MMI, mainly skin dysplasia and “methimazole-related embryopathy”, including atresia of the posterior nasal aperture and esophagus and facial malformations [61]. Therefore, PTU is preferred before pregnancy and during T1 of gestation and MMI is avoided, but recently the US FDA reported that PTU may cause liver damage and even acute liver failure and recommended using PTU only during T1 of gestation to reduce the chances of causing liver damage [62]. Therefore, MMI is preferred except during T1. the equivalent dose ratio of PTU to MMI is 10:1 to 15:1 (i.e., PTU 100 mg = MMI 7.5-10 mg ). the starting dose of ATD depends on the severity of symptoms and serum thyroid hormone levels. In general, the starting dose of ATD is as follows.
day,or PTU 50-300mg/day in divided doses daily. For acute liver failure caused by PTU there is a lack of investigation reports in China. Changes in thyroid function and adverse drug reactions (especially blood and liver function) should be monitored during PTU and MMI conversion.
Beta-adrenergic receptor blockers, propranolol 20-30 mg/day every 6-8 hours, are helpful in controlling hyperthyroidism hypermetabolic symptoms. Application of long-term treatment with β-blockers is associated with intrauterine growth restriction, fetal bradycardia, and neonatal hypoglycemia, and their use should be weighed against the benefits and avoided for long periods of time [63]. β-adrenergic receptor blockers can be used in preoperative preparation for thyroidectomy. ,.
Recommendation 7-5: To control hyperthyroidism in pregnancy, PTU is preferred in stage T1 and MMI is a second-line option. mMI is preferred in stages T2 and T3.(Recommendation level E)
Recommendation 7-6: To control hyperthyroidism in pregnancy, the combination of ATD and L-T4 is not recommended. This is because it can increase the therapeutic dose of ATD and lead to hypothyroidism in the fetus. (Recommended level D)
Q39: What are the goals of hyperthyroidism control in pregnancy?
Anti-thyroid drugs can cross the placental barrier. To avoid adverse effects on the fetus, the control goal should be achieved with the lowest dose of ATD, i.e., maternal serum FT4 values close to or mildly above the upper reference value.
TSH and FT4 should be monitored every 2-4 weeks during the initiation of treatment and every 4-6 weeks after reaching the target value [64]. Overtreatment of ATD should be avoided because of the potential for fetal goiter and hypothyroidism [65]. Maternal serum FT4 is the primary monitor for hyperthyroidism control, as serum TSH is barely measurable during pregnancy. Serum TT3 is not recommended as a monitoring indicator because it has been reported in the literature that fetal TSH is already elevated by the time maternal TT3 reaches normal [66], except in pregnant women with T3 thyrotoxicosis. In terms of the natural course, hyperthyroidism in Graves’ disease may worsen in the T1 stage of pregnancy and gradually improve thereafter. Therefore, the dose of ATD can be reduced in the second half of pregnancy and can be discontinued in 20-30% of patients in the T3 stage of pregnancy [67], except in pregnant women with high levels of TRAb, in which case ATD should be continued until delivery, and exacerbation of Graves’ disease symptoms often occurs after delivery [68].
Recommendation 7-7: Serum FT4 is the preferred indicator of control for monitoring hyperthyroidism during pregnancy. the goal of control is to achieve a serum FT4 close to or mildly above the upper limit of the reference value. (Recommendation level B)
Recommendation 7-8: In women treated with ATD, FT4 and TSH should be monitored every 2-6 weeks. (Recommendation level B)
Question 40: Can surgical therapy be used to treat hyperthyroidism during pregnancy?
The indications for thyroidectomy for hyperthyroidism in pregnancy are: (1) allergy to ATD; (2) need for high dose ATD to control hyperthyroidism; and (3) patient non-compliance with ATD therapy. If surgery is determined, the T2 stage is the best time. Maternal TRAb titers are measured at the time of surgery to assess the potential risk of fetal hyperthyroidism [69]. Application of β-blockers and short-term potassium iodide solution (50-100 mg/day) for preoperative preparation is recommended [70].
Recommendations 7-9: In principle, surgical treatment of hyperthyroidism is not used during pregnancy. If it is really necessary, the best time to choose for thyroidectomy is the second half of the T2 phase. (Recommendation level A)
Question 41: What is the significance of TRAb titer measurement in pregnant women?
An elevated TRAb titer is a major marker of Graves’ disease activity and indicates the possibility of: (1) fetal hyperthyroidism; (2) neonatal hyperthyroidism; (3) fetal hypothyroidism; (4) neonatal hypothyroidism; and (5) central hypothyroidism. The development of these complications is dependent on the following factors: i) poorly controlled hyperthyroidism during pregnancy may induce transient fetal central hypothyroidism [66,67]; ii) excessive ATD is associated with fetal and neonatal hypothyroidism [68]; iii) high titers of TRAb at 22-26 weeks of gestation are a risk factor for fetal or neonatal hyperthyroidism [71]; iv) 95% of active Graves’ hyperthyroidism has TRAb titers are elevated and continue to be elevated even after thyroidectomy [57].
Indications for TRAb monitoring in Graves’ disease in pregnancy [72]: (i) active hyperthyroidism in the mother; (ii) history of radioactive iodine treatment; (iii) history of delivery of a hyperthyroid infant; and (iv) previous thyroidectomy for hyperthyroidism during pregnancy [69]. The incidence of fetal and neonatal hyperthyroidism in pregnant women with active Graves’ disease or a previous history of Graves’ hyperthyroidism is 1% and 5%, respectively, and failure to diagnose and treat the condition in a timely manner increases the incidence of fetal/neonatal hyperthyroidism and mortality [73].
Measurement of serum TRAb between 24 and 28 weeks of gestation is useful to assess pregnancy outcome, and a TRAb more than 3 times the upper reference value suggests the need for close fetal follow-up, preferably in collaboration with the treating maternal and infant physician. Therefore, testing at 24 to 28 weeks of gestation has been recommended [74], as antibody concentrations generally begin to decrease at 20 weeks of gestation.
Recommendations 7-10: Serum TRAb should be measured at 24-28 weeks of gestation if Graves’ disease hyperthyroidism, or if there is a previous history of Graves’ disease, and TRAb titers at this time are useful in assessing pregnancy outcome. (Recommendation level B)
Question 42: What is the diagnosis of fetal and neonatal hyperthyroidism?
The prevalence of fetal and neonatal hyperthyroidism in pregnant women with Graves’ disease is approximately 1%, and Mitsuda reported a 5.6% incidence of neonatal hyperthyroidism (including subclinical hyperthyroidism) and a 10.7% incidence of transient neonatal hypothyroidism in 230 pregnant women with Graves’ disease. Maternal thyroid-stimulating antibodies reach the fetus through the placenta and stimulate the fetal thyroid gland, causing hyperthyroidism. It occurs mainly in women with Graves’ disease who have a high titer of TRAb (TRAb > 30% or TSAb > 300%). The onset is usually in the T2 phase, with fetal hyperthyroidism first and neonatal hyperthyroidism after birth. The TSAb in the newborn lasts for an average of 1 month and can extend up to 4 months after delivery. As the TSAb disappears in the newborn, the hyperthyroidism resolves.
Fetal tachycardia is the earliest sign of suspected fetal hyperthyroidism. Heart rate >170/min for more than 10 minutes. (Normal values of fetal heart rate are: 21-30 weeks of gestation, 140 beats/min; 31-40 weeks of gestation, 135 beats/min). Fetal goiter is another important sign that occurs before tachycardia. Ultrasonography is the main method of detecting goiter, and thyroid volumes have been reported at different gestational ages. Ultrasonography can also detect accelerated fetal bone age and intrauterine growth retardation [75,76].
Signs and symptoms of neonatal hyperthyroidism usually appear around 10 days after birth and may be present immediately after birth or delayed until several days later due to the coexistence of maternal antithyroid drugs or suppressive antibodies. Newborns with risk factors for hyperthyroidism, such as evidence of functional thyrotoxicosis, maternal antithyroid medication during pregnancy, high maternal thyroid-stimulating immunoglobulin titers, and a family history of neonatal hyperthyroidism secondary to TSH receptor mutations, should be closely monitored for thyroid function after birth. The presence of significant thyrotoxicosis with increased serum FT3, FT4, TT3 and TT4 levels and decreased TSH is diagnostic of neonatal hyperthyroidism.
Treatment of neonatal hyperthyroidism includes antithyroid medications, iodine and other supportive symptomatic management. Neonatal hyperthyroidism due to thyroid-stimulated immunoglobulin is temporary and returns to normal when maternal antibodies are cleared from the neonate.
Recommendation 7-11: In pregnant women with high titers of TRAb, monitoring of fetal heart rate from the T2 stage and ultrasound examination of the fetal thyroid volume are required. Thyroid function should be closely monitored in newborns with high risk factors for hyperthyroidism.
Question 43: How is Graves’ hyperthyroidism treated during breastfeeding?
ATD is safe to take in moderation during breastfeeding. MMI should be preferred because of the hepatotoxicity of PTU. MMI doses up to 20-30 mg/day are safe for both mother and infant [77]. PTU can be used as a second-line drug, and 300 mg/day is also safe. Dosing is done in divided doses after breastfeeding and the infant’s thyroid function is monitored.
Recommendation 7-12: MMI should be preferred for antithyroid drugs during lactation, and a dose of 20-30 mg/day is safe. PTU is used as a second-line drug. ATD should be taken after lactation. (Recommendation level A)