Introduction
Neonatal hyperthyroidism (NH) is an uncommon condition that affects 1–5% of newborns born to mothers who have active or past Graves’ disease (GD) [
1], and it affects 22% of pregnant women who need to take long-term antithyroid drugs (ATDs) treatment. Autoimmune NH is related to the transplacental passage of maternal anti-thyrotropin receptor antibodies (TRAbs) [
2]. The fetal thyroid gland becomes responsive to thyroid-stimulating hormone (TSH) and TRAbs at around 20 weeks of gestation [
3], those antibodies stimulating the fetal thyroid, cause in-utero and/or postnatal hyperthyroidism. Fetal hyperthyroidism can cause goiter, heart failure with nonimmune hydrops, advanced bone maturation, intrauterine growth retardation, preterm birth, and even fetal death [
4]. When fetal hyperthyroidism is present, there is a high probability of neonatal thyrotoxicosis, which is usually temporary and goes away in 4 to 6 months after birth following clearance of maternal TRAbs. Signs and symptoms of neonatal hyperthyroidism include goiter, tachycardia, poor feeding, irritability, tremors, sweating, and difficulty sleeping [
5]. There are occasional cases of proptosis, craniosynostosis, and microcephaly. Without prompt treatment with antithyroid drugs, cardiac failure and death may occur [
6].
At present, there are only more than 50 cases of NH reported in China. Due to the diversity and lack of specificity of the clinical manifestations of the disease, clinicians lack understanding of the disease, which is easy to be overlooked or misdiagnosed [
7]. To improve knowledge of early identification and treatment of NH, our study presented one case of NH with prominent clinical signs of liver and cardiac dysfunction, whose mother had received GD therapy with radioactive iodine four years prior.
Discussion
In this study, we report a typical case of NH with critical condition and impaired liver and cardiac function as the main clinical manifestations. The patient’s mother had been receiving oral euthyrox treatment since undergoing Iodine 131 radiotherapy for GD four years ago. However, TRAbs levels were not monitored during pregnancy. NH was diagnosed on the 15th day after birth. During the period, a multi-disciplinary consultation was conducted to screen for infectious diseases, inherited metabolic diseases, rheumatic immune diseases, and, other conditions. The diagnosis process was complex, providing valuable experience for future NH diagnoses.
The prevalence of hyperthyroidism in pregnancy ranges from 0.7 to 2.8% worldwide [
9,
10], with GD as the most common etiology [
11]. During pregnancy, thyroid autoantibodies can cross the placenta and either stimulate (thyroid stimulating antibody - TSAb) or block (thyroid blocking antibody - TBAb) the fetal thyroid gland [
4]. Maternally transferred antibodies can temporarily affect the thyroid function of the fetus and newborn until they are metabolized. High levels of TSAb transmission are associated with fetal and neonatal thyrotoxicosis, while maternal TBAb can lead to congenital hypothyroidism [
12]. The impact on thyroid function in the fetus and newborn depends not only on the type of maternal antibodies but also on their levels. Autoimmune hyperthyroidism can also occur in children born to mothers who were treated for GD in the past and still have detectable circulating TRAbs [
13], similar to our patient. TRAbs measurement is not routinely performed in mothers with hyperthyroidism in our hospital, which presents a challenge in identifying those who may develop NH. In our case, the mother’s TRAb levels were not regularly monitored during the 4 years after Iodine-131 radiotherapy, including pregnancy, although she was taking oral euthyrox and had stable thyroid hormone levels within the normal range. Obstetricians and neonatologists often overlook mothers with high-risk factors, leading to misdiagnosis and delayed diagnosis in newborns born to such mothers due to a lack of sufficient understanding in managing these cases.
In China, it is recommended that TRAb should be monitored from 20 to 24 weeks of gestation in pregnant women with a history of Graves’ disease or delivery of a newborn with hyperthyroidism, regardless of whether they have received effective treatment. The American Thyroid Association (ATA) 2016 guidelines [
14] recommend that patients with Graves’ disease should be tested for serum TRAb in the first trimester of pregnancy. If TRAb levels are elevated, reexamination should take place at 18–22 and 30–34 weeks of gestation. A TRAb level of ≥ 5 IU/L or > 3 times the upper limit of the reference value indicates a high risk of fetal/neonatal hyperthyroidism. Pregnant women with positive TRAb results should undergo a fetal thyroid ultrasound examination to further evaluate fetal thyroid function. Therefore, for high-risk pregnant women with a history of thyroid disease, it is crucial to detect thyroid function and serum TRAb as early as possible. Close observation of early symptoms of hyperthyroidism is the key to early diagnosis.
The clinical manifestations of NH are non-specific and diverse [
8], including tachycardia, irritability, irritability, thrombocytopenia, liver damage, jaundice, shortness of breath, hypoglycemia, hyperhidrosis, premature synostosis, intrauterine growth restriction, growth retardation, goiter, exophthalmia, pulmonary hypertension, hip dysplasia, etc. In severe cases, microcephaly, heart failure, long-term neurodevelopmental delay, and even death may occur. In our study, the neonate presented with growth retardation, tachycardia, cardiac insufficiency, dyspnea, thrombocytopenia, liver injury, and hepatosplenomegaly. Similar cases are often mistaken for intrauterine infection, sepsis, meconium aspiration, and other diseases. The main clinical manifestation in our case is damage to liver and heart function, particularly cholestatic hepatitis [
15], which is rare in NH and complicates the clinical diagnosis. Therefore, the crucial aspect in treating liver damage induced by hyperthyroidism is to manage hyperthyroidism itself. Once diagnosed, prompt administration of anti-hyperthyroidism treatment is essential.
Due to the unique nature of the neonatal period, delayed diagnosis and treatment can hurt the physical growth and neurodevelopment of newborns. It is recommended to use ATDs early in neonates showing clinical symptoms of hyperthyroidism, with MMI being the preferred choice. PTU (propylthiouracil) should only be used for a short period in patients experiencing hyperthyroidism crises or severe adverse reactions to MMI. In this case, the patient was administered oral MMI at a dose of 0.5 mg/ kg, Bid. Propranolol (1–2 mg /(kg·d), Bid) can help reduce heart rate and inhibit the conversion of peripheral T4 to T3, especially in patients with increased heart rate. The patient’s heart rate significantly decreased after propranolol was added to her treatment plan. For patients with respiratory and heart failure, it is important to provide respiratory and circulatory support. Short-term glucocorticoids [hydrocortisone 2.5–10 mg /(kg·d), Tid; prednisone 1–2 mg /(kg·d), Bid] can be used to reduce T4 synthesis and peripheral T4 to T3 conversion [
16]. In severe cases, intravenous immunoglobulin (1 g/kg for 2 days) may be administered [
17]. Adequate caloric supply is crucial in the nutritional support of neonatal hyperthyroidism, and the average course of ATDs treatment for NH is 1 to 3 months. During the initial stage of treatment, thyroid function should be regularly monitored every 1 to 2 weeks to adjust the drug dose. The symptoms gradually disappear with the decrease of TRAb concentration, and treatment can be discontinued when TRAb is negative [
16]. In our patient’s case, the total duration of methimazole treatment was 29 days, and the first improvements were FT3 and FT4 levels, with TSH returning to normal levels 13 days after discontinuation of the medication.
Pregnancy complicated with hyperthyroidism has hypermetabolism, increased nerve and muscle excitability, which can lead to uterine contraction and vasospasm, affect placental development, and cause intrauterine growth retardation, low birth weight, premature delivery, asphyxia, and even stillbirth or abortion [
7,
18]. In this particular case, the mother had thyroid disease and gave birth to a test-tube baby who was premature and experienced asphyxia after birth. This suggests that maternal thyroid disease can result in complications for the neonate or fetus. Normally, NH is transient and self-limited, resolving within 3–12 weeks. However, in cases of hyperthyroidism crisis, the mortality rate can be as high as 15-20% [
6]. Persistent cases are rare, mostly caused by gene mutations such as TSHR and GNAS, which can be inherited dominantly or occur as de novo mutations [
6]. Fortunately, in this case, the child was considered to have transient hyperthyroidism, and her thyroid function returned to normal at the age of 57 days without any lasting effects. It is important to regularly monitor the physical and neurodevelopment of children with hyperthyroidism after discharge.
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