Hyperthyroidism in pregnancy may pose a great threat to maternal and fetal health. The risk of hyperthyroid heart disease (HHD), even heart failure, is significantly elevated in pregnant women.

To investigate the clinical characteristics, prognosis, and therapy of HHD in pregnant women.

We searched the patient registry data at West China Second University Hospital of Sichuan University in Chengdu, China, following the approval by the Ethics Committee. We retrospectively analyzed the clinical characteristics of pregnant women diagnosed with HHD. The medical records of women with HHD during pregnancy from January 2012 to December 2017 were obtained from the electronic medical records system. All the included patients were followed in outpatient clinics and by telephone interviews until October 2018.

A total of 155 patients were diagnosed with thyrotoxicosis, of whom six were diagnosed with HHD. Three of them had regular antenatal care. Two patients were complicated with acute heart failure attacks, and one of them had a stillbirth. Both of these patients had a long history of Graves’ disease with poor treatment compliance. Treatments of precipitating factors such as the control of infection could relieve the symptoms and prolong gestation for a better prognosis. Hyperthyroid heart failure could be controlled with aggressive diuretics and management of the coexisting complications. Intense monitoring and timely anti-heart failure treatment were crucial in patients with severe cardiac damage. Our findings indicated the importance of regular antenatal care and treatment adherence in patients with hyperthyroidism.

The timely and accurate diagnosis of HHD and the implementation of effective management are important for a better prognosis in pregnant women with HHD. Improvement in patients’ awareness of thyrotoxicosis is needed.

Hyperthyroidism may pose great a threat to maternal and fetal health and may increase maternal and fetal mortality[1-3]. The prevalence of hyperthyroidism in pregnant women is about 0.05% to 3.0%, with approximately 85% of these cases resulting from Graves’ disease (GD)[1,4]. Cardiac function is greatly influenced by thyroid hormone levels, and an overload of thyroid hormones could can affect systematic hemodynamics and lead to high-output heart failure and cardiomyopathy[5]. Heart failure is rare when the basal high-output state is compensated in non-pregnant patients. However, the risk for developing to heart failure is elevated in pregnant patients with untreated thyrotoxicosis due to the increased cardiac burden during pregnancy[6,7], particularly in patients with precipitating factors such as preeclampsia, anaemia, and infection, in which cases, the hemodynamic workload is even more increased.

The management of hyperthyroidism in pregnancy includes the application of anti-thyroid drugs (ATDs) and regular monitoring of thyroid function[1,8]. The goal of treatment is to control thyrotoxicosis as early as possible to prevent further adverse pregnancy outcomes. Studies performed in developed countries implied the importance of immediate treatment and regular monitoring[7,9,10]. However, in China, there are economically undeveloped areas where patients rarely have antenatal care. Ignorance of doctors’ suggestions is common in patients of lower socioeconomic levels. The implementation of the “two-child” policy might make this problem even worse. The aim of our retrospective study was to review clinical cases of pregnant patients with hyperthyroid heart disease (HHD) enrolled at our hospital in order to evaluate maternal and fetal outcomes and provide a supplement to the literature.

During the 5-year study period, 69389 women delivered at our hospital. A total of 155 patients were diagnosed with hyperthyroidism, and six patients were diagnosed with HHD, with the New York Heart Association classification of cardiac function ranging from III to IV. Two of the patients with HHD were further complicated with acute heart failure attacks. Both of these two patients had been previously diagnosed with GD but used ATDs irregularly without thyroid function monitoring or preconception counselling. Only three patients had regular antenatal care. Another patient never had antenatal care during pregnancy. Thyroid function tests revealed that the total thyroxine (T4) and triiodothyronine (T3) levels ranged from 176.8 nmol/L to 390.0 nmol/L and 2.99 nmol/L to 7.67 nmol/L, respectively. The plasma levels of thyroid globulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) were very high in these six patients. The follow-up of these patients showed good outcomes. Tables 1 and 2 present the clinical features of the six patients.

The number of gestational weeks at delivery ranged from 31 + 4 wk to 39 + 4 wk. Two patients experienced acute heart failure attacks in the second stage of labour. Vacuum and forceps were implemented in these patients to shorten the labour time. One patient who had a stillbirth had several heart attacks even after delivery. NIPPV and CRRT were used. The other patient responded well to aggressive diuretics and cardiac glycosides. This was confirmed by chest radiography and echocardiography. Figure 1 presents the echocardiography, and Figure 2 presents the comparison of chest X-rays. Two patients were enrolled with manifestations of heavy cardiac burden, but after receiving appropriate treatments for GD and precipitating factors, both patients responded well and prolonged their pregnancy. Two healthy preterm infants were born vaginally at 33 wk and 36 wk, respectively. These two patients did not present any symptoms of heart failure during labour. Table 3 shows the changes in thyroid hormone levels in these two patients. Another two patients who had regular antenatal care chose an elective caesarean section delivery, and two healthy full-term infants were born. In these six patients, the identified precipitating factors included anaemia, preeclampsia, pulmonary infection, and suspected chorioamnionitis. All of the patients’ symptoms were relieved to a certain extent after the precipitating factors were treated.

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Figure 1 Echocardiography showing moderate mitral regurgitation in patient 2.

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Figure 2 Chest X-ray for patient 2. A: Chest X-ray on admission showing significant cardiomegaly and right pleural effusion. B: Repeat chest X-ray showing resolution of cardiomegaly and right pleural effusion.

The prevalence of thyrotoxicosis in pregnant women in our study was 0.22%, which is lower than that in other provinces of China[11,12]. Six of 155 patients were diagnosed with HHD, and the incidence of heart disease in the pregnancies with thyrotoxicosis was 3.87%. The clinical course and progression were different in these six patients. First, we found that the pregnancy outcomes were favorable in patients with regular antenatal care, regular ATD treatment, and continuous monitoring of maternal and fetal conditions. However, in patients without regular antenatal care who deliberately disregarded their doctors’ suggestions, the risk of adverse pregnancy outcomes was highly elevated. Particularly in patients with a long history of GD but with poor medical compliance, HHD could pose a great threat to maternal and fetal health. Second, most patients had precipitating factors, including infection, anemia, or preeclampsia. Treatment of these precipitating factors could relieve the symptoms. Prolongation of gestation for a better prognosis for the fetus is possible when the maternal cardiac burden is reduced. Considering the existing cardiac load, magnesium sulfate but not ritodrine should be applied for the prevention of preterm birth in these patients. Third, hyperthyroid heart failure responded quickly to diuretic treatment and the control of the coexistent complications. In patients with severe cardiac damage, intense monitoring of vital signs and timely treatment against acute cardiac failure attacks are still very important even after delivery.

The prognosis and pregnancy outcomes in our reported patients were similar to those reported in the literature. Sheffiled et al reported 13 patients with thyrotoxicosis, 6 of whom had heart failure. Similar decompensation reasons, such as hemorrhage and sepsis, were revealed in their study[7]. Mannisto et al analyzed singleton pregnancies from 2002 to 2008 in a single center and found that hyperthyroidism significantly elevated risks for preeclampsia, preterm birth, and ICU admission[9]. Thirty patients from a prospective study in Ukraine reported relief of cardiac symptoms following ATD treatment and improvement in the health-related quality of life[10]. The importance of good compliance and regular use of ATDs were also implicated in other studies[13,14].

Patients with HHD may have various manifestations, and focusing on the cardiac symptoms and ignoring thyroid hormones test results may lead to delays in diagnosis. One of the six patients had never been diagnosed with GD before, the first hospital that was visited provided blood transfusion for anemia and antibiotics, and these therapies partially relieved some symptoms. In pregnant patients, the correct diagnosis and administration of effective management of hyperthyroidism might be even more difficult. Both pregnancy and hyperthyroidism could manifest with symptoms of hyperdynamic circulation and hypermetabolism. The diagnosis of hyperthyroidism should be suspected if the women presents with specific symptoms like exophthalmos or symptoms of hyperdynamic circulation and hypermetabolism. A systematic blood screening including thyroid function test is also very important and sometimes might compensate if the clinical symptoms are ignored.

All six patients had symptoms including dyspnea, orthopnea, or chest tightness at 30-34 wk when the aggravation of cardiac burden was most obvious due to the expansion of blood volume. Duration and inadequate control are the main factors impacting prognosis[2,8,15]. Four of our patients were diagnosed with GD before enrollment, but only two of them adhered to ATD treatment. Differences in treatment compliance determined their differences in pregnancy outcomes. Two patients in our study had acute heart failure attacks. In a retrospective study conducted in America including 13 patients with HHD, most of the patients were also at the third trimester with precipitating factors[7]. As the heart is the main target organ of thyroid hormone, hyperthyroidism can lead to several adverse changes in cardiac function[5,16]. Increased catecholamine function and activation of the renin-angiotensin-aldosterone system also contribute[3,5]. The main manifestations of thyrotoxic cardiomyopathy include left ventricular hypertrophy, disturbances in heart rhythm, atrial fibrillation, enlargement of the heart chambers, and heart failure[5,16]. These symptoms were all present in our two patients. Hyperthyroid heart failure is considered as “curable” after the achievement of a euthyroid state, and the patient usually responds quickly to aggressive diuretics[7,14]. However, in the patient who had a stillbirth, the cardiac function was damaged irreversibly due to the long-term exposure to the thyrotoxicosis status. NIPPV and CRRT were applied. Effective treatment by a multidisciplinary medical team including obstetricians, paediatricians, cardiologists, endocrinologists, anaesthetists, and intensive care unit doctors is needed.

ATD is the first line treatment for hyperthyroidism in both nonpregnant and pregnant patients. All of our patients received ATDs, and most of the cardiovascular symptoms were relieved. A Ukrainian study revealed the beneficial effects of ATD treatment on health-related quality of life (HRQoL)[10]. Pregnancy and breastfeeding are the absolute contraindications to radioiodine therapy (RAI), and those who accepted RAI treatment should use contraception methods for at least for 6 mo[8]. One of our patients had RAI before pregnancy. She had good compliance after RAI and counselled with multidisciplinary doctors before her pregnancy. Patients who received thyroidectomy, similar to RAI, should also avoid pregnancy for 6 mo to obtain a euthyroid state and improve the successful conception rate[3,8].

ATD drugs, including MMI and PTU, are commonly used among pregnant patients with thyrotoxicosis. Both PTU and MMI can cross the placenta at comparable rates and influence fetal thyroid function. PTU has been preferred over MMI in the first trimester due to the considerably lower risk for birth defects[1,8]. But a recent study showed that there was no difference in rates of congenital malformations between women treated with MMI and those treated with PTU[17]. Reports have indicated that the rates of birth defects in PTU and MMI are similar to the overall birth defect rate in America and even lower than the birth defect rate in China[18-20]. One of our patients with regular antenatal care received PTU until the second trimester, and then she was treated with MMI. A follow-up interview of our patients showed a preference for MMI over PTU after delivery. Thyroid stimulating hormone receptor antibodies can also enter the infant’s circulation and cause fetal GD. None of the newborns of our patients were found to have GD or congenital defects. Considering the high relapse rate of GD in the puerperium period, suggestions of continuous ATD treatment were given to our patients. In all the patients diagnosed with HHD in our hospital, appointments for thyroid and heart function assessments in the puerperium period were made before discharge from the hospital, which ensured a better prognosis even after delivery.

This study addresses a significant gap in the literature on the outcomes of HHD in pregnant women in Southwest China. An extensive search of the medical record system and good follow-up ensured that detailed clinical data of importance, including blood test results and imaging examinations, were analyzed. These patients were enrolled from a single medical center and, therefore, ascertained the same diagnostic criteria, treatment, and prenatal monitoring. However, this study has limitations that should be noted. Medical records rather than direct patient interviews were used, and some information provided in the follow-up may have led to recall bias. As this was a summary of a single-center experience, the results from this study may not be generalizable to economically developed cities.

Our findings indicated the importance of regular antenatal care and treatment adherence in patients with hyperthyroidism. The importance of a multidisciplinary medical team to ensure timely and effective management in pregnant women with HHD and better prognoses for both mothers and infants was also implied. Making the correct diagnosis of HHD in pregnant women is difficult yet essential for the administration of effective management. Precipitating factors should be effectively eliminated to reduce the cardiac burden. Patients with GD should adhere to an anti-thyroid regimen as soon as possible after the diagnosis is confirmed. Consultation before pregnancy is needed. Improvement in antenatal care and enhanced awareness of thyrotoxicosis in pregnant women are needed, especially in rural and urban areas.