Neonatal hyperthyroidism in an extremely low birth weight infant born to a mother with Graves’ disease

Abstract

Neonatal hyperthyroidism (NH) mostly commonly occurs in infants born to mothers with Graves’ disease. NH in extremely low birth weight (ELBW) infants has been rarely described. Here, we report a case of NH in an infant born at 29 wk 6 d of gestation with a birth weight of 825 g. The mother had untreated Graves’ disease during pregnancy. During the 2^nd wk of life, the infant developed persistent tachycardia (heart rate > 160 beats per min). Diagnosis of NH was made according to the results of her thyroid function: thyroid-stimulating hormone,< 0.005 mU/L (Reference range: 0.8–12.0 mU/L); free triiodothyronine, 5.1 pg/mL (Reference range: 2.3–4.2 pg/mL); free thyroxine, 38.5 pmol/L (Reference range: 10–33 pmol/L); and thyroid-stimulating hormone receptor antibody, 7.6 IU/L (Reference range: ≤ 1.22 IU/L). Carbimazole was administered. After 1 wk of treatment, levothyroxine was added due to a rapid decline in thyroid function. The treatment regimen was adjusted to achieve normal thyroid function. Her heart rate normalized with no significant hemodynamic instability or long-term complications during her hospitalization or follow-up visits. NH should be considered in ELBW infants with a maternal history of Graves’ disease who present with persistent tachycardia. Monitoring thyroid function may be required more closely in ELBW infants when NH management is administered.

Highlights

● A rapid response of thyroid function to treatment may occur in extremely low birth weight infants with hyperthyroidism.

● Close monitoring of thyroid function should be considered in extremely low birth weight infants within 1 week of treatment for hyperthyroidism.

Introduction

Neonatal hyperthyroidism (NH) mostly occurs in infants born to mothers with Graves’ disease. Although NH has also been reported in newborns of mothers with other autoimmune thyroid diseases, maternal Graves’ disease remains the most common cause of NH (1, 2). NH occurs in 1–5% of infants born to mothers with Graves’ disease and is usually caused by the transfer of maternal thyroid-stimulating hormone receptor antibody (TSHR-Ab) to infants (3). The transplacental passage of TSHR-Ab and antithyroid medications from mothers with Graves’ disease to infants during the second and/or third trimester of pregnancy contributes to the development of NH (1, 3). Despite being commonly transient and self-limiting, hyperthyroidism in newborn infants can be severe and even life-threatening and may affect long-term outcomes, including growth and neural development, if appropriate management is not administered (3). Previous studies have reported congenital hyperthyroidism in low and very low birth weight (VLBW) infants (4, 5). The clinical presentation and management of NH in patients with low and VLBW have been well described. To the best of our knowledge, hyperthyroidism has been rarely reported in extremely low birth weight (ELBW) infants compared to low and VLBW infants. However, data on the clinical manifestations, management, and thyroid function response in ELBW newborns with NH due to transplacental transfer of maternal TSHR-Ab are lacking.

Case Report

A female infant was born at 29 wk 6 d of gestation to a 27-yr-old mother gravida 2 (para 1). The mother was transferred from a local hospital to our facility due to severe preeclampsia and suspected fetal distress. The infant was delivered via emergency cesarean section. The Apgar scores at 1, 5, and 10 min were 3, 5, and 6, respectively. Her birth weight, head circumference, and body length were 825 g (< 10^th percentile), 24 cm (≈ 3^rd percentile), and 36 cm (≈ 10^th percentile), respectively (6). She was intubated 7 d for respiratory distress syndrome. On day 10 of life, the infant presented with persistent tachycardia. Electrocardiography revealed sinus tachycardia with a heart rate > 160 beats per min. Echocardiography revealed no abnormalities. On physical examination, the infant’s body temperature and oxygen saturation were within normal ranges. Complete blood counts revealed no anemia, and sepsis screening was normal. Neonatal hyperthyroidism (NH) was suspected based on the infant’s clinical presentation. Her thyroid function was thyroid-stimulating hormone (TSH), < 0.005 mU/L (Reference range: 0.8–12.0 mU/L); free triiodothyronine (fT3), 5.1 pg/mL (Reference range: 2.3–4.2 pg/mL); free thyroxine (fT4), 38.5 pmol/L (Reference range: 10–33 pmol/L), and TSHR-Ab, 7.6 IU/L. NH caused by the transplacental transfer of TSHR-Ab has been diagnosed (7). The mother’s thyroid function was measured after diagnosis. Maternal thyroid function was TSH, < 0.005 mU/L (Reference range: 0.3–3.0 mU/L); fT3, 12.1 pg/mL (Reference range: 2.0–4.4 pg/mL); fT4, 60.49 pmol/L (Reference range: 9.26–13.64 pmol/L), and TSHR-Ab, 26.88 IU/L (Reference range: ≤ 1.22 IU/L). The maternal history revealed that patient’s mother had Graves’ disease and had received no treatment during pregnancy. 0.5 mg/kg per d of carbimazole was administered. After 1 wk of treatment, her thyroid function decreased as follows: TSH, 0.016 mU/L; fT4, 13.8 pmol/L. Due to the rapid decline of thyroid function, supplementation of levothyroxine (LT4) 5mcg/kg per d was added. The treatment regimen was adjusted to achieve a normal thyroid function (Fig. 1). Her hemodynamic status remained stable, and heart rate normalized within 2 wk after carbimazole was initiated. The infant’s thyroid function and TSHR-Ab were routinely monitored, and serial results revealed that TSHR-Ab was undetectable and thyroid function remained within normal range at 2 mo and 4 mo of life, respectively. Therefore, the carbimazole and LT4 treatments were discontinued. The infant no longer required oxygen support by day 19. The patient was discharged at the age of 1 mo and 7 d. Her growth and development did not show any significant abnormalities during hospitalization or follow-up visits.

Fig. 1.

The infant’s thyroid function during hospitalization and follow-up visits. TSH, thyroid-stimulating hormone; fT4, free triiodothyronine; CMZ, Carbimazole; LT4, Levothyroxine.

Discussion

Here, we report a case of transient hyperthyroidism in an extremely low birth weight (ELBW) infant born to a mother with uncontrolled Graves’ disease. Infants born to mothers who do not receive treatment for Graves’ disease may develop hyperthyroidism at birth or shortly thereafter, and are commonly diagnosed within the first 2 wk of life (8). Infants with neonatal hyperthyroidism (NH) may present with low birth weight, hyperthermia, irritability, diarrhea, feeding difficulties, poor weight gain, goiter, or tachycardia (9). Common clinical presentations of NH are nonspecific and may overlap with those of other diseases. Maternal history and thyroid-stimulating hormone receptor antibody (TSHR-Ab) levels can help predict the development of NH in newborns (1). Similarly, our patient presented with tachycardia, a common but nonspecific sign of hyperthyroidism in newborn infants during the 2^nd wk of life. An infant’s thyroid function test was performed, and hyperthyroidism was subsequently diagnosed. The infant’s thyroid function was not tested until she became symptomatic because maternal history was not initially recognized, and she remained asymptomatic until the 2^nd wk of life. Maternal thyroid function after the baby’s diagnosis showed significantly elevated TSH, decreased fT4 levels, and a high level of TSHR-Ab. In a previous case report, neonatal thyrotoxicosis in ELBW infants was made on day 10 of life, likely due to a lack of attribution to symptoms (4). Therefore, patients who are asymptomatic and clinically overlooked may be characteristic of ELBW infants. However, further studies are required to address this issue. Maternal history of thyroid diseases and TSHR-Ab status are important clues for diagnosing NH in ELBW infants, as most may be clinically asymptomatic or underestimated.

Currently, guidelines for the management of hyperthyroidism in newborns are lacking. In previous studies, the management of NH varied from clinical follow-up to treatment with antithyroid drugs alone or a combination of antithyroid drugs and β-adrenergic blockers, depending on the infant’s thyroid function and clinical presentation (4, 8,9,10). Management is recommended for infants with clinical symptoms and biochemical hyperthyroidism to prevent cardiac failure and neurological impairments (9). For those with no symptoms, treatment remains inclusive because the threshold of fT4 for treatment differs from one study to another (5, 8). Because propylthiouracil (PTU) has been reported to cause frequent acute liver failure in children, it should not be prescribed as a first-line agent in children, according to recommendations from a report by the American Thyroid Association and the Food and Drug Administration in 2009 (11). Therefore, carbimazole was selected as the treatment of choice for hyperthyroidism in infants. LT4 was administered due to a rapid decline in thyroid function. The concomitant use of carbimazole and LT4 (so-called block and replace therapy) is not recommended in current guidelines for managing Graves’ disease in children and adults (12). However, there are no consensus guidelines for the management of neonates born to mothers with Graves’. In a previous study and case report, LT4 was added to antithyroid drugs to optimize neurodevelopmental outcome when the fT4 level was below normal range (8, 13). Furthermore, Smith C and colleagues reported that hypothyroidism does not respond to carbimazole withdrawal and subsequently requires LT4 (4). To our knowledge, the available evidence remains controversial regarding the concomitant use of antithyroid drugs and LT4 in infants and is lacking for the management of hyperthyroidism in ELBW neonates. Our case report may provide evidence for optimizing the management of neonatal thyrotoxicosis in infants with ELBW. Propranolol may be added in cases of sympathetic hyperactivity such as tachycardia, hypertension, or poor feeding (9). In our case, the infant presented with only isolated tachycardia, and cardiac function was closely monitored during hospitalization, with no hemodynamic instability. Therefore, propranolol was excluded from the treatment regimen. Similar to thyroid function monitoring in low and VLBW infants, this infant’s thyroid function and TSHR-Ab were routinely monitored every 1–2 weeks. fT4 decreased remarkably within 1 week of carbimazole treatment. In our case, fT4 fell to the lower half of the normal range within 1 week of treatment initiation. Similar to our report, two ELBW infants were reported to have a rapid decline in fT4 concentration within 48 hours after treatment, suggesting that the response to treatment occurs more rapidly in ELBW infants than in low and VLBW infants (4). ELBW infants should therefore be monitored regularly, particularly within 1 week of treatment. Serial results revealed that the infant’s TSHR-Ab was not detected, and thyroid function was within the normal range until she was 2 mo and 4 mo of life, similar to low and VLBW infants in previous studies (14, 15).

In summary, the clinical presentation of hyperthyroidism in an ELBW infant born to a mother with Graves’ disease may be nonspecific and overlap with other diseases. Maternal history and TSHR-Ab levels help predict NH in ELBW infants. Monitoring thyroid function may be more frequent in ELBW infants than in low and VLBW infants when NH is administered.

Conflicts of interests

The authors have nothing to disclose.