1 Introduction

Neonatal hyperthyroidism is usually a transient condition and is mostly caused by neonatal Graves’ disease (GD) secondary to the transplacental passage of maternal TSH receptors antibodies (TRAb). GD affects 0.2% of pregnant women; 1–12.5% of the babies produced by this specific cohort may develop fetal/neonatal thyrotoxicosis [1]. Classic manifestations include tachyarrhythmia, heart failure, hypertension, vomiting, diarrhea, failure to gain weight, goiter, exophthalmos, craniosynostosis, hypoglycemia, polycythemia and thrombocytopenia [2]. Anti-thyroid drugs are vital for the management of neonatal thyrotoxicosis [3].

2 Case Description

Here, we report a preterm male baby that was born at 34 weeks of gestation by an emergency cesarean section due to fetal tachycardia and antepartum hemorrhage. His mother presented with palpitation, irritability, flushing, tremors, shortness of breath, low TSH (< 0.008 mIU/l), high free thyroxine (FT4) (40 pmol/l), high free triiodothyronine (FT3) (> 30 pmol/l) and high serum TRAb (40,000 IU/l). One day before delivery, she was started on carbimazole, propranolol, dexamethasone and lorazepam therapy. Delivery was uneventful. The baby was admitted to the NICU due to respiratory distress (RD), intrauterine growth retardation (IUGR, 1900 g) and to screen for neonatal thyrotoxicosis. The baby was initially admitted on nasal continuous airway pressure (NCPAP). Echocardiography (ECHO) on day one revealed only small atrial septal defect (ASD) and mild ventricular hypertrophy. Initial investigations revealed a TSH < 0.0083 mIU/l, FT4 22.5 pmol/l, FT3 2.5 pmol/l, TRAb 40,000 IU/l, direct serum bilirubin (DSB) 59 µmol/l, alkaline phosphatase (ALP) 442 IU/l, gamma glutamyl transferase (GGT) 307 IU/l, alanine transaminase (ALT) 60 IU/l and aspartate transaminase (AST) 56 IU/l.

The baby was started on carbimazole (0.3 mg/kg/day.) He was initially stable and weaned gradually to room air and started feeding in accordance with the NICU protocol. On day 10, the baby started to be tachypneic with labile Spo2, irritability and tachycardia. The levels of FT4 and FT3 began to rise steadily. There was also persistent cholestasis. The baby was then supported with a high flow nasal cannula (HFNC). Repeated ECHO revealed a small ASD, left to right shunt, mildly dilated and hypertrophied right ventricle (RVH), good function, ventricular septum bulging to the left indicating moderate pulmonary hypertension (PH) with no tricuspid regurgitation (TR) to calculate the RV Pressure. As a part of the work-up for cholestasis, abdominal ultrasound was unremarkable. Urinary analysis was negative for reducing substances and newborn metabolic screening was normal. The dose of carbimazole was upgraded; we also commenced oral propranolol and ursodiol. Over time, the baby improved gradually and became calmer; in addition, heart rate (HR) and oxygen saturation returned to normal on room air, with improving liver function and thyroid profile. The baby was then discharged home on day 20 of life with a body weight of 2405 g, on propranolol, carbimazole and ursodiol for regular follow-up in the clinic. Thyroid and hepatic functions were normalized by the 8th week of life and all medications were then discontinued. The baby was doing well on the next visit on day 15. The inpatient and outpatient course is summarized in Table 1.

Table 1 Inpatient and outpatient course of the patient
Full size table

3 Discussion

Neonatal thyrotoxicosis is caused by the transplacental passage of an immunoglobulin known as TRAb and can refer to either TSH receptor stimulating antibodies (TSI) or TSH receptor blocking antibodies (TBI) [1]. Although a transient problem, this condition may be associated with significant mortality and morbidities including heart failure and craniosynostosis. This disease may manifest immediately after birth or be delayed by up to 10–45 postnatal days depending on the level of TRAb, the balance between TSI and TBI and the maternal use of antithyroid medications [2].

In our case, the baby was admitted into the NICU for observation and to screen for neonatal thyrotoxicosis. Aside from IUGR, the classic manifestations did not become evident until around the 10th postnatal day.

Because of the extremely high levels of TRAb, the baby was started on anti-thyroid medications (low dose carbimazole) from the 1st postnatal day. Carbimazole (or its metabolite methimazole) is the drug of choice in neonates because of the hepatotoxic effects of propylthiouracil. Increased liver enzymes, but rarely hepatotoxicity, may be observed when administrating carbimazole/methimazole [3].

On day 10, the baby showed both clinical and chemical evidence of hyperthyroidism. Thus, the dose of carbimazole was upgraded. Propranolol therapy was also commenced due to significant tachycardia. Propranolol does not only reduce tachycardia in hyperthyroidism, but may also reduce the peripheral transformation of T4 to T3 [2].

Besides the usual manifestations reported in the literature for neonatal thyrotoxicosis, this baby presented with an additional two uncommon manifestations: PH and cholestasis.

The diagnostic workup for neonatal cholestasis included abdominal ultrasound, metabolic screening tests and urinary analysis for reducing substances; these tests were all normal. Unlike in adults, cholestasis is a rare finding in neonatal thyrotoxicosis. Our case presented with the laboratory features of cholestasis since day one of life. The disease improved over time after the initiation of carbimazole therapy. A very similar case was previously reported by Raghu et al. in a preterm baby with thyrotoxicosis that was born to an undiagnosed mother with GD. Diagnosis and treatment were not commenced until the 25th postnatal day [4]. Loomba-Albrecht and associates described a neonate who presented with cholestasis on day 15 of life with a normal workup for cholestasis. The mother reported that she had GD and was taking anti-thyroid medications. Cholestasis improved after starting anti-thyroid medications [5]. Another two cases were also reported by Almadhoun et al. Both cases were preterm babies that presented with tachypnea, tachycardia, PH, cholestasis and thrombocytopenia. Their mothers had previous histories of thyrotoxicosis and were treated with radioactive iodine; both mothers became hypothyroid and were placed on thyroxine replacement therapy. The thyroid profiles of the babies showed evidence of GD and both were started on carbimazole therapy; this led to a gradual improvement of manifestations [6]

The exact mechanism for cholestasis is not fully understood. T3 plays a role in bilirubin metabolism and increased levels are thought to cause the accumulation of bilirubin precursors. T3-induced hepatic apoptosis was also considered. Heart failure may also contribute to cholestasis [7].

The other unusual manifestation in our case was the presence of PH. The clinical (unstable Spo2) and ECHO evidence (bulging septum towards left side) became evident on day 10 when other clinical (irritability, tachycardia) and laboratory (high FT3 and FT4) evidence of thyrotoxicosis was also noticed. A significant improvement was evident after maximizing the dose of carbimazole.

In a similar report, Obeid et al. reported a 9-day-old male baby with RD and PH. His mother had GD and was receiving propylthiouracil therapy [8]. Markham et al. also reported PH in a preterm neonate delivered by a mother with GD [9]. Similarly, Meng et al. described a 12-day-old baby with PH, RD and tachycardia. All babies recovered after starting oral methimazole [10]

The exact association of PH in hyperthyroidism is unclear although proposed mechanisms include high cardiac output-induced endothelial injury, impaired production and the increased metabolism of intrinsic pulmonary vasodilating substances and reduced clearance of pulmonary artery vasoconstrictors [11].

Clinical symptoms were almost under control by the second postnatal week while the levels of FT3 and FT4 had normalized by day 30. It was not until day 60 that the levels of TSH and TRAb normalized. In general, the suppressive action of anti-thyroid drugs needs 1–2 weeks in term babies but can occur more rapidly in preterm babies [12]. Neonatal GD usually subsides in 8–20 weeks with the clearance of TRAb [2].

4 Conclusions

All babies who are positive for TRAb (regardless of manifestations) need to be observed in the NICU for at least the first 2 weeks-of-life. Neonatal thyrotoxicosis may be associated with transient cholestasis and thus further work-up may be unnecessary. This condition may be also complicated by PH. Treatment with anti-thyroid medications reduces the need or duration of other potentially injurious interventions for PH such as mechanical ventilation and the inhalation of nitric oxide.