Neonatal thyrotoxicosis with maternal hypothyroidism
- Shruthi Ravindra and
- Sahana Shetty
- Department of Endocrinology, Manipal Academy of Higher Education (MAHE), Kasturba Medical College Manipal, Udupi, Karnataka, India
- Correspondence to Dr Sahana Shetty; sahanashetty0606@gmail.com
Abstract
Neonatal Graves’ is uncommon, but a potentially fatal condition caused by transplacental transfer of thyroid stimulating immunoglobulin (TSI). It is seen in 1%–5% of infants born to a mother with Graves’ disease. Here, we report a unique case of transient neonatal thyrotoxicosis with positive TSI in a premature neonate born to the mother with primary hypothyroidism. A short course of antithyroid drug treatment leads to significant clinical and biochemical improvement followed by complete recovery.
Background
Neonatal thyrotoxicosis is less common than neonatal hypothyroidism but can have a significant impact on growth and development.1 In most cases, it results from transplacental passage of thyroid stimulating immunoglobulin (TSI) from a mother with Graves’ disease (GD).2 Only a few cases of fetal hyperthyroidism in a mother with Hashimoto’s have been described in the literature.3–5 These antibodies stimulate the fetal thyroid by binding to the thyrotropin receptor causing hyperthyroidism. Clinical features include intrauterine growth retardation, prematurity, goitre, exophthalmos, craniosynostosis, unexplained tachycardia, arrhythmias, heart failure, thrombocytopenia and hepatosplenomegaly.6 Thyrotoxicosis disappears with clearance of maternal antibodies and it is usually seen at around 3–6 months of infancy. Cardiac inefficiency is common in untreated cases and early diagnosis can prevent severe complications.7
Recently, other uncommon causes of neonatal hyperthyroidism have been described, which postulated to be resulting from activating mutations in thyrotropin receptors and alpha-subunit of G-protein.8 9
Case presentation
A newborn girl was referred on day 2 of birth with complaints of tachycardia, increased frequency of stools of around 14–16 times per day and failure to thrive. The child was the second twin, born to a 38-year-old woman at 29-week gestation by emergency caesarean section. The pregnancy was complicated by twin gestation with intrauterine death of a first twin, gestational diabetes mellitus (GDM), chronic hypertension and maternal hypothyroidism. There was no history of GD, radioactive ablation or thyroidectomy surgery in the mother. The birth weight was 1470 g and the length was 39 cm. Postdelivery baby had developed respiratory distress and was managed with endotracheal intubation and surfactant administration under the cover of appropriate antibiotics. Postsurfactant chest X-ray showed good expansion, and the baby was extubated.
On examination, the child was irritable and emaciated with the pulse rate varying between 170 and 190 beats per minute and respiratory rate of 66 /min. There was no goitre or eye signs.
Mother was diagnosed with hypothyroidism for the last 10 years and was on thyroxine replacement. The interesting fact in the history was that the maternal levothyroxine dose requirement had decreased from 162.5 µg/day in the first trimester to 25 µg/day in the last trimester of pregnancy as per the dose titration based on thyroid function tests done at periodic intervals during pregnancy. There was documentation of persistent fetal tachycardia in routine gestational ultrasound scans, the cause of which could not be ascertained previously. GDM and chronic hypertension were managed appropriately with insulin and antihypertensives, respectively.
Investigations
Neonatal TSH screening showed suppressed TSH and subsequent thyroid profile showed elevated free thyroxine with suppressed TSH.
TSH level:<0.005 µIU/mL (normal range: 3–20 µIU/mL)
T3-total: 6.02 ng/mL (normal range: 0.73–2.88 ng/mL)
T4-total: >24.86 µg/dL (normal range: 5.04–18.5 µg/dL) fT4: >7.7 ng/dL (normal range: 0.9–1.8 ng/dL)
C reactive protein (CRP): 0.22 mg/L (normal range:<5 mg/L)
In view of thyrotoxicosis and maternal thyroid dysfunction, TSI levels were tested in the neonate, the result was found to be >40 IU/L (normal range: 1.75 IU/L). An ECG showed sinus tachycardia. An echocardiogram done showed moderate pulmonary arterial hypertension (PAH) with mildly depressed biventricular function. Maternal TSI levels were also found to be elevated:>40 IU/L (normal range: 1.75 IU/L). Elevated TSI levels in both maternal and neonatal blood were suggestive of immune-mediated hyperthyroidism, possibly due to the transplacental transfer of maternal antibodies. Hence neonatal thyrotoxicosis secondary to transplacental passage of TSI was diagnosed.
Treatment
The neonate was started on oral methimazole at 1 mg/kg/day and propranolol 2 mg/kg/day.
Outcome and follow-up
At 2 weeks follow-up visit in the endocrine department, she was found to have a normal heart rate with appropriate weight gain. B-blockers and antithyroid were gradually tapered and stopped over 3 months. Repeat thyroid function tests done at 6 months were within normal limits. The child was euthyroid even on 2 years follow-up visits with normal growth and development.
Discussion
The most common autoimmune thyroid conditions are Hashimoto’s thyroiditis and Graves’ disease. TSI can be detected in the serum of patients with GD. Antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) are seen in Hashimoto’s thyroiditis as well as GD. Antibodies can be of stimulating, neutral and blocking variants. TSI stimulates thyrotropin receptors causing GD with a 1% prevalence in the population.10 Thyrotropin blocking antibodies which are competitive inhibitors of TSH binding can cause hypothyroidism.11 12 Some patients can have both stimulating and blocking antibodies, the dominant antibody dictates the clinical phenotype. Unusually, switching from stimulating to blocking or vice versa with concomitant thyroid function changes has been observed.13 These are immunoglobulin G (IgG) class antibodies that cross the placenta and can cause transient thyroid dysfunction, which disappears with clearance of antibodies from the circulation.14
In our case, we speculate that fetal and neonatal hyperthyroidism was due to the transplacental transfer of TSI levels. Decreasing requirement of levothyroxine dose by the mother, as opposed to the physiological increase in thyroxine requirement during pregnancy, could be secondary to differential levels of stimulating and blocking antibodies. Other, interesting fact is that the mother’s levothyroxine requirement decreased as the pregnancy progressed as GD tends to subside as pregnancy proceeds.15
Neonatal thyrotoxicosis can have varied clinical presentations ranging from asymptomatic healthy newborns to severe thyroid storms causing cardiopulmonary instability.16–18 Diagnosis is often delayed because of non-specific manifestations like feeding difficulty, diarrhoea, irritability, poor weight gain, hyperthermia, tachycardia, tachypnoea, etc.19 As per the recent recommendation from the American Thyroid Association (ATA) and endocrine society guidelines, maternal TSI levels should be screened between 20 and 24 weeks period of gestation, in patients with a history of GD, post-RAI hypothyroidism, and surgical thyroidectomy cases.20–22 TSI levels more than three times the upper normal limit in the second or third trimester are associated with an increased risk of fetal thyrotoxicosis.22 23 As per the literature, the earliest age at which elevated TSI may lead to fetal hyperthyroidism is around 18 weeks.24 Previous studies have shown that the lowest TSI level in mothers causing neonatal thyrotoxicosis was 4.4 U/L, which was 3.7 times the upper limit of normal.18 Banige et al suggested that serum TSH levels below 0.90 mU/L at 3–7 days of postnatal life can predict the development of hyperthyroidism in most cases.25
Our case highlights the possibility of neonatal thyrotoxicosis secondary to TSI even if the mother is hypothyroid in the presence of suggestive symptoms. It also emphasises the role of TSI testing for ascertaining the aetiology and the transient nature of the disease thus helping in the appropriate management.
Once the diagnosis is confirmed clinically and biochemically, antithyroid drugs (methimazole 0.5–1 mg/kg/day) and b-blockers (propranolol 2 mg/kg/day) are the standards of care. In severe cases, Lugol’s solution (5% iodine and 10% potassium iodide) and hydrocortisone may benefit by decreasing the peripheral conversion of T4 to triiodothyronine and inhibiting thyroid hormone release.26 The therapeutic response should be closely monitored with titration of the antithyroid drug to avoid neonatal hypothyroidism. Even though hyperthyroidism is transient, it needs treatment to avoid complications like heart failure, craniosynostosis and intellectual impairment.1
Greater emphasis needs to be placed on the importance of having thyroid disease on the differential for persistent fetal tachycardia as an early diagnosis and treatment can help to prevent complications.
Learning points
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Differential diagnosis of neonatal thyrotoxicosis should be considered in unexplained fetal/neonatal tachycardia and failure to thrive, as an early diagnosis and treatment prevent the complications.
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It is important to obtain detailed thyroid disorder history (including levothyroxine or antithyroid drug dosage history during pregnancy and any remote history of Graves’ disease /radioactive ablation/thyroid surgery), when evaluating neonatal thyrotoxicosis, as it may give clues regarding underlying autoimmune pathogenesis.
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Thyroid stimulating immunoglobulin testing should be done in pregnant women with an immune-mediated thyroid disorder and suspected fetal hyperthyroidism.
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Neonatal graves’ is a transient thyroid dysfunction that resolves completely with early diagnosis and treatment with antithyroid drugs.
Ethics statements
Patient consent for publication
Footnotes
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Contributors SR wrote manuscript under supervision of SS. SS supported in collecting other review articles and management plans. Both SR and SS contributed to final version of the manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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