The risk of congenital thyrotoxicosis may well be apparent when a pregnant woman has florid thyrotoxic Graves' disease (figure). A maternal history of Graves' disease, however, may be overlooked, especially if the mother is taking thyroxine replacement after radioablation or surgery. Maternal thyroid stimulating antibodies may persist, and consequently a woman's newborn infant is still at risk. Thyroid stimulating antibodies can be quantified by measuring the "thyroid stimulating hormone binding inhibiting immunoglobulin" (TBI) index. This competitive radioreceptor assay measures binding to a porcine thyroid stimulating hormone receptor of the patient's immunoglobulin, compared with labelled thyroid stimulating hormone. A high maternal TBI index is a useful measure to indicate increased likelihood of disease developing in the infant. Although certain prediction of an infant being affected is not possible antenatally,[2-4] a maternal TBI index of more than 30 units predicts, and more than 70 units strongly predicts, that the infant will be more likely to be affected. Therefore all infants of mothers with a history of Graves' disease must be carefully monitored, both clinically and biochemically, for up to seven days postnatally.
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Although Graves' disease complicates 0.1-0.2% of all pregnancies, congenital thyrotoxicosis is rare, occurring in 1 in 70 of these pregnancies, and its development may be irrespective of either maternal disease or antibody status alone. Congenital thyrotoxicosis is transient, lasting up to three months or more, and is due to the transplacental passage of the stimulating (infrequently inhibitory) maternal antibodies of the IgG class, which may cause substantial neonatal morbidity or death if untreated. We present two cases, the first illustrating the antenatal use of the TBI index in the mother, and the second showing morbidity in a premature infant in whom maternal Graves' disease was initially unrecognised.
A male infant was born at 36 weeks by spontaneous vaginal delivery to a mother with Graves' disease. The mother had received radioiodine (iodine-131; 248 MBq) shortly after conception, at which time her pregnancy test had been negative and she had denied the possibility of pregnancy on specific questioning. She elected to continue with the pregnancy and experienced a recurrence of her hyperthyroidism in the first trimester; she had to restart taking propylthiouracil (50 mg every eight hours), and she continued this treatment throughout her pregnancy. Her thyroid function remained normal while taking propylthiouracil until delivery.
The infant weighed 2400 g at birth (below 10th centile); birth length was 460 mm (10th centile) and head circumference 325 mm (10th centile). These measurements indicated mild intrauterine growth retardation. Apgar scores were 9 at one minute and 9 at five minutes. Clinical examination was normal. Initial jitteriness and hypoglycaemia (2.0 mmol/l) resolved over eight hours with frequent oral feeds. Thyroid function was tested on day 4 because of the maternal history. Free thyroxine (fT4) concentration was raised (50.7 pmol/l (reference range 15-40 pmol/l)), and thyroid stimulating hormone concentration was reduced (0.5 mU/l (reference range 1.0-25.0 mU/l). Maternal TBI index was raised (28 units (reference range 15 to - 15 units; TRAK assay, Brahms Diagnostica GMBH, Berlin, Germany)). The infant was noted to be jittery, and he fed poorly. He was not tachycardiac and did not exhibit excessive weight loss postpartum. Lugol's solution (1 drop every eight hours) was started, together with propylthiouracil (10 mg/kg/day). These were continued for 12 days and 4 days respectively. The clinical and biochemical hyperthyroidism resolved, and follow up to age 2 years was normal.
A 33 year old primiparous Vietnamese woman, who spoke little English, presented when the fetus was at 18 weeks' gestation. She had a history of long term hypothyroidism and was taking thyroxine 200 [micro]g daily. At 33 weeks' gestation, spontaneous rupture of the mother's membranes occurred with the onset of premature labour. A male infant was delivered vaginally with uncomplicated meconium stained liquor, and Apgar scores of 7 at one minute and 9 at five minutes. His birth weight was 2005 g (50th centile), and clinical examination confirmed length of gestation. No other clinical abnormalities were present.
By day 8, he had progressed to sucking all feeds, had left incubator care, and had begun to gain weight. On day 10, a low grade fever was noted, and over the preceding two days he had lost 70 g in weight. Clinical examination was otherwise normal. On day 11 he had fever to 38 [degrees] C and was increasingly lethargic, and he developed diarrhoea and an intermittent tachycardia up to 180 beats per minute. His mother was unwell concurrently with an upper respiratory tract infection. As the infant was normal on clinical examination and had a normal white cell count, a viral illness was diagnosed, although the possibility of septicaemia could not be excluded, and so blood, stool, and urine cultures were collected. Broad antibiotic treatment (amoxicillin and gentamicin) was started. As the cultures were negative the illness was still attributed to a virus. By the following day his temperature had settled to normal and his pulse rate fell to 140 beats per minute. Antibiotic treatment was stopped after 48 hours.
He was reviewed again on day 16 because his mother complained of his constant demands to feed. Clinical examination showed a tachycardia up to 200 beats per minute. His weight was 2050 g--a gain of only 45 g over the previous two weeks. Thyroid function tests showed a raised fT4 concentration of 60 pmol/l and a reduced thyroid stimulating hormone concentration of [is less than] 0.02 mU/l. His mother was advised to stop breast feeding by junior staff who wrongly assumed that the raised fT4 concentration might have resulted from maternal thyroxine treatment crossing to the infant in the breast milk. The infant continued to be otherwise clinically well but was increasingly hungry. By day 20 he had also developed irritability. Thyroid function tests showed continuing suppression of the thyroid stimulating hormone ([is less than] 0.02 mU/l) and an increasingly raised fT4 concentration ([is greater than] 77.3 pmol/l). Carbimazole (0.3 mg/kg/day) and propranolol (0.8 mg/kg/day) were started, resulting in prompt clinical and biochemical improvement, and were continued until day 56 and 62 respectively. Normalisation of fT4 concentration was achieved by day 28, although suppression of thyroid stimulating hormone continued until day 62.
The TBI index was not measured on maternal or infant serum in this case. Physical growth parameters to 11 months, when corrected for prematurity, followed the 50th centile for length and weight and the 75th centile for head circumference. Developmental milestones were achieved normally.
When the father, who was fluent in English, was told of the diagnosis of congenital thyrotoxicosis, he recalled his wife having had a large goitre and being very underweight when they first met. Subsequently, after radioiodine therapy for Graves' disease 11 years previously, she had become hypothyroid, requiring the thyroxine supplementation.
In infants born to mothers with Graves' disease, overt symptoms and signs with biochemical evidence of thyrotoxicosis usually occur within the first week of life. Thyrotoxicity may last for up to three months or more, proportional to the clearance of the maternal immunoglobulin from the infant's circulation. Untreated, reported mortality is up to 16-25% in disease severe enough to be clinically diagnosed, and serious long term sequelae--such as craniosynostosis resulting in microcephaly and mental retardation--can develop in untreated survivors. Affected newborns also experience significant acute morbidity. Tachycardia is common, although arrhythmia, congestive cardiac failure, and pulmonary oedema are less common, and exophthalmos and goitre are rare. There may be evidence of hypermetabolism with initial excessive weight loss and subsequent failure to regain birth weight in the neonatal period (as in case 2, in which the infant also developed diarrhoea, fever, sweating, flushing, and increased appetite). In case 1 the infant also had intrauterine growth retardation. In both cases, the infants were premature and exhibited restlessness and irritability before diagnosis, and often these non-specific symptoms, together with a tachycardia, provide the only clinical clues; the maternal history is therefore crucial.
In case 1 the infant was relatively mildly affected, and congenital thyrotoxicosis was anticipated as the mother was still taking antithyroidal drugs, and a modestly raised TBI index had been detected antenatally. In case 2 an inadequate maternal history delayed the diagnosis and resulted in significant morbidity. Although maternal antibody levels were not measured, this case illustrates their persistence long after definitive maternal treatment. This case also highlights that a diagnosis of autoimmune hypothyroidism cannot just be assumed in a pregnant woman taking thyroxine replacement. Breast feeding should not be stopped in mothers treated with thyroxine for hypothyroidism even if the infant is hyperthyroid.
Funding: No special funding.
Competing interests: None declared.
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 Mortimer R, Tyack SA, Galligan JP, Perry-Keene DA, Tan YM. Graves disease in pregnancy: TSH receptor binding inhibiting immunoglobulins and maternal and neonatal thyroid function. Clin Endocrinol 1990;32:141-52.
 McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992;2: 155-9.
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(Accepted 23 August 1999)
Maternal radioiodine therapy does not protect against congenital thyrotoxicosis--a blood test helps to predict those at risk
Mater Children's Hospital, South Brisbane, Queensland 4101, Australia
C M Smith senior registrar
A Cotterill director of paediatric endocrinology
Ipswich Hospital, Ipswich, Queensland 4305, Australia
J Gavranich staff paediatrician
Department of Paediatrics, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia
C P Rodda paediatric endocrinologist
Correspondence to: C P Rodda Christine. Rodda@ med.monash.edu.au
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