Sze May Ng1,2* and Mark A Turner1
1Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Crown Street L8 7SS, Liverpool, UK
2Department of Paediatrics, Southport and Ormskirk NHS Trust, Wigan Road, Ormskirk, L39 2AZ, UK
Received: 07 November, 2015; Accepted: 20 March, 2016; Published: 23 March, 2016
Dr, Sze May Ng, MBBS (Hons) FHEA FRCPCH MSc PhD, Consultant Paediatrician and Paediatric Endocrinologist, Honorary Senior Lecturer, University of Liverpool, Tel : 01695 656163; Fax: 01695 656282; E-mail:
Ng SM, Turner MA (2016) The Importance of Risk Stratification and Management of Newborn Babies of Women with a History of Graves’ disease. Int J Clin Endocrinol Metab 2(1): 001-004.
© 2016 Ng SM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Thyroid hormones are important for early brain development. During pregnancy, both maternal and foetal thyroid hormones contribute to foetal brain development. Maternal Graves’ can lead to transplacental transfer of antibodies that cause neonatal thyrotoxicosis. Neonatal thyrotoxicosis is rare and a high index of suspicion is needed to diagnose it. Neonatal thyrotoxicosis has significant risk of morbidity and mortality and early recognition is warranted. Babies who are at risk following birth should be identified early while avoiding the need for unnecessary blood tests or prolonged hospital admission. There are no published consensus guidelines to date as to how these babies should be managed and followed up. The purpose of this guideline is to describe the importance of risk stratification and subsequent management of babies born to mothers with a history of Graves’ disease.
Thyroid hormones are essential for normal brain development, growth and energy metabolism . During early pregnancy, the foetus is entirely dependent on maternal thyroid hormones and in the second and third trimesters, maternal thyroid hormones continue to provide sufficient thyroid hormones until birth [2,3]. Maternal thyroid disease is common during pregnancy with hyperthyroidism during pregnancy occurring in 1% and autoimmune thyroiditis in 7% of pregnant women . Neonatal thyrotoxicosis may results from antibodies crossing from the mother to foetus and can result in serious adverse effects on the foetus .
Management of thyrotoxicosis or hyperthyroidism during pregnancy is important because of the increased risk of miscarriage and preterm delivery and the potential damage to foetal neurodevelopment . It is therefore important to identify ‘at risk’ babies soon after birth according to the maternal history so that evaluation of maternal and neonatal thyroid status can be undertaken in a timely way. To date, there are no consensus guidelines as to how these babies should be managed and followed up within the United Kingdom. This may result in babies of women with a history of hyperthyroidism or Graves’ having unnecessary blood tests and prolonged hospital stay after birth . A population-based survey in Sweden  and a single-centre audit in Exeter , has shown that in fact very few babies with a maternal history of hyperthyroidism or Graves’ disease develop thyroid disease and that too many thyroid function tests are unnecessarily being performed in newborn babies . This review aims to describe an approach to risk stratification and subsequent management of babies born to mothers with a history Graves’ disease.
Babies of women with a history of Graves’ disease
Maternal Graves’ disease can lead to transplacental transfer of antibodies that cause neonatal thyrotoxicosis. Neonatal thyrotoxicosis has significant risk of morbidity and mortality. The incidence of Graves’ disease is 0.2% in pregnancy and neonatal thyrotoxicosis can occur in approximately 1% of babies born to women with Graves’ disease [9,10]. However, congenital thyrotoxicosis is rare occurring in one in 70 of these pregnancies independent of maternal Graves’ disease status. The risk of neonatal thyrotoxicosis can be assessed through a measurement of thyroid receptor antibodies (TRAb)  and assessment of maternal history . Babies of mothers with Graves’ disease may experience hypothyroidism or hyperthyroidism due to transplacental transfer of antithyroid drugs or thyroid stimulating antibodies or thyroid receptor antibodies (TRAb) . The current UK screening programme does not detect neonatal thyrotoxicosis as it screens only for high thyroid-stimulating hormone (TSH) levels in congenital hypothyroidism. Neonatal thyrotoxicosis can also rarely occur in mothers with Hashimoto’s thyroiditis due to activating mutations of the TSH receptor . The most important clue to the diagnosis of neonatal thyrotoxicosis lies in the maternal history and clinical findings.
Risk assessment of babies whose mother has a history of hyperthyroidism or Graves’’ disease
Identifying ‘at risk’ babies is important by maternal history and levels of TRAb in the mothers during the pregnancy [11,12]. Mothers with Graves’ disease who are euthyroid due to anti-thyroid medication or hypothyroid due to thyroidectomy or radioiodine therapy can still have high levels of TRAb which can cause result in neonatal thyrotoxicosis . In a recent study , none of the babies born to TRAb- negative mothers with Graves’ disease developed neonatal thyrotoxicosis. Babies should therefore be assessed as having either low risk or high risk (Table 1).
In babies who are at low risk, no other action is required. Babies do not need further follow-up of this issue and parents are advised to seek medical advice if there are any concerns. Babies who have moderate to high risk should be reviewed between day 3–7 following birth for signs and symptoms of thyroid disease with a repeat free thyroxine (FT4) measurement taken . Rapid FT4 elevation during the first postnatal week is predictive of hyperthyroidism and warrants anti-thyroid medications .
Thyrotoxic babies usually develop signs and symptoms from birth to 2 weeks of life. Signs and symptoms of thyrotoxicosis include goitre, tachycardia, arrhythmia, hydrops associated with heart failure, intrauterine growth retardation, subsequent inadequate weight gain, craniosynostosis, increased foetal motility/ jitteriness, increased sweating, hypertension, diarrhoea, vomiting, weight loss, periorbital oedema, exophthalmos, bruising/ petechiae due to thrombocytopenia and accelerated bone maturation.
In asymptomatic babies born to mothers with a history of thyrotoxicosis or Graves’ disease who are “at risk”, maternal TRAB measurements from this pregnancy should be available for assessment. This requires an integrated care pathway involving maternity service and adult endocrine specialists that reliably obtains TRAB measurements during the third trimester of the current pregnancy. Management is advised accordingly :
• If TRAb < 15 U/L and there is no family history of Graves’ noted, then no further action is required and baby can be discharged from follow-up for this problem.
• If TRAb U/L < 15 U/L and there is a family history present, baby does not need to be an in-patient following delivery. Observation, examination and history for signs or symptoms of thyrotoxicosis needs to be reviewed by an experienced member of the neonatal or midwifery staff between days 5-7 following birth. Baby’s thyroid function (TSH, FT4) and TRAb levels should also be obtained at day 5-7. If baby is well and TSH, FT4 and TRAb is normal, then baby can be discharged.
• If TRAb U/L >15 U/L, observe baby as an inpatient for 48 hours and arrange to review baby again between day 5-7. Baby’s thyroid function (TSH, FT4) and TRAb levels should be obtained. If baby is well and TSH, FT4 and TRAb is normal, then baby can be discharged.
Parents must always be informed of signs and symptoms of thyrotoxicosis at any time during first 2 weeks of life and advised to seek medical advice at any time if there are concerns. Pathway for infants with a maternal history of Graves’ disease is shown in Figure 1.
- Ng SM, Turner MA, Gamble C, Didi M, Victor S, et al. (2013) An explanatory randomized placebo controlled trial of levothyroxine supplementation for babies born <28 weeks' gestation: results of the TIPIT trial. Trials 14: 211 .
- Morreale de Escobar G, Obregon MJ, Escobar del Rey F (2000) Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85: 3975-3987 .
- Bernal J, Pekonen F (1984) Ontogenesis of the nuclear 3,5,3'-triiodothyronine receptor in the human fetal brain. Endocrinology 114: 677-679 .
- Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, et al. (2007) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 92: S1-47 .
- Medici M, Timmermans S, Visser W, de Muinck Keizer-Schrama SM, Jaddoe VW, et al. (2013) Maternal thyroid hormone parameters during early pregnancy and birth weight: the Generation R Study. J Clin Endocrinol Metab 98: 59-66 .
- Ogundele MO, Waterson M (2010) When should we be conducting thyroid function tests in newborns and young infants? Arch Dis Child 95: 151-152 .
- Wikner BN, Sparre LS, Stiller CO, Kallen B, Asker C (2008) Maternal use of thyroid hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand 87: 617-627 .
- Ogundele MO, Quinn MW, Salzmann M (2008) Investigation of infants born to mothers with thyroid disorders: a search for consensus. European Academy of Paediatrics .
- Ogilvy-Stuart AL (2002) Neonatal thyroid disorders. Arch Dis Child Fetal Neonatal Ed 87: F165-171.
- Luton D, Le Gac I, Vuillard E, Castanet M, Guibourdenche J, et al. (2005) Management of Graves’' disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 90: 6093-6098 .
- Besancon A, Beltrand J, Le Gac I, Luton D, Polak M (2014) Management of Neonates born to Women with Graves’' Disease: A Cohort Study. Eur J Endocrinol 170: 855-862 .
- Habeb AM, Zubier M, Pairaudeau P, Mathew V (2003) Do we need to assess the thyroid function in the infants of mothers with Hashimoto's thyroiditis? Arch Dis Child Fetal Neonatal Ed 88: F258 .
- Skuza KA, Sills IN, Stene M, Rapaport R (1996) Prediction of neonatal hyperthyroidism in infants born to mothers with Graves’ disease. J Pediatr 128: 264-268 .
- Laurberg P, Bournaud C, Karmisholt J, Orgiazzi J (2009) Management of Graves’' hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. European journal of endocrinology / European Federation of Endocrine Societies 160: 1-8 .
- Karras S, Tzotzas T, Kaltsas T, Krassas GE (2010) Pharmacological treatment of hyperthyroidism during lactation: review of the literature and novel data. Pediatric endocrinology reviews. PER 8: 25-33 .
- Sunshine P, Kusumoto H, Kriss JP (1965) Survival time of circulating long-acting thyroid stimulator in neonatal thyrotoxicosis: implications for diagnosis and therapy of the disorder. Pediatrics 36: 869-876 .