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Acta Pdiatrica ISSN 08035253

REGULAR ARTICLE

Permanent and transient congenital hypothyroidism in preterm infants


Ramesh Srinivasan1, Sundeep Harigopal2, Steve Turner3, Tim Cheetham (tim.cheetham@nuth.nhs.uk)1,4
1.Department of Paediatric Endocrinology, The Great North Childrens Hospital, Newcastle Upon Tyne, UK 2.Neonatal Intensive Care Unit, The Great North Childrens Hospital, Newcastle Upon Tyne, UK 3.Department of Clinical Biochemistry, The Great North Childrens Hospital, Newcastle Upon Tyne, UK 4.Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK

Keywords Congenital hypothyroidism, Prematurity, Thyroidstimulating hormone, Transient hypothyroidism Correspondence Dr Tim Cheetham, Department of Paediatric Endocrinology, Newcastle University, The Great North Childrens Hospital, Newcastle Upon Tyne, NE1 4LP, UK. Tel: +0044 191 282 9562 | Fax: +0044 191 2825485 | Email: tim.cheetham@nuth.nhs.uk Received 22 September 2011; revised 18 November 2011; accepted 18 November 2011. DOI:10.1111/j.1651-2227.2011.02536.x

ABSTRACT Aim: Transient uctuations in thyroid function are well recognized in preterm infants.
We wanted to assess TSH variation in babies with transient and permanent congenital hypothyroidism (CHT). Methods: Whole bloodspot TSH data in preterm infants (<35 weeks; 20052010) were assessed, and infants with bloodspot TSH values >6 mU L identied. Permanent CHT was dened as a requirement for thyroxine beyond 3 years of age. Results: A rst TSH sample was obtained from 5518 infants (median gestational age, 32 w; range, 2235), with a second sample obtained from 5134 infants (median gestational age, 32 w; range, 2235). Five infants had raised TSH concentrations on both occasions. Three of the ve infants had a serum TSH >80 mU L on second screen but two came off thyroxine beyond 3 years of age. All preterm babies with permanent or transient hypothyroidism were detected by the rst TSH cut-off of 6 mU L. Only one infant with a birth weight <1500 g remains on thyroxine treatment beyond 2 years of age. Conclusions: The incidence of permanent CHT in preterm infants is similar to term infants. Profound abnormalities of thyroid function can occur in preterm babies with transient hypothyroidism but both categories of hypothyroidism can be detected by a once-only TSH screening strategy with a relatively low cut-off.

INTRODUCTION National newborn screening for congenital hypothyroidism (CHT) was introduced in the UK in 1981 (1) with revised UK neonatal screening guidelines (2005) recommending that the preterm infant should have a second blood spot sample for measurement of thyroid-stimulating hormone (TSH) taken at the equivalent of 36 weeks gestation (2). In practice, this means all babies born before 35 weeks gestation are re-screened because older babies will be at or beyond the equivalent of 36 weeks when the rst sample is taken and so will not be eligible for the second test. This strategy reected a concern that some preterm infants might be unable to mount an appropriate TSH response in the presence of an abnormal thyroid gland (3) a pattern that has been described as atypical hypothyroidism (4,5). It is recognized that TSH uctuations that result in an infant screening positive can reect temporary factors such as exposure to topical iodine (6,7) or drugs (8,9). These factors are more likely to be a consideration in the preterm infant. Hence, preterm babies with an increased TSH may have transient rather than permanent hypothyroidism (10) and not require long-term thyroxine therapy. Both transient and permanent CHT could fall under the atypical hypothyroid umbrella. The increased prevalence of transient CHT may account for the reported increase in CHT in the preterm (11,12).

Whether babies with transient hypothyroidism benet from intervention is unknown (13). Many of the reports of preterm screening programmes focus on babies under 1500 g but all preterm infants are currently re-screened in the UK and not just those with a weight below a specic threshold. We have previously reported the results of a preterm screening programme Korada et al. (14) and in our current study we wanted to focus on the natural history of the uctuations in TSH that occur in early life in a larger group of babies. We also wanted to see whether the TSH threshold in our region of the UK would detect both permanent CHT and transient hypothyroidism. METHOD Ethics approval was obtained for these studies. The Northeast and North Cumbria region of England has on average

Key notes
Profound abnormalities of thyroid function can occur in preterm babies who do not have permanent CHT. A lower TSH cut-off, using a contemporary assay, can detect both transient and permanent CHT without the need for a second screen.

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35 000 live births per year. Whole blood TSH in preterm infants (<35 week gestation) was obtained from the Northern Regional Newborn screening database over a period of 5 years (April 2005March 2010). Blood spotscreening protocol The National recommended cut-off for investigation into (CHT) in the UK is a blood spot TSH of 10 mU L (2) but our regional threshold (north-east England) is 6 mU L. This reects the fact that TSH values around 10 mU L in earlier assays equated to TSH values of 6 mU L with the new method. Infants with a blood spot (TSH) concentration >20 mU L are considered to have a positive screening result. Infants with an initial blood spot TSH concentration between 6 mU L and 20 mU L are considered to have a borderline result, and the assay is repeated on a blood spot from the same card. If the concentration remains >6 mU L on re-assay, a repeat blood spot sample is collected. If the repeat blood spot result is 6 mU L, then this is considered a positive result and the infant referred for further investigation. Preterm infants then undergo a second test at a corrected age of 36 weeks using the same 6 mU L TSH cut-off. Permanent versus transient CHT Permanent CHT can be dened by a requirement for thyroxine beyond 3 years of age. However, it would be possible to rene this further by stating that unequivocal permanent CHT is dened by an ongoing need for T4 beyond 3 years of age with a baseline serum TSH that is > 10 mU L. Transient CHT can be dened as an elevated serum TSH > 10 mU L in early life with no long-term requirement for T4 therapy beyond 3 years of age. Assay performance Interassay coefcients of variation for blood spot TSH assays were 11% and 12% for the Dissociation-Enhanced Lanthanide Fluorescent Immunoassay (DELFIA) (Perkin Elmer, Boston, MA, USA) uoroimmunometric assay at TSH values of 16 mU L and 60 mU L, respectively. Blood spot TSH values are typically 4050% of serum concentrations.

32 weeks; range, 2335). In 38 infants, the TSH concentration fell from above to below the screening threshold and in 6 infants values rose from below the screening threshold to 610 mU L on the second screen. However, TSH concentrations fell below 6 mU L in ve of these infants when they were subject to the second screen and the remaining baby had a serum TSH of 6.8 mU L with a normal free thyroxine. Five infants had raised TSH concentrations (>6 mU L) on both occasions (birth weight 8302810 g). Three of the ve infants had a biochemical picture that was thought highly suggestive of true CHT (serum TSH >80 mU L on second screen; Table 1). Infant 1 had an initial TSH concentration of 8.5 mU L (subsequent serum TSH, 134.7 mU L; free thyroxine, 10.4 pmol L; birth weight, 2810 g). She was treated with thyroxine but is now off treatment after a trial off therapy at the age of 3 years. She did not undergo thyroid imaging. Infant 2 had an initial TSH concentration of 12.2 mU L (subsequent serum TSH, 86.7 mU L; free thyroxine, 11 pmol L; birth weight, 1710 g). She was treated with thyroxine but is now off treatment after a trial off therapy at the age of 4 years. Her thyroid ultrasound examination was normal. Infant 3 had an initial TSH concentration of 21.6 mU L (subsequent serum, TSH 303 mU L; free thyroxine, 12.5 pmol L; birth weight, 1910 g). She was treated with thyroxine and is still on therapy at the age of 4 years. She has not undergone thyroid gland imaging to date. Infant 4 had an initial TSH concentration of 6.8 mU L (subsequent serum TSH, 19.7 mU L; free thyroxine, 16 pmol L; birth weight, 830g). He was treated with thyroxine and is still on therapy at the age of 2 years. His thyroid ultrasound examination was normal. Infant 5 had an initial TSH concentration of 11 mU L (subsequent serum, TSH 8.3 mU L; free thyroxine, 13 pmol L; birth weight, 2760 g). He was treated with thyroxine and is still on therapy at the age of 18 months. His thyroid ultrasound examination was normal. On the basis of these data, the incidence of permanent CHT in the population of preterm infants is at most 3 per 5100 infants. However, unequivocal CHT with a conrmed requirement for long-term replacement has an incidence of 1 per 5100 infants.

RESULTS A rst TSH sample was obtained from 5518 infants (median gestational age, 32 weeks; range, 2335), with a second sample obtained from 5134 (median gestational age,

DISCUSSION Our experience has highlighted a number of highly topical issues including the problem of CHT denition.

Table 1 Preterm infants with rst and second blood spot thyroid-stimulating hormone (TSH) >6 mU L Infant 1 2 3 4 5 Sex F F F M M Gestation 35 33 33 32 34 TSH1 (mU L) 8.5 12.2 21.6 6.8 11 TSH2 (mU L) 11.8 126 188 7 7.6 Serum TSH (mU L) 134.7 86.7 303 19.7 8.3 Free T4 (pmol L) 10.4 11 12.5 16.3 13 BW and patient details 2.8 kg. Off thyroxine at 3 years of age 1.7 kg. Off thyroxine at 4 years of age 1.9 kg. On thyroxine 50 75 mcg alternate days at 4 years of age 0.835 kg. On thyroxine 30 mcg at 2 years of age 2.7 kg. On thyroxine 40 mcg at 18 months of age

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TSH in preterm infants

A second screening test will detect a small number of babies who demonstrate a profound increase in TSH following an initial blood spot that is in the borderline range between 6 and 20 mU L on a bloodspot TSH assay (10,14). Most of the repeat testing literature has focused on a birthweight cut-off such as 1500 g (1517) but our data conrm that major uctuations can occur in infants with a birth weight greater than this. Whilst the initial conclusion might be that repeat testing is therefore justied, our data have conrmed that some of these babies do not have permanent CHT as reected by the fact that they do not require long-term thyroxine treatment. A profound increase in TSH does not, therefore, necessarily indicate permanent CHT here dened by the need for long-term thyroxine supplementation (18). Even serum TSH values >80 mU L in early life do not necessarily reect a requirement for long-term thyroxine therapy. Whether babies with such profound but transient alterations in TSH benet from temporary thyroxine therapy is unknown. Although biochemistry is the most important parameter when deciding upon which babies to treat with thyroxine, information about underlying thyroid gland morphology can be useful when advising families about the need for longer term treatment. We did not have the comprehensive imaging data required to establish the precise aetiology in all of these babies although the only infant requiring longterm replacement, who has not been imaged, has required an increasing dose of thyroxine replacement. The fact that imaging is not an essential component of management and the fact that it does not usually inuence the decision to initiate treatment has been highlighted in a recent review (19). Another potential limitation of our data is the fact that babies were managed in different centres by different clinicians and hence we cannot be certain that the criteria for reassessment and for withdrawing thyroxine therapy were the same. Although our population of preterm infants is not particularly large, the incidence of unequivocal permanent CHT appears to be similar to gures for CHT as a whole (20). In summary, our data have shown that profound abnormalities of thyroid function can occur in preterm babies who do not have permanent CHT. These abnormalities can occur in babies with a birth weight >1500 g. The extent of these uctuations helps to explain why gures documenting the incidence of CHT in preterm infants can be relatively high in comparison with those for CHT in term infants (21). Our data underline the importance of all babies undergoing a formal trial off T4 therapy at around 3 years of age (13,22) if TSH values have not been elevated whilst on therapy beyond the rst few months of life. Finally, it is possible that a lower TSH cut-off, using a contemporary assay, will detect both transient and permanent forms of CHT without the need for a second screen.

References
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CONFLICT OF INTEREST AND FUNDING None.

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19. LaFranchi SH. Approach to the diagnosis and treatment of neonatal hypothyroidism. J Clin Endocrinol Metab 2011; 96: 295967. 20. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis 2010; 5: 17. 21. Harris KB, Pass KA. Increase in congenital hypothyroidism in New York State and in the United States. Mol Genet Metab 2007; 91: 26877.

22. Yang RL, Zhu ZW, Zhou XL, et al. Treatment and follow-up of children with transient congenital hypothyroidism. J Zhejiang Univ Sci B 2005; 6:12069.

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