Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage?
-
Steven J. Korzeniewski
, Carmen L. Soto-Rivera
, Raina N. Fichorova , Elizabeth N. Allred , Karl C.K. Kuban , T. Michael O’Shea , Nigel Paneth , Michael Agus , Olaf Dammann and Alan Leviton
Abstract
Background: We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage.
Methods: We measured the concentrations of thyroid-stimulating hormone (TSH) on day 14 and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on 2 separate days a week apart during the first 2 postnatal weeks. We first assessed the risk of brain damage indicators by comparing 1) neonates who had HTT to those without (regardless of ISSI) and 2) neonates with HTT only, ISSI only, or HTT+ISSI to those who were exposed to neither HTT nor ISSI.
Results: In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [odds ratios (ORs) 2–6], whereas those with HTT only were at significantly reduced risk of a hypoechoic lesion (ORs 0.2–0.4). Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis (ORs 1.6–2.4). Elevated risk of a very low mental development score was associated with both ISSI only and HTT+ISSI, whereas a very low motor development score and microcephaly were associated with HTT+ISSI.
Conclusions: The association of HTT with increased or decreased risk of indicators of brain damage depends on the presence or absence of ISSI.
Acknowledgments
The authors gratefully acknowledge the contributions of their subjects, their subjects’ families, as well as those of their colleagues.
Participating institutions and ELGAN study collaborators who made this report possible:
Children’s Hospital, Boston, MA
Kathleen Lee, Anne McGovern, Jill Gambardella, Susan Ursprung, Ruth Blomquist Kristen Ecklund, Haim Bassan, Samantha Butler, Adré Duplessis, Cecil Hahn, Catherine Limperopoulos, Omar Khwaja, Janet S. Soul
Baystate Medical Center, Springfield, MA
Karen Christianson, Frederick Hampf, Herbert Gilmore, Susan McQuiston
Beth Israel Deaconess Medical Center, Boston, MA
Camilia R. Martin, Colleen Hallisey, Caitlin Hurley, Miren Creixell, Jane Share,
Brigham & Women’s Hospital, Boston, MA
Linda J. Van Marter, Sara Durfee
Massachusetts General Hospital, Boston, MA
Robert M. Insoft, Jennifer G. Wilson, Maureen Pimental, Sjirk J. Westra, Kalpathy Krishnamoorthy
Floating Hospital for Children at Tufts Medical Center, Boston, MA
Cynthia Cole, John M. Fiascone, Janet Madden, Ellen Nylen, Anne Furey Roy McCauley, Paige T. Church, Cecelia Keller, Karen J. Miller
U Mass Memorial Health Care, Worcester, MA
Francis Bednarek (deceased), Mary Naples, Beth Powers, Jacqueline Wellman, Robin Adair, Richard Bream, Alice Miller, Albert Scheiner, Christy Stine
Yale University School of Medicine, New Haven, CT
Richard Ehrenkranz, Joanne Williams, Elaine Romano
Wake Forest University Baptist Medical Center and Forsyth Medical Center, Winston-Salem, NC
T. Michael O’Shea, Debbie Gordon, Teresa Harold, Barbara Specter, Deborah Allred, Robert Dillard, Don Goldstein, Deborah Hiatt (deceased), Gail Hounshell, Ellen Waldrep, Lisa Washburn, Cherrie D. Welch
University Health Systems of Eastern Carolina, Greenville, NC
Stephen C. Engelke, Sherry Moseley, Linda Pare, Donna Smart, Joan Wilson, Ira Adler, Sharon Buckwald, Rebecca Helms, Kathyrn Kerkering, Scott S. MacGilvray, Peter Resnik
North Carolina Children’s Hospital, Chapel Hill, NC
Carl Bose, Gennie Bose, Lynn A. Fordham, Lisa Bostic, Diane Marshall, Kristi Milowic, Janice Wereszczak
Helen DeVos Children’s Hospital, Grand Rapids, MI
Mariel Poortenga, Dinah Sutton, Bradford W. Betz, Steven L. Bezinque, Joseph Junewick, Wendy Burdo-Hartman, Lynn Fagerman, Kim Lohr, Steve Pastyrnak
Sparrow Hospital, Lansing, MI
Carolyn Solomon, Ellen Cavenagh, Victoria J. Caine, Nicholas Olomu, Joan Price
Michigan State University, East Lansing, MI
Nigel Paneth, Padmani Karna, Madeleine Lenski
University of Chicago Medical Center, Chicago, IL
Michael D. Schreiber, Grace Yoon, Kate Feinstein, Leslie Caldarelli, Sunila E. O’Connor, Michael Msall, Susan Plesha-Troyke
William Beaumont Hospital, Royal Oak, MI
Daniel Batton, Beth Kring, Karen Brooklier, Beth Kring, Melisa J. Oca, Katherine M. Solomon
Arkansas Children’s Hospital
Joanna J Seibert
Children’s Hospital of Atlanta
Robert Lorenzo
Conflict of interest statement
Authors’ conflict of interest disclosure: None of the authors has any financial issue or conflict of interest to disclose.
Financial support: This study was supported by the National Institute of Neurological Disorders and Stroke (5U01NS040069-05; 2R01NS040069-06A2), the National Eye Institute (1-R01-EY021820-01), and the National Institute of Child Health and Human Development (5P30HD018655-28).
References
1. Horn S, Heuer H. Thyroid hormone action during brain development: more questions than answers. Mol Cell Endocrinol 2010;315:19–26.10.1016/j.mce.2009.09.008Search in Google Scholar PubMed
2. Fisher DA. Thyroid system immaturities in very low birth weight premature infants. Sem Perinatol 2008;32:387–97.10.1053/j.semperi.2008.09.003Search in Google Scholar PubMed
3. Belcari F, Placidi G, Guzzetta A, Tonacchera M, Ciampi M, et al. Thyroid-stimulating hormone levels in the first days of life and perinatal factors associated with sub-optimal neuromotor outcome in pre-term infants. J Endocrinol Invest 2011;34:E308–13.Search in Google Scholar
4. Azizi F, Afkhami M, Sarshar A, Nafarabadi M. Effects of transient neonatal hyperthyrotropinemia on intellectual quotient and psychomotor performance. Int J Vit Nutr Res 2001;71:70–3.10.1024/0300-9831.71.1.70Search in Google Scholar PubMed
5. Alm J, Hagenfeldt L, Larsson A, Lundberg K. Incidence of congenital hypothyroidism – retrospective study of neonatal laboratory screening versus clinical symptoms as indicators leading to diagnosis. Br Med J 1984;289:1171–5.10.1136/bmj.289.6453.1171Search in Google Scholar PubMed PubMed Central
6. Tyfield LA, Abusrewil SS, Jones SR, Savage DC. Persistent hyperthyrotropinaemia since the neonatal period in clinically euthyroid children. Eur J Pediatr 1991;150:308–9.10.1007/BF01955927Search in Google Scholar PubMed
7. Miki K, Nose O, Miyai K, Yabuuchi H, Harada T. Transient infantile hyperthyrotrophinaemia. Arch Dis Child 1989;64:1177–82.10.1136/adc.64.8.1177Search in Google Scholar PubMed PubMed Central
8. Cody D, Kumar Y, Ng SM, Didi M, Smith C. The differing outcomes of hyperthyrotropinaemia. J Pediatr Endocrinol Metab 2003;16:375–8.10.1515/JPEM.2003.16.3.375Search in Google Scholar
9. Kohler B, Schnabel D, Biebermann H, Gruters A. Transient congenital hypothyroidism and hyperthyrotropinemia: normal thyroid function and physical development at the ages of 6–14 years. J Clin Endocrinol Metab 1996;81:1563–7.Search in Google Scholar
10. Oken E, Braverman LE, Platek D, Mitchell ML, Lee SL, et al. Neonatal thyroxine, maternal thyroid function, and child cognition. J Clin Endocrinol Metab 2009;94:497–503.10.1210/jc.2008-0936Search in Google Scholar PubMed PubMed Central
11. Dilli D, Eras Z, Andiran N, Dilmen U, Sakrucu ED. Neurodevelopmental evaluation of very low birth weight infants with transient hypothyroxinemia at corrected age of 18–24 months. Indian Pediatr 2012;49:711–5.10.1007/s13312-012-0162-xSearch in Google Scholar PubMed
12. Scratch SE, Hunt RW, Thompson DK, Ahmadzai ZM, Doyle LW, et al. Free thyroxine levels after very preterm birth and neurodevelopmental outcomes at age 7 years. Pediatrics 2014;133:e955–63.10.1542/peds.2013-2425Search in Google Scholar PubMed PubMed Central
13. Osborn DA, Hunt RW. Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2007;1:CD005948.10.1002/14651858.CD005948.pub2Search in Google Scholar PubMed PubMed Central
14. Shih JL, Agus MS. Thyroid function in the critically ill newborn and child. Curr Opin Pediatr 2009;21:536–40.10.1097/MOP.0b013e32832cbc12Search in Google Scholar PubMed
15. Chopra IJ. Clinical review 86 – Euthyroid sick syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997;82:329–34.10.1210/jcem.82.2.3745Search in Google Scholar PubMed
16. Dilli D, Dilmen U. The role of interleukin-6 and C-reactive protein in non-thyroidal illness in premature infants followed in neonatal intensive care unit. J Clin Res Pediatr Endocrinol 2012;4:66–71.10.4274/jcrpe.625Search in Google Scholar PubMed PubMed Central
17. Williams FL, Visser TJ, Hume R. Transient hypothyroxinaemia in preterm infants. Early Hum Dev 2006;82:797–802.10.1016/j.earlhumdev.2006.09.007Search in Google Scholar PubMed
18. Leviton A, Kuban K, O’Shea TM, Paneth N, Fichorova R, et al. The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN Study. J Pediatr 2011;158:897–903.e5.10.1016/j.jpeds.2010.11.059Search in Google Scholar PubMed
19. Leviton A, Kuban KC, Allred EN, Fichorova RN, O’Shea TM, et al. Early postnatal blood concentrations of inflammation-related proteins and microcephaly two years later in infants born before the 28th post-menstrual week. Early Hum Dev 2011;87:325–30.10.1016/j.earlhumdev.2011.01.043Search in Google Scholar PubMed
20. Dammann O, Leviton A. Intermittent or sustained systemic inflammation and the preterm brain. Pediatr Res 2014;75:376–80.10.1038/pr.2013.238Search in Google Scholar PubMed PubMed Central
21. O’Shea TM, Allred EN, Dammann O, Hirtz D, Kuban KC, et al. The ELGAN study of the brain and related disorders in extremely low gestational age newborns. Early Hum Dev 2009;85:719–25.10.1016/j.earlhumdev.2009.08.060Search in Google Scholar PubMed PubMed Central
22. Leviton A, Fichorova R, Yamamoto Y, Allred EN, Dammann O, et al. Inflammation-related proteins in the blood of extremely low gestational age newborns. The contribution of inflammation to the appearance of developmental regulation. Cytokine 2011;53:66–73.10.1016/j.cyto.2010.09.003Search in Google Scholar PubMed PubMed Central
23. Kuban K, Adler I, Allred EN, Batton D, Bezinque S, et al. Observer variability assessing US scans of the preterm brain: the ELGAN study. Pediatr Radiol 2007;37:1201–8.10.1007/s00247-007-0605-zSearch in Google Scholar PubMed PubMed Central
24. Bayley N. Bayley Scales of Infant Development-II. San Antonio, TX: Psychological Corporation, 1993.Search in Google Scholar
25. Kuban KC, O’Shea M, Allred E, Leviton A, Gilmore H, et al. Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study. J Child Neurol 2005;20:829–31.10.1177/08830738050200101001Search in Google Scholar PubMed
26. Kuban KC, Allred EN, O’Shea M, Paneth N, Pagano M, et al. An algorithm for diagnosing and classifying cerebral palsy in young children. J. Pediat 2008;153:466–72.e1.10.1016/j.jpeds.2008.04.013Search in Google Scholar PubMed PubMed Central
27. CDC. CDC Growth charts: United States, 2007. http://www.cdc.gov/growthcharts/clinical_charts.htm (accessed 15 May 2014).Search in Google Scholar
28. Bernal J, Nunez J. Thyroid-hormones and brain-development. Eur J Endocrinol 1995;133:390–8.10.1530/eje.0.1330390Search in Google Scholar PubMed
29. Kamath J. Cancer-related fatigue, inflammation and thyrotropin-releasing hormone. Curr Aging Sci 2012;5:195–202.10.2174/1874609811205030005Search in Google Scholar PubMed
30. Yu YT, Ho CT, Hsu HS, Li CI, Davidson LE, et al. Subclinical hypothyroidism is associated with elevated high-sensitive C-reactive protein among adult Taiwanese. Endocrine 2013;44:716–22.10.1007/s12020-013-9915-0Search in Google Scholar PubMed
31. De Groot LJ. Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:151–64.10.1210/jcem.84.1.5364Search in Google Scholar PubMed
32. Simpson J, Williams FL, Delahunty C, van Toor H, Wu SY, et al. Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness. J Clin Endocrinol Metab 2005;90:1271–9.10.1210/jc.2004-2091Search in Google Scholar PubMed
33. Romagnoli C, Currò V, Luciano R, Tortorolo G, Segni G, et al. Serial blood T4 and TSH determinations in low birth weight infants. Influence of gestational age, birth weight and neonatal pathology on thyroid function. Helv Paediatr Acta 1982;37:331–44.Search in Google Scholar
34. Paul DA, Mackley A, Yencha EM. Thyroid function in term and late preterm infants with respiratory distress in relation to severity of illness. Thyroid 2010;20:189–94.10.1089/thy.2009.0012Search in Google Scholar PubMed
35. Paul DA, Leef KH, Voss B, Stefano JL, Bartoshesky L. Thyroxine and illness severity in very low-birth-weight infants. Thyroid 2001;11:871–5.10.1089/105072501316973136Search in Google Scholar PubMed
36. Williams FL, Ogston SA, van Toor H, Visser TJ, Hume R. Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab 2005;90:5954–63.10.1210/jc.2005-1049Search in Google Scholar PubMed
37. Dammann O, Leviton A. Brain damage in preterm newborns: might enhancement of developmentally regulated endogenous protection open a door for prevention? Pediatrics 1999;104:541–50.10.1542/peds.104.3.541Search in Google Scholar PubMed
38. Arnold CC, Kramer MS, Hobbs CA, McLean FH, Usher RH. Very low birth weight: a problematic cohort for epidemiologic studies of very small or immature neonates. Am J Epidemiol 1991;134:604–13.10.1093/oxfordjournals.aje.a116133Search in Google Scholar PubMed
©2014 by De Gruyter
Articles in the same Issue
- Frontmatter
- Highlight: Cushing syndrome
- Fundamental principles of clinical and biochemical evaluation underlie the diagnosis and therapy of Cushing’s syndrome
- Cushing syndrome secondary to CRH-producing Wilms tumor in a 6 year old
- Cushing’s disease presenting as cholestatic hepatitis
- How early can one diagnose Cushing’s disease? An early diagnosis in a case of prepubertal Cushing’s disease
- Review article
- Subclinical hypothyroidism in childhood and adolescense
- Original articles
- Energy substrate metabolism in pyruvate dehydrogenase complex deficiency
- Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia
- Measures of pituitary gland and stalk: from neonate to adolescence
- Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage?
- Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification
- Association of serum 25-hydroxyvitamin D with race/ethnicity and constitutive skin color in urban schoolchildren
- A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects
- Acanthosis nigricans, vitamin D, and insulin resistance in obese children and adolescents
- Clinical characteristics and chromosome 11p15 imprinting analysis of Silver-Russell syndrome – a Chinese experience
- Change in reference body mass index percentiles and deviation in overweight and obesity over 3 years in Turkish children and adolescents
- Long-term outcomes of pediatric Graves’ disease
- Accessibility of the reference center as a protective factor against ketoacidosis at the onset of diabetes in children
- Vitamin D, parathormone, and insulin resistance in children born large for gestational age
- Prevalence of vitamin D deficiency in apparently healthy children in north India
- Prevalence of autoantibodies in type 1 diabetes patients and its association with the clinical presentation – UAE Eastern Region experience
- Clinical and molecular studies related to bone metabolism in patients with congenital adrenal hyperplasia
- Islet neogenesis-associated protein-related pentadecapeptide improves the function of allograft after islets transplantation
- Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents
- Early infant feeding practice and childhood obesity: the relation of breast-feeding and timing of solid food introduction with childhood obesity
- Late onset X-linked adrenal hypoplasia congenita with hypogonadotropic hypgonadism due to a novel 4-bp deletion in exon 2 of NR0B1
- The correlation between GnRH stimulation testing and obstetric ultrasonographic parameters in precocious puberty
- The DATAC study: a new growth database. Description of the epidemiology, diagnosis and therapeutic attitude in a group of Spanish children with short stature
- Concentrations of tumour necrosis factor-α and its soluble receptors in the serum of teenagers with atherosclerosis risk factors: obesity or obesity combined with hypertension
- Are HDL levels lower in children with type 1 diabetes and concurrent celiac disease compared with children with type 1 diabetes only?
- Patient reports
- Hereditary vitamin D rickets: a case series in a family
- Two heterozygous mutations of the AMH gene in a Japanese patient with persistent Müllerian duct syndrome
- Two case reports of severe pediatric hyperosmolar hyperglycemia and diabetic ketoacidosis accompanied with rhabdomyolysis and acute renal failure
- Acquired hypothyroidism due to iodine deficiency in an American child
- Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome
- Amylase/creatinine clearance ratio in diabetic ketoacidosis: a case report
- Worsening hypertriglyceridemia with oral contraceptive pills in an adolescent with HIV-associated lipodystrophy: a case report and review of the literature
- Congenital hyperinsulinism in a newborn with a novel homozygous mutation (p.Q392H) in the ABCC8 gene
- Short communications
- Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient
- Post-hemorrhagic hydrocephalus and diabetes insipidus in preterm infants
- Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease
- Letter to the Editor
- And what about septin 9 (SEPT9) as a binding partner of survivin in heart regeneration?
Articles in the same Issue
- Frontmatter
- Highlight: Cushing syndrome
- Fundamental principles of clinical and biochemical evaluation underlie the diagnosis and therapy of Cushing’s syndrome
- Cushing syndrome secondary to CRH-producing Wilms tumor in a 6 year old
- Cushing’s disease presenting as cholestatic hepatitis
- How early can one diagnose Cushing’s disease? An early diagnosis in a case of prepubertal Cushing’s disease
- Review article
- Subclinical hypothyroidism in childhood and adolescense
- Original articles
- Energy substrate metabolism in pyruvate dehydrogenase complex deficiency
- Chromosome 6q24 transient neonatal diabetes mellitus and protein sensitive hyperinsulinaemic hypoglycaemia
- Measures of pituitary gland and stalk: from neonate to adolescence
- Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage?
- Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification
- Association of serum 25-hydroxyvitamin D with race/ethnicity and constitutive skin color in urban schoolchildren
- A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects
- Acanthosis nigricans, vitamin D, and insulin resistance in obese children and adolescents
- Clinical characteristics and chromosome 11p15 imprinting analysis of Silver-Russell syndrome – a Chinese experience
- Change in reference body mass index percentiles and deviation in overweight and obesity over 3 years in Turkish children and adolescents
- Long-term outcomes of pediatric Graves’ disease
- Accessibility of the reference center as a protective factor against ketoacidosis at the onset of diabetes in children
- Vitamin D, parathormone, and insulin resistance in children born large for gestational age
- Prevalence of vitamin D deficiency in apparently healthy children in north India
- Prevalence of autoantibodies in type 1 diabetes patients and its association with the clinical presentation – UAE Eastern Region experience
- Clinical and molecular studies related to bone metabolism in patients with congenital adrenal hyperplasia
- Islet neogenesis-associated protein-related pentadecapeptide improves the function of allograft after islets transplantation
- Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents
- Early infant feeding practice and childhood obesity: the relation of breast-feeding and timing of solid food introduction with childhood obesity
- Late onset X-linked adrenal hypoplasia congenita with hypogonadotropic hypgonadism due to a novel 4-bp deletion in exon 2 of NR0B1
- The correlation between GnRH stimulation testing and obstetric ultrasonographic parameters in precocious puberty
- The DATAC study: a new growth database. Description of the epidemiology, diagnosis and therapeutic attitude in a group of Spanish children with short stature
- Concentrations of tumour necrosis factor-α and its soluble receptors in the serum of teenagers with atherosclerosis risk factors: obesity or obesity combined with hypertension
- Are HDL levels lower in children with type 1 diabetes and concurrent celiac disease compared with children with type 1 diabetes only?
- Patient reports
- Hereditary vitamin D rickets: a case series in a family
- Two heterozygous mutations of the AMH gene in a Japanese patient with persistent Müllerian duct syndrome
- Two case reports of severe pediatric hyperosmolar hyperglycemia and diabetic ketoacidosis accompanied with rhabdomyolysis and acute renal failure
- Acquired hypothyroidism due to iodine deficiency in an American child
- Continuous subcutaneous IGF-1 therapy via insulin pump in a patient with Donohue syndrome
- Amylase/creatinine clearance ratio in diabetic ketoacidosis: a case report
- Worsening hypertriglyceridemia with oral contraceptive pills in an adolescent with HIV-associated lipodystrophy: a case report and review of the literature
- Congenital hyperinsulinism in a newborn with a novel homozygous mutation (p.Q392H) in the ABCC8 gene
- Short communications
- Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient
- Post-hemorrhagic hydrocephalus and diabetes insipidus in preterm infants
- Two novel mutations in acid α-glucosidase gene in two patients with Pompe disease
- Letter to the Editor
- And what about septin 9 (SEPT9) as a binding partner of survivin in heart regeneration?