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Thyroid physiology and screening in preterm infants

Stephen LaFranchi, MD
Section Editors
David S Cooper, MD
Mitchell Geffner, MD
Deputy Editor
Alison G Hoppin, MD


Congenital hypothyroidism occurs in approximately 1 in 2000 to 1 in 4000 newborns worldwide, with considerable regional and racial/ethnic variation. It is one of the most common treatable causes of intellectual disability (mental retardation). However, most newborn babies with this disorder have few or no clinical manifestations of thyroid deficiency, and the majority of cases are sporadic. As a result, it is not possible to predict which infants are likely to be affected. For these reasons, newborn screening programs in which either thyroxine (T4) or thyrotropin (TSH) are measured in heel-stick blood specimens were developed in the mid-1970s to detect and treat this condition as early as possible. (See "Clinical features and detection of congenital hypothyroidism".)

Interpretation of screening tests requires an understanding of thyroid physiology in newborn babies. This topic will review normal thyroid physiology in the fetus and in preterm and term infants.


The bilobed thyroid shape is evident by seven weeks of gestation, and thyroid follicles containing colloid are seen histologically by 10 weeks. With respect to thyroid function, thyroglobulin synthesis can be detected at four weeks, iodine trapping at 8 to 10 weeks, and thyroxine (T4) and, to a lesser extent, triiodothyronine (T3) synthesis and secretion at 12 weeks. Hypothalamic neurons contain thyrotropin-releasing hormone (TRH) at six to eight weeks, the pituitary-portal vascular system begins to develop at 8 to 10 weeks, and TSH secretion can be detected at 12 weeks. Maturation of the hypothalamic-pituitary-thyroid axis occurs during the second half of gestation, but completely normal feedback relationships are not mature until one to two months of postnatal life. (See "Thyroid hormone synthesis and physiology".)

The pattern of changes during gestation is as follows (figure 1) [1,2]:

During the first trimester, T4 in the circulation is of maternal origin, as the fetal thyroid does not produce significant amounts of T4 until the second half of pregnancy [3]. Thereafter, the rise in serum T4 concentrations is a result of both an increase in hepatic production of serum thyroxine-binding globulin (TBG) and, to a lesser degree, an increase in fetal thyroidal T4 production stimulated by TSH secretion. Fetal serum T4 concentrations rise from a mean of approximately 2 mcg/dL (26 nmol/L) at 12 weeks to 10 mcg/dL (128 nmol/L) at term [1,2]. Fetal serum free T4 concentrations also increase progressively, from a mean value of approximately 0.1 ng/dL (1.3 pmol/L) at 12 weeks to 2.0 ng/dL (25.7 pmol/L) at term.


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Literature review current through: Sep 2016. | This topic last updated: Jan 21, 2016.
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  1. Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al. Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 1991; 324:532.
  2. Thorpe-Beeston JG, Nicolaides KH, McGregor AM. Fetal thyroid function. Thyroid 1992; 2:207.
  3. Obregon MJ, Calvo RM, Del Rey FE, de Escobar GM. Ontogenesis of thyroid function and interactions with maternal function. Endocr Dev 2007; 10:86.
  4. Delange F. Iodine requirements during pregnancy, lactation and the neonatal period and indicators of optimal iodine nutrition. Public Health Nutr 2007; 10:1571.
  5. Fisher DA, Brown RS. Thyroid physiology in the perinatal period and during childhood. In: Werner's and Ingbar's The Thyroid, Braverman LE, Utiger RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2000. p.959.
  6. Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab 2004; 89:5314.
  7. Williams FL, Mires GJ, Barnett C, et al. Transient hypothyroxinemia in preterm infants: the role of cord sera thyroid hormone levels adjusted for prenatal and intrapartum factors. J Clin Endocrinol Metab 2005; 90:4599.
  8. Klein AH, Oddie TH, Parslow M, et al. Developmental changes in pituitary-thyroid function in the human fetus and newborn. Early Hum Dev 1982; 6:321.
  9. Adams LM, Emery JR, Clark SJ, et al. Reference ranges for newer thyroid function tests in premature infants. J Pediatr 1995; 126:122.
  10. Murphy N, Hume R, van Toor H, et al. The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life. J Clin Endocrinol Metab 2004; 89:2824.
  11. Ares S, Escobar-Morreale HF, Quero J, et al. Neonatal hypothyroxinemia: effects of iodine intake and premature birth. J Clin Endocrinol Metab 1997; 82:1704.
  12. Carrascosa A, Ruiz-Cuevas P, Potau N, et al. Thyroid function in seventy-five healthy preterm infants thirty to thirty-five weeks of gestational age: a prospective and longitudinal study during the first year of life. Thyroid 2004; 14:435.
  13. Uhrmann S, Marks KH, Maisels MJ, et al. Frequency of transient hypothyroxinaemia in low birthweight infants. Potential pitfall for neonatal screening programmes. Arch Dis Child 1981; 56:214.
  14. Mitchell ML, Walraven C, Rojas DA, et al. Screening very-low-birthweight infants for congenital hypothyroidism. Lancet 1994; 343:60.
  15. Hunter MK, Mandel SH, Sesser DE, et al. Follow-up of newborns with low thyroxine and nonelevated thyroid-stimulating hormone-screening concentrations: results of the 20-year experience in the Northwest Regional Newborn Screening Program. J Pediatr 1998; 132:70.
  16. Mandel SJ, Hermos RJ, Larson CA, et al. Atypical hypothyroidism and the very low birthweight infant. Thyroid 2000; 10:693.
  17. Vigone MC, Caiulo S, Di Frenna M, et al. Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism. J Pediatr 2014; 164:1296.
  18. Woo HC, Lizarda A, Tucker R, et al. Congenital hypothyroidism with a delayed thyroid-stimulating hormone elevation in very premature infants: incidence and growth and developmental outcomes. J Pediatr 2011; 158:538.
  19. Aitken J, Williams FL. A systematic review of thyroid dysfunction in preterm neonates exposed to topical iodine. Arch Dis Child Fetal Neonatal Ed 2014; 99:F21.
  20. Frank JE, Faix JE, Hermos RJ, et al. Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening. J Pediatr 1996; 128:548.
  21. Léger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 2014; 99:363.
  22. LaFranchi SH. Screening preterm infants for congenital hypothyroidism: better the second time around. J Pediatr 2014; 164:1259.
  23. Bijarnia S, Wilcken B, Wiley VC. Newborn screening for congenital hypothyroidism in very-low-birth-weight babies: the need for a second test. J Inherit Metab Dis 2011; 34:827.
  24. Deming DD, Rabin CW, Hopper AO, et al. Direct equilibrium dialysis compared with two non-dialysis free T4 methods in premature infants. J Pediatr 2007; 151:404.
  25. Niwa F, Kawai M, Kanazawa H, et al. Hyperthyrotropinemia at 2 weeks of age indicates thyroid dysfunction and predicts the occurrence of delayed elevation of thyrotropin in very low birth weight infants. Clin Endocrinol (Oxf) 2012; 77:255.
  26. van Tijn DA, de Vijlder JJ, Vulsma T. Role of the thyrotropin-releasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants. J Clin Endocrinol Metab 2008; 93:410.
  27. Srinivasan R, Harigopal S, Turner S, Cheetham T. Permanent and transient congenital hypothyroidism in preterm infants. Acta Paediatr 2012; 101:e179.
  28. Fisher DA. Euthyroid low thyroxine (T4) and triiodothyronine (T3) states in prematures and sick neonates. Pediatr Clin North Am 1990; 37:1297.
  29. Fily A, Pierrat V, Delporte V, et al. Factors associated with neurodevelopmental outcome at 2 years after very preterm birth: the population-based Nord-Pas-de-Calais EPIPAGE cohort. Pediatrics 2006; 117:357.
  30. Uhrmann S, Marks KH, Maisels MJ, et al. Thyroid function in the preterm infant: a longitudinal assessment. J Pediatr 1978; 92:968.
  31. Simpson J, Williams FL, Delahunty C, et al. Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness. J Clin Endocrinol Metab 2005; 90:1271.
  32. 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.
  33. Job L, Emery JR, Hopper AO, et al. Serum free thyroxine concentration is not reduced in premature infants with respiratory distress syndrome. J Pediatr 1997; 131:489.
  34. Arai H, Goto R, Matsuda T, Takahashi T. Relationship between free T4 levels and postnatal steroid therapy in preterm infants. Pediatr Int 2009; 51:800.
  35. Carrascosa A, Ruiz-Cuevas P, Clemente M, et al. Thyroid function in 76 sick preterm infants 30-36 weeks: results from a longitudinal study. J Pediatr Endocrinol Metab 2008; 21:237.
  36. Hadeed AJ, Asay LD, Klein AH, Fisher DA. Significance of transient postnatal hypothyroxinemia in premature infants with and without respiratory distress syndrome. Pediatrics 1981; 68:494.
  37. Den Ouden AL, Kok JH, Verkerk PH, et al. The relation between neonatal thyroxine levels and neurodevelopmental outcome at age 5 and 9 years in a national cohort of very preterm and/or very low birth weight infants. Pediatr Res 1996; 39:142.
  38. Reuss ML, Paneth N, Pinto-Martin JA, et al. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Engl J Med 1996; 334:821.
  39. Simic N, Asztalos EV, Rovet J. Impact of neonatal thyroid hormone insufficiency and medical morbidity on infant neurodevelopment and attention following preterm birth. Thyroid 2009; 19:395.
  40. Simic N, Westall C, Astzalos EV, Rovet J. Visual abilities at 6 months in preterm infants: impact of thyroid hormone deficiency and neonatal medical morbidity. Thyroid 2010; 20:309.
  41. Hollanders JJ, Israëls J, van der Pal SM, et al. No Association Between Transient Hypothyroxinemia of Prematurity and Neurodevelopmental Outcome in Young Adulthood. J Clin Endocrinol Metab 2015; 100:4648.
  42. Mercado M, Szymonowicz W, Yu VY, Gold H. Symptomatic hypothyroxinemia with normal TSH levels in preterm infants. Clin Pediatr (Phila) 1987; 26:343.
  43. Williams FL, Visser TJ, Hume R. Transient hypothyroxinaemia in preterm infants. Early Hum Dev 2006; 82:797.
  44. Osborn DA, Hunt RW. Prophylactic postnatal thyroid hormones for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2007; :CD005948.
  45. Chowdhry P, Scanlon JW, Auerbach R, Abbassi V. Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia. Pediatrics 1984; 73:301.
  46. Ng SM, Turner MA, Gamble C, et al. An explanatory randomised placebo controlled trial of levothyroxine supplementation for babies born <28 weeks' gestation: results of the TIPIT trial. Trials 2013; 14:211.
  47. van Wassenaer AG, Kok JH, de Vijlder JJ, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation. N Engl J Med 1997; 336:21.
  48. Van Wassenaer AG, Kok JH, Briët JM, et al. Thyroid function in preterm newborns; is T4 treatment required in infants < 27 weeks' gestational age? Exp Clin Endocrinol Diabetes 1997; 105 Suppl 4:12.
  49. Briët JM, van Wassenaer AG, Dekker FW, et al. Neonatal thyroxine supplementation in very preterm children: developmental outcome evaluated at early school age. Pediatrics 2001; 107:712.
  50. van Wassenaer AG, Westera J, Houtzager BA, Kok JH. Ten-year follow-up of children born at <30 weeks' gestational age supplemented with thyroxine in the neonatal period in a randomized, controlled trial. Pediatrics 2005; 116:e613.
  51. Amato M, Guggisberg C, Schneider H. Postnatal triiodothyronine replacement and respiratory distress syndrome of the preterm infant. Horm Res 1989; 32:213.
  52. Valerio PG, van Wassenaer AG, de Vijlder JJ, Kok JH. A randomized, masked study of triiodothyronine plus thyroxine administration in preterm infants less than 28 weeks of gestational age: hormonal and clinical effects. Pediatr Res 2004; 55:248.
  53. van Wassenaer-Leemhuis A, Ares S, Golombek S, et al. Thyroid hormone supplementation in preterm infants born before 28 weeks gestational age and neurodevelopmental outcome at age 36 months. Thyroid 2014; 24:1162.
  54. Williams F, Hume R. The measurement, definition, aetiology and clinical consequences of neonatal transient hypothyroxinaemia. Ann Clin Biochem 2011; 48:7.
  55. La Gamma EF, Paneth N. Clinical importance of hypothyroxinemia in the preterm infant and a discussion of treatment concerns. Curr Opin Pediatr 2012; 24:172.