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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 123

Guideline for the treatment of hypothyroidism in prematurity


1 Department of Pediatrics, School of Medicine, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
2 Pediatric Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran

Date of Submission25-Jul-2020
Date of Acceptance21-Jan-2021
Date of Web Publication29-Sep-2021

Correspondence Address:
Setila Dalili
Pediatric Diseases Research Center, Guilan University of Medical Sciences, Rasht
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpvm.IJPVM_424_20

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  Abstract 


Congenital hypothyroidism is one of the most common endocrine disorders in infants and children. Thyroid hormone effects the function of most organs of the body. In premature neonates, thyroid abnormalities are very common but transient. There is a significant difference between the appropriate time for screening in premature and term neonates and there are different viewpoints in treating hypothyroidism in prematurity. According to the probable exceptions in this issue, there is no definite guideline. Therefore, regarding this confusion, this guideline aimed to help clinicians for rapid on-time decision making.

Keywords: Hypothyroidism, infant, premature birth


How to cite this article:
Hashemipour M, Rad AH, Dalili S. Guideline for the treatment of hypothyroidism in prematurity. Int J Prev Med 2021;12:123

How to cite this URL:
Hashemipour M, Rad AH, Dalili S. Guideline for the treatment of hypothyroidism in prematurity. Int J Prev Med [serial online] 2021 [cited 2021 Nov 28];12:123. Available from: https://www.ijpvmjournal.net/text.asp?2021/12/1/123/327229




  Introduction Top


Congenital hypothyroidism is one of the most common endocrine disorders in infants and children. Thyroid hormone effects the function of most organs of the body.[1] It has diverse risk factors and treatment in different societies, however its treatment in prematurity have significant considerations.[2],[3],[4] Although, low levels of thyroid hormones and delay in treatment in preterm infants can be associated with neurodevelopmental impairments.[1] No untreated disease can have this much impact on growth and development. With regards to the importance of early diagnosis and treatment in preventing complications, recently in many countries, newborns are examined for congenital hypothyroidism at birth to diagnose the disease. The embryo's thyroid gland is developed in the 12 weeks of gestation, and thyroid function is completed in 4 weeks after childbirth.[5],[6],[7]

In premature neonates, thyroid abnormalities are very common but transient.[1] The frequency of congenital hypothyroidism is high in preterm and low-birth-weight (LBW) newborns compared to normal ones due to insufficient development of the hypothalamic-pituitary axis (1/400 vs 1/4000).[8],[9]

Causes of hypothyroxinemia in prematurity hypothyroxinemia, which is defined as the decreased level of T4 in premature neonates is physiologic and should not be considered as a disease.[10],[11],[12]

The causes of hypothyroxinemia are as below:

  • Low thyroid binding globulin (TBG) during the first 2 weeks of life
  • Decreased T4 binding affinity to TBG
  • Limited thyroid gland reserve
  • Obtunded neonatal thyroid stimulating hormone (TSH) surge
  • Minimal T4 to T3 conversion
  • Immaturity of the hypothalamic-pituitary-thyroid
  • medications including dopamine, dexamethasone, aminophylline, etc.
  • Respiratory distress syndrome
  • Sepsis
  • Necrotizing entrocolitis
  • Nonthyroidal illness
  • Iodine deficiency
  • Transfer withdrawal of maternal-placental T4
  • Perinatal asphyxia
  • Limited thyroglobulin iodine stores.


Treatment and screening of hypothyroidism are challenging. Though some studies suggested repeated screening in VLBW newborns, others recommended other strategies such as lowering the TSH screening cutoff.[13],[14],[15],[16],[17]

The challenges for screening occur because of physiologic hypothyroxinemia and delayed hyper thyrothyotropinemia. Treatment of hypothyroidism depends on the nonthyroidal illness process, which worsens the interpretation of the disease. On the other hand, the normal value of T4 and the variant duration for reaching normal thyroid hormones (T4, TSH, FREE T4) is commonly based on gestational age. For instance, <30 weeks of gestation needs 1 month, >30 weeks of gestation needs 1to 2 weeks, early low birth weight infants need 4 to 12 weeks, and very low birth weight and low birth weight need 1 to 2 weeks to be normal.

In preterm newborns, the amount of umbilical cord T4 is less than term neonates. Gestational age and birth weight usually determine the level of T4. Decreased level of TBG causes a significant reduction of T4 in preterm infants at birth, an abrupt rise in thyrotropin (TSH), T4, and T3 occurs in term neonates as well as preterm newborns, however, this increase is lower in preterm neonates compared to term ones. Furthermore, a decrease in the levels of T3 and T4 during the first week of life can be reported in preterm neonates. It can be as a result of nutritional problems and reduced production of liver TBG, immaturity of the hypothalamus-hypothyroid axis, an increase in the use of T4 in the tissues, and complications of prematurity, such as respiratory distress syndrome, and nonthyroid disease.[10],[18]

In the first 2 weeks of birth, in premature babies, the TSH level is low, and then it increases until the 5th week of birth. Up to the 14th week, the level of TSH can become normal. In addition, in 10–14 days after birth, the lowest level of T4 is commonly reported, the normal level would be identified within 2–8 weeks, and the highest at 12 weeks of birth. Also, a normal level of free T4 is commonly reported within 1 to 2 weeks after birth.[19],[20] On the other hand, premature neonates may face sick euthyroid syndrome after birth, which occurs under stress. In this setting, the body tries to decrease the basal-metabolic-rate and uses energy to combat the disease. T3 regulates the basal-metabolic-rate in the body. Accordingly, in this process, at the beginning, conversion of T4 to reverse T3 will be increased, but if it does not succeed, the levels of T4 and eventually TSH will be decreased in premature neonates. But during the recovery period, TSH will be increased. Therefore, the occurrence of this process in premature neonates, and the treatment by levothyroxine will worsen the patient's condition.

However, for survival in neonates aged <28 weeks of gestation at birth, basal-metabolic-rate is needed and the mentioned treatment with levothyroxine could be acceptable (there is no consensus on the onset of treatment in these children).[21],[22],[23],[24]

There is a significant difference between the appropriate time for screening in premature and term neonates.

As, there is a delayed increase in TSH in premature infants, thyroid screening (TSH) is recommended for 1 to 2 weeks until the 38 weeks of gestation. In most countries, this screening is conducted at the age of 2, 6, and 10 weeks, therefore, the normal TSH level in newborns with hypothyroidism cannot rule out the hypothyroidism.[9],[10],[16],[17],[18]

The most sensitive test for diagnosis of hypothyroidism is TSH and the level of TSH above 10 miu/L has a diagnostic value.[7],[10],[24],[25] Regarding the transient hypothyroxinemia, sick euthyroid illness, and different levels of thyroid hormones, the diverse duration for being normal, and the complications of untreated status in preterm neonates, authors aimed to provide this guideline for the treatment of congenital hypothyroidism.

Normal levels of free T4 and T4 in premature neonates was summarized in [Table 1]. To mitigate the confusion, the free T4 normal values was considered as 0.8 to 2.6 ng/dL. If the level of T4 is below 2 standard deviation of the mean, it can be considered abnormal.[9] Also, the normal value of free T4 in preterm infants based on gestational age in the first week after birth is 0.8–2.6 ng/dL. Owing to the low level of T4 in the first weeks after birth in premature neonates, the table is used to interpret the normal level of this hormone. If the level of T4, is below 2 standard deviation, the level of the hormone would be considered low.
Table 1: Levels of Thyroid hormones in different gestational ages

Click here to view



  Treatment Top


Regarding the levels of T4 and free T4 in gestational age, free T4 lower than 0.8 and TSH upper than 10 should be considered as the first and second positive points, respectively. The strategy of treatment is summarized in [Table 2] and [Figure 1]. The treatment initiates for patients with TSH >20 with and the existence of two positive points.
Figure 1: The flowchart for treating abnormal TSH of heel

Click here to view
Table 2: The indication of treatment in prematurity

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If the patient had one positive point, laboratory findings should be rechecked 2 weeks later, and if one positive point was reported in a recheck, the treatment should be initiated.

In patients with TSH levels between 6 to 10 and no positive point, physician clinical judgment defines the treatment process.

Generally, a high level of TSH indicates the need for treatment regarding its impact on the occurrence of developmental disorders.[26],[27],[28]

In premature neonates weighed <1,000 grams and aged <28 weeks of gestation, some clinicians recommend levothyroxine therapy at 4 μg/kg, but this is not a consensus on it, yet.[28],[29],[30]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hashemipour M, Hovsepian S, Ansari A, Keikha M, Khalighinejad P, Niknam N. Screening of congenital hypothyroidism in preterm, low birth weight and very low birth weight neonates: A systematic review. Pediatr Neonatol 2018;59:3-14.  Back to cited text no. 1
    
2.
Dalili S, Rad AH, Dalili H. Congenital Hypothyroidism (An Overview to Incidence, Etiology, Risk Factors and Outcomes). J Dis Markers. 2014;1:1016. ISSN:2380-0682.  Back to cited text no. 2
    
3.
Rovshan B, Hassanzadeh Rad A, Dalili S, Gholi Famian AR. Developmental Skills of Children with and Without Congenital Hypothyroidism. ISMJ. 2020; 10;23:321-9.  Back to cited text no. 3
    
4.
Dalili S, Rezvany SM, Dadashy A, Mohamady H, Dalili H, Medghalchy A, et al. Congenital Hypothyroidism: A Review of the Risk Factors. Archives of Disease in Childhood. 2012:97 (Suppl 2): A437-A438.  Back to cited text no. 4
    
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Murphy N, Hume R, van Toor H, Matthews TG, Ogston SA, Wu SY, et al. The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life. J Clin Endocrinol Metab 2004;89:2824-31.  Back to cited text no. 5
    
6.
Hunter MK, Mandel SH, Sesser DE, Miyahira RS, Rien L, Skeels MR, 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;132:70-4.  Back to cited text no. 6
    
7.
Woo HC, Lizarda A, Tucker R, Mitchell ML, Vohr B, Oh W, et al. Congenital hypothyroidism with a delayed thyroid-stimulating hormone elevation in very premature infants: Incidence and growth and developmental outcomes. J Pediatr 2011;158:538-42.  Back to cited text no. 7
    
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Tfayli H, Charafeddine L, Tamim H, Saade J, Daher RT, Yunis K. Higher incidence rates of hypothyroidism and late TSH rise in preterm very-low-birth-weight infants at a Tertiary care center. Horm Res Paediatr 2018;89:224-32.  Back to cited text no. 8
    
9.
Chung M. Incidence and risk factor of permanent hypothyroidism in preterm infants. J Neonatal Biol 2017;6:254.  Back to cited text no. 9
    
10.
Chung ML, Yoo HW, Kim K-S, Lee BS, Pi S-Y, Lim G, et al. Thyroid dysfunctions of prematurity and their impacts on neurodevelopmental outcome1. J Pediatr Endocrinol Metab 2013;26:449-55.  Back to cited text no. 10
    
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Gruneiro-Papendieck L, Prieto L, Chiesa A, Bengolea S, Bossi G, Bergada C. Usefulness of thyroxine and free thyroxine filter paper measurements in neonatal screening for congenital hypothyroidism of preterm babies. J Med Screen 2000;7:78-81.  Back to cited text no. 11
    
12.
Osborn DA, Hunt R. Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia. Cochrane Database Syst Rev 2007;2007:CD005945.  Back to cited text no. 12
    
13.
La Gamma EF, Korzeniewski SJ, Ballabh P, Paneth N. Transient hypothyroxinemia of prematurity. NeoReviews 2016;17:e394-402.  Back to cited text no. 13
    
14.
DeMartino L, McMahon R, Caggana M, Tavakoli NP. Gender disparities in screening for congenital hypothyroidism using thyroxine as a primary screen. Eur J Endocrinol 2018;179:161-7.  Back to cited text no. 14
    
15.
Mandel SJ, Hermos RJ, Larson CA, Prigozhin AB, Rojas DA, Mitchell ML. Atypical hypothyroidism and the very low birthweight infant. Thyroid 2000;10:693-5.  Back to cited text no. 15
    
16.
Uchiyama A, Watanabe H, Nakanishi H, Totsu S. Small for gestational age is a risk factor for the development of delayed thyrotropin elevation in infants weighing less than 2000 g. Clin Endocrinol 2018;89:431-6.  Back to cited text no. 16
    
17.
Giraldo GA, Suárez-Obando F, Mora L, Sánchez P, Prieto J. Evaluation of TSH levels in the program of congenital hypothyroidism newborn screening in a pilot study of preterm newborns in Bogotá, Colombia. J Inborn Errors Metab Screen 2015;3. http://dx.doi.org/10.1177/2326409815597706.  Back to cited text no. 17
    
18.
Cuestas RA. Thyroid function in healthy premature infants. J Pediatr 1978;92:963-7.  Back to cited text no. 18
    
19.
Deming DD, Rabin CW, Hopper AO, Peverini RL, Vyhmeister NR, Nelson JC. Direct equilibrium dialysis compared with two non-dialysis free T4 methods in premature infants. J Pediatr 2007;151:404-8.  Back to cited text no. 19
    
20.
Zung A, Yehieli A, Almashanu S. Neonatal hyperthyrotropinemia is associated with low birth weight: A twin study. Eur J Endocrinol 2013;168:263-9.  Back to cited text no. 20
    
21.
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.  Back to cited text no. 21
    
22.
Uchiyama A, Kushima R, Watanabe T, Kusuda S. Effect of L-thyroxine supplementation on very low birth weight infants with transient hypothyroxinemia of prematurity at 3 years of age. J Perinatol 2017;37:602-5.  Back to cited text no. 22
    
23.
Ng SM, Turner MA, Gamble C, Didi M, Victor S, Manning D, 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.  Back to cited text no. 23
    
24.
Ng SM, Turner MA, Gamble C, Didi M, Victor S, Atkinson J, et al. Effect of thyroxine on brain microstructure in extremely premature babies: Magnetic resonance imaging findings in the TIPIT study. Pediatr Radiol 2014;44:987-96.  Back to cited text no. 24
    
25.
Hyman SJ, Greig F, Holzman I, Patel A, Wallach E, Rapaport R. Late rise of thyroid stimulating hormone in ill newborns. J Pediatr Endocrinol Metab 2007;20:501-10.  Back to cited text no. 25
    
26.
Kaluarachchi D, Colaizy T, Pesce L, Tansey M, Klein J. Congenital hypothyroidism with delayed thyroid-stimulating hormone elevation in premature infants born at less than 30 weeks gestation. J Perinatol 2017;37:277-82.  Back to cited text no. 26
    
27.
Dembinski J, Arpe V, Kroll M, Bartmann P, Hieronimi G. Thyroid function in healthy and sick very-low-birth-weight infants–thyrotropin and free thyroxine levels until the sixth week of age. Neonatology 2001;80:210-4.  Back to cited text no. 27
    
28.
Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, Van Vliet G, et al. European society for paediatric endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paediatr 2014;81:80-103.  Back to cited text no. 28
    
29.
La EG, Ares S, Golombek S, Kok J, Quero J, Hong T, et al. Phase 1 trial of 4 thyroid hormone regimens for transient hypothyroxinemia in neonates of <28 weeks' gestation. Pediatrics 2009;124:e258-68.  Back to cited text no. 29
    
30.
Osborn DA. Thyroid hormones for preventing neurodevelopmental impairment in preterm infants. Cochrane Database Syst Rev 2001;(4):CD001070.  Back to cited text no. 30
    


    Figures

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    Tables

  [Table 1], [Table 2]



 

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