Recovery Rate of Hyperthyrotropinemia and Its Associated Factors: A Prospective Observational Study

Document Type : Original article


1 School of Medicine, Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran

2 School of Medicine, Islamic Azad University Sari Branch Faculty of Medicine, Sari, Mazandaran, Iran

3 School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 School of Rehabilitation Sciences, Iran University of Medical Sciences, Tehran, Iran.

5 Department of Pediatrics, Boali Hospital, Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran.


Introduction:Hyperthyrotropinemia (HT) can be transient or permanent. There is no specific protocol in confirmatory tests to discriminate between transient and permanent forms. The aim of this study was to investigate the prevalence of transient HT and the factors that help to discriminate transient from permanent HT.
Methods:This was an observational prospective study in all neonates diagnosed with HT referred to the pediatric clinic of Boali Hospital, affiliated to Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran during September 2017 and January 2019. The recovery rate was investigated during a three-month follow-up while withholding medical treatment. Data were analyzed with SPSS Version 22.0.
Results: Totally, 80 neonates (65% girls) were enrolled in this study. Among them, 62 participants (77.5%) recovered without any treatment during the three months of follow-up. The recovery rate was significantly higher in term newborns (p < 0.01). The mean weight of recovered neonates (2767.7 ± 440.2 gr) was significantly higher than that of the neonates who did not recover (2141.7 ± 755.2) (p < 0.01). The mean level of thyroid-stimulating hormone (TSH) of the recovered neonates (9.4 ± 3.0 mIU/L) was significantly lower than in the neonates who did not recover (22 ± 6.5 mIU/L) (p < 0.01).
Conclusion: The outcome of HT became mostly permanent in patients with a higher level of TSH. The prematurity and low birth weight were the influential factors on TSH level, which could indirectly increase the risk of HT permanence.


Congenital hypothyroidism (CH) is the most common congenital endocrine disorder in neonates. The thyroid hormone has a fundamental role in the growth and development of the brain. Hypothyroidism remains asymptomatic in many neonates. Therefore, a thyroid-screening test is carried out for all newborns during the first three to five days after birth, by measuring the thyroid-stimulating hormone (TSH) from the heel prick blood spot, to prevent the consequences of late diagnosis and treatment of CH. In the case of abnormal results of the primary screening test, a confirmatory test is requested (1, 2). Newborns who have an abnormal screening test and elevated TSH and normal T4 in the confirmatory test are considered hyperthyrotropinemia (HT).
HT has two types, namely transient and permanent. Transient HT is often resolved after a few weeks to a few months, but neonates with permanent HT will maintain the abnormal TSH level (3). A specific incidence rate for transient HT has not yet been determined, and various studies suggested an incidence range of 1 in every 8000 live births to 1 in every 17600 live births per year (4).
Different studies have suggested several causes for transient HT, such as prenatal iodine deficiency, prenatal iodine excess, maternal antithyroid medication, maternal hypothyroidism, and prematurity (5). Notably, 10% of neonatal hypothyroidism cases in the world are not detected despite the implementation of the thyroid screening protocol (6). Accordingly, a study recommended that hypothyroidism should be considered a potential cause in neonates with symptoms of developmental delay and prolonged jaundice (7).
Although a specific definition for transient HT has been proposed, there is no specific protocol in the confirmatory tests to discriminate between transient and permanent forms of HT in neonates (4). The management approach for these patients has been controversial. Some clinicians withhold treatment. Others treat the HT patients with thyroid hormone replacement for the first few years of life, and then gradually reduce the dose of levothyroxine (3, 8-10).
Although the latter approach can reduce the risk of side effects of neonatal hypothyroidism, it can increase the risk of overtreatment and complications for transient HT neonates (11). This study aimed to investigate the prevalence of transient HT, its associated factors, and the recovery rate without medical treatment to prevent the long-term potential side effects of this disorder, especially on brain development.

Study design
The present observational prospective study was conducted on neonates with HT referred to the pediatric clinic of Boali Hospital, affiliated to Islamic Azad University Tehran Faculty of Medicine, Tehran, Iran during September 2017 and January 2019. The recovery rate was investigated during a three-month follow-up, withholding medical treatment. The protocol of this study was approved by the ethics committee of Islamic Azad University Tehran Faculty of Medicine (Ethics code: IR.IAU.TMU.REC.1396.182). Written informed consent was obtained from the parents of all neonates before their participation in the study. All information was used privately and without mentioning the patients’ names.
Study population
During this study, 2,556 neonates were referred to the vaccination section or pediatric clinic of Boali Hospital for the thyroid screening test. To measure the qualitative TSH level in these neonates, the heel prick blood spot was conducted in the first three to five days after birth. Those who had an abnormal screening test were referred to the laboratory department of Boali Hospital to measure the serum level of TSH and free T4 (FT4). All neonates with an abnormal screening thyroid test who had a TSH level between 6 and 60 mIU/L and normal FT4 (1.3 to 2.8 ng/dL) entered the study with the diagnosis of hyperthyrotropinemic hypothyroidism. The secondary assessment was done by measuring TSH at three months of age. During these three months, the neonates underwent a routine physical examination, every two weeks. The exclusion criteria were as follows: The primary TSH level of lower than 6 mIU/L or higher than 60 mIU/L, or the primary FT4 level lower than 1.3 ng/dL. Known cases of metabolic diseases and those whose parents did not give consent were also excluded from the study. Sampling was done with the convenience method, and all neonates who fulfilled our criteria entered the study.

Data gathering
In this study, the neonate’s data including gender and maturity status (term, preterm), and history of jaundice (physiological, pathological, or none), congenital anomaly, and collagen vascular diseases were collected. Maternal data, including age and history of hypothyroidism, were also recorded. Weight measurement was done by a pediatrician using the same scaling instrument. The TSH and FT4 levels were assessed using the automated immune chemiluminescence assay kits (Abbott, IL, USA) in the laboratory of Boali Hospital. To investigate the recovery rate, the TSH level was measured again after three months of follow-up, and recovery was defined as a TSH level of 0.5 to 5.5 mIU/L.

Statistical analysis:
All data were analyzed with SPSS Version 22.0 (SPSS Inc., Chicago, IL, USA). Quantitative variables are described using mean ± standard deviation, and qualitative variables are presented using frequency and percentages. Chi-square test, one-way ANOVA, and independent sample T-test were applied to evaluate the difference between groups in terms of the target variables. A P-value < 0.05 was considered statistically significant.

This study included 80 neonates with HT (65% girls). None of the neonates had a congenital anomThis study included 80 neonates with HT (65% girls). None of the neonates had a congenital anomaly or collagen vascular disease. The descriptive information of the participants is shown in Table 1. Overall, 62 neonates (77.5%) recovered without any treatment during three months of follow-up.
The mean level of TSH in all neonates was 12.2 ± 6.6 mIU/L, and the TSH level was significantly higher in boys and preterm newborns (p < 0.05). The recovery rate was also significantly higher in term newborns (p < 0.01). Neonates with a history of maternal hypothyroidism had a lower level of TSH, but the difference (versus others) was not statistically significant (p > 0.05). Further, 60% of neonates had a history of physiological jaundice, and the level of TSH was higher among them, but the relation was not statistically significant (p > 0.05). The recovery rate did not have any significant relation with gender, maternal hypothyroidism, and history of jaundice (p>0.05).
The mean weight of the participants was 2626.8 ± 584.4 grams. The mean weight of the neonates who recovered (2767.7 ± 440.2 g) was significantly higher than that of the neonates who did not recover (2141.7 ± 755.2 g) (p < 0.01). There was also a significant relationship between the TSH level and birth weight (p < 0.01). Moreover, the mean age of mothers in participants was 26.9 ± 3.7 years, with a minimum and maximum of 12 and 35 years, and did not have any significant relation with the level of TSH and with the recovery rate (p > 0.05).
The mean level of TSH in neonates who recovered within three-month was 9.4 ± 3 mIU/L, and in neonates who did not recover was 22 ± 6.5 mIU/L. The relation between the recovery and TSH level




















The present study showed that the prevalence of febrile seizures was associated with gender, living place, temperature, family history of seizure, and the serum level of zinc. In this regard, the frequency of zinc deficiency was higher in patients with febrile seizures compared to febrile patients without seizure, before and after adjusting for gender.
Zinc plays a vital role in the neuronal terminals of the hippocampus and amygdala by producing pyridoxal phosphate and affecting glutamatergic, gamma-aminobutyric acidergic (GABAergic), and glycinergic synapses (13).
Glutamic acid decarboxylase (GAD) acts as a major inhibitory neurotransmitter in the synthesis of gamma-aminobutyric acid (GABA) (14). A study by Ganesh R. and Janakiraman L. on 38 children with febrile convulsion and 38 children as a control group, aged between 3 months and 5 years, indicated that a serum zinc deficiency was significantly more prevalent in their case group than in the control group (15). Another study has reported that there is a correlation between disruption in Zn2+ homeostasis and fever seizure (16).
In studies by Papierkowski A., Mollah M.A., and Gündüz Z. et al., the mean serum zinc level in the febrile convulsion group was significantly lower than in the control group, which indicates the role of zinc in febrile seizure. Comparing the groups in terms of age and gender, no significant difference was found, similar to our study (17-19). Abdel Hameed Z.A. et al. (20), in a study on 100 infants in Egypt, observed that temperature had no significant difference between the case and control groups. But Berg A.T. (21), Ahmed B.W. (22), and our study showed the importance of temperature in febrile seizure. The geographic area can be the cause of this difference. Duangpetsang J. in a study from 2014 to 2017 reported that a high fever with electrolyte disturbance hyponatremia has an important role in FS (23). Sharifi R. et al., in a study in 2007-2014, showed the importance of family history in febrile seizure (24), which is similar to our results.

The findings of this study show that zinc deficiency is significantly associated with the occurrence of febrile seizures. Zinc supplementation in children can therefore be helpful for the prevention and treatment of FS.

Conflict of interest
The authors declare no conflicts of interest. 

  1. Hashemipour M, Hovsepian S, Kelishadi R, et al. Permanent and transient congenital hypothyroidism in Isfahan-Iran. J Med Screen. 2009;16:11-6.
  2. Mehran L, Khalili D, Yarahmadi S, et al. Evaluation of the congenital hypothyroidism screening programme in Iran: a 3-year retrospective cohort study. Arch Dis Child Fetal Neonatal Ed. 2019;104:F176-F181.
  3. Zung A, Tenenbaum-Rakover Y, Barkan S, et al. Neonatal hyperthyrotropinemia: population characteristics, diagnosis, management and outcome after cessation of therapy. Clin Endocrinol (Oxf). 2010;72:264-271.
  4. Unüvar T, Demir K, Abacı A, et al. The role of initial clinical and laboratory findings in infants with hyperthyrotropinemia to predict transient or permanent hypothyroidism. J Clin Res Pediatr Endocrinol. 2013;5:170-173.
  5. Cuestas E, Gaido MI, Capra RH. Transient neonatal hyperthyrotropinemia is a risk factor for developing persistent hyperthyrotropinemia in childhood with repercussion on developmental status. Eur J Endocrinol. 2015;172:483-490.
  6. Wassner AJ. Pediatric Hypothyroidism: Diagnosis and Treatment. Paediatr Drugs. 2017;19:291-301.
  7. Ford GA, Denniston S, Sesser D, et al. Transient versus Permanent Congenital Hypothyroidism after the Age of 3 Years in Infants Detected on the First versus Second Newborn Screening Test in Oregon, USA. Horm Res Paediatr. 2016;86:169-177.
  8. Kara C, Gunindi F, Can Yilmaz G, et al. Transient Congenital Hypothyroidism in Turkey: An Analysis on Frequency and Natural Course. J Clin Res Pediatr Endocrinol. 2016;8:170-179.
  9. Oren A, Wang MK, Brnjac L, et al. Mild neonatal hyperthyrotrophinaemia: 10-year experience suggests the condition is increasingly common but often transient. Clin Endocrinol (Oxf). 2013;79:832-837.
  10. Tamam M, Adalet I, Bakır B, et al. Diagnostic spectrum of congenital hypothyroidism in Turkish children. Pediatr Int. 2009;51:464-468.
  11. Wassner AJ, Brown RS. Congenital hypothyroidism: recent advances. Curr Opin Endocrinol Diabetes Obes. 2015;22:407-412.
  12. Cody D, Kumar Y, Ng SM, et al. The differing outcomes of hyperthyrotropinaemia. J Pediatr Endocrinol Metab. 2003;16:375-378.
  13. Calaciura F, Motta RM, Miscio G, et al. Subclinical Hypothyroidism in Early Childhood: A Frequent Outcome of Transient Neonatal Hyperthyrotropinemia. J Clin Endocrinol Metab. 2002;87:3209-3214.
  14. Tfayli H, Charafeddine L, Tamim H, et al. 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;89:224-232.
  15. Nishiyama S, Mikeda T, Okada T, et al. Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine intake. Thyroid. 2004;14:1077-1083.
  16. Travers CA, Guttikonda K, Norton CA, et al. Iodine status in pregnant women and their newborns: are our babies at risk of iodine deficiency? Med J Aust. 2006;184:617-620.
  17. Nohr SB, Laurberg P. Opposite variations in maternal and neonatal thyroid function induced by iodine supplementation during pregnancy. J Clin Endocrinol Metab. 2000;85:623-627.
  18. Babaniamansour S, Hematyar M, Babaniamansour P, et al. The Prevalence of Vitamin D Deficiency Among One to Six Year Old Children of Tehran, Iran. J Kermanshah Univ Med Sci. 2019; 23:e95185.
  19. Jaruratanasirikul S, Sangsupawanich P, Koranantakul O, et al. Maternal iodine status and neonatal thyroid-stimulating hormone concentration: a community survey in Songkhla, southern Thailand. Public Health Nutr. 2009;12:2279-2284.
  20. Arshi S, Dehghani Firouzabadi F, Ghalehbaghi B, et al. Otitis Media with Effusion in Children and the Impact of Risk Factors on Serum Cytokine Levels. Iran J Otorhinolaryngol. 2017;29:75-81.
  21. Ershadinia N, Mortazavinia N, Babaniamansour S, et al. The prevalence of autoimmune diseases in patients with multiple sclerosis: A cross-sectional study in Qom, Iran, in 2018. Curr J Neurol 2020; 19: 98-102.
  22. Parks JS, Lin M, Grosse SD, et al. The impact of transient hypothyroidism on the increasing rate of congenital hypothyroidism in the United States. Pediatrics. 2010;125 Suppl 2:S54-63.
  23. Underland L, Kenigsberg L, Derrick KM, et al. Thyroid Function Testing in Neonates With Maternal History of Disease. Clin Pediatr (Phila). 2018;57:436-441.
  24. Kvetny J, Poulsen H. Transient hyperthyroxinemia in newborns from women with autoimmune thyroid disease and raised levels of thyroid peroxidase antibodies. J Matern Fetal Neonatal Med. 2006;19:817-822.
  25. Banakar MK, Formosa M. Serum thyroid function tests in neonates of mothers with thyroid disease. Indian J Pediatr. 2011;78:870-873.
  26. Unachak K, Dejkhamron P. Primary congenital hypothyroidism: clinical characteristics and etiological study. J Med Assoc Thai. 2004;87:612-617.
  27. Singh B, Ezhilarasan R, Kumar P, et al. Neonatal hyperbilirubinemia and its association with thyroid hormone levels and urinary iodine excretion. Indian J Pediatr. 2003;70:311-315.
  28. kayıran sm, Berkan G. Correlation of third day TSH and thyroxine values with bilirubin levels detected by a neonatal screening system. Medical Journal of Bakırköy, 6. 2010.
  29. Sepideh B, Ehsan A, Ghasem B, et al. Simultaneous Volvulus of Transverse Colon and Cecum in a Patent With Down Syndrome: A Case Report. Spring 2019, 4.