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Evaluation of the therapeutic interventions effects on body growth pattern of infants with congenital hypothyroidism

Author for correspondence: Sajjad Rahimi Pordanjani e-mail: Sajadrahimi@gmail.com Evaluation of the therapeutic interventions effects on body growth pattern of infants with congenital hypothyroidism Koorosh Etemad, Zaher Khazaei, Sajjad Rahimi Pordanjani, Masoumeh Shahsavand, Fatemeh Ajam, Seyed-Mohammad Riahi, Zahra Zare, Sohrab Iranpour, Isan Darvishi and Malihe Sohrabivafa 1MD, MPH, PhD, Department of Epidemiology, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2MSc of Epidemiology, Department of Public Health, School of Health, Sabzevar University of Medical Sciences, Sabzevar, Iran 3Student Research Committee, Department of Epidemiology, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran 4BSc Student of Public Health, Student Research Committee, Semnan University of Medical Science, Semnan, Iran 5PhD in Epidemiology, Department of Public Health, Faculty of Health, Birjand University of Medical Sciences, Birjand, Iran 6Road Traffic Injury Research center, Department of statistics and epidemiology, Faculty of health, Tabriz University of Medical Sciences, Tabriz, Iran 7Ph.D. Student of Epidemiology, Department of Community Medicine, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran 8MSc of Surgical Technology, Surgical Technology Department, School of Nursing and Midwifery, Shiraz University of Medical Sciences and Healthcare Services 9Department of Health and Community Medicine, Faculty of Medicine, Dezful University of Medical Sciences, Dezful, Iran

Furthermore, the thyroid's normal function plays an important role in brain development prognosis. The patients that their T4 level becomes normal during 2 or more weeks after onset of treatment significantly acquired a lower mark of brain development than whom reach to normal level of T4 during 1 week after onset of treatment [19]. On the other hand, the several authors reported a more severe pattern of brain development disorder in patients, undergone late treatment and low dosage of Levothyroxine [19][20][21].
In a study performed to evaluate the various effects of early dosages of Levothyroxine on the growth pattern of patients with congenital hypothyroidism, there wasn't significant difference between weight, height, and head circumference size of the patients groups, but the growth mean of them was near to the normal growth mean basis on age. Although beginning of treatment with high dosage of Levothyroxine immediately normalized the TSH serum level during a month and leaded to Intelligence Quotient improvement in 4-year-old even in patients with severe congenital hypothyroidism in the time of diagnosis, it couldn't affect their growth [22].
The findings of several studies that have performed to evaluate the growth pattern of infants with congenital hypothyroidism and related factors were various and controversial. Some studies indicated the findings portraying delaying of growth in infants with congenital hypothyroidism, but the early treatment leads to their normal growth pattern. Conversely, some studies reported no significant difference in growth pattern between the infants with congenital hypothyroidism and healthy ones [20,[23][24][25].
Few studies performed to evaluate the therapeutic interventions effects and the related factors on growth pattern of the infants with congenital hypothyroidism in Iran, to our knowledge, and most of them assessed the patients' mental disorders [11,26]. Therefore, given that the physical problems associated with this disease are as important as the mental disabilities that it is producing and affect the infants' future life. Also, considering the high incidence of the congenital hypothyroidism in Iran, the current study was conducted to evaluate the therapeutic interventions' effect on growth pattern of infants with congenital hypothyroidism in Yazd.
With the exception of Hashemipour's study in Isfahan, such a study has not been conducted in Iran and Yazd province so far. As regard very high prevalence of this disease in Iran, especially in Yazd and also implementation of the neonatal screening program in this city for many years which lead to early diagnosis and treatment interventions, therefore, this study was conducted with the aim of evaluation of the therapeutic interventions' effects on the growth pattern of infants with congenital hypothyroidism in Yazd city. Consequently, timely and proper implementations of screening programs and treatment interventions could be done by comparing the pattern of physical growth of children in terms of the therapeutic factors taken by specialist physicians and sending these results to doctors, healthcare policy officers and healthcare professionals.

Methods (a) Design and implementation method of study
The current study was designed as a retrospective cohort and carried out on all of the newborns with congenital hypothyroidism diagnosed through screening program and undergone treatment. All of the newborns from 2007 to 2009 with hypothyroidism were diagnosed through congenital hypothyroidism screening program and undergone treatment, were enrolled to the study after meeting the inclusion and exclusion criteria; afterwards, the effect of related-indices to the therapeutic interventions were assessed by physicians on growth pattern of height, weight, and head circumference size of the infants with congenital hypothyroidism including the age of treatment onset, the administered first dosage of Levothyroxine and normalization period of serum T4 and TSH.
The inclusion criteria was all of the Yazd newborns diagnosed with congenital hypothyroidism through screening program and referred to the healthcare center of Yazd to receive the healthcare services. The exclusion criteria was all of the newborns of other regions diagnosed with congenital hypothyroidism together with another disease including pre-mature newborns, intrauterine growth restriction (IUGR), subjects with genetic disorders such as Down syndrome as well as infants with severe anomaly. Moreover, the lack of knowledge related to study's main variables was considered as exclusion criteria; for instance, undetermined age, and anthropometric variables or apparent error in measurements.

(b) Screening program, diagnosis and treatment
The abnormal values based on screening function to diagnose congenital hypothyroidism were included as TSH> 10 mU/L and T4< 6.5 µg/dl. The anthropometric indices were measured from early infancy to 1 year of age every 3 months, from 1 to 2 year(s) of age every 6 months, and 2 to over-2 years of age annually. In addition, height and weight as well as head circumference size were measured to 5 and 2 years of age, respectively. Therefore, every infant were evaluated in 10 episodes for height and weight and 7 episodes for head circumference size after enrolling to the study. According to the congenital hypothyroidism screening program of the infants in Iran, The treatment begin was classified based on the newborn's age as the following: -Less than 28 days (favorable), from 28 to 40 days (acceptable), more than 41 days (unfavorable) -The normalization period of serum T4 and TSH level was categorized as the following based on the aforementioned instruction. The normalization period of T4 level was classified to two groups as ≤14 and >14 days after initiating the treatment, respectively. Also, the normalization period of TSH level was classified to two groups as ≤30 and >30 days after treatment begin, respectively. The infants with congenital hypothyroidism were assigned to two groups as ≤25 and >25 µg/day based on the first administered therapeutic dosage.
Generally, a total of 69 patients diagnosed with congenital hypothyroidism. Ultimately 55 patients were enrolled to the study after meeting the inclusion criteria. Then, the effectiveness of therapeutic interventions on growth pattern was assessed.

(c) Data collection
In the present study, after coordination with an expert on congenital hypothyroidism and obtaining the necessary permissions from the provincial health center and in coordination with the doctor responsible for the treatment of affected children, an Excel file related to the information of newborns diagnosed with hypothyroidism from 2006 -2008. This file included information about the factors of treatment interventions implemented for children with hypothyroidism. Related variables were extracted from this file.
Furthermore, to collect data related to the anthropometric indices and physical growth pattern (variables such as of height, weight, and head circumference) by referring to the form of monitoring and care of newborns in health centers was executed by using data collection form.

(d) Data analysis
The collected data were analyzed using SPSS software version 22. In order to descriptive analyses height, weight, head circumference size means were estimated based on gender, treatment age, the first administered dosage of Levothyroxine and normalization period of serum T4 and TSH level. In addition, independent sample t-test, repeated measures and ANOVA were utilized for analytical analyses.
(e) Ethical consideration -Obtaining informed consent from the doctor responsible for treatment interventions and parents of patients.
-Data and information collected and published collectively. -The collected data have been kept confidential.
-Collected data have been used only to achieve the purpose of the study.

Results
The results of the current study were surveyed in two parts including descriptive and analytical analyses. The descriptive results are presented in Table 1 showing 5 year-old growth, height, weight, and head circumference size means of the infants with congenital hypothyroidism based on gender, the administered dosage of Levothyroxine, age of treatment begin, normalization period of T4 and TSH level. The 5 year-old growth mean of height, weight, and head circumference in males was higher than that in the females. Also, the 5 year-old growth means of height, weight, and head circumference in infants, undergone lower dosage of Levothyroxine was greater than that in subjects, undergone higher dosage of Levothyroxine. The 5 year-old growth means of height, weight, and head circumference in infants, undergone treatment in early age was higher than that in the subjects, undergone treatment in late age. Furthermore, the 5 year-old growth means of height, weight, and head circumference in infants with shortterm normalization time to adjust serum T4 and TSH was higher than that in the subjects with long-term normalization time.
The trend of 5 year-old growth of height was assessed based on the administered dosage of Levothyroxine (Figure 1 ) showing a significant trend of height growth in infants undergone lower dosage of Levothyroxine being statistically insignificant through using Repeated Measure (P= 0.37). Figure 2 indicates the 5 year-old growth of height in infants with congenital hypothyroidism based on age of treatment begin showing a significant height growth of infants undergone treatment earlier than other subjects in all periods. A statistical significant difference was observed between the height growth of infants, undergone treatment less than 28 days of diagnosis and the subjects, undergone treatment more than 41 days of diagnosis (P< 0.001). Conversely, there was no significant difference between the 5 year-old growth of height in infants, undergone treatment from 28 to 40 days of diagnosis with other infants (P> 0.05). Figure 3 indicates the 5 year-old growth of height in infants with congenital hypothyroidism based on normalization period of serum TSH level showing a better height growth pattern of infants with normalization period during 30 days as compared to the infants with normalization period more than 30 days being statistically significant (P= 0.031). Figure 4 indicates the 5 year-old growth of height in infants with congenital hypothyroidism based on normalization period of serum T4 level showing a better height growth pattern of infants with normalization period during 14 days as compared to the infants with normalization period more than 14 days being statistically significant (P= 0.028).     Comparison of weight growth of the infants with congenital hypothyroidism in different periods was presented in Figures 5, 6, 7 and 8 based on the therapeutic indices from early infancy to 60 months of age. Figure 5 indicates weight growth of infants with congenital hypothyroidism based on the administered dosage of Levothyroxine from early infancy to 60 months of age showing better weight growth pattern of infants with lower dosage of Levothyroxine (≤ 25 µg/day) as compared to the infants with higher dosage of Levothyroxine (>25 µg/day) being statistically insignificant (P=0.33). Figure 6 indicates weight growth of infants with congenital hypothyroidism based on the age of treatment begin showing a better weight growth pattern of infants undergone treatment immediately as compared to the infants undergone treatment lately.
The insignificant physical and weight growth was observed in infants, undergone medical treatment lately (41 days after diagnosing). There was a significant difference between the weight growth of infants undergone treatment after 41 days of diagnosis and the subjects undergone treatment before 41 days of diagnosis, but the height growth was not substantial in these infants (P= 0.012). Figure 7 indicates weight growth of infants with congenital hypothyroidism based on the normalization period of serum TSH level showing a more significant weight growth of infants with short-term normalization period (less than 30 days after applying the therapeutic interventions) as compared to the subjects with long-term normalization period being statistically significant (P= 0.041). Figure 8 indicates weight growth of infants with congenital hypothyroidism based on the normalization period of serum T4 level showing a more significant weight growth of infants with short-term normalization period (less than 14 days after applying the therapeutic interventions) as compared to the subjects with long-term normalization period (more than 14 days after applying the therapeutic interventions) being statistically significant from early infancy to 24 months of age (P= 0.041), but there was no significant difference between the groups in terms of weight growth trend after 24 months of age (P> 0.05).  Comparison of head circumference growth of the infants with congenital hypothyroidism in different periods was presented in Figures 9, 10, 11 and 12 based on the therapeutic indices from early infancy to 60 months of age. A remarkable similarity in head circumference development was observed between the infants. Therefore, there was no statistical significant difference between the head circumference growth in infants (P> 0.05).

Discussion
The current study was designed as a longitudinal retrospective cohort performed on a total of 55 infants with congenital hypothyroidism diagnosed through the screening program undergone      Comparison of the growth pattern of the patient's child at different time points from birth to 60 months of age.

Figure 12. Comparison of Head Circumference growth pattern according to normalization time TSH level.
Comparison of the growth pattern of the patient's child at different time points from birth to 60 months of age. treatment afterwards. They were evaluated in terms of 5 year-old growth of height, weight, and head circumference based on the therapeutic interventions indices including age of treatment begin, the administered dosage of Levothyroxine and normalization time of T4 and TSH level.
The results of the current study showed a significant increase in height, weight, and head circumference in infants from early infancy to 60 months of age as well as an ascending trend of the aforementioned variables. Too many challenges were proposed for administering the necessary dosage of Levothyroxine as well as the normal level of TSH in recent years [27]. The effect of medication dosage and time of alternative treatment onset on newborns with congenital hypothyroidism has been always controversial. The European and American Guidelines have suggested the high dosage of Levothyroxine for treatment begin which has been controversial [7,28]. Also, according to a systematic review, there was little evidence to represent the effects of starting dosage of Levothyroxine on the growth of newborns with congenital hypothyroidism [29]. The starting dosage of Levothyroxine was suggested as 10-15 µg/kg based on the severity of hypothyroidism [30].
The trend of 5 year-old growth of height was assessed in the current study based on the administered dosage of Levothyroxine and infants who had received lower dosage of Levothyroxine (25 µg/day>) had better trend of height growth.
The trend of weight growth of infants with congenital hypothyroidism was assessed based on the administered dosage of Levothyroxine from early infancy to 60 months of age showing a higher weight growth of infants with lower dosage of Levothyroxine (≤ 25 µg/day) as compared to the infants with higher dosage of Levothyroxine (>25 µg/day).
The newborns with congenital hypothyroidism receiving higher dosage of 9.5 µg/kg/day of Levothyroxine before 13 days of diagnosis reached to growth and development comparable to reference population in the study of Jacoba et al. [20]. Moreover, several studies reported significant growth improvement in infants with severe congenital hypothyroidism undergone administration of higher starting dosage of Levothyroxine as 10-15 µg/kg/day as well as early treatment [31][32][33]. The results of the current study showed a better physical and weight growth in infants, undergone medical treatment immediately after diagnosis (less than 28 days) as compared to the infants received treatment lately (41 days after diagnosing). Some studies demonstrated a significant correlation between the weight growth with age of treatment onset and therapeutic starting dose while a significant correlation was observed between the head circumference size with therapeutic starting dose [34]. Grant (1994) and Hashemipour et al. (2015) reported that the growth status of the infants with congenital hypothyroidism depends on the several factors such as therapeutic dose of medication [16,34]. Furthermore, a study reported the normal physical growth of the infants in first 3 years of life, immediately diagnosed and undergone treatment [35]. Nevertheless, some studies reported the latency in height growth improvement of the infants depends on LT4 dosage and, ages of treatment begin [1,36,37]. The height and weight of the patients with the age of treatment begin less than 30 days were significantly higher in some studies which are compatible with the results of the current study [34,38,39]. Moschini et al. (1986) reported the normal height growth in 6 years old with the age of treatment begin during 33 days after birth [39].
There was no significant correlation between the final height of the patients, age of treatment begin, and administered dosage of Levothyroxine in the studies carried out in Japan and Italy [14,40]. In the study conducted in Italy on a total of 215 patients during 2 decades, in spite of using screening programs and treatment, the height growth of patients was increased. However, this increase has not improved since the last 20 years and also ultimate height is not affected by the birth date, the patient's age at the time of diagnosis, the initial dose of levothyroxine [14]. The significant effect of the starting dosage of Levothyroxine was reported on the height and weight distribution of the patients with congenital hypothyroidism in a study performed in Isfahan. The study indicated higher height and weight growth in patients received the starting dosage of Levothyroxine as ≥33.33 µg/day as compared to the subjects received lower starting dosage. Moreover, there was a significant correlation between the longitudinal growth of height and weight with the age of treatment begin and starting dosage of Levothyroxine in all percentiles [41].
The results of the current study showed the similarity of head circumference growth trend in different periods of time from early infancy to 60 months of age being statistically insignificant in the therapeutic interventions' indices. Conversely, a study reported the significant correlation between height and weight growths with starting dose as compared to the insignificant correlation between head circumference growth with starting dose [13].
A study carried out in Isfahan showed a significant correlation between head circumference growth with starting dosage of Levothyroxine as compared to the insignificant correlation with the age of treatment begin. The head circumference growth in patients with starting dosage of Levothyroxine ≥33.33 µg/day was better in patients with starting dosage <33.33 µg/day [41]. The heterogeneity effect of normalization age of T4 was reported on head circumference as compared to the significant effect of normalization age of TSH on physical growth of patients with congenital hypothyroidism [16,34].

Conclusions
The significant effect of therapeutic interventions was reported on height, weight, and head circumference growths of patients with congenital hypothyroidism. The age of treatment begin less than 30 days plays an important role in promoting of height and weight growth of patients with congenital hypothyroidism. The better trend of height and weight growth was reported in infants with normalization time of TSH during 30 days after diagnosing. The substantial trend of weight and height growths might be demonstrated in infants with normalization age of T4 less than 14 days. The pattern of head circumference growth would be increased equally and similarly in patients after treatment.