Height, weight, and head circumference size are considered as one of the best indicators of infants’ general health. The abnormal growth may indicate the presence of a disease and/or a disorder in apparently normal infants. The congenital hypothyroidism is one of the causes of growth disorder in infants [1][2]. The congenital hypothyroidism was described as the lack of thyroid hormone in birth time reported as one of the most common congenital endocrine disorders as well as the most preventable causes of mental retardation and body growth disorders [3][4]. The incidence of congenital hypothyroidism was substantially increased in recent years with ratio of 1:1400 to 1:2800 [4]. According to the studies performed in Iran, the incidence of the aforementioned disorder was increased from the ratio of 1:1400 to 1:1900 being statistically higher than the global average [5]. A meta-analysis study reported the incidence of newborns’ congenital hypothyroidism with the ratio of 2:1000 in Iran [6].

The studies reported the prevalence of congenital hypothyroidism in different ranges in the world being 7.14 in Nigeria to 14 per 1000 births in Japan [3][7]. The reports stated the higher incidence of congenital hypothyroidism in Iran than other regions of the world before and after applying the congenital hypothyroidism screening program [8][9]. in this regard, the national studies have shown various incidence of congenital hypothyroidism in Iran with the ratio of 1:1000, 1:370, 1:1433, 1:400 and 1:1608 live births in Tehran, Isfahan, Shiraz, Kurdistan, and Yazd, respectively [10]–[13]. Nowadays, the infants’ screening program application leads to the early diagnosis of patients with various genetic and/or congenital diseases such as congenital hypothyroidism and accordingly applying the suitable treatment with Levothyroxine alternative dosage administration suppressing its adverse outcomes [14][15]. It has been accepted that hypothyroidism in childhood, in spite of proper treatment, can disrupt growth in adulthood; however, many studies have reported that children with congenital hypothyroidism are normal from the onset of infancy by screening programs and treatment [16].

Some authors believe that several factors including age of treatment onset, utilized therapeutic dosage, Thyroid Stimulating Hormone (TSH) normalization age and the severity of disorder might affect the growth status of infants with congenital hypothyroidism. The effect of aforementioned factors on growth pattern in infants with congenital hypothyroidism undergone diagnosis through screening and early treatment in the onset of infancy was remained controversial [16]–[18]. The studies demonstrated a normal pattern of body growth and height in adulthood in infants with congenital hypothyroidism using the continuous treatment [17][18].

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]–[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]–[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.

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 short- term 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 Figure 5 , Figure 6 , Figure 7 and Figure 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 01 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 Figure 9 , Figure 10 , Figure 11 and Figure 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).

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 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]–[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].

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.

It is suggested to refer the infants with congenital hypothyroidism to healthcare center so as to receive medical treatment immediately after diagnosing of the disease; then, the treatment must not be stopped after normalizing of serum T4 and TSH levels, the laboratory tests should be repeated afterwards, and received a significant treatment.

It is suggested to refer the infants with congenital hypothyroidism to healthcare center so as toreceive medical treatment immediately after diagnosing of the disease; then, the treatment mustnot be stopped after normalizing of serum T4 and TSH levels, the laboratory tests should berepeated afterwards, and received a significant treatment.

This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

CH: Congenital Hypothyroidism; IUGR: Intrauterine Growth Restriction; SD: Standard Deviation; TSH: Thyroid Stimulating Hormone

The current research is the extract of MSc Epidemiology dissertation (no. 17.1.193030), Yazd University of Medical Sciences and Health Services, Iran. This study was approved by the ethical committee for MSc Epidemiology dissertation (no. 17.1.193030), Yazd University of Medical Sciences and Health Services, Iran.

The authors declare that there is no conflict of interest.

Yazd University of Medical Sciences, Yazd, Iran.

All authors contributed to the design of the research. ZZ, SMR, FA, SI, SLD, MS, ID and MS collected the data. ZKH, SRP, ZZ conducted analysis and interpretation of data. All authors drafted the first version. ZKH, SRP, ZZ, SMR, KE and ID edited the first draft. All authors reviewed, commented and approved the final draft.