Increasing prevalence of congenital hypothyroidism emerges as a growing concern in Jordan

Abstract

BACKGROUND

Congenital hypothyroidism (CH) is a prevalent childhood endocrine disorder associated with irreversible neurological consequences. Its global incidence is on the rise.

AIM

To estimate CH incidence in Jordan and assess the potential utility of incorporating (fT4) measurements into the screening process.

METHODS

This retrospective analysis examined thyroid function test results for infants born at our center between 2016 and 2020. Infants born before 28 weeks and those screened after 14 days of life were excluded. Screening occurred between days 3 and 7 of life, and thyroid-stimulating hormone (TSH) and T4 levels were measured concurrently from peripheral venipuncture blood samples. A TSH cutoff of < 5 mIU/L was considered normal. Values between 5 and 20 mIU/L were equivocal, requiring repeat tests. TSH levels exceeding 20 mIU/L were considered critical.

RESULTS

A total of 10521 infants were included in the study, and 26 were diagnosed with CH, yielding an incidence of 1 in 400 live births. Females constituted 57.7% of CH cases. All CH cases had initial TSH values exceeding 5.0 mIU/L, with clustering above 20 mIU/L. Six CH infants had Down syndrome, accounting for 23.1% of CH cases.

CONCLUSION

Our study revealed a high incidence of CH in Jordan, marking a significant increase from previously reported rates. We recommend a national study to investigate risk factors and underlying causes of CH in our population. Furthermore, we advocate for the use of TSH alone with a cutoff value of < 5 mIU/L for screening purposes.

Key Words: Congenital hypothyroidism; Screening; Thyroid-stimulating hormone; fT4; Neonate

Core Tip: This study reveals a high incidence of congenital hypothyroidism (1 in 400 live births) in Jordan, a significant increase from previously reported rates. It emphasizes the importance of TSH screening with a cutoff of < 5 mU/L and advocates for further investigation into the underlying causes and risk factors for CH in the Jordanian population.

INTRODUCTION

Congenital hypothyroidism (CH) is a common yet preventable endocrine disorder in children[1]. The full clinical presentation of CH typically appears between the third and sixth months of life, highlighting the importance of early detection and intervention to prevent irreversible neurological impairment[2]. Before the implementation of newborn screening programs, CH was identified based on clinical symptoms, with an estimated incidence ranging from 1 in 7000 to 1 in 10000 live births[2]. However, since the introduction of newborn screening in 1973, reported incidence rates have increased to between 1 in 3000 and 1 in 4000 live births[3].

Globally, the incidence of CH has continued to rise, influenced by several factors, including demographic shifts, improved survival rates of preterm infants, and modifications in screening protocols—particularly the adoption of lower thyroid-stimulating hormone (TSH) cutoff values[4-7]. These developments emphasize the critical need for early CH detection and the implementation of effective screening programs, especially in regions where CH incidence is higher[8].

Screening programs for CH typically rely on measuring TSH and thyroxine (T4) serum levels in neonates. While both hormones are important, TSH is considered a more specific screening marker, whereas T4 offers higher sensitivity. This distinction gives each test a different diagnostic utility[9]. Importantly, the rate of false-positive results decreases when samples are collected between 48 and 120 hours after birth[10].

Today, CH screening is a routine practice in most countries, supported by a wealth of research evaluating the effectiveness and outcomes of these programs[11]. Neonatal screening was initiated at Jordan University Hospital in the late 1990s, initially targeting congenital hypothyroidism and glucose-6-phosphate dehydrogenase (G6PD) deficiency. A similar nationwide program was later launched by the Ministry of Health in the early 2000s[12].

The objectives of this study were to retrospectively estimate the incidence of congenital hypothyroidism in Jordan and to evaluate the potential benefit of incorporating fT4 measurements into the current screening methodology.

MATERIALS AND METHODS

Study design & ethical approvals

This study employed a retrospective analysis of thyroid function test results for all infants born at Jordan University Hospital between January 2016 and March 2020. Ethical approval was obtained from the Deanship of Scientific Research at the University of Jordan and the Institutional Review Board Committee at the University of Jordan Hospital. Informed consent requirements were waived, as the study involved a retrospective chart review without participant identification. The study was conducted in accordance with the ethical standards outlined in the 1964 Declaration of Helsinki and its subsequent amendments.

Inclusion and exclusion criteria

All newborns screened at our hospital during the study period were included. Exclusion criteria comprised pre-term infants born before 28 weeks of gestation and those screened after 14 days of age. Infants with insufficient initial samples that required delayed repeat testing beyond 14 days of age were also excluded. Additionally, infants whose results normalized and did not require treatment were excluded from the study.

Data collection

Demographic and clinical data were extracted from electronic medical records. Screening was typically conducted between the third and seventh day of life. TSH and T4 Levels were measured concurrently using whole blood samples obtained via peripheral venipuncture. Repeated test results within the first 2 weeks of life, performed due to inadequate initial sample volume, were included in the analysis.

Blood samples were collected in sterile VACUETTE^® CAT serum separator clot activator tubes, requiring a minimum volume of 2-3 mL. Samples were stored at temperatures ranging from 2 °C to 8 °C for up to 2 days prior to analysis. TSH and T4 measurements were performed using the Atellica IM 1300 analyzer via chemiluminescent immunoassay (Siemens Healthcare Diagnostics Inc., Erlagen, Germany). The TSH assay was designed to have within-laboratory precision of ≤ 0.0032 μIU/mL (mIU/L) SD for samples < 0.020 μIU/mL (mIU/L), ≤ 16% coefficient of variation (CV) for samples from 0.021-0.299 μIU/mL (mIU/L), ≤ 8% CV for samples from 0.300-90.000 μIU/mL (mIU/L), and ≤ 10% CV for samples > 90.000 μIU/mL (mIU/L) TSH. fT4 assay was designed to have withinlaboratory precision of ≤ 0.03 SD for samples < 0.5 ng/dL (5.16 pmol/L), ≤ 8.0% CV for samples from 0.5-1.0 ng/dL (5.16-12.9 pmol/L), and < 6.0% CV for samples > 1.0 ng/dL (12.9 pmol/L).

Cutoff values and reporting

In our practice, a TSH level below 5 mIU/L was considered normal. Newborns with TSH levels between 5 and 20 mIU/L were classified as equivocal, prompting repeat testing within 1 week of result availability. Repeated results with TSH < 5 mIU/L were considered normal. TSH values exceeding 20 mIU/L were classified as critical and led to immediate notification of the attending physician or admitting team by the laboratory technician. Parents were contacted by phone within 24 hours of result availability. Infants diagnosed with congenital hypothyroidism were referred for full evaluation by pediatric endocrinologists and initiated on Thyroxine treatment. If the serum TSH concentration was 6-20 mIU/L beyond 21 days of age in an otherwise healthy neonate with an fT4 concentration within the age-specific reference range, LT4 treatment was either initiated immediately with plans for off-treatment retesting at a later stage, or treatment was withheld and testing was repeated 1 to 2 weeks later to allow re-evaluation of the need for treatment according to current guidelines[13]. Treatment was initiated in cases with persistent elevation of TSH especially above 10 mIU/L.

It is noteworthy that in Jordan, parents may choose their preferred follow-up location for newborn care. Infants born at our hospital are routinely scheduled for appointments at our neonatal screening clinic. If these appointments are missed or not attended within 2 weeks of the scheduled date, follow-up is assumed to have occurred at Ministry of Health primary care centers instead.

Statistical analysis

Data for each newborn included in the study were entered into a spreadsheet, and statistical analysis was performed using Microsoft Excel 2010. Results were expressed as mean ± SD and frequency. Associations between variables were analyzed using the χ² test, with statistical significance set at P < 0.05.

RESULTS

During the study period from January 2016 to March 2020, a total of 23140 newborns were delivered at Jordan University Hospital. Of these, 11149 infants (48%) were voluntarily enrolled for follow-up at our screening clinic. The primary objective of this study was to assess congenital hypothyroidism (CH) using a comprehensive screening approach that included evaluation of both TSH and thyroxine (T4) levels.

Screening assessments were conducted at a mean age of 5 ± 2 days postnatally. The newborns had a mean gestational age of 38 ± 2 weeks and an average birth weight of 2922 ± 580 g. Prematurity, defined as a gestational age of less than 37 weeks, was observed in 18.7% of the infants, while 7.2% exhibited intrauterine growth restriction.

Among the screened newborns, 8.9% were diagnosed with pathological hyperbilirubinemia. Additionally, 1.4% had a confirmed positive family history of hypothyroidism. A total of 27 infants (0.27%) had Down syndrome (Table 1).

Table 1 Demographic data and clinical characteristics of screened newborn, n (%).

Number of neonates screened	11149
Number analyzed	10521 (95)
Birth weight (mean ± SD)	2922 ± 580
Gestational age (mean ± SD)	38 ± 2
Gestational age < 37 weeks	1928 (18.3)
Male sex	5284 (50.2)
Cesarean section delivery	4996 (47.4)
Small for age (< 10th centile)	760 (7)
Pathological hyperbilirubinemia	937 (9)
Family history of hypothyroidism	143 (1.3)
Down syndrome	27 (0.27)
Screening age in days (mean ± SD)	5 ± 2

Of the 11149 screened newborns, 10521 met the criteria for inclusion in the final analysis. Among these, 26 infants were diagnosed with congenital hypothyroidism, resulting in an incidence rate of 1 case per 400 live births, as shown in (Figure 1). The female-to-male ratio among affected infants was 1.4:1.

Figure 1 Participants’ flow chart according to thyroid tests results. TSH: Thyroid-stimulating hormone.

Infants diagnosed with CH had a mean gestational age of 37 weeks and a mean birth weight of 2553 g. Among the 1928 preterm infants included in the cohort, 11 (0.57%) were diagnosed with hypothyroidism. In contrast, among the 10821 term infants, 15 (0.14%) had hypothyroidism, yielding a statistically significant difference (P < 0.004). Notably, females accounted for 57.7% of the CH cases (Table 2).

Table 2 Demographic data and clinical characteristics of hypothyroid newborns.

Variable	Hypothyroid newborns (n = 26)
Gestational age (mean ± SD)	37 ± 2
Gestational age < 37 weeks	11 (42)
Birth weight (mean ± SD)	2553 ± 664
Small for age	5 (19.2)
Female sex	15 (57.7)
Family history of hypothyroidism	2 (7.7)
Pathological hyperbilirubinemia	4 (15.4)
Down syndrome	6 (23.1)

All infants diagnosed with CH had initial TSH values exceeding 5.0 μU/mL, with a substantial proportion presenting levels greater than 20 μU/mL. Remarkably, 6 infants diagnosed with CH also had Down syndrome, representing 23.1% of the CH cases.

DISCUSSION

This study aimed to assess the incidence of congenital hypothyroidism (CH) in Jordan and evaluate the effectiveness of our hospital’s neonatal screening program. Worldwide, various strategies are employed for newborn CH screening, with initial thyrotropin (TSH) measurement being the most widely adopted[1]. Although measuring initial thyroxine (T4) levels offers high sensitivity for detecting central CH, its specificity is relatively low, especially in low birth weight and premature infants, often resulting in a high number of false positives[9]. Some countries have adopted simultaneous T4 and TSH measurements to detect both central and primary CH, including mild and subclinical forms[8,9]—a strategy also implemented in our screening program. Unfortunately, benign thyroxine-binding globulin deficiency, which is relatively common, can lead to low fT4 Levels with normal TSH, causing a significant number of false-positive referrals[9,10]. As a result, many neonatal screening programs have transitioned to or adopted a TSH-based approach, which primarily detects primary CH cases[11]. This shift is supported by the view that central CH is both rare and typically mild, with most affected neonates presenting with combined pituitary hormone deficiency and being diagnosed clinically soon after birth.

In our cohort, only 36 infants exhibited low T4 Levels (< 10 ng/dL), of whom three also had low TSH levels (< 1.2 mIU/L). Two of these infants later demonstrated normalized thyroid function, while one was lost during follow-up. Assuming the latter had central hypothyroidism, the estimated incidence of central CH in our study was 0.001%[14]. These findings underscore the advantages of a TSH-based screening approach, as relying on T4 measurement would not only double the cost but also lead to unnecessary follow-up investigations.

The incidence of CH observed in our study was notably high, with a rate of 1 in 400 live births and a female-to-male ratio of 1.4:1. Our institution is located in Jordan’s capital, where approximately 40% of the population resides. Therefore, we consider our cohort to be broadly representative of the Jordanian population. For context, we compared our findings to a previous study from 2014[12], which reported an incidence of 1 in 2242 newborns. Both studies featured comparable sample sizes, screening ages, and cutoff values. However, our study utilized venipuncture for screening, whereas the earlier study used the heel prick method. Additionally, the previous study covered the period from 2010 to 2013, while our investigation spanned 2016 to 2020. It is worth noting that our laboratory has been performing thyroid function tests since the 1990s, contributing to the consistency and reliability of our results. Our study also employed strict exclusion criteria, and all abnormal results were assessed by pediatric endocrinologists.

The rising incidence of CH, a trend observed globally[15], may in part be due to the use of more accurate diagnostic tools in certain regions. Additionally, improved detection of transient CH has been proposed as a contributing factor[16]. Interestingly, some countries have reported increasing CH incidence even without changes in diagnostic methodology[17], highlighting the need for further investigation into potential causes within our community. Iodine deficiency is not a prevalent concern in Jordan, as table salt is fortified with iodine. However, demographic shifts and the population growth resulting from the influx of refugees following the Syrian crisis may have influenced the observed increase. Although not explored in this study, the high rate of consanguineous marriage in Jordan, reported to be as high as 27.5%, could also play a role in the elevated incidence[18]. Furthermore, some diagnosed cases may later be identified as transient hypothyroidism upon follow-up beyond 2 years of age[19]. The higher rates of preterm births and infants with Down syndrome may also contribute to the elevated CH incidence. When these two groups were excluded from analysis, the incidence decreased to 1 case per 1170 live births.

When compared to neighboring countries, similar or even higher rates have been reported. Two studies from Iran found comparable incidence rates[11,20], while a study from Shadegan Province, Iran, reported an incidence five times greater than ours[21]. In Saudi Arabia, CH incidence varies by region, ranging from 1.97% in a small study from the Mecca region[22] to 1 in 834 in another single-city study[23]. A larger study encompassing Jeddah and Riyadh reported an incidence of 1 in 2470[24].

As observed in many screening programs[25], our study also demonstrated a higher incidence of CH in females (57.7%), yielding a male-to-female ratio of 1:1.4, consistent with previous findings. Additionally, CH incidence was higher among preterm infants. Of the 1928 preterm infants included in our study, 11 (0.57%) were diagnosed with CH, compared to 15 out of 10821 term infants (0.14%), a statistically significant difference (P < 0.004). Among the infants diagnosed with CH, there was a greater proportion of preterm births (42%), small-for-gestational-age infants (19.2%), and cases of Down syndrome (23.1%) compared to the euthyroid group (10%, 7%, and 0.2%, respectively). These are established risk factors for CH worldwide. Furthermore, a positive family history of hypothyroidism was more common in the CH group (7.7%) than in the euthyroid group (1.3%). Lastly, the incidence of pathological neonatal hyperbilirubinemia requiring phototherapy was also higher in CH patients (15.4%) compared to thyroid-normal infants (9%).

CONCLUSION

One limitation of this study is its retrospective nature. It is a single center study, and did not include long term follow up. We recommend a national study to investigate the risk factors and underlying causes of CH in our population. In conclusion, our study revealed a high incidence of CH in Jordan, marking a significant increase from previously reported rates. Furthermore, we advocate for the use of TSH alone with a cutoff value of < 5 mIU/L for screening purposes.