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ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 68-72

Compliance of diagnosis and early management of congenital hypothyroidism


1 Department of Pediatrics, Neonatology Division, Ministry of National Guard Health Affairs, King Abdulaziz Medical City; Department of Pediatrics, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Western Region, Jeddah, Saudi Arabia
2 Department of Pediatrics, King Fahd Central Hospital, Jizan, Saudi Arabia
3 Department of Pediatrics, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Western Region; Department of Pathology, King Abdulaziz Medical City, Jeddah, Saudi Arabia
4 Department of Pediatrics, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Western Region, Jeddah, Saudi Arabia
5 Department of Pathology, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
6 Department of Pediatrics, Neonatology Division, Ministry of National Guard Health Affairs, King Abdulaziz Medical City, Jeddah, Saudi Arabia

Date of Submission13-Dec-2020
Date of Decision04-Jan-2021
Date of Acceptance06-Jan-2021
Date of Web Publication15-May-2021

Correspondence Address:
Mohammed Yasir Al-Hindi
Department of Pediatrics, Neonatology Division, Ministry of National Guard Health Affairs, King Abdulaziz Medical City, Western Region, Jeddah 21482
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_201_20

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  Abstract 


Objective: This study aimed to estimate the prevalence and the compliance of early diagnosis and early management of congenital hypothyroidism (CH). Materials and Methods: This retrospective cohort study gathered data from all infants born over 10 years from January 2007 to December 2016. All children diagnosed with CH as per standard definition of cord and follow-up thyroid-stimulating hormone (TSH) levels were analyzed to calculate the prevalence and the compliance rates to early treatment goal and time normalization of TSH. These children were evaluated for neurodevelopment outcomes. Results: 31,311 newborns screened for CH with a prevalence over 10 years of 1:3085 per live births. Among the 11 cases, five were found to have thyroid dysgenesis (1:6200), 5 thyroid dyshormonogenesis (1:6200), and only one case of generalized resistance to thyroid hormone (1:31000). The compliance with an early diagnosis within the first 2 weeks was 100%, and compliance with the initial treatment goal was 40%. Normalization was achieved in all cases within 16 weeks; however, all had normal hearing, vision, and development at their current age. Conclusion: The prevalence of CH in this single tertiary care center is similar to national and international data. Dyshormonogenesis has a higher prevalence than global data. Moreover, compliance with early diagnosis is excellent due to the strict adherent cord TSH protocol. The compliance with the initial treatment goal in our center is comparable with international data. However, large population-based studies are needed to establish a benchmark on such compliance rates. The long-term hearing, vision, and development milestone assessments of diagnosed cases were age appropriate.

Keywords: Compliance, congenital hypothyroidism, early diagnosis, early management, neurodevelopment, screening


How to cite this article:
Al-Hindi MY, Aziabi MY, Borai A, Alharbi SY, Alamri AS, AlQurashi MA, Altwaim A. Compliance of diagnosis and early management of congenital hypothyroidism. J Clin Neonatol 2021;10:68-72

How to cite this URL:
Al-Hindi MY, Aziabi MY, Borai A, Alharbi SY, Alamri AS, AlQurashi MA, Altwaim A. Compliance of diagnosis and early management of congenital hypothyroidism. J Clin Neonatol [serial online] 2021 [cited 2021 Jun 12];10:68-72. Available from: https://www.jcnonweb.com/text.asp?2021/10/2/68/316184




  Introduction Top


Congenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation if not detected and managed early. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. Thus, the primary thyroid-stimulating hormone (TSH) screening has become standard in many parts of the world. Early treatment is needed because consequences of delayed or inadequately treated CH are potentially significant; if untreated, a newborn baby can have irreversible losses of up to 0.5 IQ points a day. Under the American Academy of Pediatrics (AAP) guidelines, primary CH – defined as a serum TSH of 20 mIU/L or higher – should be diagnosed no later than the 14th day of life. Children should be biochemically euthyroid by 4–6 weeks, with a serum TSH level below 5 mIU/L.[1],[2] Even though there are these adherent guidelines, some cases may be missed, and some centers report poor compliance.[3] This study aimed to estimate the prevalence of CH at King Abdulaziz Medical City (KAMC), Jeddah, Kingdom of Saudi Arabia (KSA), and the compliance of early diagnosis and early treatment of CH. Long-term outcomes of the affected children were measured at their current age as secondary outcomes.


  Materials and Methods Top


The Institutional Review Board approved the study. This is a retrospective cohort study that included all infants born at a tertiary care center, Jeddah, Saudi Arabia, over 10 years between January 01, 2007, and December 31, 2016. Infants with significant congenital anomalies and those who were born in other hospitals were excluded from the study. The data were medical records, birth registry, and the electronic Laboratory Information System database before 2012, after which data were collected solely from the Electronic Health Record. Patient's demographics and characteristics data were also obtained. A trained research team member collected the data according to predefined variables agreed upon by the research team.

Screening for CH: the screening program for cord TSH was established in the KSA in 1987, soon after the publication of the AAP guidelines, with KAMC being the second hospital to implement this program in the KSA. The national newborn screening program through filter papers was started in 2012 and included screening for CH; however, we did not stop the cord TSH screening. Our study will analyze only these results. Hospital policy was developed following AAP, in which midwives routinely collected blood from the umbilical vein of the placenta soon after delivery. About 4–6 ml of cord blood is collected in a plain tube from the cord's placental side before delivery of the placenta. Cord blood tubes were then sent to the lab within 1–2 h. Samples were left at room temperature before separated by centrifuge (3600 ×g) for 10 min. Serum separated and aliquoted into 1.0 mL Eppendorf tube with 500 μL of serum. The Eppendorf tube is then loaded on the immunoassay analyzer ADVIA Centaur XP (from January 2007 to May 2013) and Architect i2000 (from June 2013 to December 2016). The methods for TSH and free thyroxin (FT4) on both analyzers are based on chemiluminescent immunoassay. Cord serum TSH <30 mIU/L is considered normal.

In case, TSH is ≥30 mIU/L then FT4 will be promptly analyzed using the system of reflex testing. For quality control of TSH and FT4 determinations, quality control sera (normal, low, and high) are performed in each working shift. The quality control materials were from Biorad lyphocheck immunoassay control serum, California, USA. All tests were done in the section of clinical chemistry, Department of Pathology and Laboratory Medicine, KAMC, Jeddah, Saudi Arabia. The department is accredited by the College of American Pathologists from 2002 until now. Once reported abnormal, a confirmatory serum sample was sent within 72 h. Around the clock, laboratory personnel will alert the physician and nursery charge nurse about any abnormal cord TSH. A dedicated team that includes a nurse coordinator, neonatologist, and pediatric endocrinologist assures the results' follow-up. No suspected newborn is discharged from the postnatal wards until released by the team. Primary CH is defined as a serum TSH level of 20 mlU/L or higher, which should be diagnosed no later than 14 days of the newborn's life. The endocrinologist starts L-thyroxine immediately after the withdrawal of the confirmatory tests with a target by 4–6 weeks should be biochemically euthyroid, with a serum TSH level below 5 mlU/L. Endocrinologists conduct full investigations to diagnose the subtype of the CH and assure compliance of the initiation and maintenance of the treatment with thyroxin.[1],[2]

Long-term follow-ups are conducted by endocrinologists aided by pediatricians and neurologists if requested. It included history and physical examination. The follow-up team provides hearing, vision, and a standard developmental milestone assessment before 6 years of age, followed by school performance after 6 years of age.[4]

Analyses were conducted using Excel and SPSS version 24.0 for Windows (SPSS, Chicago, IL, USA). Descriptive statistics used include tables of frequencies and bar charts for categorical variables or measures of central tendencies, mean and standard deviations for normally distributed data, or median and interquartile ranges (IQRs) for skewed data. A paired sample t-test was used to compare the mean of the continuous variables at the time of diagnosis and follow-up.


  Results Top


From January 2007 to December 2016, 31,311 infants were enrolled in this study. The prevalence of CH over 10 years was 1:3085 per live births; 1:3670 in the first 5-year period and 1:2375 in the second 5-year period. Among the 31,311 infants, 192 cases have been identified and confirmed to have an abnormal cord TSH; seven were female while the rest were male. Their mean birth weight was 2998 g (standard deviation [SD] 430). All patients were full term with a mean gestational age of 38.6 weeks (SD 1.4). Five of them were born to primigravida, while the rest were born to multigravida mothers. Their current ages ranged from 5 to 12 years. Out of the 192 patients that were retested using serum TSH and free T4 for a confirmatory diagnosis of CH, 11 were confirmed to have an abnormal serum TSH with backup T4; this gives us a recall rate (notification of a physician to arrange for a confirmatory blood test) of 0.6%. The median time to get confirmatory results was 2 days with 50% IQR (2–5 days). Furthermore, the types of CH have been identified, and 5 of the cases were found to have thyroid dysgenesis (i.e., 1:6200 live birth), while the other 5 thyroid dyshormonogenesis (1:6200 live birth), and only one case of generalized resistance to thyroid hormone (1:31,000 live birth) as shown in [Table 1]. Furthermore, compliance with an early diagnosis within the first 2 weeks was 100%, and compliance with the initial treatment goal (achieved normal TSH values by 4–6 weeks of age) was 40%. The median time to reach normal TSH was 9 weeks (50% IQR: 4-12). For subcategories, the median time to normalize the TSH was 9 (4-12) and 5 weeks (50% IQR 4-14) for dysgenesis and dyshormonogenesis, respectively. However, this difference trend was not statistically significant (cox regression, Wald 1.5, P = 0.21).
Table 1: Prevalence of causes of congenital hypothyroidism

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The mean ± standard error of mean confirmatory TSH was 245.2 ± 77.5 mIU/L decreased significantly with follow-up and therapy to 8.2 ± 1.8 mIU/L (P = 0.014). The confirmatory FT4 increased significantly from 9.3 ± 1.3 mIU/L to 19.8 ± 2.9 mIU/L (P = 0.016), as illustrated in [Table 2]. All of the CH children had normal hearing and vision. The developmental milestones were appropriate for age in their last follow-up.
Table 2: Comparison of confirmatory and follow-up thyroid-stimulating hormone and free thyroxin 4

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  Discussion Top


The prevalence of CH over 10 years (2007–2016) was 1:3085 out of 31,331 live birth underwent screening; 1:3670 in the first 5-year period (2007–2011) and 1:2375 in the second 5-year period (2011–2016). In comparison to national figures, the country average was 1:3293; our results suggested that the prevalence of CH in KAMC was in the middle between figures such as Bisha province, which had a prevalence of 1:1173 using cord blood TSH screening, the highest in the region. On the other hand, Baha and Hail had the lowest prevalence in the country, 1:7709 and 1:6550, respectively.[7] The high prevalence at Bisha might be attributable to the sample size used (4124 newborn infants vs. 31,331 infants in our study). Al-Jurayyan et al. explained that the higher prevalence rate in Southern KSA provinces such as Bisha and Najran might be due to the high rate of consanguinity.[8],[9] Meanwhile, our study results were similar to studies such as Al-Maghamsi et al. study in the Madina region, which estimated the prevalence of 1:4208 and Riyadh Al-Kharj 1:2759. Moreover, Al-Maghmasi et al. and Henry et al. noted a male-to-female ratio of 1:3 and 1:2, similar to the ratio in our study 1:2.[10],[11] Internationally, our prevalence of CH is also comparable. It is in the middle between the lowest prevalence in both Kuwait and Japan, 1:7686 in both, and the highest prevalence in California and Iran, 1:1706 newborns of different ethnic groups and 1:748, respectively.[12],[13]

The recall rate for confirmatory testing (0.6%) was compared to local and international figures.[14],[15] For centers using cord TSH screening methods and using a similar cut value to ours (29 mIU/L), the recall rates ranged between 0.14% and 5.4%. Our figure was considered acceptable and cost effective since all our newborns are still present in the postnatal wards by the time the results are released. Hence, much burden is relieved in terms of calling parents and transportation.

CH remains a significant disease that requires surveillance. Our center's compliance with an early diagnosis within 2 weeks was excellent (100%). Our screening method proved to be effective in diagnosing various causes of CH with a compliance rate of 100% compared to other reported centers in the United States such as Utah (84%).[16] Furthermore, the compliance rate was comparable to international centers such as the federal state of “Hessen” in Germany (99.1%).[17] This is related to the excellent well-established screening program of the cord TSH in newborns coupled with a national newborn screening program. We have a strict surveillance system that includes 100% compliance to all newborns who cannot be discharged unless a checklist of discharge orders that carry screening tests is completed. Moreover, we have dedicated multidisciplinary teams including neonatologists, endocrinologists, and nurse coordinators. This team is responsible for following all labs, tracing missing results – if any, and calling back parents for confirmatory diagnostic and therapeutic interventions.

Our compliance with the initial treatment goal was reported as 40%, which was slightly better than the compliance rate in Utah (34%).[16] This compliance measured the days needed to normalize TSH levels to <5 mIU/L by 4 weeks of age. Up to our knowledge, no other studies apart from Utah and our research reported such compliance measurements. Hence, it is not easy to establish a national or international benchmark rate based on two centers. Therefore, population-based studies are needed to establish such compliance rates. The AAP recommended to normalize T4 within 2 weeks and TSH within 1 month, optimally.[1] Despite this recommendation, we considered the normalization time between 4 and 6 weeks reasonable based on a study that the IQ levels were similar in those normalized in 4 and 6 weeks. Furthermore, we assume that the figure of 4 weeks suggested by AAP to normalize TSH was established to set a strict goal for centers to thrive for. However, it is reasonably documented that achieving normal levels for TSH and free T4 as soon as possible, in our cases by 16 weeks of life, and maintaining these levels in the first 3 years of life is crucial to achieving normal cognitive development later in life.[1],[18] This could explains why our long-term outcomes were reasonable, and no abnormalities were detected.

Using cord TSH with backup FT4 could potentially miss cases of central hypothyroidism (secondary/tertiary), hypothyroxinemia, thyroid-binding globulin deficiency, and delayed TSH elevation such as seen in premature infants. We have a backup program for the latter group, in which all preterm infants admitted to neonatal intensive care units are screened within 2 weeks of life. For those very low birth weights (<1500 g), another screening is done before discharge. For the rest of the rare causes of permeant CH, our endocrinology team did not report any cases in the study period as such cases are very rare. The combination of both TSH and free T4 screening-based programs is optimal; however, it is not cost effective and not being carried out in any screening program around the world.[1]

As of 2012, as part of the national screening program, our center commenced collecting blood spots for screening for inborn error of metabolism through filter paper, which also includes screening TSH with a cut value of 20 mIU/L. These are collected on the 2nd to 5th day of life. This could act as a safeguard in cases of missing cord TSH collection. Our center decided to continue to collect cord TSH despite the newer filter paper program as sensitivity and specificity were not established until recently.[18] Moreover, after discharge, the recall of parents still faced logistic issues in our society, like not answering, no show-up, or even refusal.

Our study is one of few studies in Saudi Arabia to report the other causes of CH. For example, thyroid dysgenesis was slightly lower in our center (1:6200 vs. 1:4500 worldwide). However, thyroid dyshormonogenesis was almost five times higher than worldwide figures (1:6200 vs. 1:30,000 worldwide). Furthermore, generalized resistance to thyroid hormone type (1:31,000) was also comparable to reported worldwide cases, which suggested that it is scarce as shown in [Table 1].[5],[6] Nationally, Al-Jurayyan and Al Jurayyan reported 303 cases of CH out of 1,007,350 screens done around major cities of Saudi Arabia, of which only 147 patients (48%) were adequately studied, and their data were available to delineate the subtypes of CH. They reported 94 (1:10,716) of thyroid dysgenesis and 53 (1:19,006) of thyroid dyshormonogenesis. They did not report generalized resistance to thyroid hormone, [Table 1].[7]

All the diagnosed CH in our center were fully corrected by 15 weeks maximum except the generalized resistance to thyroid hormone case (Patient 2), who took nearly 16 weeks for the TSH to normalize. This might be due to the bioavailability of crushed tablets and parents' compliance with giving thyroxin daily, which is why achieving normalization by 3 months was pragmatic, however could be considered safe since the neurodevelopmental outcome is excellent. Further studies that include multidomain socioeconomic factors to assess their treatment compliance burden and desired outcomes are warranted.[19]

Finally, follow-up of the 11 confirmed and treated patients showed no major hearing, vision, and developmental milestones abnormalities. This could indicate that the early initiation of the treatment is a key factor rather than the TSH normalization time based on the APP guidelines, which outlines the importance of prompts diagnosis and initiation of therapy to control the TSH and free T4 to acceptable levels. However, we do not have enough late diagnosis cases to compare. Finally, our center used commonly available developmental milestone for assessment, a more definitive neurodevelopmental assessment by a multidisciplinary team including physiotherapists, occupational therapists, and speech and language therapists is warranted.[20]


  Conclusion Top


The prevalence of CH in this single tertiary care center is similar to national and international data. Dyshormonogenesis has a higher prevalence than global data. Moreover, compliance with early diagnosis is excellent due to the strict adherent cord TSH protocol. The compliance with the initial treatment goal in our center is comparable with international data. However, large population-based studies are needed to establish a benchmark on such compliance rates. The long-term hearing, vision, and development milestone assessments of diagnosed cases were age appropriate.

Acknowledgment

We are thankful to our NICU nurse coordinator Eman Al-Thubaiti, clinical pharmacist Mohammed Al-Harbi, and Family Medicine resident Yara Mubarki, for their important role in data collection and technical support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Fisher DA. Effeteness of newborns screening programs for congenital hypothyroidism: Prevalence of missed cases. Pediatr Clin North Am 1987;34:881-90.  Back to cited text no. 5
    
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Mehran L, Khalili D, Yarahmadi S, Amouzegar A, Mojarrad M, Ajang N, et al. Worldwide recall rate in newborn screening programs for congenital hypothyroidism. Int J Endocrinol Metab 2017;15:e55451. Published 2017 Jun 25.  Back to cited text no. 14
    
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Höpfner S, Höpfner B, Rauterberg EW. Neonatal screening for congenital hypothyroidism in Hessen, Germany: Efficiency of the screening program and school achievement of 129 children at an age of 8-12 years. J Perinat Med 2005;33:543-8.  Back to cited text no. 17
    
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