Congenital Hypothyroidism: Optimal Initial Dosage and Time of Initiation of Treatment: A Systematic Review
Context: Appropriate management of neonates, tested positive for congenital hypothyroidism (CH), in particular, the initial dosage of levothyroxine and the time of initiation of treatment is a critical issue. The aim of this study was to assess all current evidence available on the subject to ascertain the optimal initial dose and optimal initiation time of treatment for children with CH.
Evidence Acquisition: In this study, all published research related to the initiation treatment dose and the onset time of treatment in congenital hypothyroidism were reviewed. The searched electronic databases included Medline, Science direct, Scopus EMBASE, PsycINFO, Cochrane, BIOSIS and ISI Web of Knowledge. Additional searches included websites of relevant organizations, reference lists of included studies, and issues of major thyroid and pediatrics journals published within the past 35 years. Studies were included if they were written in English and investigated levothyroxine dose or timing of treatment or both, used for the treatment of children with congenital hypothyroidism.
Results: Two thousand three hundred and seventy-four articles (excluding duplicates) were retrieved from the primary search. After reviewing the titles, abstracts and full-texts of studies, eventually, 22 studies were found that met our inclusion criteria. Amongst these, 17 and 12 evaluated outcomes of different treatment doses and treatment timing, respectively. Overall, the majority of these studies emphasized the initial high dose of levothyroxine and early treatment of newborns with hypothyroidism. There were, however, some studies that disagreed with increasing levothyroxine dose at initiation of treatment.
Conclusions: Considering the results of this review, apparently there is no difference in opinion regarding the early initiation of treatment, whereas determining the optimal dose of levothyroxine for start of treatment in CH patients still remains a controversial issue, demonstrating the need for further studies, despite the fact that use of high doses can lead to rapid normalization of biochemical indices, although this may cause complications.
Keywords: Congenital Hypothyroidism; Starting Treatment Dose; Treatment Initiation Timing; Review Article
Congenital hypothyroidism (CH), one of the most prevalent endocrine diseases, is known as a common preventable cause of mental retardation (1). Mass population screening of newborn infants for CH, first introduced in 1974, is today a routine and effective tool of timely/early diagnosis of CH, used throughout the world (2). Detection of children with CH by screening programs and treatment with levothyroxine is currently the standard method for the control of CH, a cause of mental retardation (3). Available data shows that during pregnancy very little thyroxine crosses the placenta from the mother to the fetus and most children are born without signs or symptoms of hypothyroidism (4, 5). Following diagnosis, if tested positive for CH, what is important is the early treatment of children with CH, using an appropriate initiation dose of levothyroxine sodium.
Previous studies, conducted over the past three decades earlier, show that initiation of treatment within the first two to three weeks of life resulted in both normal IQ and physical growth (6, 7). Intellectual outcomes in children with CH are affected by bone age, initial serum T4, hypothyroidism etiology, and age at which treatment is started. Those with bone ages of < 36 weeks’ gestation, had the lowest T4, and were a thyroid, and those treated later than four weeks were most vulnerable to mental retardation and physical incomplete growth (8, 9).
From the very beginning of treatment of congenital hypothyroidism with levothyroxine (LT4), initially recommended doses of this medication were in the 5 - 7 µg/kg/day range; subsequently, the recommend dose was changed to 8 - 10 µg/kg/day and, most recently, 10 - 15 µg/kg/day was recommended by the American academy of pediatrics, e.g. a 50 µg tablet for infants with a T4 < 5 µg/dL (60 nmol/L (10, 11). Episodes of overtreatment during the first six months of CH treatment period may be a risk factor for sustained attention and inhibitory control at school age (12). Lower doses of thyroxine, account for poorer outcomes in some children (13), indicating the criticality of proper management of these children.
Available data show that there is an excellent prognosis for infants with CH, if detected early and treated without delay (14); however since determination of the optimal initial treatment dose of Levothyroxine and also specification of time of CH treatment are still considered challenging issues, in this review article, based on reviewing all existing evidence and latest findings of this field, we sought to put together and provide the most relevant, updated information on the optimal initial dose and the precise initiation timing for treatment in children with congenital hypothyroidism. This study aimed at providing more information on controversial issues regarding the optimal initial dosage of levothyroxine and onset time of treatment in children with congenital hypothyroidism.
2. Evidence Acquisition
In this review, different combinations of the terms levothyroxine dose, initial levothyroxine dose, initiation levothyroxine dose, congenital hypothyroidism treatment timing, initiation time of congenital hypothyroidism treatment and congenital hypothyroidism therapy were used in Cochrane library, PubMed and Scopus to search for all relevant articles published until 28th of September 2015. In addition, by hand-searching we searched reference lists in review articles, relevant textbooks, relevant websites, and expert reports. Forward citation searches were conducted for all studies that met the inclusion criteria and were published before the mentioned date. Our search was not limited to clinical trials, and all studies that met the inclusion criteria were included in the review. Our eligibility criteria were inclusion of studies related to the treatment of children with congenital hypothyroidism, without considering their gender. Two reviewers independently reviewed and scanned the titles and abstracts of all studies generated by the search. For all potentially relevant articles, hard copies were retrieved, and these studies were assessed by the two reviewers independently to determine whether or not they met the inclusion criteria. All of the studies found in this review, were researches that assessed initial treatment dose or timing (time of initiation of therapy) or both. Hence, we classified the results of studies in two categories, including the initiation time of treatment and initial dose of L-thyroxine for management of congenital hypothyroidism. All selected studies were critically evaluated in terms of the probability of bias and confounding effects; for each article included in this systematic review, using the STROBE 2007 (v4) Statement-Checklist (15), risk of biases including probability of selection bias, loss during follow up bias, and confounders were assessed. After critical appraisal of the studies selected for this review, we extracted the study design and main results for each study and classified its findings, the initial treatment dose and initiation time of treatment, separately. Finally, using the results of these studies to collect evidence, the authors extracted and highlighted/underscored the most critical issues regarding the initiation time and optimal dose of levothyroxine in treatment of children with CH.
2.1. Search Strategy
2.2. Study Selection
2.3. Critical Assessment of Articles
2.4. Studies Analysis
In this review, different combinations of the terms levothyroxine dose, initial levothyroxine dose, initiation levothyroxine dose, congenital hypothyroidism treatment timing, initiation time of congenital hypothyroidism treatment and congenital hypothyroidism therapy were used in Cochrane library, PubMed and Scopus to search for all relevant articles published until 28th of September 2015. In addition, by hand-searching we searched reference lists in review articles, relevant textbooks, relevant websites, and expert reports. Forward citation searches were conducted for all studies that met the inclusion criteria and were published before the mentioned date. Our search was not limited to clinical trials, and all studies that met the inclusion criteria were included in the review. Our eligibility criteria were inclusion of studies related to the treatment of children with congenital hypothyroidism, without considering their gender.
Two reviewers independently reviewed and scanned the titles and abstracts of all studies generated by the search. For all potentially relevant articles, hard copies were retrieved, and these studies were assessed by the two reviewers independently to determine whether or not they met the inclusion criteria.
All of the studies found in this review, were researches that assessed initial treatment dose or timing (time of initiation of therapy) or both. Hence, we classified the results of studies in two categories, including the initiation time of treatment and initial dose of L-thyroxine for management of congenital hypothyroidism.
All selected studies were critically evaluated in terms of the probability of bias and confounding effects; for each article included in this systematic review, using the STROBE 2007 (v4) Statement-Checklist (15), risk of biases including probability of selection bias, loss during follow up bias, and confounders were assessed.
After critical appraisal of the studies selected for this review, we extracted the study design and main results for each study and classified its findings, the initial treatment dose and initiation time of treatment, separately. Finally, using the results of these studies to collect evidence, the authors extracted and highlighted/underscored the most critical issues regarding the initiation time and optimal dose of levothyroxine in treatment of children with CH.
Two thousand three hundred seventy-four articles (excluding duplicates) were retrieved from the primary search in electronic databases, and another 74 from additional search methods, including hand-searches of textbooks, reports opinions, and the forward citation search. We did not find any randomized controlled trials related to the treatment of CH, and we found only one randomized, double-blind trial that compared a full starting levothyroxine dose of 1.6 μg/kg with a low starting dose of 25 μg (increased every four weeks) in patients (not children) with newly diagnosed cardiac asymptomatic hypothyroidism (16). Fifty-three potentially relevant studies were evaluated against the inclusion criteria. Finally, 22 studies were found that met our inclusion criteria and were consistent with our study objectives (references available). Figure 1 shows the flow chart of the studies included in this review.
Flow Chart of Studies Assessed and Selected to be Included in the Review
Of the 22 studies included in this review, 17 assessed the starting treatment dose in children with CH. The characteristics of these 17 articles including study design, year of the study, participants, initial levothyroxine doses, follow up duration, main outcomes and results are illustrated in Table 1.
As seen in Table 1, initial levothyroxine doses, for treatment of CH, evaluated in different studies varied between 3.21 and 23.6 µg/kg/d. The only clinical trial ever conducted in this area (17), demonstrated that by using a high dose at beginning of treatment (12 - 17 µg/kg/d), T4 and free T4 concentrations increased in the target range, three days after the treatment commenced; for normalization of TSH, the time required is a week. In other studies, several important outcomes such as mental developmental, psychomotor development etc. were assessed in order to evaluate the success of treatment related to various dosages of levothyroxine. Results of most studies favor using high doses at initiation of treatment. The study of Boileau et al. showed that infants treated with a dose of LT4 ≥ 6 μg/kg/d had a higher IQ performance (117.3 +/-1.8 vs. 112.8 +/- 1.2), in comparison with the results at doses < 6 μg/kg/d (18). In another study conducted by Dimitropoulos A, authors concluded that using 14.7 μg/kg/d at initiation of treatment led to significant higher IQ compared to the control group (111.4 versus 101.7; P < 0.0001) (19). Despite much data available in favor of using high doses, in one study it was mentioned that a dose of 3.21-5.81 µg/kg/d was adequate for the treatment of transient CH (20) and in another study elevated levels of FT4 were observed in many patients, showing that a systematic higher initial dosage could expose many children to the complications of hyperthyroidism (21).
Of the 22 studies included in this review, 13 studies assessed the time of initiation of treatment in hypothyroid infants. The characteristics of these 13 articles including study design, year of the study, participants, levothyroxine doses, follow up duration, main outcomes and results are summarized in Table 2.
Results summarized in Table 2 indicate that early detection and prompt treatment in the shortest possible time is very critically important part of CH treatment. Almost all the studies in Table 2 have consensus on early treatment, specifically in the first month of infants’ lives. In this review however we found only one study reporting no correlations between initiation time of treatment and IQ or motor outcomes (22).
As mentioned in the evidence acquisition section, in this study we also evaluated risk of bias in articles that were entered in the review. For this, we used the STROBE check list, and for each study the probability of exist potentially confounders, selection bias and loss to follow up were examined. The results of critical appraisal for assessing risk of bias of studies are shown in Table 3.
In this study, we reviewed studies assessing the effects of initial dosage of levothyroxine and the timely initiation of treatment in children with congenital hypothyroidism. In general, 22 studies met our aims, of which in, 17 and 13 studies initial dosage and initiation time of treatment was discussed, respectively. It should be noted that 22 studies were included in the review whereas in some studies, both the subjects’ starting dose and onset initiation time of treatment, were assessed simultaneously.
Regarding the use of a high dose at onset of treatment, although there is much evidence supporting treatment with a high dose (14), some studies not only showed that there are no adverse effects in using high dose thyroxine therapy bet also suggested better outcomes using higher childhood treatment doses (23). However, we found several studies that contradict these results, e.g. in a study conducted by Rovet in 1995, the authors showed that although the infants that received a higher dose of L-thyroxine at initiation of treatment, had better performances and indexes of intelligence, verbal ability, and memory, they also had more behavioural problems, including increased anxiety, poorer concentration and social withdrawal (24).
Although, neonatal screening for detection of congenital hypothyroidism has a history of over 35 years and today this program has been integrated in the public healthcare systems of most countries worldwide, in this systematic review we found no randomised clinical trial (RCT), except for one study (17), assessing and evaluating effects of different initial treatment dose on clinical outcomes, and most studies were cohort.
On the issue of time of initiation of treatment or, in other words, earlier onset of treatment, numerous studies have demonstrated the importance of early treatment of congenital hypothyroidism to prevent developmental defects. A few studies, however, have documented controversial results in this context, e.g. Kempers et al., who examined cognitive and motor functioning in 70 young adults with CH and median age at initial treatment of 28 days (range, 4 - 293 days), published in the journal of clinical endocrinology and metabolism, 2006, concluded that the severity of CH, and not the timing of treatment initiation, is the main factor determining long-term cognitive and motor outcomes (25).
In studies included in this systematic review, different outcomes were assessed, e.g. serum T4 and free T4, psychological development, hearing-speech performance scales, practical reasoning, pre-pubertal and pubertal growth, including anthropometric measurements, viz. height and intelligence quotient (IQ). Because of the large amount of outcomes examined and also due to the lack of homogeneity in the studies, running of any meta-analysis was not possible.
Overall, based on the results of our systematic review, we conclude that early detection is a fundamental key in dealing with congenital hypothyroidism; hence, there is no controversy or dispute regarding the issue of timing and initiation of treatment. Initiating treatment immediately after diagnosis and during the first days of life is absolutely imperative. However, in contrast with timing, we could not find strong evidence determining the precise optimal dosage of L-thyroxine to initiate treatment in children diagnosed with CH. Regarding the initial L-thyroxin (L-T4) dose, although both the American academy of pediatrics and the European Society for pediatric endocrinology recommend 10 - 15 μg/kg/day as the initial dose (26, 27), we still could not reach a definitive conclusion. Although, most studies included in our review favor using a high initial treatment dose (17, 28-33), some studies disagree. For instance, the study of Touati et al. found that a systematic higher initial dosage could expose many infants to complications of hyperthyroidism, whereas an initial dosage of 7.5 - 8.0 μg/kg per day, with early assessment of FT4, FT3, and TSH levels, is adequate for treatment of the majority of infants with CH (21). Hence, considering the results of previous studies, despite much evidence supporting the use of a high dose of levothyroxine at the start of treatment, we still could not conclude that treatment with high doses can be very helpful, but it can be said that treatment with very low doses could delay the normalization of thyroid hormones and occurrence of related complications. Hence further studies providing stronger evidence regarding this issue are required to reach a definitive decision.
Although the extensive search of databases worldwide and close examination of the available evidence are considered the strong point for this study, there were some potential limitations in this review. One limitation of this study was the lack of studies, especially studies with high level of evidence such as systematic reviews and meta-analyses, in this field. Also, because the studies investigating the optimal initiation levothyroxine dose and its initiation time of treatment in children with congenital hypothyroidism did not have identical methodologies, we were unable to conduct a statistical meta-analysis on these issues.
Main Characteristics of the Studies That Assessed the Starting Dose in Congenital Hypothyroidism
Main Characteristics of Studies Assessing Timing of Initiation of Treatment in Congenital Hypothyroidism
Risk of Bias in Studies Evaluating Initial Dose of T4 and Initiation Time of Treatment of Children With Congenital Hypothyroidism (Author’s Judgment)a
The authors wish to acknowledge Ms Niloofar Shiva for critical editing of English grammar and syntax of the manuscript.
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