The present systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (6).

No formal ethical approval was required. An extensive literature search of four electronic databases: PubMed, Cochrane Library, Scopus, and PsycINFO via EBSCO was undertaken for studies regarding DS and growth hormone, published until January 2021. The general keywords were ‘Down syndrome’ and ‘growth hormone’, while the search strategy was updated and adapted for each database. Vocabulary supplemented with keywords were used for searches that were conducted separately for each topic and combined later. The search was restricted to humans, and no other restriction was made. Studies in all languages were included. Full-text articles of potentially relevant studies not available through the university library were requested from the authors. We repeated the search on September 2022 and received 27 additional records. A review of the title or abstract was enough to determine that they are not suitable for inclusion in this review.

The scope of data reporting in much of the original works did not allow for a full quality and risk of bias assessment to be carried out on the individual original studies; therefore, no individual quality assessment was carried out.

We used ROBIS, a tool for assessing quality and risk of bias in systematic reviews. The tool is completed in three phases: assess relevance (optional), identify concerns with the review process by 21 questions divided to 4 domains, and judge risk of bias in the review. It is the first rigorously developed tool designed specifically to assess the risk of bias in systematic reviews (7).

Eligible studies enrolled pediatric DS patients who were treated with GH during childhood and examined the effect of treatment on longitudinal growth and other aspects or dealt with the ethical aspects of such treatment. Studies that answered one of the following two questions were included:

Data extraction included a full description of participants if available. Foreign language articles were translated by multilingual reviewers. The main outcome extracted from studies for mini meta-analysis were GH treatment characteristics, during and post-treatment height effects, head circumference, cognitive and motor function, additional therapeutic effects, adverse effects, IGF1, bone age response, and ethical arguments in favor and against GH therapy in DS patients. Additionally, we collected the number and age of the participants in the research groups as well as in the control groups, inclusion criteria, type of dose, and duration of growth hormone treatment.

We used a random effects meta-analysis in order to assess heterogeneity. We assessed the degree of inconsistency in the results between studies using the I² statistic; this statistic explains the proportion of inconsistency between studies that cannot be explained by chance alone, and is likely due to real differences in the population or the conduct of the studies (8).

Height standard deviation scores (SDS) were estimated in each study and pooled using a random effects meta-analysis (9). SDS expressed height differences in terms of the SD for the height of the reference population. Most studies reported SDS in reference to their national databases. To compare the change in height SDS along time between GH treated and untreated DS patients and also between DS patients with and without proven growth hormone deficiency under GH treatment, we extrapolated data using studies in which we could extract mean and standard deviations for all children in the different time points. We used two-way repeated-measures ANOVA to assess the difference between groups over time. R statistical programming language was used for extrapolation and statistical analysis. Publication selection bias could not be calculated due to missing relevant data.

An initial search of the literature yielded 281 publications and 24 eligible studies ( Figure 1 ). Sixteen reports detailed medical effects of treatment with GH. Some are follow-up studies reporting late treatment outcomes or completing statistical analyses that did not appear in the initial report. Eight studies dealt with the ethical aspects of GH treatment in DS patients. The main characteristics and findings of the included studies are presented in Supplementary Table 1 and Table 1.

There was a significant change in cognitive function compared to the control group in one study alone. Approximately 15 years after GH therapy termination, there was no statistical preference to the GH therapy group in brief IQ scores, but significantly higher scores in all subtests of cognitive tests Leiter-R and WISC-III and in all but one subtest of the motor BOT-2 test (27). The other studies that tested cognitive function found no change (25, 29–31).

One study showed possible craniofacial growth and dental maturation that may be associated to the treatment (31).

Although the length of menstrual cycles in DS is within the normal range, a reduction in reproductive function is generally observed. A study examining the function of HPG axis showed reduced sensitivity of ovaries to FSH in patients with DS compared to controls. A treatment with GH normalized the ovarian response to FSH (33).

Two studies reported an increase in mean neutrophil lobe count (25, 34). One study also showed an increase in neutrophil count during treatment and a fall thereafter (25). One study (three articles) reported on a single child with slightly elevated liver enzymes (22, 25, 29). Another study reported on mild subclinical hypothyroidism (19). Precocious puberty was observed in one boy 3.4 yrs after GH treatment initiation (24). In no study was the development of leukemia reported.

The ethical legitimacy of GH therapy in children with DS has been widely questioned over the years. The claim put forth in Torrado et al. (23), which argues that responsiveness to GH therapy by DS children justifies prescribing a course of treatment, was challenged by several respondents.

Various arguments have been presented for and against the treatment. These arguments can be divided into 3 categories: safety of GH treatment, necessity for GH treatment, and agreement, justice, and autonomy. A summary of all arguments that have appeared in the various studies on this subject appear in Table 1 .

Consistent with the results of this meta-analysis, it can be concluded that there is a significant short-term beneficial effect of GH therapy on longitudinal growth in children with DS. The growth velocity of patients with DS treated with GH was found to be significantly higher than in non-treated DS patients.

Except for a single study that reported on the maintenance of the therapeutic effect even after stopping treatment, all the other studies show that the effect of short-term treatment gradually fades after the end of treatment. Importantly, there is almost no data on the effect of long-term treatment. It is possible that long-term treatment until the end of growth may preserve and even increase the therapeutic effect, even if the final height does not ultimately reach the forecasted height.

In addition, we have shown that there is a probable effect on head circumference and a possible effect on motor and even cognitive function. A discrepancy between longitudinal and head circumference results may indicate that the reduced head circumference in DS is not only a result of growth retardation but is mainly due to limited brain growth.

Despite the great importance of the treatments’ effect on quality of life, no study has formally examined this aspect by accepted and valid questionnaires.

No significant adverse effect of GH treatment in DS patients was ever reported even in the long- term. Certainly, more research is needed to describe the effect of longer-term treatment, but the results of this review provide a strong basis for considering that the risks of GH therapy in children with DS are not significantly different from other children.

The literature on height outcome in DS pediatric patients, who were treated with recombinant human GH, is heterogeneous, with variable age at diagnosis, years of follow-up, and variable criteria and methods of height measures. Although the number of studies included in this mini meta-analysis is not large, it is important to note that to the best of our knowledge this review included all studies that examined the effect of GH treatment in children with DS, from whom a reliable and comparable measurement tool, like height SDS, could be derived. It is also noteworthy that even studies that could not be included in the analysis reached the same conclusions about the beneficial effect of GH therapy on the longitudinal growth of children with DS.

Recently, an original study assessed whether anthropometric measurements of children with DS correlate with their IQ. The results showed that full-scale, verbal, and nonverbal IQ correlated with height percentile in a multiple linear regression analysis. The results of this study suggest an association between growth and IQ in children with DS, and this finding may be valuable for this population in light of increasing access to GH therapy in various genetic syndromes associated with short stature (35). DS shares many common clinical features with other genetic syndromes such as Prader-Willi syndrome (PWS). Children with PWS are also treated by GH treatment starting from the first year of life. Early GH treatment has been shown to promote mental and motor development as well as adaptive functioning in the PWS population in addition to improving growth velocity and metabolism (36).

Heterogeneity indices were calculated and were found to be relatively high. It is reasonable to conclude that one study (23) is responsible for the most heterogeneity from looking at the forest plot graph and from other calculations. In this study, the initial height index was significantly lower compared to the other studies. However, the growth rate through the treatment period was very similar to the growth rate observed in the other studies, as can be seen from Figure 2 .

GH treatment was found to be effective equally in DS children who were diagnosed with GH deficiency and in DS children who were not diagnosed with GH deficiency. This finding corresponds to the conclusion that despite the increased prevalence of GH deficiency in children with DS, the quantitative component of the growth hormone is only one of the possible damaged elements in the GHRH-GH-IGF1 axis in DS patients, and apart from that, an impairment was also detected in GH neurosecretory function and in the bio-activity of GH, both of which are likely to be missed if relying solely on growth hormone stimulation tests (4).

It should be noted that all three of the above components negatively affect the level of IGF1 in patients with DS. It was recently found that biomarkers of neurodegeneration are associated with IGF1 deficiency in DS and that short stature is associated with lower IGF1 and with higher biomarkers (37).

Exogenous growth hormone treatment is expected to provide a response to these three issues.

In contrast to more distal disturbances such as growth hormone receptor resistance and IGF-1 receptor deficiency, the administration of proper recombinant GH circumvents both the quantitative and qualitative disturbances in the production and secretion of GH, as well as any defects in the endogenous protein structure. It seems that a diagnosis of growth hormone deficiency in children with DS should not be a criterion for GH treatment.

The main ethical arguments that have been raised over the years concerning GH treatment of DS patients consider the safety and necessity of GH treatment, while also raising the issue of patient autonomy and agreement ( Table 1 ).

In the “safety” category, the main health concern that has been raised is the fear of developing leukemia, importantly as DS patients have a predisposition to developing leukemia. The fear of developing leukemia arose at a time when there was a similar general concern about growth hormone treatment in the general population. Since then, large studies have already shown that this fear is unwarranted in the general population. Correspondingly, we have shown herein that there is no evidence of the development of leukemia in small studies, most of which have documented short-term follow-up but also in the minority that documented long-term follow-up.

In the “necessity” category, it has been argued that short stature does not constitute a significant limitation to DS patients necessitating the need for potentially harmful and expensive GH treatment because of their developmental intellectual disability. Also, growth hormone treatment is given every day by subcutaneous injection which involves discomfort for the patient. Identifying with the purpose of the treatment makes it easier for the patient to cope with the pain. In the absence of such identification, as in the case of a child with Down syndrome due to developmental delay, the child’s difficulty in dealing with the pain and the parent’s difficulty in providing the treatment may increase.

In the “agreement, justice, and autonomy” category, it has been argued that informed consent is difficult because many of these children are limited in their ability to understand issues involved with GH treatment. Further, there is concern of the psychologic effects of repeated GH injections to children who may not understand the purpose of the treatment and may view the treatment as an additional “punishment” to their condition.

The degree of developmental intellectual disability in DS patients is highly variable. Average IQ of standard DS is around 50 and that of mosaic DS is around 65, showing that most DS patients have a mild degree of developmental intellectual disability. A large survey in the US reported that 57 percent of adult DS people were working a paid job (38).

Gradual but dramatic changes over time in life expectancy, quality of life, social involvement, and functional level highlight some of the important values associated with GH treatment that should not be ignored. While GH treatment may not improve intellectual performance, by improving stature, it may affect a variety of factors which are beyond mere centimeters. It is well established that short stature impairs outlook for socialization, employment, general well-being, and happiness (39). Some parents of DS children have stressed the fact that restricting DS children of GH therapy risks layering handicaps on handicaps, ultimately depriving them of any chance of living a healthy and happy life as contributing members of society, since attaining a “normal” height and growth becomes just as important for children with DS as for any other child (16).

It seems ethically, morally, and legally right that children with DS receive the same treatment as any other child without bias or judgement, and pediatricians need to respect and consider the experiences of parents and their wishes regarding decisions about GH therapy. At the same time, GH responsiveness and DS diagnosis should not be an automatic indication for GH therapy, rather the decision should be made based on well-informed consultations with caregivers and their wishes after discussing benefits and potential risks of GH therapy and clarifying potential misconceptions.

Inferences presented in this review are weakened by the risk of potential bias caused by the design of included studies. Any attempt at pooling the data should be done with caution to derive a clinically meaningful result. The relatively small total number of participants, especially the control groups, limits our ability to draw unambiguous conclusions.

On the other hand, the systematic nature of this review, which is not limited by language or a year limit, gives it its strength.

There is a significant short-term beneficial effect of GH therapy on longitudinal growth in children with DS. The presented findings may be valuable for improving access to GH therapy for pediatric DS patients. However, these findings should be confirmed by further research with a longitudinal sample of children with DS.