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Growth hormone effect on body composition of children born small for gestational age: a systematic review

Abstract

Objective

The present study aimed to evaluate the effects of GH treatment on the body composition of children born with SGA.

Methods

This study is a systematic review of the literature. CINAHL, Embase; Medline/Pubmed, Scopus and Web of Science were searched from inception to March 2022.

Results

Four studies met the inclusion criteria, with an intervention time of 1 to 3 years, using doses from 0.03 to 0.07 mg/kg/day of GH. Bone densitometry by dual-energy X-ray absorptiometry (DXA) with whole-body scans was the most used method to assess body composition. Most studies (n= 3) had SGA children as a control group with the same characteristics as the case group; the mean age was similar between the groups (minimum of 5.1 ± 1.4 years and maximum of 6.7 ± 1 0.8 years) and all participants had an average height ≤ -3DP. The Lean Mass (LM) and Fat Mass (FM) outcomes of the studies were not presented in a standardized manner; thus, they cannot be compared. There was a significant increase in LM in the group treated with GH in relation to the pre-treatment period and in comparison, to the untreated control group. Three studies showed a significant decrease in FM at the end of the intervention period, and in two studies, this decrease occurred in the control group.

Conclusions

Despite the differences in the presentation of results and in the evaluation periods, the results of the studies showed that growth hormone favors the gain and maintenance of lean mass, and it also affects fat mass reduction and redistribution.

Keywords
Infant, small for gestational age; Growth hormone; Body composition; Systematic review

Introduction

Children born small for gestational age (SGA) are those whose birth weight and/or length are less than −2SD of the mean for gestational age.11 Lee P.A., Czernichow S.D., Hokken-Koelega A.C., Chernausek P. International small for gestational age advisory board consensus development conference statement: management of short children born small for gestational age. Pediatrics. 2003;111:1253-61. The birth rate of SGA children varies between countries: it is lower in developed countries such as Sweden and the Netherlands and higher in countries located in Asia, such as India and Bhutan.22 Francis A., Hugh O., Gardosi J. Customized vs INTERGROWTH-21st standards for the assessment of birthweight and stillbirth risk at term. Am J Obstet Gynecol. 2018;218:S692-9. Countries such as Italy and China have a prevalence of SGA children between 3.6% and 12.3%, respectively.33 He H., Miao H., Liang Z., Zhang Y., Jiang W., Deng Z., et al. Prevalence of small for gestational age infants in 21 cities in China, 2014-2019. Sci Rep. 2021;11:7500.,44 Tamaro G., Pizzul M., Gaeta G., Servello R., Trevisan M., Böhm P., et al. Prevalence of children born small for gestational age with short stature who qualify for growth hormone treatment. Ital J Pediatr. 2021;47:82.

In Brazil, it was found that 7.8% to 8.7% of live newborns are classified as SGA according to the Intergrowth-21st reference curve. This range is strongly associated with demographic and maternal factors and prenatal care. The chance of being born SGA increases when two or more factors are associated, either at the beginning or during pregnancy.55 Souza R.T., Vieira M.C., Esteves-Pereira A.P., Domingues R.M., Moreira M.E., da Cunha Filho E.V., et al. Risk stratification for small for gestational age for the Brazilian population: a secondary analysis of the Birth in Brazil study. Sci Rep. 2020;10:14725.

6 Barreto C.M., Pereira M.A., Rolim A.C., Abbas S.A., Junior D.M., dos Santos A.M. Incidence of small for gestational age neonates, according to the fenton and intergrowth-21st curves in a level II maternity. Rev Paul Pediatr. 2021;39:e2019245.
-77 Falcão I.R., Ribeiro-Silva R.D., de Almeida M.F., Fiaccone R.L., Silva N.J., Paixao E.S., et al. Factors associated with small- And large-for-gestational-age in socioeconomically vulnerable individuals in the 100 Million Brazilian Cohort. Am J Clin Nutr. 2021;114:109-16.

The growth and development of these newborns (NB) may be restricted during the intrauterine period, as a result of environmental, nutritional, and placental factors.88 Alves T.L., Ribeiro H da C., Costa M de L., Valois S.S. Newborn risk factors according to gestational age: a review. Nutrire. 2015;40:376-82. Growth recovery can occur up to two years of age; however, a portion of approximately 10% of SGA children remains smaller than their peers of the same age and sex, resulting in short height in childhood and, consequently, in adulthood.99 Boguszewski MC, Cardoso-Demartini AA. Management of endocrine disease: growth and growth hormone therapy in short children born preterm. 2017;176:R111-22.,1010 Cardoso-Demartini Ade A., Bagatin A.C., Silva R.P., Boguszewski M.C. [Growth of preterm-born children]. Arq Bras Endocrinol Metabol 2011;55:534-40.

On the other hand, these children may experience rapid body weight gain in the first few months of life, which in the long term may result in changes in metabolic programming, with increased insulin resistance, blood pressure, weight, abdominal fat, and blood pressure as well as a small amount of lean mass.1111 Hernández M.I., Mericq V. Metabolic syndrome in children born small-for-gestational age—síndrome metabólica em crianças nascidas pequenas para a idade gestacional. Arq Bras Endocrinol Metabol. 2011;55:583-9.,1212 van der Steen M., Hokken-Koelega A.C. Consequences of being born small for gestational age. Pediatr Adolesc Med. 2020;22:43-58.

These changes in body composition may occur in childhood and persist into adulthood,1212 van der Steen M., Hokken-Koelega A.C. Consequences of being born small for gestational age. Pediatr Adolesc Med. 2020;22:43-58. as shown in studies carried out with SGA children under 10 years of age, who have high-fat mass with predominantly abdominal distribution,1313 Marcovecchio M.L., Gorman S., Watson L.P.E., Dunger D.B., Beardsall K. Catch-up growth in children born small for gestational age related to body composition and metabolic risk at six years of age in the UK. Horm Res Paediatr. 2020;93:119-27. and when adults, a lower proportion of lean mass compared to adults born with adequate weight and/or length for gestational age.1414 Prioreschi A., Munthali R.J., Kagura J., Said-Mohamed R., Rolfe E.D., Micklesfield L.K., et al. The associations between adult body composition and abdominal adiposity outcomes, and relative weight gain and linear growth from birth to age 22 in the birth to twenty plus cohort, South Africa. PLoS One. 2018;13:e0190483.

Recombinant growth hormone (GH) has been used for decades to treat individuals with GH deficiency. In short, children born SGA, and GH have shown safe and positive results in height recovery, lipid metabolism, and blood pressure regulation, especially when treatment is started in prepuberty. In addition, GH treatment has shown favorable changes in body composition, with an increase in lean mass and a decrease in fat mass.1212 van der Steen M., Hokken-Koelega A.C. Consequences of being born small for gestational age. Pediatr Adolesc Med. 2020;22:43-58.,1515 Hwang I.T. Efficacy and safety of growth hormone treatment for children born small for gestational age. Korean J Pediatr. 2014;57:379-83.

The action of GH on the body composition of SGA children found in the literature is described by the amount of lean mass and total fat mass before and after a given intervention period, as well as the distribution of body fat and the relationship with metabolic and cardiovascular risk.1616 Aurensanz Clemente E., Samper Villagrasa P., Ayerza Casas A., Ruiz Frontera P., Moreno Aznar L.A., Bueno Lozano G. Body composition and metabolic risk in small for gestational age children treated with growth hormone. Med Clin. 2016;147:231-7.

17 de Kort S.W., Willemsen R.H., van der Kaay D.C., Hokken-Koelega A.C. The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children. Clin Endocrinol. 2009;71:65-73.

18 Hokken-Koelega A.C., van Pareren Y., Sas T., Arends N. Final height data, body composition and glucose metabolism in growth hormone-treated short children born small for gestational age. Horm Res. 2003;60:S113-4.
-1919 Maeyama T., Ida S., Onuma S., Shoji Y., Yamamoto T., Etani Y., et al. Fat distribution in short-stature children born small for gestational age. Pediatr Int. 2020; 62:1351-6.

Previous systematic reviews have addressed the action of GH in different conditions; for example, there was a study that evaluated the effects of GH in children and adolescents with idiopathic short stature,2020 Bryant J., Baxter L., Cave C.B., Milne R. Recombinant growth hormone for idiopathic short stature in children and adolescents. Cochrane Database Syst Rev. 2007;3:CD004440. however, there is no systematization of the findings on the change that occurred in the body composition of SGA children without associated syndromes. To promote further knowledge of how this treatment has been carried out and of the results found for lean mass and fat mass, the present systematic review aimed to evaluate the effects of GH treatment on the body composition of children born SGA.

Methods

This is a systematic review of effectiveness with a protocol registered and approved in PROSPERO (International Prospective Register of Systematic Reviews), under number CRD42020223292 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=223292). The methodological approach followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines2121 Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:1-11. (Supplementary Table 1) and the PICO strategy (population, intervention, comparator and “outcomes”) was used for the formulation of the research question and for the bibliographic search (Table 1).

Table 1
PICOS criteria used to define research question and literature search.

Data search was performed in March 2022 in the following electronic databases: CINAHL, Embase; Medline/Pubmed, Scopus and Web of Science, using specific descriptors and their synonyms, according to the MeSh terms and the Emtree terms: “Growth Hormone”, “Infant, Small for Gestational Age”, “SGA”, “Body Composition”, and their variations, combined with the Boolean operators OR or AND. The detailed search strategy with terms used for this study can be found in Supplementary Table 2. There was no restriction on language and date of publication.

Table 2
Summary of the characteristics of the studies included in the systematic review.

The selection was performed separately by two researchers. After the exclusion of duplications, performed mechanically by the EndNote® version 8 reference manager and manually by the researchers, the documents were initially evaluated by title, later by abstracts, and then by reading the full text, while considering the eligibility criteria. Any disagreements were resolved through discussion with a third independent reviewer. A manual search was performed in the references of the articles included in the final analysis.

Randomized controlled trials (RCTs) that evaluated body composition through the outcomes of lean mass and/or total fat mass after GH treatment were included. The intervention should be a single therapy with GH, marketed under any brand, with subcutaneous administration, regardless of the administered dose, for a minimum period of one year.

The study population should consist of prepubescent children, who, according to the criteria of Marshall & Tanner2222 Marshall W.A., Tanner J.M. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970;45:13-23.,2323 Marshall W.A., Tanner J.M. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969;44:291-303. are girls with infant breasts (B1) and boys with infant genitalia (G1); born SGA, with weight or height ≤ −2SD for gestational age and sex, as recommended by the World Health Organization.2424 World Health Organization. Child growth standards: methods and development: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age. World Health Organization; 2006. 336 p. Studies that evaluated children with any associated syndrome, hormonal and/or metabolic changes, and who had the intrauterine chronic disease were excluded.

Data extraction was based on the recommendations of the PRISM checklist.2121 Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Syst Rev. 2021;10:1-11. Data on authorship, year, country, research design, intervention, participants, primary outcomes, and study characteristics were independently extracted by the two researchers using a data extraction spreadsheet in Excel® software.

The methodological quality of the selected studies was evaluated by the two researchers independently, according to the guidelines and criteria of the JBI (Joanna Briggs Institute), using the specific instrument for RCTs: “JBI Critical Appraisal Checklist for Randomized Controlled trials”.2525 Aromataris E, Munn Z (Editores). JBI Evidence Synthesis Manual. JBI, 2020. Disponível em: https://synthesismanual.jbi.global.
https://synthesismanual.jbi.global...

Results

A total of 2184 documents were identified in the databases; after checking for duplications, there were 1785 documents left. First, they were independently evaluated by title, and 1706 documents were excluded; thus, 79 documents remained for abstract reading.

After reading the abstracts, 14 documents were selected for a full reading. At this stage, there was 80% agreement among the evaluators; 4 articles met the inclusion criteria and were classified as eligible for the study. The reasons for exclusion were: 1 presence of comorbidities, 2 follow-up periods of less than 12 months, 1 child in the pubertal phase, 2 non-randomized clinical trials, and 4 studies that required additional information, without feedback from the authors (Figure 1).

Figure 1
PRISMA flowchart.

Table 2 shows that all studies were randomized clinical trials, carried out in Europe, with broadly similar inclusion criteria among them. Regarding the intervention, GH was used as a single therapy in all studies, at doses of 0.03 mg/kg/day and 0.07 mg/kg/day, administered once a day by subcutaneous injection. Intervention time ranged from 1 to 3 years and the most used method for assessing body composition was bone densitometry by double x-ray absorption (DXA) using whole-body scans.

For the control group, one study compared the treatment group with prepubertal children born with adequate weight and/or height for gestational age without GH treatment.2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6. In the other studies,2727 Boonstra V.H., Arends N.J., Stijnen T., Blum W.F., Akkerman O., Hokken-Koelega AC. Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res. 2006;65:23-30.

28 de Schepper J., Thomas M., Beckers D., Craen M., Maes M., de Zegher F. Growth hormone treatment and fat redistribution in children born small for gestational age. J Pediatr. 2008;152:327-30.
-2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. the control group consisted of SGA children with the same inclusion criteria as the case group who remained untreated during the study period, but who subsequently had the opportunity to receive treatment.

Table 3 shows the characteristics of the population, with similar ages at the beginning of treatment, both in the case group and in the control group, with a minimum age of 5.1 ± 1.4 years and maximum age of 6.7 ± 1.8 years. All children had average overall height ≤ −3DP. The number of participants varied widely, from 21 to 88.

Table 3
Baseline characteristics of the population.

Tables 4 and 5 describe the results of the assessment of lean mass and fat mass, respectively. It can be seen that the presentation of outcomes is not standardized; the results are presented as percentage of change in body composition or standard deviation (SD), standard deviation adjusted for age (SD-age), standard deviation adjusted for height (SD-height), total kilograms (kg) and total percentage (%).

Table 4
Results summary to Lean Mass (LM).
Table 5
Results summary to Fat Mass (FM).

There was a significant increase in lean mass in the pretreatment period in virtually all assessments, with the exception of the study carried out by Willemsen et al. (2007)2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. using SD height. They found a reduction from 0.5 ± 2.1SD-height to −0.3 ± 0.9SD-height after three years of intervention. All studies found that the GH treatment resulted in additional lean mass gain at the end of treatment compared to the untreated control group (Table 4).

Three studies found a significant decrease in fat mass at the end of the intervention period in comparison to pre-treatment values, after one year of follow-up (−16.4 ± 3.4%; p= 0.001), after two years (19 ± 4 to 15 ± 2%, p < 0.05) and after three years of treatment with GH (−1.0 ± 0.8 to −1.5 ± 0.7 SD -age; p < 0.01). For the control group, only two studies (Boonstra et al.; 2006 and Schepper et al.; 2008) found significant differences (Table 5).

Table 6 shows the assessment of the risk of bias carried out in the studies. None of the studies presented a low risk of bias, as all of them presented uncertain or high risk in some of the items evaluated. The greatest risk of bias referred to blinding, as 2 studies were open-labeled,2727 Boonstra V.H., Arends N.J., Stijnen T., Blum W.F., Akkerman O., Hokken-Koelega AC. Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res. 2006;65:23-30.,2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. while this information was not adequately described in the other 2.2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6.,2828 de Schepper J., Thomas M., Beckers D., Craen M., Maes M., de Zegher F. Growth hormone treatment and fat redistribution in children born small for gestational age. J Pediatr. 2008;152:327-30. There was also an uncertain risk of bias regarding allocation concealment because the method used to conceal the allocation sequence was not described in the studies.

Table 6
Risk of bias summary.

Discussion

This systematic review evaluated the effect of the GH intervention on the body composition of children born SGA and all included studies showed that GH treatment significantly increased lean body mass at the end of the follow-up period and also in comparison to the control group, while half of the studies found a decrease in fat mass.

In all studies, children started treatment with a lower proportion of fat mass than non-SGA children of the same age and sex, and SGA children remained with a proportion of truncal fat or visceral adipose tissue below the reference values even after the treatment with GH.1616 Aurensanz Clemente E., Samper Villagrasa P., Ayerza Casas A., Ruiz Frontera P., Moreno Aznar L.A., Bueno Lozano G. Body composition and metabolic risk in small for gestational age children treated with growth hormone. Med Clin. 2016;147:231-7.,1919 Maeyama T., Ida S., Onuma S., Shoji Y., Yamamoto T., Etani Y., et al. Fat distribution in short-stature children born small for gestational age. Pediatr Int. 2020; 62:1351-6.,2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92.

30 Ibáñez L., Lopez-Bermejo A., Díaz M., Jaramillo A., Marín S., de Zegher F. Growth hormone therapy in short children born small for gestational age: effects on abdominal fat partitioning and circulating follistatin and high-molecular-weight adiponectin. J Clin Endocr Metab. 2010;95:2234-9.
-3131 Thankamony A., Jensen R.B., O'Connell S.M., Day F., Kirk J., Donaldson M., et al. Adiposity in children born small for gestational age is associated with β-cell function, genetic variants for insulin resistance, and response to growth hormone treatment. J Clin Endocr Metab. 2016;101:131-42.

The reduction in fat mass and the increase in lean mass were more evident in children who started treatment at younger ages and during the first year of treatment2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6.,2727 Boonstra V.H., Arends N.J., Stijnen T., Blum W.F., Akkerman O., Hokken-Koelega AC. Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res. 2006;65:23-30.,2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. corroborating with the studies by Aurensanz Clemente et al. (2016)1616 Aurensanz Clemente E., Samper Villagrasa P., Ayerza Casas A., Ruiz Frontera P., Moreno Aznar L.A., Bueno Lozano G. Body composition and metabolic risk in small for gestational age children treated with growth hormone. Med Clin. 2016;147:231-7. and Thankamony et al. (2016).3131 Thankamony A., Jensen R.B., O'Connell S.M., Day F., Kirk J., Donaldson M., et al. Adiposity in children born small for gestational age is associated with β-cell function, genetic variants for insulin resistance, and response to growth hormone treatment. J Clin Endocr Metab. 2016;101:131-42. However, the beneficial effects of GH on lean body mass were maintained in the long term, with a significant increase in all years of treatment.2727 Boonstra V.H., Arends N.J., Stijnen T., Blum W.F., Akkerman O., Hokken-Koelega AC. Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res. 2006;65:23-30.,2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92.

Previous studies have shown that this increase in lean mass after one year of treatment is positively correlated with gestational age,1919 Maeyama T., Ida S., Onuma S., Shoji Y., Yamamoto T., Etani Y., et al. Fat distribution in short-stature children born small for gestational age. Pediatr Int. 2020; 62:1351-6. birth weight, sex, and lean body mass at baseline.1717 de Kort S.W., Willemsen R.H., van der Kaay D.C., Hokken-Koelega A.C. The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children. Clin Endocrinol. 2009;71:65-73. According to Boonstra et al. (2006)2727 Boonstra V.H., Arends N.J., Stijnen T., Blum W.F., Akkerman O., Hokken-Koelega AC. Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res. 2006;65:23-30. the greater amount of lean mass is also due to the higher intake of calories and carbohydrates. This outcome signals that food components are used as energy to increase lean mass but not to increase fat mass.

Willemsen et al. (2007)2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. found that the increase in lean mass occurred proportionally to height gain, which did not represent an additional increase in lean mass beyond what was expected for normal growth, and it was also reported later by Lem et al. (2013)3232 Lem A.J., van der Kaay D.C., Hokken-Koelega A.C. Bone mineral density and body composition in short children born sga during growth hormone and gonadotropin releasing hormone analog treatment. J Clin Endocr Metab. 2013;98:77-86.; however, untreated SGA children had a decrease in lean body mass, which was preserved in GH-treated children.2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. Moreover, De Kort et al. (2009)1717 de Kort S.W., Willemsen R.H., van der Kaay D.C., Hokken-Koelega A.C. The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children. Clin Endocrinol. 2009;71:65-73. found that SGA children born at term had an additional gain in lean mass beyond what was expected for normal growth during GH treatment compared to those born preterm.

For fat mass, the authors claimed that the significant reduction during the first year of treatment corroborates the action induced by GH administration on adipose tissue lipolysis.2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6. and that there is also an increase in basal energy expenditure, causing the body to use fat mass stores to obtain energy to assist in the production of lean mass.2727 Boonstra V.H., Arends N.J., Stijnen T., Blum W.F., Akkerman O., Hokken-Koelega AC. Food intake of children with short stature born small for gestational age before and during a randomized GH trial. Horm Res. 2006;65:23-30.

GH treatment affects several fat stores differently2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6. leading to a redistribution of fat mass with a possible reduction in the peripheral region and greater distribution in the trunk region.2828 de Schepper J., Thomas M., Beckers D., Craen M., Maes M., de Zegher F. Growth hormone treatment and fat redistribution in children born small for gestational age. J Pediatr. 2008;152:327-30.,2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. However, other studies have found that this increase in trunk fat mass is possibly related to a decrease in limb fat, increasing the limb fat to trunk fat zratio.1717 de Kort S.W., Willemsen R.H., van der Kaay D.C., Hokken-Koelega A.C. The effect of growth hormone treatment on metabolic and cardiovascular risk factors is similar in preterm and term short, small for gestational age children. Clin Endocrinol. 2009;71:65-73.,3131 Thankamony A., Jensen R.B., O'Connell S.M., Day F., Kirk J., Donaldson M., et al. Adiposity in children born small for gestational age is associated with β-cell function, genetic variants for insulin resistance, and response to growth hormone treatment. J Clin Endocr Metab. 2016;101:131-42.

According to Willemsen et al. (2007),2929 Willemsen R.H., Arends N.J., Bakker-Van Waarde W.M., Jansen M., van Mil E.G., Mulder J., et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born small-for-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol. 2007;67:485-92. this greater distribution of fat in the trunk region does not differ between SGA children treated with GH and those untreated, and it can only be linked to the process of growth and development expected for their age; this outcome is corroborated by the study by Leger et al. (1998)2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6. in which a progressive increase in body fat was found in SGA children after the first year of treatment, similar to the finding for the control group of non-SGA children. This change did not significantly alter the Body Mass Index (BMI).

Further studies are needed to determine whether the reduction in fat mass in SGA children is a factor resulting from the reduction in adipose tissue stores or just a consequence of the low weight at which they start treatment.2626 Leger J., Garel C., Fjellestad-Paulsen A., Hassan M., Czernichow P. Human growth hormone treatment of short-stature children born small for gestational age: effect on muscle and adipose tissue mass during a 3-year treatment period and after 1 year's withdrawal. J Clin Endocr Metab. 1998;83:3512-6.

Finally, it should be noted that the way in which the outcomes were presented influenced the findings, as the treatment with GH significantly reduced fat mass percentage, but the total fat mass was not affected. Previous studies have suggested that the reductions in fat mass percentage by the treatment with GH are not caused by the reduction of the total volume, but by the change in the total body composition, resulting in a lower percentage of fat in the whole body, limbs and trunk.1919 Maeyama T., Ida S., Onuma S., Shoji Y., Yamamoto T., Etani Y., et al. Fat distribution in short-stature children born small for gestational age. Pediatr Int. 2020; 62:1351-6.,3131 Thankamony A., Jensen R.B., O'Connell S.M., Day F., Kirk J., Donaldson M., et al. Adiposity in children born small for gestational age is associated with β-cell function, genetic variants for insulin resistance, and response to growth hormone treatment. J Clin Endocr Metab. 2016;101:131-42.

The main limitations of this review were the variations across the studies in terms of the administered dose, follow-up time, and a number of evaluations, as well as the way in which the results were presented. This way, an adequate analysis could not be made to verify the effect of GH on the body composition of children born SGA. The methodological quality assessment pointed to an uncertain to high bias in all studies. However, a strong point to be highlighted is that this systematic review included only RCTs, e.g., studies that are considered the gold standard to assess health outcomes.

Evidence suggests that GH treatment has a positive effect on the body composition of children born SGA, with a significant increase in LM that is proportional to the gain in body height. Regarding FM, some studies described a reduction in body fat, but it is still unclear if it was a consequence of the decrease in total fat or the result of modification of total body composition. Some answers could be obtained with new ERC; however, as GH treatment of short stature in children born SGA is well established, it probably will be difficult to conduct new studies with an untreated group.

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.11.010.

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Publication Dates

  • Publication in this collection
    16 June 2023
  • Date of issue
    May-Jun 2023

History

  • Received
    20 June 2022
  • Accepted
    11 Nov 2022
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